Antihistamines

Antihistamines
 
Three types of histaminergic receptors
 

 

H1

H2

H3

Selective agonists

2-Methyl histamine

2-Pyridylethylamine

2-Thiazolyl ethylamine

Dimaprit

Impromidine

α- methyl histamine

Imetit

Selective antagonist

Mepyramine

Clorpheniramine

Cimetidine

Ranitidine

Thioperamide

Impromidine

Tiprolisant

Receptor type

Gq-protein coupled

Gs- protein coupled

Gi/Go protein coupled

Effector pathway

PIP2 hydrolysis – IP3/DAG: release of Ca2+ from intracellular stores

Protein kinase C activation

NO release - cGMP

Adenylyl cyclase activation – cAMP increase – phosphorylation of specific proteins

Restricting Ca2+ influx

K+ channel activation

cAMP decrease

Distribution in the body:

Action mediated

Smooth muscle contraction

Blood vessels: vasoconstriction, increase capillary permeability

Stimulation of afferent nerve endings

Ganglionic cell stimulation

Release of CAs in adrenal medulla

Brain: transmitter

Gastric glands: acid secretion

Blood vessels: vasodilatation

Heart: + chronotropy,

+ ionotropy

Uterus: relaxation

Brain: transmitter

Brain: inhibition of histamine release – sedation

Lung, spleen, skin, gastric mucosa- decrease histamine release

Vasodilatation

 
Clinical classification of antihistaminics
 
Highly sedative
  • Diphenhydramine : 25-50 mg oral
  • Dimenhydrinate: 25-50 mg oral
  • Promethazine: 25-50 mg oral, im
  • Hydroxyzine: 25-50 mg oral, im
 
Moderately sedative
  • Pheniramine: 25-50 mg oral, im
  • Cyproheptadine: 4 mg oral
  • Meclozine (Meclizine): 25-50 mg oral
  • Cinnarizine: 25-50 mg oral
 
Mild sedative
  • Chlorpheniramine: 2-4 mg (0.1 mg/kg) oral, im
  • Dexchlorpheniramine: 2 mg oral
  • Triprolidine: 2.5-5 mg oral
  • Clemastine: 1-2 mg oral
 
Second generation anti histaminics
  • Fexofenadine: 120-180 mg oral
  • Loratadine: 10 mg oral
  • Desloratadine: 5 mg oral
  • Cetirizine: 10 mg oral
  • Levocetirizine: 5-10 mg oral
  • Azelastine: 4 mg oral, 0.28 mg intranasal
  • Mizolastine: 10 mg oral
  • Ebastine: 10 mg oral
  • Rupatadine: 10 mg oral
 
 
 
Pharmacological actions
 
1. Antagonism of histamine
  • They effectively block histamine induced bronchoconstriction, contraction of intestinal and other smooth muscle and triple response- especially wheal, flare and itch
  • Fall in BP produced by low doses of histamine is blocked
  • Release of adrenaline from adrenal medulla in response to histamine is abolished
  • Action of histamine on gastric secretion is not affected by these drugs
  • Cyproheptadine has additional 5-HT2 receptor blocking activity
 
2. Antiallergic action
  • Many manifestation of immediate hypersensitivity (type 1 reaction) are suppressed
  • Urticaria, itching and angioedema are well controlled
  • Anaphylactic fall in BP is only partially prevented
  • Asthma is practically unaffected.
 
3. CNS
 
  • Causes variable degree of CNS depression. It depends on the ability of the compound to cross the blood brain barrier and  its affinity for the central H1 receptors
  • Also causes sedation. 2nd generation antihistaminics are practically non sedating
  • Excitement and convulsions are frequently seen in toxic doses
  • Certain antihistamines are effective in preventing motion sickness. They are also effective to control vomiting of pregnancy and other causes
  • Promethazine and few other antihistaminics also reduce tremor, rigidity and sialorrhea of parkinsonism
  • Some antihistaminics like cyproheptadine have appetite stimulating effect
  • Some antihistamines are also effective antitussives
 
4. Anti cholinergic actions
 

High

Low

Minimal/ absent

Promethazine

Chlorpheniramine

Fexofenadine

Diphenhydramine

Hydroxyzine

Astemizole

Dimenhydrinate

Triprolidine

Loratidine

Pheniramine

Cyproheptadine

Cetirizine

 

 

Mizolastine

 
 
5. Local anesthetic
  • Some drugs like pheniramine, promethazine, diphenhydramine have strong while others have weak membrane stabilizing property
  • Membrane stabilizing property also confers antiarrhythmic property to these compounds
 
6. BP
  • Most antihistamines cause a fall in BP on iv injection (direct smooth muscle relaxation or α adrenergic blockade as in promethazine)
 
Pharmacokinetics
 
  • Conventional H1 antihistamines are well absorbed from oral and parental routes, metabolized in the liver and excreted in urine
  • They are widely distributed in the body and enters brain
  • The newer compounds penetrate brain poorly accounting for low or absent sedative action
  • Duration of action of most agents is 4-6 hours except for meclozine, chlorpheniramine, mesolastine, loratidine, cetirizine and fexofenadine which act for 12-24 hours or more
Side effects and toxicity
  • Sedation
  • Diminished alertness and concentration
  • Light headedness
  • Motor incoordination
  • Fatigue
  • Tendendency to fall asleep
  • Impairment of psychomotor performance
  • Regular use in children causes CNS depression which may interfere with learning and academic tasks
  • Anticholinergic effects like dryness of mouth, alteration of bowel movement, urinary hesitance and blurring of vision
  • Epigastric distress and headache
  • Local application causes contact dermatitis
Acute overdosage causes following symptoms:
  • Central excitation
  • Tremors
  • Hallucinations
  • Muscular incoordination
  • Convulsions
  • Flushing
  • Hypotension
  • Fever
  • Death due to respiratory or cardiovascular failure
 
Second generation antihistaminics
​They have following properties:
  • Absence of CNS depressant property
  • Higher H1 selectivity, no anti cholinergic side effects
  • Additional anti allergic mechanisms apart from histamine  blockade
  • Does not impair psychomotor performance
  • Produce no sedation, do not potentiate alcohol or benzodiazepines
  • Their principal indications are:Allergic rhinitis and conjunctivitis, hay fever, pollinosis- control sneezing, runny but not blocked nose, and red watering itchy eyes; Urticaria, dermographism, atopic eczema; Acute allergic reactions to drugs and food
  • They have poor antipruritic, antiemetic and antitussive actions
Uses
 
1. Allergic disorders
  • Itching, urticaria
  • Seasonal hay fever
  • Allergic conjunctivitis
  • Angioedema of lips
  • Not effective in bronchial asthma due to following reasons:

i. Leukotrienes (C4, D4) and PAF are more important mediators than histamine

ii. Concentration of antihistamines attained at the site may not be sufficient to block high concentration of histamine released locally in the bronchi

  • Type 1 hypersensitivity reactions to drugs (except asthma and anaphylaxis) are suppressed
2. Other conditions involving histamine
  • Insect bite
  • Ivy poisoning
  • Abnormal demographism are suppressed
3. Pruritides
4. Common cold
5. Motion sickness
6. Vertigo
7. Pre anesthetic medication
8. Cough
9. Parkinsonism
10. Acute muscle dystonia
11. As sedative, hypnotic, anxiolytic
 
 
Diphenhydramine 
  • Injectable 1% diphenhydramine is a safe, inexpensive and effective local anesthetic for simple dermatological procedured in patients with caine allergies. (1)
  • Diphenhydramine may not be an effective sedative/hypnotic in elderly women. (2)
  • Diphenhydramine and dextromethorphan are not effective in providing nocturnal symptom relief for children with cough and sleep difficulty. (3)
  • The valerian-hops combination and diphenhydramine may be a useful adjunts in the treatment of mild insomnia. (4)
  • Opsoclonus occurs due to diphenhydramine poisoning. (5)
  • The sedative effect of diphenhydramine might be caused by coadministration of CYP2D6 sustrates/ inhibitors. The large differences in the metabolic activities of CYP2D6 and those of CYP1A2, CYP2C9 and CYP2C19 could cause the individual differences in anti-allergy efficacy and the sedative effect of diphenhydramine. (6)
  • Haloperidol abuse can be treated with diphenhydramine. (7)
  • Life threatening diphenhydramine overdose can be treated with charcoal hemoperfusion and hemodialysis. (8)
  • Diphenhydramine is less potent than bupivacaine at producing cutaneous analgesia. At equipotent doses for infiltrative cutaneous analgesia, the duration of action of diphenhydramine is equal to that of bupivacaine. (9)
  • Diphenhydramine may be useful as a palliative treatment for patients dying with Parkinson's disease and tremors. (10)
  • Metoclopramide administered with diphenhydramine (MAD) regimen is effective for the treatment of headaches in pregnant women when acetaminophen alone is ineffective, using codeine as standard for comparison. (11)
  • Topical diphenhydramine may be a safe alternative in patients requiring topical ocular anesthesia who have multiple allergies to topical anesthetics. (12)
  • Hyponatermia and obstructive uropathy can be induced by the antihistamine diphenhydramine in patient with no psychiatruc history. (13)

Dimenhydrinate 

  • Oral dimenhydrinate does not significantly decrease the frequency of vomiting in children with acute gastroenetritis. (14)
  • Dimenhydrinate and betahistine should not be used together because of their opposite effects on the vestibular system. Dimenhydrinate can be used to treat acute episode of vertigo. (15)
  • A lower rate of obstructive uropathy is found in infants born to mothers treated with dimenhydrinate during the first trimester of pregnancy than in infants whose mothers did not take the drug at that time. (16)
  • Intramuscularly administered dimenhydrinate seemed to reduce postoperative vomiting in patients. (17)
  • Rectal administration of dimenhydrinate is an effective means of reducing postoperative vomiting in children undergoing strasbismus surgery. (18)
  • Overdose with dimenhydrinate and diphenhydramine, both of which are over-the-counter drugs, can result in rapid central nervous system stimulation, including status epilepticus. Death can occur within two hours. (19)
  • Erythema multiforme can occur secondary to dimenhydrinate in a patient with previous similar reactions to pamabrom. (20)
  • Fixed drug eruptions can be caused by dimenhydrinate. (21)
  • The antimotion sickness property of diphenhydramine and dimenhydrinate may be due to diminished excitability of the vestibular nuclear complex. (22)
  • Prophylactic dimenhydrinate in a dose of 50 mg effectively decreases the incidence of emesis  without any increase in side effects following cesarean delivery with intrathecal morphine. (23)
  • Clozapine helps to reduce carvings for dimenhydrinate. (24)
  • Dimenhydrinate degrades night-vision, reaction time and stereopsis in patients. (25)
  • Intra-operative dimenhydrinate followed by three further administrations after surgery, reduces the incidence and the severity of postoperative nausea and vomiting without side effects. (26)
  • The use of dimenhydrinate in children with vomiting is associated with a risk of delay in the diagnosis of treatable medical conditions. (27)
  • The fixed low dose combination of cinnarizine 20 mg + dimenhydrinate 40 mg is effective, clinically beneficial and well tolerated in patients with vestibular vertigo of central and/ or peripheral origin. (28)
  • Lansoprazole, clonazepam and dimenhydrinate is capable of attenuating the symptoms of patients with intractable hiccups. (29)
  • Dimenhydrinate augments heart rate responses to baroreceptor unloading, but does not alter resting muscle sympathetic nerve activity (MSNA), the sympathetic baroreflexes or the vestibulosympathetic reflex. (30)

Promethazine:

  • Intravenous promethazine administration results in serious tissue injury like burning, erythema, pain, swelling, severe spasm of vessels, thrombophlebitis, venous thrombosis, nerve damage, paralysis, abscess, tissue necrosis and gangrene. (31)
  • Promethazine potentiates the action of different narcotics like morphine, pethidine, oxymorphine, hydromorphone, fentanyl and pentazocine. (32)
  • Promethazine is not recommended as a first line agent in the treatment of post operative nausea and vomiting, but can be considered for use as a rescue antiemetic. (33)
  • Physiostigmine is used in the treatment of promethazine poisoning. (34)
  • Phenothiazine has a potent sedative action, marked antiemetic effect, and has synergism with narcotocs, barbiturates and anesthetic agents. Induction and maintenance of general anesthesia is facilitated by promethazine. It should not be used in patients with a history of preeclampsia, epilepsy, convulsions, intracranial trauma and severe hypertension. (35)
  • Haloperidol plus promethazine is effective in the management of psychosis induced aggresion. (36)
  • Depression can be treated with combination of chlorpromazine and promethazine. (37)
  • Topical promethazine can cause contact dermatitis, inflammmation and photosensitivity. It may cause acute or chronic urticaria, eczema, pruritis, papular rash or erythema, fixed drug eruptions (FDE). (38)
  • The intranasal microsphere formulation of promethazine offers great promise as an effective non-invasive alternative for treating space motion sickness due to its rapid absorption and bioavailability equivalent to the im dose. (39)
  • Promethazine is reported to cause significant sedation, agitation, hallucinations, seizures, dystonic reactions and apparent life threatening evets or sudden infant death syndrome. It should be used only for appropriate indications and only in children greater than 2 years of age. (40)
  • Promethazine works significantly better than promethazine for relieving symptoms of nausea and vomiting more quickly and completely in ED patients withuncomplicated nausea and vomiting. (41)
  • Promethazine appers to have less sedative and peripheral vasodilator effects than acepromazine, thus it could be safer than acepromazine in patients suffering from hypotension. (42)
  • Pretreatment with rpomethazine significantly decreases mivacurium induced histamine release in children and provide stable hemodynamics during administration of anesthesia. (43)

