- Email: [email protected]
ANTIHISTAMINES AND SEDATION
211
persist to the next day, despite continuing peripheral activity. This possibility has been studied with triprolidine hydrochloride (10 mg) and brompheniramine maleate (12 mg). After ingestion of brompheniramine or triprolidine, performance is impaired for up to 5 and 7 h, respectively,though drowsiness may last longer. If they are given in the early evening, performance during the next working day is unlikely to be affected, though the question remains whether antihistaminic cover will then be adequate. sedation may
Therapeutics ANTIHISTAMINES AND SEDATION ANTHONY N. NICHOLSON
Royal Air Force Institute of Aviation Medicine, Farnborough, Hampshire With careful use of antihistamines central effects may be minimised or even largely while avoided adequate peripheral antihistaminic activity is to central effects may develop quickly Tolerance preserved. so that sedation is no longer troublesome with some drugs, after a few days. With sustained-release antihistamines, earlyevening dosage may provide sufficient activity, without sedation, the next day. For patients in whom daytime sedation is troublesome three drugs, astemizole, mequitazine, and terfenadine, are likely to prove useful. However, the response of the individual patient cannot be predicted, and the possibility of sedation can never be completely excluded.
Summary
INTRODUCTION
THE use of H1-antihistamines is likely to be associated with impairment of central nervous function, though severity and persistence vary between drugs and between patients, and may even vary from day to day with the same drug in the same individual. With some, such as chlorpheniramine, impairment appears shortly after ingestion and is of limited severity and duration, whereas with others, such as clemastine and promethazine, impairment may be delayed and much more obvious.] Clearly, antihistamines free from central effects would be a useful advance, and there has been increasing interest in their development. Histamine may well prove to be a neurotransmitter with an important role in sedation and wakefulness. Indeed, drowsiness with antihistamines has been attributed to inhibition of histamine N-methyltransferase3 and blockade of central histaminergic receptors.4-6 However, serotonergic antagonism, anticholinergic activity, and blockade of alpha adrenoreceptors must also be borne in mind since antihistamines are rarely pure Hl-antagonists. Anticholinergic activity is particularly relevant, and, though alpha blockade and sedation may not correlate well for the antihistamines, such a mechanism probably contributes to the sedation seen with promethazine. Whatever may be the mechanism of sedation, it depends on the drug crossing the blood-brain barrier: most antihistamines are highly liposoluble and do so with ease. Apart from a trial-and-error search for an antihistamine that in a particular patient does not induce drowsinesswhich may be successful-there are several ways of avoiding daytime sedation. Some drugs may be useful even in low doses; and with others tolerance to the central-nervoussystem effects may readily develop. For instance, even with triprolidine-a potent inhibitor with obvious sedative effects-tolerance seems to develop with twice daily ingestion,’ and sustained-release preparations can provide useful antihistaminic activity beyond the period of impaired
performance.88
SUSTAINED RELEASE
The particular advantage of sustained-release preparations is that, when they are ingested during the early evening,
not
In this context, measurements of weal-and-flare responses to intradermal histamine suggest a persistent antihistaminic effect of triprolidine for up to 24 h after ingestion, 10 and there is pharmacokinetic evidence of maintained plasma levels with brompheniramine. Clinical data are scarce, and the use in this
way of sustained-release
preparations
must
depend
on
experience. ANTIHISTAMINES WITHOUT SEDATION
More recently there has been interest in antihistamines which for various reasons are likely to be free of central effects. In animals some H] -antagonists, even at high doses, cause little, if any, sedation. Such agents are believed to have a higher affinity for peripheral than for central receptors-a property enhanced if the drug has difficulty in crossing the blood-brain barrier. Activity of drugs with poor central access may be restricted to antagonism of the HI-receptor; in the absence of, say, anticholinergic activity, impaired performance would be even less likely. At the moment there are three drugs which are claimed to provide antihistaminic therapy without sedation. However, even with these drugs the possibility of sedation cannot be excluded, and so trial and error may still be a useful approach to attain therapy free of sedation. Astemizole In practical terms the activity of astemizole is restricted to antagonism of H] -receptors. It has no affinity for acetylcholine receptors, and is devoid of beta-adrenergic activity. At high doses there is some evidence of serotonin antagonism and affinity for alpha-adrenergic receptors but, since it crosses the blood-brain barrier with difficulty, interactions are highly unlikely. It is rapidly absorbed and distributed with peak plasma levels around 1 h, but it
is slowly eliminated with an estimated half-life of 104 h. The slow elimination of the drug is shown not only by pharmacokinetic but also by pharmacodynamic studies. Indeed, dermal responses to histamine are modified for several days after a single 10 mg oral dose. Studies on the effects of astemizole on vision and on performance suggest that the drug is likely to be free of impairment in doses up to 20 mag. 12,13 The dose currently for adults is 10 mg once daily. The long duration of action should maintain protection if a dose is missed, but in view of the slow elimination more studies are needed on the most appropriate dose.