Hydroxyzine 

  • Hydroxyzine apperas to be safe and effective in adults with generalized anxiety disorder. (44)
  • The incidence of bone pain with Granulocyte-Colony Stimulating Factor (G-CSF) may be higher clinically than reported before. Hydroxyzine is effective to the bone pain, and it also protects against the onset of the bone pain. (45)
  • Hydroxyzine 25 mg at bed time improves sleep behaviour in patients with cirrhosis and minimal hepatic encephalopathy (HE). The risk of precipitating over HE warrants some caution when prescribing this drug. (46)
  • The anxiolytic effects of chloral hydrate and hydroxyzine are not additive or synergistic. (47)
  • Hydroxyzine 0.7 mg/kg three timed daily is as effective as hydroxyzine 1.4 mg/kg three times daily in relieving pruritis and promoting resolution of the skin lesions in children with atopic dermatitis. The 0.7 mg/kg tid dose causes significantly less sedation than the 1.4 mg/kg tid dose. (48)
  • The addition of hydroxyzine to ephedrine may enhance its antiemetic efficacy. The combination may offer a more suitable alternative to droperidol or ephedrine alone in the outpatient setting. (49)
  • Hydroxyzine and benztropin selectively inhibits hepatitis C virus infection. They inhibit viral entry at a post-binding step of geotypes 1,2,3 and 4 without affecting entry of other viruses. (50)
  • Hydroxyzine has a tranquillizing effect but is not sufficient for treatment of psychotic conditions. It may be effective in minor disturbances like neuroses. (51)
  • Hydroxyzine may be used in the treatment of restless leg syndrome. (52)
  • Hydroxyzine, 25 mg to 100 mg nightly, seems to be effective in adults and geriatric patients and it is more rational choice in patients with insomnia. (53)
  • Hydroxyzine is clinically effective in the treatment of acute arrhythmias particularly ventricular premature beats, paroxysmal tachycardias, ventricular extrasystoles complicating atrial fibrillation. (54)
  • Hydroxyzine 1-2 mg/kg after an appropriate premedication-interval provides no better anxiolysis than placebo in the pre-operative period. (55)
  • First generation H1 blockers are not associated with an increased risk of major malformations or any other adverse fetal effects when given to a pregnant women. Second generation H1 blockers have also not been associated with an increased risk of adverse pregnancy outcomes. None of the antihistamines is excreted in the breast milk in an appreciable amount so as to have any adverse effects on breastfeeding infant. (56)

Pheniramine 

  • Acute renal failure can be caused by pheniramine maleate induced rhabdomyolysis. (57)
  • Prophylactic pheniramine/ naphazoline are more effective than olopatadine and plcebo in alleviating the signs and symptoms of acute ocular allergic reaction. (58)
  • Pheniramine overdisage can lead to central anticholinergic syndrome with choreiform movements. (59)
  • Pheniramine has a protective effect against ischemic/ reperfusion injury in rat lung. (60)
  • Therapeutic levels of pheniramine after taking 75 mg pheniramine maleate vary from 0.01 to 0.19 µg/ml of blood. (61)
  • A comparison of the urinary excretion data of pheniramine and its halogenated derivatives indicate the compounds to be metabolized in the following order: pheniramine < chlorpheniramine < brompheniramine. This is inverse to the order of total free and N-demethylated drug excreted in the urine. (62)
  • Loratidine is found to be more effective than pheniramine maleate in chronic idiopathic urticaria. (63)
  • There is occurence of psychotic syndromes with heavy pheniramine use. The psychopathology can vary from an independent psychotic syndrome to an organic brain syndrome like disorder. (64)
  • The metabolism of phenirmaine maletae can be impaired in Gilbert syndrome and anticholinergic effects can cause accomodation paralysis. (65)

Cyproheptadine 

  • Cyproheptadine inhibits growth hormone and ACTH secretion during sleep in man probably by antagonizing serotonergic mechanisms. (66)
  • Patients receiving cyproheptadine show marked increase in appetite, an associated weight gain and accleerated linear growth rate. (67)
  • There is a significant weight gain, increase in subjective hunger ratings and food intake with cyproheptadine. Drowsiness is the most frquent side effect. (68)
  • Cyproheptadine may be useful adjunct to baclofen and benzodiazepines in the management of acute intrathecal baclofen withdrawal syndrome. (69)
  • Cyproheptadine act as an appetite stimulant at a dose which appear to have antiserotoninergic activity. Administered orally for upto 6 oestrous cycles, it does not affect 24h food intake. It reduces 24h liquid intake and 24h urine output. (70)
  • Cyproheptadine may be effective as a migraine-preventive treatment for patients in whom conventional drugs have been ineffective or have caused side effects. (71)
  • Cyproheptadine can reduce spasticity and enhance locomotor function in spinal cord injured patients. (72)
  • The ability of cyproheptadine to antagonize the intestinal effects of methadone suggests a potentially useful means of overcoming one of the most troublesome side effects of the narcotic drugs. (73)
  • Cyprohepatdine suppresses the PI3K/AKT signalling pathway, which is probably critical for cyproheptadine induced myeloma cell apoptosis. It displays anti-blood cancer activity. (74)
  • Cyproheptadine and citalopram can cause fatality. (75)
  • The combination of cyproheptadine and propanolol is effective in migraine prophylaxis. (76)
  • Use of cyproheptadine in cystic fibrosis patients shows a significant weight gain and increase in BMI after 12 weeks. It can be an alternative approach for patients who need nutritional support for a short period of time. (77)
  • Cyproheptadine may be safe, rapidly effective treatment of serotonin syndrome. Physicians should be aware of its anticholinergic effects like urinary retention which may be potentiated by monoamine oxidase inhibitors. (78)
  • Cyproheptadine is safe and effective for treating dyspeptic symptoms in children, particularly in young children and those with early vomiting and retching after fundoplication. (79)
  • The primary action of cyproheptadine in preventing contractions of the canine basilar artery is antagonism of calcium channels. Thus it can be used for migraine prophylaxis and in the treatment of headache and other neurological disorders. (80)
  • Cyproheptadine may be effective in post traumatic stress disorder (PTSD) nightmare treatment. (81)
  • Cyproheptadine may be useful in neuroleptic- induced akathisia. (82)

Meclizine

  • Meclizine attentuates mitochondrial respiration by directly inhibiting the Kennedy pathway of phosphatidylethanolamine biosynthesis. (83)
  • Meclizine hold therapeutic potential in the treatment of polyQ toxicity disorderd such as Huntington's disease. (84)
  • Meclizine is effective for preventing nausea and vomiting associated with Yuzpe regimen of emergency contraceptive pills. Women using this drug should be cautioned to anticipate drowsiness. (85)
  • Meclizine reduces the severity and frequency of attacks as well as signs and symptoms associated with vertigo including nausea, positional and positioning nystagmus and postural instability. (86)
  • Meclizine ehnaces sensorimotor gating in healthy male subjects with high startle responses and low prepulse inhibition. (87)
  • Meclizine does not act as a human constitutive androstane receptor (hCAR) inverse agonist or antagonist in human hepatocytes. Therefore, it is not appropriate to use this drug as a pharmacological tool to study hCAR function in this cell type. (88)
  • Meclizine is effective for the prevention and treatment of motion sickness, particularly dring mild civilian travel. It is well tolerated with few adverse efefcts. Its oral dosage form is convineient for patients to take prior to exposure to motion as a preventative measure. (89)
  • Meclizine hydrochloride-niacin combination is found to be very useful for treatment of ambulatory patients with vestibular disease. (90)

Cinnarizine 

  • Cinnarizine is safe and effective in reducing both headache and vertigo aspects of migraine plus vertigo among the patients who suffer from either vestibular migraine or migraine with brainstem aura associated with vertigo. (91)
  • Betahistine has better effect on symptom reduction in patients with Meniere's disease compared to cinnarizine. (92)
  • Cinnarizine can be used for prophylaxis of car sickness in childre. (93)
  • Cinnarizine aggravates the symptoms of Parkinson's disease. (94)
  • Cinnarizine is an efficacious and well tolerated prophylactic antimigraine medication which has early onset effectiveness. (95)
  • Cinnarizine and flunarizine have a potential risk to induce extrapyramidal reactions and depression. (96)
  • Cinnarizine has an antagonist effect on dopamine D2 receptors, has a potential antipsychotic effect with an atypical profile which should be evaluated clinically. (97)
  • Pediatric patients with cinnarizine overdose need to be observed in a health care facility for potential neurologic complications (alterations in consciousness, stupor, coma, vomiting, extrapyramidal symptoms, convulsions and hypotonia) and be treated symptomatically. The delay to onset of clinical effect should be considered in the observation period. (98)
  • Cinnarizine and betahistine is used in the treatment of vertigo and meniere's disease. (99)
  • Cinnarizine could well prove to be the first of a new family of anti-asthmatic drugs pffering a protective effect when taken systematically. (100)
  • Cinnarizine impoves the haloperidol induced brain oxidative stress and impairment of learning and memory in the water maze test in mice. (101)
  • Flunarizine and cinnarizine induced parkinsonism is a recognized condition with specific clinical features and is the second most common cause of parkinsonism in many countries. (102)
  • A neuroleptic like action of flunarizine and cinnarizine seems to be the major reason for their extra-pyramidal side effects. Older age and long term treatment are predisposing factors of these effects. (103)
  • Chronic treatment with cinnarizine alters both D1 and D2 receptor densities, with a higher sensitivity of the D1 subtype. This indicates that the interactions between dopamine recpetor subtypes may be necessary for the full expression of behavioural event mediated by the D2 receptors. (104)
  • A patient with angioedema with C1 esterase inhibitor deficiency responds well to cinnarizine and alcohol abstinence. (105)

Chlorpheniramine

  • Chlorpheniramine/ paracetamol combination may be useful as a medication for colds in hypertensive patients since it does not induce cardiovascular effects such as those observed with pseudoephedrine. (106)
  • Chlorpheniramine analogues reverse chloroquine resistance in plasmodium falciparum by inhibiting PfCRT. (107)
  • Parallel infusion of hydrocortisone ± chlorpheniramine bolus injection to prevent acute adverse reactions to antivenom for snakebites. (108)
  • Chlorpheniramine is an effective treatment on anxiety and emotional memory in mice. (109)
  • Terfenadine and chlorpheniramine maleate is effective in the treatment of perennial rhinitis. (110)
  • Chlorpheniramine is a safe, non-cardiotoxic and well tolerated antidepressant. (111)
  • Chlorpheniramine plasma concentrations do not predict H1 receptor antagonist in plasma. There is a role of CYP2D6 in formation of a potent active metabolite of chlorpheniramine. (112)
  • Intentional overdose of lamotrigine, chlorpheniramine and citalopram causes reduced level of consciousness and ECG abnormalities, a widened QRS and a prolonged corrected QT (QTc) interval. Prompt treatment with early intubation, along with magnesium for cardioprotection and administration of sodium bicarbonate leads to quick recovery with a short intensive care stay and good outcome. (113)
  • Chlorpheniramine maleate may be a good candidate as an add-on therapy for epilepsy. (114)
  • Chlorpheniramine impairs the consolidation of learning both on telencephalon ablated animals and in sham operated ones through its action on mesencephalic structures of the brain and/ or on the cerebellum in teleost fish. (115)
  • There is an interaction of phenytoin with chlorpheniramine. (116)
  • Levamisole and chlorpheniramine maleate combination is found to more effective than antihistamine alone in the treatment of patient with urticaria. (117)
  • Chlorphenimramine is a widely used drug for managemnt of allergic reaction. The serious adverse reaction is extremely rare. A case has been reported of acute anaphylactic reaction due to expired chlorpheniramine injection. (118)
  • A fixed dose combination of paracetamol, chlorpheniramine and phenylephrine is safe and effective symptomatic treatment of the common cold or flu-like syndrome in adults. (119)
  • Cetrizine given once daily or in divided doses twice daily and chlorpheniramine given 3 times daily are effective in the treatment of seasonal allergic rhinitis in children aged 6-11 years. It has a rapid onset and is not associated with worsening of asthma. (120)

Triprolidine 

  • The fraction of the dose of triprolidine excreted in breast milk is estimated to be 0.06-0.2% in nursing mothers. (121) 
  • Hallucination has been reported in a child after drinking triprolidine/ pseudoephedrine linctus. (122)
  • The absolute oral bioavailability of triprolidine in the dog is low. There is similarity in the elimination characteristics of triprolidine in dogs, rabbits, rats and humans. (123)
  • Pseudoephedrine alone or in combination with triprolidine is effective in the treatment of common cold symptoms like sneezing, nasal obstruction etc. (124) 
  • The plasticizer and penetration enhancer increase the skin penetration of triprolidine and the triprolidine-EVA matrix system could be developed as a transdermal delivery system providing the increased constant plasma concentration and antihistamine effects. (125)
  • Under oxidative stress conditions, triprolidine undergoes distint biotransformation to give two degradation products: Triprolidine N-Oxide and Pyridin-2-yl-p-tolyl-methanone. (126)
  • Triprolidine 10 mg causes impairment of psychomotor and cognitive function in an individual while ebastine in a dose of 10-20 mg is free from impairment of psychomotor and cognitive function. (127)

 

Clemastine 

  • Clemastine is a useful antipruritic agent in the cats. (128)
  • Clemastine, a specific H1 receptor antagonist is an effective broncholdilator. (129)
  • Clemastine is effectibe in the management of allergic pruritis in dogs. (130)
  • Clemastine fumarate is effective in the treatment of rhinorrhea and sneezing associated with the common cold. (131)
  • Clemastine might be of use in the treatment of acute reactions to aspirin. (132)
  • Inhalation of 0.6 mg clemastine provides significant protection against histamine induced bronchoconstriction in normal and asthmatic patients is comparable to intravenous administration of 1.0 mg clemastine. In normal subjects 2.0 mg clemastine orally was significantly less effective than iv and inhalational routes whereas in asthmatics n enhanced reaction to histamine is observed. (133)
  • Both c-Myc and STAT transcription factors are highly expressed in proliferating tumours, whgich are inhibited by clemastibe, desloratidne. Thus, they could complement established chemotherapies for cutaneous T-cell lymphomas and other cancers. (134)
  • Drowsiness can occur due to clemastine transmitted in breast milk. (135)
  • Clemastine is a high potency inhibitor of the HERG K+ channel. (136)
  • The antihistamine drug clemastine does not abolish the potentiation, which suggest that the effect of PGE1 on itch does not depend on the liberation of endogenous histamine. (137)
  • Clemastine is not appropriate for oral administration due to low bioavailability. When using repeated iv administration, the drug has to be administered atleast three to four times daily to maintain therapeutic plasma concentrations because of the short half life. If sufficient plasma concentrations is maintained, the drug is efficacious in reducing histamine induced wheal formation. (138)
  • Clemastine causes immune suppression through inhibition of extracellular signal-regulated kinase-dependent proinflammatory cytokines. (139)
  • Clemastine is the first choice antihistamine as well as an effective alternative where tolerance to other antihistamines develops in the treatment of hay fever. (140)
  • Ketotifen has antihistaminic actions in man equivalent in potency to clemastine but does not appear to have additional effects on immediate skin or bronchial responses to allergen in atopic patients. (141)
  • Low dose clemastine provides relief for sneezing and rhinorrhea and might be useful in the treatment of allergic rhinitis. (142)

Fexofenadine 

  • In a skin test model of wheal and flare suppression, fexofenadine shows rapid distribution into the skin compartment with faster onset of action and greater potency vs loratidine. (143)
  • Fexofenadine at doses up to 180 mg appears free from disruptive effects on aspects of psychomotor and cognitive function. (144)
  • The antihistamine fexofenadine does not affect IKr currents in case of drug induced arrhythmia. (145)
  • Fexofenadine demonstrates no antitussive activity against capsaicin-induced cough in healthy volunteers and subjects with URI. This reflects the lack of anticholinergic activity and central nervous penetrance that is characteristic of forst generation antihistamines. (146)
  • Fexofenadine HCl at doses of 180 mg and 240 mg once daily is effective and well tolerated in the treatment of chronic idiopathic urticaria. (147)
  • Fexofenadine-pseudoephedrine and loratidine-montelukast have comparable efficacy in improving symptoms, Rhinoconjunctivitis Quality of life questionnaire (RQLQ) scores and nasal obstruction in seasonal allergic rhinitis. (148)
  • Fexofenadine is effective for the treatment of allergic rhinitis and chronic idiopathic urticaria. (149)
  • Although central nervous system (CNS) activation occurs after fexofenadine treatment, the magnitude of the centrally activating effects is too small to produce relevant performance improvement at the behavioural level. (150)
  • Patients who are dissatisfied with loratidine reports equal or better satisfaction with desloratidine as fexofenadine. Patients with severe allergic rhinitis reports greater satisfaction when converted from loratidine to desloratidine than fexofenadine. (151)
  • Fexofenadine HCl 180 mg has a faster onset of action at suppressing histamine induced flare and provides greater overall flare and wheal suppression than desloratidine 5 mg. (152)
  • QT lengthening and arrhythmias are seen in patients treated with fexofenadine. (153)
  • Desloratodine, fexofenadine and levocetrizine are appropriate options for the treatment of nasal congestion in patients with allergic rhinitis. (154)
  • The combination therapy of fexofenadine and montelukast is effective in patients with conventional therapy resistant prurigo nodularis and pemphigoid nodularis. (155)
  • Fexofenadine HCl at a single daily dose of 180 mg is an effective nonsedating antihistamine for the treatment of chronic idiopathic urticaria and is devoid of any significant adverse effect including cardiotoxicity. (156)
  • Fexofenadine at its recommended therapeutic dose of 120 mg is free from impairment effects on aspects of psychomotor function and hence can be used safely. (157)

Loratadine 

  • In the present study, maternal exposure to loratadine does not appear to be associated with an increased risk of hypospodias when compared with other antihistamines, although it should be noted that the statistical precision of the risk estimates might be limited. (158)
  • Ketoconazole alters the pharmacokinetic profile of loratadine. Thus it should not be coadministered with loratadine. (159)
  • Loratadine reduces cough induced by ultrasonically nebulised distilled water (UNDW). The release of histamine may contribute to the chronic cough in patients with unexplained chronic cough or nasal disease. (160)
  • Loratadine plus pseudoephedrine improves nasal and asthma symptoms, pulmonary function and quality of life in patients with seasonal allergic rhinitis and concomitant mild asthma. (161)
  • Concomitant nefazodone treatment with loratadine is associated with marked QTc prolongation. (162)
  • Montelukast alone or in combination with loratadine is well tolerated and provides clinical and quality of life benefits for patients with seasonal allergic rhinitis. (163)
  • Levocetrizine is superior to loratadine for chronic idiopathic urticaria. (164)
  • The pharmacokinetics of loratadine in pediatric subjects is similar to that in healthy adult volunteers. The maximum concentration (Cmax) of loratadine and descarboethoxyloratadine were approximately 4 ng/ml each. The AUC of the metabolite was about 6 times that of loratadine. The elimination half half life of descarboethoxyloratadine averaged about 13.8 hr. (165)
  • Loratadine may be a promising option for severe, resistant pegfilgrastim induced bone pain. (166)
  • The onset of action following treatment with loratadine/ montelukast was 1 hour 15 min for total symptoms score as well as for nasal congestion. Loratadine/ montelukast was well tolerated. (167)

Desloratadine

  • Rupatadine is a very good choice for seasonal allergic rhinitis due to its contribution to the improvement of nasal (including obstruction) and non-nasal symptoms to a similar degree as desloratadine. (168)
  • There is reduction in allergic rhinitis symptoms and improvement in nasal airflow in patients treated with desloratadine. (169)
  • There is no significant difference in efficacy whether desloratadine is given in the morning or in the evening. This gives the patients more flexibility in choosing dosing time. (170)
  • Desloratadine 5 mg once daily significantly decreased symptoms of chronic idiopathic urticaria and improved the quality of life. (171)
  • Desloratadine is effective for the relief of nasal and non nasal allergy symptoms. (172)
  • For persistent allergic rhinitis, the combination of montelukast and either desloratadine or levocetrizine is more effective than monotherapy with these agents. (173)
  • Desloratadine is a well tolerated and effective treatment of chronic idiopathic urticaria. (174)
  • Levocetrizine may be preferred to desloratadine as a treatment option for allergic rhinitis because of its faster onset of action and greater consistency of effect. (175)
  • There is a better overall protection of a single dose of levocetrizine compared to desloratadine in an nasal provocation test with grass pollen allergen. (176)
  • Pill esophagitis is a rare complication which occurs after taking desloratadine without liquid immediately before going to bed. (177)
  • Desloratadine syrup is safe and effective in the treatment of childhood atopic dermatitis. (178)
  • Desloratadine inhibits human skin mast cell activation and histamine release. (179)
  • Single dose co-administration of desloratadine and montelukast 2 h prior to allergen inhalation clinically abolished the late asthmatic response and eosinophil recruitment. (180)
  • Diphenhydramine 50 mg given for 1 week provides statistically significant and clinically superior improvements in symptoms compared with 5 mg of desloratadine in patients with moderate to severe seasonal allergic rhinitis. (181)
  • A single dose of desloratadine does not potentiate alchohol mediated CNS impairment. Desloratadine alone or in combination with alcohol is safe and well tolerated. (182)
  • Loaratadine and the active metabolites desloratadine and 3-OH-desloratadine are unlikely to affect the pharmacokinetics of coadministered drugs which are metabolized by these five cytochrome P-450 enzymes. (183)

Cetirizine 

  • Canine atopic dermatitis can be effectively treated with cetirizine. (184)
  • Cetirizine exerts its beneficial effects on viral myocarditis by suppressing expression of pro-inflammatory cytokines, genes related to cardiac remodelling in the herats of mice. (185)
  • Hypertonic saline aerosol can elicit airway obstruction in patients with moderate or severe chronic obstructive pulmonary disease. Cetirizine has some effects on hypertonic saline induced airway obstruction in patients with moderate to severe COPD. (186)
  • Cetirizine is well tolerated and effective in reducing symptoms of seasonal allergic rhinitis in patients undergoing controlled pollen challange. (187)
  • Cetirizine is approved by US FDA for allergic rhinitis in all age groups. It induces dystonic reactions in pediatric population. A case has v=been reported of involuntary movements associated with cetirizine use and discontinuation in adult. (188)
  • Cetrzine is considered to be safe in pregnancy. First trimester exposures to cetirizine is associated with no adverse pregnancy outcomes. (189)
  • In patients aged > 12 years who had allergic rhinitis, cetirizine us epromotes somnolence and decreased motivation to perform activities during the workday compared with loratadine. (190)
  • Recurrent acute hepatitis is associated with the use of cetirizine. (191)
  • Combined treatment with cetirizine and ranitidine in patients with functional dyspepsia shows a significant reduction in the severity and number of mast cells in gastric mucosa and leads to high rate of satisfaction among patients. (192)
  • Cetirizine is safe and effective in the treatment of allergic rhinitis. (193)
  • Cetirizine is proved to be more effective than terfenadine in controlling urticaria symptoms in patients with chronic idiopathic urticaria. (194)
  • Cetirizine may be useful antihistamine in the treatment of perennial allergic rhinitis for its long action, non-sedative property and convenient dosing schedule. (195)
  • Increasing the dose of cetirizine may lead to better control of chronic idiopathic urticaria. (196)

Levocetirizine 

  • Levocetirizine is safe and effective treatment for allergic rhinitis, seasonal allergic rhinitis, perennial allergic rhinitis and chronic idiopathic urticaria. (197)
  • Levocetirizine does not produce ant deleterious effect on cognitive and psychometric functions in healthy male volunteers. (198)
  • Once daily levocetirizine is safe and effective in the treatment of allergic rhinitis and chronic idiopathic urticaria. (199)
  • Levocetirizine may be preferred to desloratadine as treatment option for allergic rhinitis because of its faster onset of action and greater consistency of effect. (200)
  • Levocetirizine has consistently high response rates, fast onset and a favorable side effect profile in patients with chronic idiopathic urticaria. (201)
  • Levocetirizine is superior to lotratadine in terms of safety and efficacy in patients with chronic idiopathic urticaria. (202) 
  • Levocetirizine improves the quality of life and symptoms and decrease the overall costs of the disease over the 6-month treatment period in patients with persistent allergic rhinitis. (203)
  • Levocetirizine 2.5 mg has comparable antihistaminic activity to cetrizine 5 mg, whereas its other enantiomer ucb 28557 has no pharmacodynamic effect suggesting that the antihistaminic properties of cetirizine observed in the management of allergic skin conditions are likely to be attributable to levocetrizine. (204)
  • The combined therapy with fluticasone furoate nasal spray and levocetirizine significantly suppressed the induced seasonal allergic rhinitis symptoms and delayed the onset of symptoms compared with levocetirizine monotherapy. (205)
  • Fexofenadine has the earliest onset of action while levocetirizine shows maximum inhibition of wheal response after three and six hours. (206)
  • Levocetirizine is a better option for treatment of seasonal allergic rhinitis both in terms of efficacy and safety when compared to cetirizine. (207)
  • Levocetirizine effectively reduces the activation and migration of antigen presenting cells to local draining lymph nodes and induces differentiation of Treg cells as one possible mechanism of its anti-inflammatory action. (208)
  • A double dose of levocetirizine leads to better control of histamine-induced flare, wheal response and itch in healthy donors. (209)
  • Second generation non-sedating antihistamines are recommended as first line therapy in the management of chronic spontaneous urticaria. If not responding, higher dose (up to four fold) of non sedating antihistamines is recommended. (210)

 

Azelastine

  • Compared to oral antihistamines, azelastine nasal spray has superior efficacy and more rapid onset of action in patients with seasonal allergic rhinitis. (211)
  • Azelastine nasal spray is effective in the treatment of vasomotor (perennial nonallergic) rhinitis. (212)
  • Azelastine nasal spray monotherapy is as effective as the combination of oral loratadine plus intranasal beclomethasone in treating moderate-to-severe symptoms of seasonal allergic rhinitis. (213)
  • A single oral dose of 4.4 mg of azelastine causes significant bronchodilation and attenuation of exercise-induced bronchoconstriction in patients with exercise induced asthma. (214)
  • A combination of azelastine and fluticasone propionate is highly effective in the treatment of moderate to severe seasonal allergic rhinitis. (215)
  • Azelastine posseses complementary antiallergic, antihistaminic, anti-inflammatory and antiasthmatic activities which may be of greater clinical benefit than an agent that interferes with a single mediator. (216)
  • Azelastine is more effective and yield higher patient satisfaction scores than olopatadine in the treatment of allergic cunjunctivitis. (217)
  • Azelastine, 6 mg twice per day can reduce the need for inhaled coticosteriods in patients with chronic bronchial asthma and not lead to a deterioration in pulmonary function. (218)
  • Azelastine is a genuine Ca++ antagonist that inhibits voltage gated Ca++ inward current and agonist-induced Ca++ release and Ca++ sensitization. (219)
  • The TNF-alpha secretion is suppressed by azelastine in a rat mast (RBL-2H3) cell line. This suggests that the release process of TNF-alpha in mast cells is regulated by a mechanism distinct from that of degranulation, and that in Ca2+-ionophore-stimulated cells, it is also different from that of transcription/production, and possibly involves protein kinase C activation. (220)
  • Azelastine, similar to capsaicin, exhibit direct activity on TRPV1 ion channels that may represent a novel mechanistic pathway explaining its clinical efficacy in nonallergic rhinitis. (221)
  • At the recommneded dosage (one spray per nostril twice daily), azelastine is a useful addition to the currently available therapies for allergic rhinitis in children. (222)
  • The inhibition of ovalbumin induced contraction of sensitized parenchymal tissues of Guinea pig in vitro study is dose dependent and controlled better with verapamil than azelastine. (223)
  • MP29-02 (a novel intranasal formulation of azelastine hydrochloride and fluticasone propionate in an advanced delivery system) is well tolerated and safe for long term use in the treatment of allergic rhinitis. (224)

Mizolastine 

  • MIzolastine is more active than loratadine on the wheal and lare inhibition from 3 up to 6 and 8 h respectively, as active as terfenadine on both parameters and as active as cetirizine on wheal inhibition while less active than cetirizine on flare inhibition at 2 and 12 h post-dosing. (225)
  • Cetirizine (10 mg) suppresses skin reactivity to histamine more effectively than mizolastine (10 mg) 24 h after intake in healthy volunteers. (226)
  • Mizolastine provides effective symptom relief in perennial allergic rhinitis together with a satisfactory safety profile. (227)
  • Mizolastine 10 mg once daily is at least as effective as cetirizine in relieving symptoms of seasonal allergic rhinoconjunctivitis, onset of action is rapid with clinical effects evident within 2 hours. (228)
  • Mizolastine is effective and well tolerated in the treatemnt of chronic idiopathic urticaria. (229)
  • Mizolastine is effective in the treatment of primary acquired cold urticaria. (230)
  • Mizolastine, 10 mg once daily at steady state is devoid of sedation and detrimental effect on skilled performance and memory. (231)
  • MIzolastine is an effective and well tolerated antihistamine in the treatemnt of seasonal allergic rhinitis, 10 mg is the optimal dose. (232)
  • MIzolastine has inhibitory effects on ultraviolet B-induced leukotriene B4 production and 5-lipoxygenase expression in normal human dermal fibroblasts in vitro. It may play a protective role in the pathogenesis of UV radiation-induced acute photodamage of the skin. (233)
  • Allergic reaction has been reported with mizolastine use. (234)
  • Mizolastine appears to be devoid of sedative effects in experimental models irrespective of the route of administration used. This predicts a lack of sedative action in humans with mizolastine at therapeutic doses. (235)
  • Mizolastine is effective and well tolerated in long term treatment of perennial allergic rhinoconjunctivitis. (236)
  • A single oral dose of mizolastine failed to induce subjective drowsiness and produces no detrimental effects on psychomotor performance or on short-term and long term memory in elderly patients. Thus mizolastine 10 mg can be safely used in elderly out patients as it preserves functions involved in activities of daily living. (237)

Ebastine 

  • A superior efficacy of 20 mg of ebastine is compared with 10 mg ebastine and 10 mg cetirizine on the skin wheal response 24 h after the last dose of a 6 day long treatment.Ebastine has no negative effective on cognitive performance or mood. (238)
  • Ebastine is an effective and well tolerated antihistamine for the treatment of allergic rhinitis. (239)
  • Ebastine is an effective and generally well tolerated treatment for allergic rhinitis and chronic idiopathic urticaria. In addition to regular tablet formulation, it is available as a fast dissolving tablet, providing a treatment option that is particularly convenient for patients. (240)
  • Ebastine 20 mg once daily is significantly superior to loratadine 10 mg once daily at improving the rhinitis total symptom score throughout the day and at awakening over a 4 week period. Ebastine 20 mg and 10 mg doses are both efficacious and well tolerated in the treatment of seasonal allergic rhinitis. (241)
  • In nonatopic white subjects, inhibition of the response to histamine injection is significantly greater with ebastine 20 mg fast dissolving tablet compared with desloratadine 5 mg capsule and placebo after 1 and 5 days of administration. (242)
  • Ebastine at its recommended daily dose of 10 mg is free from disruptive effects on the CNS and should therefore prove valuable in the treatment of various allergic disorders in patients who wish to continue their activities without experiencing decrements in their psychomotor and cognitive abilities. (243)
  • Ebastine 20 mg have advantages over ebastine 10 mg and cetirizine 10 mg in terms of reduced time to achieve maximal efficacy and a superior level of efficacy in patients with more severe symptoms in patients with seasonal allergic rhinitis. (244)
  • Ebastine, an effective H1 rceptor antagonist with a prompt onset of action and a long duration of action, is suitable for once daily administration to children. (245)
  • Both CYP2J2 and CYP3A play important roles in ebastine sequential metabolism: dealkylation of ebastine and its metabolites is mainly catalyzed by CYP3A4, whereas the hydroxylation reactions are preferentially catalyzed by CYP2J2. (246)
  • Ebastine fast dissolving tablet is associated with a very high satisfaction rate and significant relief of rhinitis symptoms. (247)
  • Ebastine is an effective and well tolerated alternative to other non-sedating antihistamines in the treatment of chronic urticaria. (248)
  • Ebastine is efficacious 2nd generation antihistamine in treatment of allergic rhinitis in pediatric patients with minimal incidence of sedation. (249) 

Rupatadine 

  • Once daily rupatadine (10 and 20 mg) is an efficacious and safe treatment for the management of patients with perennial allergic rhinitis. (250)
  • The use of rupatadine is associated with heart rhythm disturbances. (251)
  • Rupatadine oral solution (1mg.ml) is effective in reducing nasal symptoms at 4 and 6 week and is well tolerated in the treatment of persistent allergic rhinitis in children. (252)
  • Rupatadine use is associated with Torsades de pointes. (253)
  • Rupatadine is superior to desloratadine in chronic idiopathic urticaria patients in terms of safety and efficacy because of its multiple mechanisms of action. (254)
  • Olopatadine is a better choice in seasonal allergic rhinitis in comparison to rupatadine due to its better efficacy and safety profile. (255)
  • Rupatadine is a dual inhibtor of histamine H1 and well tolerated treatment for allergic rhinitis and chronic urticaria. It possesses a broader profile of anti-inflammatory properties inhibiting both inflammatory cells and a range of mediators involved in the early and late phase inflammatory response. (256)
  • Rupatadine 20 mg/d shows high efficacy and is well tolerated in the treatment of acquired cold urticaria. (257)
  • Platelet activating factor (PAF) stimulates human mast cell release of proinflammatory mediators that is inhibited by rupatadine. This action endows rupatadine with additional properties in treating allergic inflammation. (258)
  • Rupatadine promotes the resolution of pulmonary inflammation and fibrosis by attenuating the PAF mediated senescence response. Rupatadine holds promise as a novel drug to treat the devastating disease of pulmonary fibrosis. (259)
  • Concomitant intake of food with a single 20 mg oral dose of rupatadien exhibits a significant increase in  rupatadine bioavailability. Despite the absene of bioequivalence, the drug is well tolerated under fed and fasting conditions, an dno major changes in severity and/ or prevalence of adverse events were reported. (260)
  • Rupatadine 10 mg may be valuable and safe alternative for symptomatic treatment of seasonal allergic rhinitis. (261)

Reference:

  1. Peter G Pavlidakey, Erin E Brodell, Stephen E Helms. Diphenhydramine as an alternative local anesthetic agent. J Clin Aesthet Dermatol. Oct 2009;2(10):37-40. 
  2. William G Berlinger, Mark J Goldberg, Reynold Spector, Chao-Kuo Chiang, MM Ghoneim. Diphenhydramine: Kinetics and psychomotor effects in elderly women. Clinical Pharmacology and Therapeutics. 1982;32:387-391. 
  3. Ian M Paul, Katharine E Yoders, Kathryn R Crowell et al. Effect of dextromethorphan, diphenhydramine and placebo on nocturnal cough and sleep quality for coughing children and their parents. Pediatrics. July 2004;114(1):e85-e90. 
  4. Charles M Morin, Uwe Koetter, Celyne Bastien, Catesby Ware, Virgil Wooten M. The Valerian-Hops combination and diphenhydramine for treating insomnia: A randomized placebo-controlled clinical trial. Sleep 2005;28(11). 
  5. Shaun D Carstairs, Aaron B Schneir. Opsoclonus due to diphenhydramine poisoning. N Engl J Med 2010;363:e40. 
  6. Tomoko Akutsu, Kaoru Kobayashi, Koichi Sakurada, Hiroshi Ikegaya, Tomomy Furihata, Kan Chiba. Identification of human cytochrome P450 isoenzymes ivolved in diphenhydramine N-Demethylation. DMD. Jan 2007;35(1):72-78. 
  7. Arthur L Doenecke, Robert C Heuermann. Treatment of haloperidol abuse with diphenhydramine. Am J Psychiatry. 1980;137:487-488. 
  8. Michael E Mullins, Robert V Pinnick, John M Terhes. Life threatening diphenhydramine overdose treated with charcoal hemoperfusion and hemodialysis. Annals of Emergency Medicine. Jan 1999;33(1):104-107. 
  9. Yu Wen Chen, Jann Inn Tzeng, Ting Yun Chen, Jhi Joung Wang, Yu Chung Chen, Ching Hsia Hung. Diphenhydramine produces local cutaneous analgesia in response to dorsal skin noxious stimuli in the rat. Fundamental & CLinical Pharmacology. Aug 2014;28(4):439-444. 
  10. Faustino Gonzalez. Diphenhydramine may be useful as a palliative treatment for patients dying with Parkinson's disease and tremors: A case report and discussion. Am J Hosp Pallait Care. Dec 2009;26(6):474-475. 
  11. Katherine Scoari Childress, Christina Dothager, Jeffrey Gavard, Sara Lebovitz, Dorothea Mostello. Methoclopramide and diphenhydramine: a randomized controlled trial of a treatment for headache in pregnancy when acetaminophen alone is ineffective (MAD headache study). American Journal of Obstetrics & Gynecology. Jan 2014;210(1):S277. 
  12. Phillip J Suffridge, Michael N Wiggins, Reid D Landes, Richard A Harper. Diphenhydramine as a topical ocular anesthetic. Canadian Journal of Ophthalmology. April 2009;44(2):181-184. 
  13. Regan Pyle, Micheal Scott, Jennifer Bartholomew, Steven McGrath, Bryan Moffett. Accidnetal polydipsia and hyponetremia from diphenhydramine urinary retention. The American Journal of Medicine. Oct 2011;124(10):e5-e6. 
  14. Serge Gouin, Thuy-Tien Vo, Michel Roy, Denis Lebel, Jocelyn Gravel. Oral dimenhydrinate versus placebo in children with gastroenteritis: A randomized controlled trial. Pediatrics June 2012;129(6). 
  15. M Mete Kiroglu, Muhammed Dagkiran, Suleyman Ozdemir, Ozgur Surmelioglu, Ozgur Tarkan. The effects of betahistine and dimenhydrinate on caloric test parameters; slow phase velocity of nystagmus. Int Adv Otol. 2014;10:68-71. 
  16. AE Czeizel, P Vargha. A case control study of congenital abnormality and dimenhydrinate usage during pregnancy. Archives of Gynecology and Obstetrics. Feb 2005;271(2):113-118. 
  17. Daniel C Moore, L Donald Bridenbaugh, John C Green, Vincent F Piccioni, Pliny A Adams, Carl A Lindstrom. Intramuscular use of dimenhydrinate (dramamine) to control postoperative vomiting. JAMA. 1955;159(14):1342-1345. 
  18. A Schlager, G Mitterschiffthaler, F Puhringer. Rectally administered dimenhydrinate reduces postoperative vomiting in children after strasbismus surgery. Br J Anaesth. 2000;84(3):405-406. 
  19. Richard E Winn, Kenneth P McDonnell. Fatality secondary to massive overdose of dimenhydrinate. Annals of Emergency Medicine. Sept 1993;22(9):1481-1484. 
  20. Doreen Su-Yin tan, Grant E Sklar. Erythema multiforme secondary to dimenhydrinate in a patient with previous similar reactions to pamabrom. Ann Pharmacother. March 2014;48(3):425-428. 
  21. Sophia Giatrakou, Evangelia Papadavid, Dimitrios Kalogeromitros et al. Fixed drug eruption caused by dimenhydrinate. Journal of the American academy of dermatology. March 2011;64(3):608-610. 
  22. BP Jaju, SC Wang. Effects of diphenhydramine and dimenhydrinate on vestibular neuronal activity of cat: A search for the locus of their antimotion sickness action. JPET. March 1971;176(3):718-724. 
  23. Apiliogullari S, Gok F, Canpolat A, Soysal S, Toy H. Comparison of prophylactic dimenhydrinate and metoclopramide for prevention of nausea-vomiting caused by intrathecal opioids in parturients undergoing caesarean delivery. Regional anesthesia & Pain medicine. Sept/Oct 2008;33(5):e131. 
  24. Eric Prost, Richard C Millson. Clozapine treatment of dimenhydrinate abuse. Am J Psychiatry. 2004;161:1500. 
  25. SM Luria, JA Kinney, CL McKay, HM Paulson, AP Ryan. Effects of aspirin and dimenhydrinate on visual processes. British Journal of Clinical Pharmacology. June 1979;7(6):585-593. 
  26. LHJ Eberhart, W Seeling, TI Bopp, AM Morin, M Georgieff. Dimenhydrinate for prevention of post-operative nausea and vomiting in female in patients. European Journal of Anaesthesiology. May 1999;5:284-289. 
  27. KW Anquist, S Panchanathan, PC Rowe, RG Peterson, A Sirnick. Diagnostic delay after dimenhydrinate use in vomiting children. CMAJ. October 1991;145(8):965-968. 
  28. Joseph Pytel, Gyorgy Nagy, Agnes Toth, Sandor Spellenberg, Mario Schwarz, Gabor Repassy. Efficacy and tolerability of a fixed low dose combination of cinnarizine and dimenhydrinate in the treatment of vertigo: A 4 week, randomized, double blind, active and placebo controlled, parallel group, outpatient study. Clinical Therapeutics. Jan 2007;29(1):84-98. 
  29. Georgi Konstantinov Maximov, Deepak Kamnasaran. The adjuvant use of lansoprazole, clonazepam and dimenhydrinate for treating intractable hiccups in a patient with gastritis and reflux esophagitis complicated with myocardial infarction: a case report. BMC Research Notes. 2013;6:327. 
  30. Jason R Carter, Chester A Ray. Effect of dimenhydrinate on the vestibulosypathetic reflex and baroreflexes in humans. The FASEB Journal. 2007;21:612.10. 
  31. Matthew Grissinger. Preventing serious tissue injury with intravenous promethazine. Pharmacy and Therapeutics. 2009;34(4):175-176. 
  32. M Keeri Szanto. The mode of action of promethazine in potentiating narcotics drugs. Br J Anaesth. 1974;46(12):918-924. 
  33. Josko Markic, Anna Louise Ridge. Promethazine in the treatment of postoperative nausea and vomiting: a systematic review. Signa Vitae 2011;6(2):9-16. 
  34. Geoffrey Cleghorn, Geofrey Bourke. Physiostigmine for promethazine poisoning. The Lancet. Aug 1980;316(8190):368-369. 
  35. Milton H Adelman, Elliott Jacobson, Philip A Lief, Seymour A Miller. Promethazine hydrochloride in surgery and obstetrics. JAMA 1959;169(1):5-7. 
  36. Haloperidol plus promethazine effective for psychosis induced aggression. Evid Based Mental Health. 2010;13:23. 
  37. Joseph A Barsa, Nathan S Kline. Depression treated with chlorpromazine and promethazine. Am J Psychiatry. 1957;113:744-745, 
  38. C Cantisani, S Ricci, T Grieco, G Paolino, V Faina, E Silvestri, S Calvieri. Topical promethazine side effects: our experience and review of literature. Biomed Research International. 2013, Article ID 151509, 9 pages. http://dx.doi.org./10.1155/2013/151509. 
  39. Raghupathy Ramanathan, Richard S Geary, David WA Bourne, Lakshmi Putcha. Bioavailability of intranasal promethazine dosage forms in dogs. Pharmacological Research. July 1998;38(1):35-39. 
  40. Gerald B Hickson, William A Altemeier, Ellen W Clayton. Should promethazine in liquid form be available without prescription? Pediatrics 1990;86(2):221-225. 
  41. Ernst AA, Weiss SJ, Park S, Takakuwa KM, Diercks DB. Prochlorperazine versus promethazine for uncomplicated nausea and vomiting in the emergency department: a randomized, double blind clinical trial. Ann Emerg Med. Aug 2000;36:89-94. 
  42. Manuel Pequito, Helene Amory, Didier Serteyn, Valeria Busoni, Brieuc de Moffarts, Charlotte Sandersen. Comparison of the sedative and hemodynamic effects of acepromazine and promethazine in the standing horse. Journal of equine veterinary Science. Dec 2012;32(12):799-804. 
  43. Zhou Xiang, Qu Yan-Liang, Song Xiao-Yang, Zhang Yan Hui et al. Effects of promethazine or dexamethasone pretreatment on mivacurium induced histamine release in children. Pediatric Anesthesia. March 2014;24(3):322-326. 
  44. Hydroxyzine may be safe and effective in generalized anxiety disorder. Evid Based Mental Health. 2003;6:91. 
  45. S Ogata, K Ito, K Kadoike, T Egawa, Y Kinugasa, M Kozuki. The incidence of bone pain with granulocyte stimulating factor (G-CSF) administration and the effect of hydroxyzine. Journal of Clinical Oncology. 2005;23(16S):8242. 
  46. Laurent Spahr, Alessandra Coeytaux, Emiliano Giostra, Antoine Hadengue, Jean-Marie Annoni. Histamine H1 blocker hydroxyzine improves sleep in patients with cirrhosis and minimal hepatic encephalopathy: A randomized controlled pilot trial. The American Journal of Gastroenetrology. 2007;102:744-753. 
  47. M Gladney, RT Stanley, SE Hendricks. Anxiolytic activity of chloral hydrate and hydroxyzine. Pediatr Dent. 1994;16:183-89. 
  48. Paul S Lietman, F Estelle, R Simons, Keith J Simons, Allan B Becker, Richard P Haydey. Pharmacokinetics and antipruritic effects of hydroxyzine in chldren with atopic dermatitis. The Journal of Pediatrics. Jan 1984;104(1):123-127. 
  49. Garbin GS, Bogetz MS. Efficacy of ephedrine and hydroxyzine in preventing post-operative nausea and vomiting. Anesthesiology. Sept 1992;77(3A). 
  50. Lidia Mingorance, Martina Friesland, Mairene Coto-Llerena et al. Selective inhibtion of hepatitis C virus infection by hydroxyzine and benztropin. Antimicrobial agents and chemotherapy. Apri 2014. DOI: 10.1128/AAC.02619-14.  
  51. M Saaael, FG Sulman, HZ Winnik. Clinical and endocrinological effects of hydroxyzine. The British Journal of Psychiatry. 1960;106:1027-1030. 
  52. R Di Fabio, C Casali, F Pisrelli. Hydroxyzine hydrochloride in restless legs syndrome. The internet journal of neurology. 2008;10(2).  
  53. Schiffman Jason, Davis Michael, Pierre Joseph, Saunders C Scott. HYdroxyzine: Rational choice for inpatients with insomnia. Current Psychiatry. March 2011;10(3). 
  54. James A Salmons. Treatment of cardiac arrhythmias with hydroxyzine. Chest 1960;38(1):105-106. 
  55. JH Boon, D Hopkins. Hydroxyzine premedication- does it provide better anxiolysis than a placebo? SAMJ. JUne 1996;86(6). 
  56. Miranda So, Pina Bozzo, Miho Inoue, Adrienne Einarson. Safety of antihistamines during pregnancy and lactation. Canadian family physician. May 2010;56(5):427-429. 
  57. G Paul, P Sood, S Puri. Acute renal failure caused by pheniramine maleate induced rhabdomyolysis: An unusual case. Indian J Crit Care Med. Oct-Dec 2009;13(4):221-223. 
  58. Jack V Greiner, Ira J Udell. A comparison of the clinical efficacy of pheniramine maleate/ naphazoline hydrochloride ophthalmic solution and olopatadine hydrochloride ophthalmic solution in the conjunctival allergen challenge model. Clinical Therapeutics. May 2005;27(5):568-577. 
  59. George Mendelson. Pheniramine aminosalicylate overdosage. Reversal of delirium and choreiform movements with tacrine treatment. Arch Neurol. 1977;34(5):313.  
  60. Orhan Gokalp, Ismail Yurekli, Muge Kiray et al. Assessment of protective effects of phenitramine maleate on reperfusion injury in lung after distant organ ischemia. A Rat model. Vasc Endovascular Surg. APril 2013;47(3):219-224. 
  61. Eileen A Queree, Stuart J Dickson, Alan W Missen. Therapeutic and toxic levels of pheniramine in biological specimens.  J Anal Toxicol. Nov-Dec 1979;3(6):253-255. 
  62. Peter Kabasakalian, Marilyn Taggart, Edward Townley. Urinary excretion of pheniramine and its N-demethylated metabolites in man- comparison with chlorpheniramine and brompheniramine data. Journal of Pharmaceutical Sciences. April 1968;57(4):621-623. 
  63. C Ranjan Raval, FE Bilimoria, A Himanshu Patel. A comparative study of loratidine versus phenirmaine maleate in chronic idiopathic urticaria. IJDVL 1995;61(3):137-139. 
  64. Hemraj Pal, Rajesh Kumar, Shahsi Bhushan, Neeraj Berry. Psychiatric co-morbidity associated with pheniramine abuse and dependence. Indian Journal of Psychiatry. 2005;47(1):60-62. 
  65. Pinar Bingol Kizitunc, Huban Atilla, F Nilufer Yalcindag. Accomodation paralysis after pheniramine maleate injection: A case report. Neuro-opthalmology. Dec 2013;37(6):257-259. 
  66. K Chihara, Y Kato, K Maeda, S Matsukura, H Imura. Suppression of cyproheptadine of human growth hormone and cortisol secretion during sleep. J Clin Invest. June 1976;57(6):1393-1402. 
  67. Arnold F Lavenstein, Eleanora P Dacaney, Louis Lasagna, Thomas E Van Metre. Effect of cyproheptadine on asthmatic children. Study of appetite, weight gain and linear growth. JAMA 1962;180(11):912-916. 
  68. T Silverstone, D Schuyler. The effect of cyproheptadine on hunger, calorie intake and body weight in man. Psychopharmacologica. 1975;40(4):335-340. 
  69. Jay M Meythaler, James F Roper, Robert C Brunner. Cyproheptadine for intrathecal baclofen withdrawal. Archives of physical medicine and rehabilitation. May 2003;84(5):638-642. 
  70. Maria Konstandi, Anastasia Dellia-Sfikaki, Denis Varonos. Effect of cyproheptadine hydrochloride on ingestive behaviours. Pharmacological Research. Jan 1996;33(1):35-40. 
  71. Hirohisa Okuma, Kazuyuki Iijima, Takashi Yasuda, Kentaro Tokuoka, Yasuhisa Kitagawa. Preventive effect of cyproheptadine hydrochloride in refractory patients with frequent migraine. SpringerPlus 2013;2:573. 
  72. M Wainberg, H Barbeau, S Gauthier. The effects of cyproheptadine on locomotion and on spasticity in patients with spinal cord injuries. J Neurol Neurosurg Psychiatry. 1990;53:754-763.
  73. Diana K Kennedy, Margaret N Grubb, Thomas F Burks. Antagonism of methadone's intestinal effects by cyproheptadine. Gastroenterology. March 1974;66(3):396-402. 
  74. Jie Li, Biyin Cao, Shunye Zhou, Jingyu Zhu, Zubin Zhang et al. Cyproheptadine induced myeloma cell apoptosis is associated with inhibition of the PI3K/AKT signalling. European Journal of Haematology. Dec 2013;91(6):514-521. 
  75. Veronica Hargrove, D Kimberley Molina. A fatality due to cyproheptadine and citalopram. J Anal Toxicol. 2009;33(8):564-567. 
  76. Rao BS, Das DG, Taraknath VR, Sarma Y. A double blind contrlled study of propanolol and cyproheptadine in migraine prophylaxis. Neurology India. 2000;48(3):223-6. 
  77. Matias Epifanio, Paulo C Marostica, Rita Mattiello et al. A randomized, double blind, placebo controlled trial of cyproheptadine for appetite stimulation in cystic fibrosis. J Pediatr. Mar/Apr 2012;88(2). 
  78. Richard I Lappin, Elizabeth L Auchincloss. Treatment of the serotonin syndrome with cyproheptadine. N Engl J Med. 1994;331:1021-1022. 
  79. Leonel Rodriquez, Juan Diaz, Samuel Nurko. Safety and efficacy of cyproheptadine for treating dyspeptic symptoms in children. The Journal of Pediatrics. July 2013;163(1):261-267. 
  80. Stephen J Peroutka, George S Allen. The calcium antagonist properties of cyproheptadine. Implications for antimigraine action. Neuology. March 1984;34(3):304. 
  81. Gholamhossien Ahmadzadeh, Ghorbanali Asadolahi, Gavad Mahmodi, Arezoo Farhat. Effect of cyproheptadine on combat related PTSD nightmares. Annals of general psychiatry. 2006;5(Suppl 1):S159. 
  82. D Weiss, D Aizenberg, H Hermesh, Z Zemishlany, H Munitz, M Radwan A Weizman. Cyproheptadine treatment in neuroleptic induced akathisia. The British Journal of Psychiatry. 1995;167:483-486. 
  83. Vishal M Gohil, Lin Zhu, Charli D Baker, Valentin Cracan, Abbas Yaseen et al. Meclizine inhibits mitochondrial respiration through direct targeting of cytosolic phosphoethanolamine metabolism. The Journal of Biological Chemistry. October 19,2013. DOI: 10.1074/jbc.M113.489237. 
  84. Vishal M Gohil, Nicolas Offner, James A Walker, Sunil A Sheth et al. Meclizine is neuroprotective in models of Huntington's disease. Hum Mol Genet. 2011;20(2):294-300. 
  85. Elizabeth G Raymond, Mitchell D Creinin, Kurt T Barnhart, Amy E Lovvorn, R Wesley Rountree, James Trussell. Meclizine for prevention of nausea associated with the use of emergency contraceptive pills: a randomized trial. Obstetrics & Gynecology. Feb 2000;95(2):271-277. 
  86. Bernard Cohen, JMB Vianney deJong. Meclizine and plcebo in treating vertigo of vestibular origin. Arch Neurol. 1972;27(2):129-135. 
  87. Jose A Larrauri, Lisalynn D Kelley, Mason R Jenkins, Eric C Westman et al. Meclizine enhancement of sensorimotor gating in healthy male subjects with high startle responses and low prepulse inhibition. Neuropsychopharmacology. 18 Sept 2013. doi: 10.1038/npp.2013.248. 
  88. Aik Jiang Lau, Guixiang Yang, Ganesh Rajaraman, Chritie C Baucom, Thomas KH Chang. Meclizine is not an inverse agonist or antagonist of human constitutive androstane receptor. The FASEB Journal 2011;25:1014.7. 
  89. Priti N Patel, Emily M Ambizas. Meclizine: safety and efficacy in the treatment and prevention of motion sickness. Clinical Medicine Insights: Therapeutics. 2011;3:179-183. 
  90. N Martin, WJ Oosterveld. The vestibular effects of meclizine hydrochloride-niacin combination (Antivert). Acta Oto-Laryngologica. July 1970;70(1):6-9. 
  91. The Foad Taghdiri, Mansoureh Togha, Soodeh Razeghi Jahromi, Farshod Refaeian. Cinnarizine for the prophylaxis of migraine associated vertigo: a retrospective study. SpringerPlus 2014;3:231. 
  92. Jasminka Djelilovic-Vranic, Azra Alajbegovic, Merita Tiric-Campara, AIda Volic et al. Betahistine or cinnarizine for treatment of Meniere's disease. Med Arh. 2012;66(6):396-398. 
  93. Alexander L Macnair. Cinnarizine in the prophylaxis of car sickness in childre. 1983;8(7):451-455. 
  94. JF Marti Masso, JA Obeso, N Carrera, JM Martinez-Lage. Aggravation of Parkinson's disease by cinnarizine. J Neurol Neurosurg Psychiatry. 1987;50:804-805. 
  95. Mansooreh Togha, Hossein Ashrafian, Parvin Tajik. Open-Label trial of cinnarizine in migraine prophylaxis. Headache 2006;46:498-502. 
  96. F Micheli, MF Pardal, M Gatto, M Torres, G Paradiso, IC Parera, R Giannaula. Flunarizine and cinnarizine- induced extrapyramidal reactions. Neurology. May 1987;37(5):881. 
  97. Oscar P Dall'igna, Adriano BL Tort, Diogo O Souza, Diogo R Lara. Cinnarizine has an atypical antipsychotic profile in animal models of psychosis. J Psychopharmacol. July 2005;19(4):342-346. 
  98. Dan Turner, Yael Lurie, Yoram Finkelstein, Tal Schmid et al. Pediatric cinnarizine overdose and toxicokinetics. Pediatrics. 2006;117(5):e1067-e1069. 
  99. Drug treatment of vertigo and meniere's disease cinnarizine and betahistine. DTB 1981;19:17-18. 
  100. MB Emanuel, JA Chamberlain, S Whiting, BG Rigden, AH Craven. Cinnarizine in the treatment of chronic asthma. British Journal of Clinical Pharmacology. Feb 1979;7(2):189-195. 
  101. Omar ME Abdel-Salam, Marwa El-Sayed El-Shamarka, Naveen A Salem, Aliaa EMK El-Mosallamy, Amany A Sleem. Amelioration of the haloperidol-induced memory impairment and brain oxidative stress by cinnarizine. EXCLI Journal. 2012;11:517-530. 
  102. Helio AG Teive, Andre R Troiano, Francisco MB Germiniani, Lineu C Werneck. Flunarizine and cinnarizine induced parkinsonism: a historical and clinical analysis. Parkinsonism & related disorders. June 2004;10(4):243-245. 
  103. T Brucke, Ch Wober, I Podreka, C Wober Bingol, S Asenbaum, S Aull, S Wenger et al. D2 receptor blockade by flunarizine and cinnarizine explains extrapyramidal side effects. A SPECT study. Journal of cerebral blood flow & metabolism. 1995;15:513-518. 
  104. Camps M, Ambrosio S, Reiriz J, Ballarin M, Cutills B, Mahy N. Effect of age and cinnarizine treatment on brain dopamine receptors. Pharmacology 1993;46:9-12. 
  105. Sandra Braz, Emilia Arranhado. Angioedema in a patient with C1 esterase inhibitor deficiency. Iranian Journal of Allergy, Asthma and Immunology. Sept 2005;4(3). 
  106. SS Chua, SI Benrimoj, RD Gordon, G WIlliams. Cardiovascular effects of a chlorpheniramine/ paracetamol combination in hypertensive patients who were sensitive to the pressor effect of psudoephedrine. Br J Clin Pharmacol, Mar 1991;31(3):360-362. 
  107. Karen J Deane, Robert L Summers, Adele M Lehane, Rowena E Martin, Russell A Barrow. Chlorpheniramine analogues reverse chloroquine resistance in plasmodium falciparum by inhibiting PfCRT. ACS Med Chem Lett. 2014;5(5):576-581. 
  108. S Abeysingha, M Kularatne, Indika B Gawarammana. Parallel infusion of hydrocortisone ± chlorpheniramine bolus injection to prevent acute adverse reactions to antivenom for snakebites. Med J Aust. 2004;180(8):428. 
  109. Anna Carolyna Gianlorenco, Kelly regina Serafim, Azair Canto-de-Souza, Rosana Mattioli. Effects of chronic treatment with chlorpheniramine on anxiety and emotional memory in mice. ConScientae Saude 2013;12(3). 
  110. Jonathan Brostoff, JDF Lockhart. COntrolled trial of terfenadine and chlorpheniramine maleate in perennial rhinitis. Postgrad Med J. 1982;58:422-423. 
  111. Einar Hellbom. Chlorpheniramine, selective serotonin-reuptake inhibitors (SSRIs) and over-the-counter (OTC) treatment. Medical Hypotheses. 2006;66(4):689-690. 
  112. Sally Usdin Yasuda, Anton Wellstein, Paul Likhari, Jean T Barbey, Raymond L Woosley. Chlorpheniramine plasma concentration and histamine H1 receptor occupancy. Clinical Pharmacology & Therapeutics. 1995;58:210-220. 
  113. M Venkatraman, D O'Neil, AP Hall. Life-threatening overdose with lamotrigine, citalopram and chlorpheniramine. JOurnal of Postgraduate Medicine. 2008;54(4):316-317. 
  114. Nithya S. An experimental study of the anticonvulsant effect of chlorpheniramine maleate in mice. International Journal of of pharmaceutical and chemical sciences. Jan-Mar 2012;1(1). 
  115. Fernanda Romaguera, Rosana Mattioli. Chlorpheniramine impairs spatial choice learning in telencephalon-ablated fish. Biol Res 2008;41:341-348. 
  116. RN Bugh, AM Geddes, WB Yeoman. Interaction of phenytoin with chlorpheniramine. British Journal of Clinical Pharmacology. April 1975;2(2):173-175. 
  117. Amiyakuamr Mukhopadhyay, S Nitin Vora, Jayend Dave. A comparative study of various therapeutic regimens in urticaria. IJDVL. 1995;61(2):91-93. 
  118. Beuy Joob, Viroj Wiwanitkit. Acute anaphylactic reaction to expired chlorphenirmaine injection. Journal of acute disease. 2014:161-162. DOI: 10.1016/S2221-6189(14)60035-4. 
  119. Paulo Dornelles Picon, Marisa Boff Costa, Rafael de Veiga Picon, Lucia Costa Cabral Fendt et al. Symtomatic treatment of the common cold with a fixed dose combination of paracetamol, chlorpheniramine and phenylephrine: a randomized, placebo-controlled trial. BMC Infectious Diseases. 2013;13:556. 
  120. David G Tinkelman, James Kemp, Don Q Mitchell, Stanley P Galant. Treatment of seasonal allergic rhinitis in children with cetrizine or chlorpheniramine: A multicenter study. Pediatric Asthma, allergy & immunology. 1996;10(1):9-17. 
  121. JW Findlay, RF Butz, JM Sailstad, JT Warren, RM Welch. Pseudoephedrine and triprolidine in plasma and breast milk of nursing mothers. Br J Clin Pharmacol. Dec 1984;18(6):901-906.
  122. FM Ackland. Hallucinations in a child aftre drinking triprolidine/ pseudoephedrine linctus. The Lancet. May1984;323(8387):1180. 
  123. John WA Findlay, Robert F Butz, Geoffrey G Coker, Richard L Deangelis, Richard M Welch. Triprolidine radioimmunoassay: Disposition in animals and humans. Journal of Pharmaceutical Sciences. Oct 1984;73(10):1339-1344. 
  124. CE Bye, J Cooper, DW Empey, AS Fowle, DT Hughes, E Letley, J O'Grady. Effect of pseudoephedrine and triprolidine, alone and in combination, on symptoms of the common cold. BMJ 1980;281:189. 
  125. Shin SC, Choi JS. Enhanced efficacy of triprolodone by transdermal application of the EVA matrix system in rabbits and rats. European Journal of Pharmaceutics and Biophramaceutics. 2005;61(1-2):14-19. 
  126. Mone Mahesh Kumar, Chandrasekhar KB, Vyas Samir. Degradation studies of triprolidine: isolation, characterization of oxidative degradation products and development of a validated stability indicating UHPLC method. Journal of liquid chromatography & related technologies. Jan 2011;34(8):652-669. 
  127. I Hindmarch, Z Shamsi. The effects of single and repeated administration of ebastibe on cognition and psychomotor performance in comparison to triprolidine and placebo in healthy volunteers. Current medical research and opinion. 2001;17(4):273-281. 
  128. WH MIller Jr, DW Scott. Clemastine fumarate as an antipruritic agent in pruritic cats: results of an open clinical trial. Can Vet J, Aug 1994;35(8):502-504. 
  129. RL Henry, IG Hodges, AD Milner, GM Stokes. Bronchodilator effects of the H1 receptor antagonist- clemastine. Arch Dis Child. Apr 1983;58(4):304-305. 
  130. William H Miller Jr, Danny W Scott, Jocelyn R Wellington. A clinical trial on the efficacy of clemastine in the management of allergic pruritis in dogs. Can Vet J. Jan 1993;34(1):25-27. 
  131. Ronald B Turner, Steven J Sperber, James V Sorrentoni, Robert R O'Connor et al. Effectiveness of clemastine fumarate for treatment of rhinorrhea and sneezing associated with the common cold. Clin Infect Dis. 1997;25(4):824-830. 
  132. A Szczeklik, M Serwonska. Inhibition of idiosyncratic reactions to aspirin in asthmatic patients by clemastine. Thorax 1979;34:654-657. 
  133. V Hartmann, H Magnussen, JP Holle, E Schuler. Modulation of histamine induced bronchoconstriction with inhaled, oral and intravenous clemastibe in normal and asthmatic subjects. Thorax 1981;36:737-740. 
  134. Udo Dobbeling, Ying Waeckerle-Men, Frnziska Zabel, Nicole Graf, Thomas M Kundig, Pal Johansen. The antihistamines clemastine and desloratidine inhibit STAT3 and c-Myc activities and induce apoptosis in cutaneous T-cell lymphoma cell lines. Experimental Dermatology. Feb 2013;22(2):119-124. 
  135. THHG Kok, LS Taitz, MJ Bennett, DW Holt. Drowsiness due to clemastine transmitted in breast milk. The Lancet. April 1982;319(8277):914-915. 
  136. John M Ridley, James T Milnes, JUles C Hancox, Harry J Witchel. Clemastine, a conventional antihistamine, is a high potency inhibitor of the HERG K+ channel. Journal of Molecular and Cellular Cardiology. Jan 2006;40(1):107-118. 
  137. Michael Boss, John L Burton. Lack of effect of the antihistamine drug clemastine on the potentiation of itch by prostaglandin E1. Arch Dermatol. 1981;117(4):208-209. 
  138. K Torneke, C Ingvast-Larsson, K Pettersson et al. Pharmacokinetics and pharmacodynamics of clemastine in healthy horses. J Vet Pharmacol Therap. 2003;26:151-157. 
  139. Pal Johansen, Andreas Weiss, Antonia Bunter, Ying Waeckerle-Men, Antonia Fettelschoss, Bernhard Odermatt, Thomas M Kundig. Clemastine causes immune suppression through inhibition of extracellular signal-regulated kinase-dependent proinflammatory cytokines. Journal of allergy and Clinical Immunology. Dec 2011;128(6):1286-1294. 
  140. J Munro Sherriff, MG Wallace. A comparative study of clemastine and chlorpheniramine maleate in the treatment of hay fever. Current medical research and opinion. 1976;4(4):245-249. 
  141. Esau S, Del Carpio J, Martin JG. A comparison of the effects of ketotifen and clemastine on cutaneous and airway reactivity to histamine and allergen in atopic asthmatic patients. The journal of allergy and clinical immunology. 1984;74(3 Pt 1):270-274. 
  142. Chung JH, DeTineo ML, Naclerio RM, Sorrentino JV, Winslow Cm, Baroody FM. Low dose clemastibe inhibits sneezing and rhinorrhea during early nasal allergic reaction. Annals of allergy, asthma and immunology. 1997;78(3):307-312. 
  143. Michael A Kaliner, Martha V White, Athena Economides et al. Relative potency of fexofenadine HCl 180 mg, loratadine 10 mg and placebo using a skin test model of wheal and flare suppression. Annals of allergy, asthma & immunology. June 2003;90(6):629-634. 
  144. I Hindmarch, Z Shamsi, DB Fairweather. A double blind, placebo controlled investigation of the effects of fexofenadine, loratidine and promethazien on cognitive and psychomotor function. Br J Clin Pharmacol. Aug 1999;48(2):200-206. 
  145. Constanze R Scherer, Christian Lerche, Kalus Steinmeyer. The antihistamine fexofenadine does not affect IKr currents in a case report of drug induced cardiac arrhythmia. Br J Pharmcol. Nov 2002;137(6):892-900. 
  146. Peter V Dicpinigaitis, Y vonne E Gayle. Effect of the secong generation antihistamine, fexofenadine, on cough reflex sensitivity and pulmonary function. Br J Clin Pharmacol. Nov 2003;56(5):501-504. 
  147. E Paul, J Berth-Jones, JP Ortonne, M Stern. Fexofenadine hydrochloride in the treatment of chronic idiopathic urticaria: A placebo-controlled, parallel group, dose ranging study. Journal of dermatological treatment. 1998;9(3):143-149. 
  148. Rizwan Moinuddin, Marcy de Tineo, Barbara Maleckar, Robert M Naclerio, Fuad M Baroody. Comparison of the combinations of fexofenadine-pseudoephedrine and loratadine-montelukast in the treatment of seasonal allergic rhinitis. Annals of allergy,asthma & immunology. Jan 2004;92(1):73-79. 
  149. David Axelrod, Leonard Bielory. Fexofenadine hydrochloride in the treatment of allergic disease: a review. Journal of asthma & allergy. Sept 2008;1:19-29. 
  150. Eef L Theunissen, Lisa M Jonkman, Kim PC Kuypers, Johannes G Ramaekers. A combined neurophysiological and behavioural study into the stimulating effects of fexofenadine on performance. J Psychopharmacol. July 2006;20(4):496-505. 
  151. Daniel J Glass, Anne S Harper. Assessing satisfaction with desloratidine and fexofenadine in allergy patients who report dissatisfaction with loratidine. BMC Family Practice. 2003;4:10. 
  152. EO Meltzer, SA Gillman, S Meeves, Y Liao, G Georges. Fexofenadine HCl 180 mg provides greater and faster histamine induced flare suppression than desloratidine 5 mg. Journal of Allergy and Clinical Immunology. Feb 2004;113(2):S26-S27. 
  153. Thierry Giraud. QT lengthening and arrhythmias associated with fexofenadine. The Lancet. JUne 1999;353(9169):2072-2073. 
  154. Claus Bachert. A review of the efficacy of desloratadine, fexofenadine and levocetrizine in the treatment of nasal congestion in patients with allergic rhinitis. Clinical Therapeutics. May 2009;31(5):921-944. 
  155. Takako Shintani, Chika Ohata, Hiroshi Koga, Bungo Ohyama, Takahiro Hamada et al. Combination therapy of fexofenadine and montelukast is effective in prurigo nodularis and pemphigoid nodularis. Dermatologic Therapy. May/June 2014;27(3):135-139. 
  156. Sandipan Dhar, Debasis Basu, Goutam Mistri, Prakash K Hazra et al. Evaluation of the efficacy and safety of fexofenadine in the management of chronic idiopathic urticaria: A prospective study of 512 patients. IJDVL. 2002;68(2):73-76. 
  157. Seema Gupta, Bhuvneshwar Kapoor, Z Gillani, V Kapoor, BM Gupta. Effects of fexofenadine, cetrizine and diphenhydramine on psychomotor performance in adult healthy volunteer. JK Science. October-December 2004;6(4). 
  158. Lars Pedersen, Mette Vinther Skriver, Hennik Toft Sorensen. Maternal use of loratadine during pregnancy and risk of hypospodias in offspring. Int J Med Sci. 2006;3(1):21-25. 
  159. P Chaikin, MS Gillen, DJ Roberts. Co-administration of ketoconazole with H1 antagonists ebastine and loratadine in healthy subjects: pharmacokinetic and pharmacodynamic effects. Br J Clin Pharmacol. Mar 2005;59(3):346-354. 
  160. S Tanaka, K Hirata, N Kurihara, J Yoshikawa, T Takeda. Effect of loratadine, an H1 antihistamine, on induced cough in non-asthmatic patients with chronic cough. Thorax. AUg 1996;51(8):810-814. 
  161. Jonathan Corren, Alan G Harris, Donald Aaronson, Wilfred Beaucher, Robert Berkowitz et al. Efficacy and safety of loratadine plus pseudoephedrine in patients with seasonal allergic rhinitis and mild asthma. Journal of Allergy and Clinical Immunology. Dec 1997;100(6):781-788. 
  162. Darrell R Abernethy, Jean T Barbey, John Franc et al. Loratadine and terfenadine interaction with nefazodone: both antihistamines are associated with QTc prolongation. Clinical Pharmacology & Therapeutics. 2001;69:96-103. 
  163. Anjuli S Nayak, George Philip, Susan Lu, Marie-Pierre Malice et al. Efficacy and tolerability of montelukast alone or in combination with loratadine in seasonal allergic rhinitis: a multicenter, randomized, double blind, placebo controlled trial performed in the fall. Annals of allergy, asthma & immunology. June 2002;88(6):592-600. 
  164. P Anuradha, Rituparna Maiti, J Jyothirmai, Omer Mujeebuddin, M Anuradha. Loratadine versus levocetrizine in chronic idiopathic urticaria: A comparative study of efficacy and safety. Indian Journal of Pharmacology. 2010;42(1):12-16. 
  165. Lin Chin-Chung, Radwanski Elaine, Affrime Melton, Cayen Mitchell. Pharmacokinetics of lortadine in pediatric subjects. American Journal of Therapeutics. June 1995;2(6). 
  166. Cristina Romeo, Quan Li, Larry Copeland. Severe pegfilgastrim induced bone pain completely alleviated with loratadine: A case report. J Oncol Pharm Pract. March24, 2014. DOI: 10.1177/1078155214527858. 
  167. JH Day, MP Briscoe, JD Ratz, AK Ellis, M Danzig, R Yao. Onset of action of loratadine/ montelukast combination in subjects with seasonal allergic rhinitis in the environmental exposure unit. Allergy, Asthma & Clinical Immunology. 2010;6(Suppl 1):P29. 
  168. KF Lukat, P Rivas, A Roger, ML Kowalski, U Botzen, F Wessel, F Sanquer et al. A direct comparison of efficacy between desloratadine and rupatadine in seasonal allergic rhinoconjunctivitis: a randomized, double blind, placebo controlled study. Journal of Asthma and Allergy. Feb 2013;6:31-39. 
  169. GW Canonica, F Tarantini, E Compalati, M Penagos. Efficacy of desloratadine in the treatment of allergic rhinitis: a meta-analysis of randomized, double blind controlled trials. Allergy. April 2007;62(4):359-366. 
  170. Rolf Haye, Kjetil Hoye, Olof Berg, Sissel Frones, Tone Odegard. Morning versus evening dosing of desloratadine in seasonal allergic rhinitis: a randomized controlled study. Clinical and Molecular Allergy. 2005;3:3. 
  171. Harold Kim, Charles Lynde. Impact of desloratadine on symptoms and quality of life in subjects with chronic idiopathic urticaria: A multicenter, practice based study. Arch Drug Inf. Sept 2008;1(2):63-69. 
  172. Werner Aberer. Desloratadine for the relief of nasal and non-nasal allergy symptoms: An observational study. Arch Drug Inf. JUne 2009;2(2):17-22. 
  173. Maciej Ciebiada, Malgorzata Gorska-Ciebiada, Lawrence M DuBuske, Pawel Gorski. Montelukast with desloratadine or levocetrizine for the treatment of persistent allergic rhiniits. Annals of Allergy, Asthma & Immunology. Nov 2006;97(5):664-671. 
  174. Eugene Monroe, Albert Finn, Piyush Patel, Robinson Guerrero, Paul Ratner et al. Efficacy and safety of desloratadine 5 mg once daily in the treatment of chronic idiopathic urticaria: A double blind, randomized, placebo controlled trials. Journal of the MAerican Academy of Dermatology. April 2003;48(4):535-541. 
  175. Giovanni Passalacqua, Giorgio Walter Canonica. A review of the evidence from comparative studies of levocetrizine and desloratadine for the symptoms of allergic rhinitis. July 2005;27(7):979-992. 
  176. Cedric Deruaz, Annette Leimgruber, Monika Berney, Estelle Pradervand, Francois Spertini. Levocetrizine better protects than desloratadine in a nasal provocation with allergen. Journal of Allergy and Clinical Immunology. April 2004;113(4):669-676. 
  177. Huseyin Alkim, Mustafa Iscan. Desloratadine induced pill esophagitis. Gastroenterology Research. 2012;5(1):37-38. 
  178. Nicola NB Balato, Francesca Guadiello, Fabrizio Ayala, Fabio Ayala. Evaluation of efficacy and safety of desloratadine syrup in childhood atopic dermatitis. Journal of the AMerican Academy of Dermatology. March 2004;50(3):P63. 
  179. Karsten Weller, Marcus Maurer. Desloratadine inhibits human skin mast cell activation and histamine release. Journal of Investigative dermatology. 2009;129:2723-2726. 
  180. BE Davis, C Illamperuma, GM Gauvreau, RM Watson et al. Single dose desloratadine and montelukast and allergen induced late airway responses. ERJ. JUne 2009;33(6):1302-1308. 
  181. Raphael GD, Angello JT, Wu MM, Druce HM. Efficacy of diphenhydramine vs desloratadine and placebo in patients with moderate to severe seasonal allergic rhinitis. Ann Allergy Asthma Immunol. Apr 2006;96(4):606-14. 
  182. Martin Scharf, David Berkowitz. Effects of desloratadine and alcohol coadministration on psychomotor performance. Current Medical Research and Opinion. 2007;23(2):313-321. 
  183. Mary E Barecki, Christopher N Casciano, William W Johnson, Robert P Clement. In vitro characterization of the inhibition profile of loratadine, desloratadine and 3-OH-Desloratadine for five human cytochrome P-450 enzymes. DMD. Sept 2001;29(9):1173-1175. 
  184. Christopher P Cook, Danny W Scott, Shaun M Cobb. Treatment of canine atopic dermatitis with cetrizine, a second generation antihistamine: A single-blinded, placebo controlled study. Can Vet J. May 2004;45(5):414-417. 
  185. Akira Matsumori, Kanjo Yamamoto, Miho Shimada. Catrizine a histamine H1 receptor antagonist improves viral myocarditis. Journal of inflammation. 2010;7:39. 
  186. Lars Gronke, Jens Schlenker, Olaf Holz, Theo A Out et al. Effect of cetirizine dihydrochloride on the airway response to hypertonic saline aerosol in patients with chronic obstructive pulmonary disease (COPD). Respiratory Medicien. Oct 2005;99(10):1241-1248. 
  187. James H Day, Maureen Briscoe, MIchael D Widlitz. Cetirizine, loratadine or placebo in subjects with seasonal allerguc rhinitis: effects after controlled ragweed pollen challenge in an environmental exposure unit. Journal of Allergy and Clinical Immunology. May 1998;101(5):638-645. 
  188. Candace A Romo, Kaustubh G Joshi, Brian M Waters. Involuntary movements associated with cetirizine use. AM J Psychiatry. 2011;168:855. 
  189. Miranda So, Pina Bozzo, Miho Inoue, Adrienne Einarson. Safety of antihistamines during pregnancy and lactation. Canadian Family Physician. May 2010;56(5):427-429. 
  190. Luis M Salmun, Davis Gates, Martin Scharf, Leonardo Greiding, Fabian Ramon, Kim Heithoff. Loratadine versus cetirizine: Assessment of somnolence and motivation during the workday. Clinical Therapeutics. May 2000;22(5):573-582. 
  191. Recurrent acute hepatitis associated with the use of cetirizine. Ann Pharmacother. Nov 2004;38:1844-1847. 
  192. Kurosh Masnadi Shirazinezhad, Amirtaher Eftekharossadat, Sayyed Mohammad Sadrkabir. Effects of cetirizine on symptoms and gastric mucosal mast cells in patients with functional dyspepsia. Govaresh 2014;19(2):102-108. 
  193. Zhang L, Cheng L, Hong J. The clinical use of cetirizine in the treatment of allergic rhinitis. Pharmacology 2013;92:14-25. 
  194. G Chatterjee, PK Banerjee. A comparison of the efficacy of cetirizine and terfenadine in chronic idiopathic urticaria. Indian Journal of Dermatology. 1996;41(3):82-86. 
  195. S Rajaram, C Suthakaran, SC Pradhan, NK Majumder, JS Bapna. Double blind randomized clinical trial of cetirizine in the treatment of perennial allergic rhinitis. Indian JOurnal of Pharmacology. 1994;26(2):112-116. 
  196. Kameyoshi Y, Tanaka T, Mihara S, Takahagi S, Niimi N, Hide M. Increasing the dose of cetirizine may lead to better control of chronic idiopathic urticaria: an open study of 21 patients. Br J Dermatol. Oct 2007;157(4):803-4. 
  197. Dubuske LM. Levocetirizine: THe latest treatment option for allergic rhinitis and chronic idiopathic urticaria. Allergy Asthma Proc. Nov-Dec 2007;28(6):724-34. 
  198. JM Gandon, H Allain. Lack of effect of single and repeated doses of levocetirizine, a new antihistamine drug, on cognitive and psychomotor functions in healthy volunteers. Br J Clin Pharmacol. Jul 2002;54(1):51-58. 
  199. E Nettis, GF Calogiuri, E Di Leo, F Cardinale, L Macchia et al. Once daily levocetirizine for the treatemnt of allergic rhinitis and chronic idiopathic urticaria. Journal of Allergy and Asthma. Dec 2008;2:17-23. 
  200. Giovanno Passalacqua, Giorgio Walter Canonica. A review of the evidence from comparative studies of levocetirizine and desloratadine for the symptoms of allergic rhinitis. Clinical Therapeutics. July 2005;27(7):979-992. 
  201. Erin E Ducharme, Jeffrey M Weinberg. Levocetirizine for idiopathic urticaria: A review. Journal of drugs in dermatology. March 2009;8(3). 
  202. P Anuradha, Rituparna Maiti, J Jyothirmai, Omer Mujeebuddin, M Anuradha. Loratadine versus levocetirizine in chronic idiopathic urticaria: A comaparative study of efficacy and safety. Indian Journal of Pharmacology. 2010;42(1):12-16. 
  203. Claus Bachert, Jean Bousquet, Walter Canonica, Stephen R Durham. Levocetirizine improves quality of life and reduces costs in long term management of persistent allergic rhinitis. Journal of allergy and Clinical Immunology. Oct 2004;114(4):838-844. 
  204. JL Devalia, F Hanotte, E Baltes, C de Vos. A randomized double blind crossover comparison among cetirizine, levocetirizine and ucb 28557 on histamine-induced cutaneous response in healthy adult volunteers. Allergy. Jan 2001;56(1):50-57. 
  205. Kazuhiro Hashiguchi, Sho Kanzaki, Ken-ichiro Wakabayashi, Nobuaki Tanaka et al. Efficacy of fluticasone furoate nasal spray and levocetirizine in patients with Japanese cedar pollinosis subjected to an artificial exposure chamber. Journal of Drug Assessment. 2013;2:94-105. 
  206. NB Dhanya, Z Thasleem, Reena Rai, CR Srinivas. Comparative efficacy of levocetirizine, desloratadine and fexofenadine by histamine wheal suppression test. IJDVL. 2008;74(4):361-363. 
  207. Seema Rani, MC Gupta, Prem Verma, Dalbir Singh. A comparative study of clinical efficacy and tolerability of second generation (Cetirizine) and third generation (Levocetirizine) antihistaminics in seasonal allergic rhinitis. JARBS 2012;4(2):152-155. 
  208. Sihomara Garcia-Zepeda, Elizabet Estrada-Muniz, Guillermo Elizondo, Luis I Terrazas et al. Levocetirizine inhibitsmigration of immune cells to lymph nodes and induced treg cells in a murine type 1 allergic conjunctivitis model. The Open Ophthalmology Journal. 2012;6:129-136. 
  209. Tanizaki H, Nakamizo S, Nakahigashi K, Miyachi Y, Kabashima K. A double dose of levocetirizine leads to better control of histamine-induced flare, wheal and itch in healthy donors. Pharmacology. 2013;92:1-2.  
  210. Anant D Patil. Up-dosing of non-sedating antihistamines in chronic urticaria: Need for well designed clinical trials in India. Research Methodology. 2014;5(2):88-90. 
  211. Friedrich Horak. Effectiveness of twice daily azelastine nasal spray in patients with seasonal allergic rhinitis. Therapeutic and clinical risk management. Sept 2008;4(5):1009-1022. 
  212. Charles H Banov, Phil Lieberman. Efficacy of azelastine nasal spray in the treatment of vasomotor (perennial nonallergic) rhinitis. Annals of ALlergy, Asthma & Immunology. Jan 2001;86(1):28-35. 
  213. William E Berger, Stanley M Fineman, Phillip Lieberman, Robert M Miles. Double blind trial of azelastine nasal spray monotherapy versus combination therapy woth loratadine tablets and beclomethasone nasal spray in patients with seasonal allergic rhinitis. Annals of allergy, Asthma & Immunology. JUne 1999;82(6):535-541. 
  214. H Magnussen, G Reuss, R Aurich. The effect of azelastine on exercise induced asthma. Chest 1988;93(5):937-940. 
  215. Warner Carr, Jonathan Bernstein, Phil Lieberman, Eli Meltzer et al. A novel intranasal therapy of azelastine with fluticasone for the treatment of allergic rhinitis. Journal of Allergy and Clinical Immunology. May 2012;129(5):1282-1289. 
  216. Phillip Lieberman. Preclinical evidence of azelastine hydrochloride activity. Current therapeutic Research. Sept 2002;63(9):556-571. 
  217. AM Oliva, CB Slonim. Patient evaluation of azelastine HCl versus olopatadine HCl in the treatment of allergic conjunctivitis. Invest Ophthalmol Vis Sci 2005;46:E-abstract 937. 
  218. WW Busse, E Middleton, W Storms, RJ Dockhorn et al. Corticosteroid sparing effect of azelastine in the managment of bronchial asthma. AMerican Journal of Respiratory and Critical Care Medicine. 1996;153(1):122-7. 
  219. M Masuo, T Shimada, T Kitazawa. Mechanism of inhibitory effects of azelastine on smooth muscle contraction. JPET. March 1992;260(3):1300-1308. 
  220. I HIde, N Toriu, T Nuibe, A Inoue et al. Suppression of TNF-alpha secretion by azelastine in a rat mast (RBL-2H3) cell line: evidence for differential regulation of TNF-alpha release, transcription and degranulation. The Journal of Immunology. Sept,1997;159(6):2932-2940. 
  221. Singh Umesh, Bernstein Jonathan A, Haar Lauren, Luther Kristin, Jones Walter K. Azelastine desensitization of transient receptor potential vanilloid 1: A potential mechanism explaining its therapeutic potential in nonallergic rhinitis. American Journal of Rhinology & ALlergy. May/June 2014;28(3):215-224. 
  222. Stanley M Fineman. Clinical experience with azelastine nasal spray in children: Physician survey of case reports. Pediatric Asthma, Allergy & Immunology. March 2001;15(1):49-54. 
  223. Syed Saud Hasan, Musarrat Sultana, Sheikh Nadeem Ahmed, Muhammad Yousuf Salat. COmparative study of azelastine and verapamil in the modification of ovalbumin sensitized lung parenchymal tissues in guinea pigs in vitro. Pakistan Journal of Pharmacology. Jan 2012;29(1):45-50. 
  224. William E Berger, Shailen Shah, Phil Lieberman, James Hadley, David Price, Ullrich Munzel, Sanjay Bhatia. Long term, randomized safety study of MP29-02 (a novel intranasal formulation of azelastine hydrochloride and fluticasone propionate in an advanced delivery system) in subjects with chronic rhinitis. The Journal of Allergy and Clinical Immunology: In practice. March-April 2014;2(2):179-185. 
  225. P Rosenzweig, H Caplain, S Chaufour, N Ulliac, MJ Cabanis, JJ Thebault. COmparative wheal and flare study of mizolastine vs terfenadine, cetirizine, loratadine and placebo in healthy volunteers. Br J Clin Pharmacol. Nov 1995;40(5):459-465. 
  226. A purohit, M Melac, N Frossard. Comparative activity of cetirizine and mizolastine on histamine-induced skin wheal and flare responses at 24 h. Br J Clin Pharmacol. Mar 2002;53(3):250-254. 
  227. Charles Freche, Francisque Leynadier, FRiedrich Horak, David Hide et al. Mizolastine provides effective symptom relief in patients suffering from perennial allergic rhinitis: a double-blind, placebo controlled study versus loratadine. Annals of Allergy, Asthma & Immunology. Sept 2002;89(3):304-310. 
  228. Alfred Sabbah, Jacques Daele, Alan Grierson Wade, Paul Ben-Soussen, Pierre Attali. Comparison of the efficacy, safety and onset of action of mizolastine, cetirizine and placebo in the management of seasonal allergic rhinoconjunctivitis. Annals of Allergy, Asthma & Immunology. Oct 1999;83(4):319-325. 
  229. H Li, J Yin, L Wen, F Yue, Q Fang, R Wang, H Zhang. Mizolastine provides effeective symptom relief in patients suffering from chronic idiopathic urticaria. Journal of Allergy and Clinical Immunology. Feb 2004;113(2):S136. 
  230. Louis Dubertret, Catherine Pecquet, Margarita Murrieta-Aguttes, Francisque Leynadier. Mizolastine in primary acquired cold urticaria. Journal of the American Academy of Dermatology. APril 2003;48(4):578-583. 
  231. A Palat, MC Perault, B Vandel, N Ulliac, I Zieleniuk, P Rosenzweig. Lack of interaction between a new antihistamine, mizolastine and lorazepam on psychomotor performance and memory in healthy volunteers. British Journal of Clinical Pharmacology. Jan 1995;39(1):31-38. 
  232. Francisque Leynadier, Jean Bousquet, Margarita Murrieta, Pierre Attali. Efficacy and safety of mizolastine in seasonal allergic rhinitis. Annals of Allergy, Asthma & Immunology. Feb 1996;76(2):163-168.
  233. Yan Yan, Baoxi Wang, Ya-Gang Zuo, Tao Qu. Inhibitory effects of mizolastine on ultraviolet B-induced leukotriene B4 production and 5-lipoxygenase expression in normal human dermal fibroblasts in vitro. Photochemistry and Photobiology. Vol 82. 
  234. Vythoulka A, Pitsios C, Kompoti E. Allergic reactions due to mizolastine. Annals of Allergy, Asthma & Immunology. 2006;97(2):262-263. 
  235. Depoortere H, Decobert M, Granger P, Francon D. Mizolastine, a novel selective histamine H1 receptor antagonist: lack of sedative potential on the EEG in the rodent. Neuropsychobiology. 1995;32:214-221. 
  236. GK Scadding, AJ Tasman, M Murrieta-Aguttes, Claus Bachert. Mizolastine is effective and well tolerated in long term treatment of perennial allergic rhinoconjunctivitis. Journal of International Medical Research. 1999;27(6):273-285. 
  237. Patat A, Gram LF, Dubruc C, Brohier S, Cabanis MJ, Rosenzweig P. Effects of mizolastine, a new antihistamine, on psychomotor and memory in elderly subjects. International Clinical Psychopharmacology. 1994;9(2):101-108. 
  238. KIran V Godse. Ebastine in chronic spontaneous urticaria in higher doses. Indian J Dermatol. Sept-Oct 2011;56(5):597-598. 
  239. Giorgio Ciprandi. Clinical utility and patient adherence with ebastine for allergic rhinitis. Patient Prefer Adherence. 2010;4:389-395. 
  240. J Sastre. Ebastine in allergic rhinitis and chronic idiopathic urticaria. Allergy. Dec 2008;63(S89):1-20. 
  241. Paul H Ratner, Janet C Lim, George C Georges. Comparison of once-daily ebastine 20 mg, ebastine 10 mg, loratadine 10 mg and placebo in the treatemnt of seasonal allergic rhinitis. Journal of Allergy and Clinical Immunology. June 2000;105(6):1101-1107. 
  242. Rosa Antonijoan, Consuelo Garcia-Gea, Montserrat Puntes, Joselin Perez, Ramon Esbri, Cristina Serra, JOsep Fortea, Manuel J Barbanoj. Comparison of inhibition of cutaneous histamine reaction of ebastine fast dissolving tablet (20 mg) versus desloratadine capsule (5 mg): A randomized, double blind, double dummy, placebo controlled, three period crossover study in healthy, nonatopic adults. Clinical Therapeutics. MAy 2007;29(5):814-822. 
  243. I Hindmarch, Z Shamsi. The effects of single and repeated administration of ebastine on cognition and psychomotor performance in comparison to triprolidine and placebo in healthy volunteers. Curr Med Res Opin. 2001;17(4). 
  244. Pierre Gehanno, Clothilde Bremard-Oury, Philippe Zeisser. Comparison of ebastine to cetirizine in seasonal allergic rhinitis in adults. Annals of ALlergy, Asthma & Immunology. June 1996;76(6):507-512. 
  245. F Estelle, R Simons, Wade TA Watson, Keith J Simons. Pharmacokinetics and pharmacodynamics of ebastine in children. The JOurnal of Pediatrics. April 1993;122(4):641-646. 
  246. Kwang-Hyeon Liu, Mi-Gyung Kim, Dong-JUn Lee, Yune-Jung Yoon et al. Characterization of ebastine, hydroxyebastine and carebastine metabolism by human liver microsomes and expressed cytochrome P450 enzymes: Major roles for CYP2J2 and CYP3A. Drug metabolism & disposition. Nov 2006;34(11):1793-1797. 
  247. Albert Roger, Josep Fortea, M Jose Plazas, Sheila Mora, Maite Artes. Assessment of patient satisfaction with ebastine fast dissolving tablets in patients suffering from allergic rhinitis. Therapy May 2009;6(3):407-415. 
  248. J Peyri, J Vida, J Marron, E Fonseca, E Suarez, A ledo, JM Zayas, X Luria. Ebastine in chronic urticaria: A double-blind placebo controlled study. Journal of dermatological treatment. 1991;2(2):51-53. 
  249. Gurudutt Nayak, Harsha KP. Efficacy of ebastine 5 mg in the treatment of children with allergic rhinitis: A post marketing surveillance study. Journal of Pharmacy Research. 2012;5(1). 
  250. Marek L Kowalski, Dariusz Jurkiewicz, Jerzy Kruszewski, Dariusz Nowak et al. Rupatadine 10 and 20 mg are effective and safe in the treatemnt of perennial allergic rhinitis after 4 weeks of treatment: a randomized, double blind, controlled trial with loratadine and placebo. Therapy. May 2009;6(3):417-425. 
  251. A Carvajal, D Macias, I Salado, M Sainz, S Ortega et al. Heart rhythm disturbances associated with rupatadine: A case series from the spanish and portugese pharmacovigilance systems. Clinical Pharmacology & Therapeutics. 2009;85(5):481-484. 
  252. Paul Potter, JOrge F Maspero, Jan Vermeulen, Laszlo Barkai, IIdiko Nemeth et al. Rupatadine oral solution in children with persistent allergic rhinitis: A randomized, double blind, placebo controlled study. Pediatric Allergy and Immunology. March 2013;24(2):144-150. 
  253. Ramon Fite-Mora. Torsades de Pointes associated with rupatadine. Rev Esp Cardiol. 2009;62:330-1. 
  254. Bhanu Prakash Kolasani, Raghunandan Mudium, Norattam Reddy. A comparative study of efficacy and safety of rupatadine versus desloratadine in patients with chronic idiopathic urticaria. Asian Journal of Biomedical and Pharmaceutical Sciences. 2013;3(21):42-47.
  255. Rituparna Maiti, Jyothirmai Jaida, Anuradha Palani. Olopatadine hydrochloride and rupatadine fumarate in seasonal allergic rhinitis: A comparative study of efficacy and safety. J Pharmacol Pharmacother. Oct-Dec 2011;2(4):270-276. 
  256. J Mullol, J Bousquet, C Bachert, WG Canonica et al. Rupatadine in allergic rhinitis and chronic urticaria. Allergy. 2008;63(Suppl 87):5-28. 
  257. Martin Metz, Elisabeth Scholz, Marta Ferran, Inaki Izquierdo, Ana Gimenez-Arnau, Marcus Maurer. Rupatadien and its effects on symptom control, stimulation time and temperature thresholds in patients with acquired cold urticaria. Annals of allergy, asthma & immunology. Jan 2010;104(1):86-92. 
  258. Michail Alevizos, Anna Karagkouni, Magdalini Vasiadi, Nikolaos Sismanopoulos et al. Rupatadine inhibits inflammatory mediator release from human labortaory of allergic diseases 2 cultured mast cells stimulated by platelet-activating factor. Annals of allergy, asthma & immunology. Dec 2013;111(6):542-547. 
  259. Lv X-x, Wang X-x, Li K, Wang Z-y, Li Z et al. Rupatadine protects against pulmonary fibrosis by attenuating PAF mediated senescence in rodents. PLoS ONE 2013;8(7):e68631. 
  260. Anna Solans, Marcel-Li Carbo, Juana Pena, Teresa Nadal, Inaki Izquierdo, Manuel Merlos. Influence of food on the oral bioavailability of rupatadine tablets in healthy volunteers: A single dose, randomized, open label, two way crossover study. Clinical Therapeutics. May 2007;29(5):900-908. 
  261. C Martinez-Cocera, M De Molina, E Marti-Guadano, J Pola, J Conde et al. Rupatadine 10 mg and cetirizine 10 mg in seasonal allergic rhinitis: A randomized, double blind parallel study. J Invest Allergol Allergol Clin Immunol 2005;15(1):22-29.