Mequitazine Mequitazine possesses in man a greater affinity for peripheral and this, together with difficulty than for central in crossing the blood-brain barrier, is believed to explain the absence of sedative effects at doses providing optimum peripheral activity. It has some anticholinergic activity, but there is no evidence of central effects at the recommended dose of 5 mg twice daily. With mequitazine peak plasma concentrations are reached around 6 h after ingestion, and the elimination half-life is around 38 h. Several centres’have examined effects on performance and on vision in man. ]6,]7 The recommended single dose of 5 mg (adults) does not impair performance, whereas 10 mg does have central effects. Mequitazine seems to have a useful therapeutic window around 5 mg, with well-established clinical efficacy.
H] -receptors, 14,15
212
Terfenadine This antagonist is highly specific. It is without alpha or beta adrenergic receptor activity, and is free of serotonin or acetylcholine antagonism. Terfenadine has equal affinity for peripheral and central
HI-receptors, 18
and absence of central effects is due
excreted in the urine and faeces. The elimination half-life is between 16 and 23 h. Performance, studiesl9 show that 60 mg is without adverse effects on the central nervous system-indeed, there may be an alerting effect. 1,]2,13,20 (Performance was unaffected by 3 days of the recommended regimen-60 mg twice
daily.21)
Antihistamines, like most medications, should not be used in pregnancy, and adequate contraceptive precautions should be taken with women of childbearing potential. At the moment the use of these drugs in children (6-12 years) is uncertain. Astemizole and mequitazine have not been studied in children and so are not recommended. However studies have not been carried out with terfenadine. 22 It is available in an oral suspension, and half the adult dose (ie, 30 mg) is recommended twice daily. CHRONOPHARMACOLOGY
of the human skin to histamine varies time the according of day, 23 and an interesting aspect of the of antihistamines is that their duration of effect may activity differ with morning and evening dosage. The activity of terfenadine has been studied in this way. 20 Antihistamine protection can be provided’for 24 h by 60 mg given at 0700 h and 30 mg given at 1900 h-the smaller dose in the evening allowing for the drug’s possible alerting effect. Whether a regimen based on chronological principles would also be appropriate for mequitazine is now being investigated. 17,24 It is possible that optimum therapy with antihistamines could involve different doses at different times of the day, though at the moment two equal doses a day are being recommended for both terfenadine (60 mg) and mequitazine (5 mg).
response to
REFERENCES 1. Clarke
CH, Nicholson AN. Performance studies with antihistamines. Br J Clin Pharmacol 1978; 6: 31-36. 2. Schwartz J-C, Garbarg M, Quach TT. Histamine receptors in brain as targets for tricyclic antidepressants. Trends Pharmacol Sci 1981; 2: 12-125. 3. Netter KJ, Bodenschatz K. Inhibition of histamine-N-methylation by some antihistamines Biochem Pharmacol 1967; 16: 1627-31. 4. Krnjevic KJ; Phyllis JW Actions of certain amines on cerebral cortical neurones. Br J Pharmacol 1963; 20: 471-90. 5. Quach TT, Duchemin AM, Rose C, Schwartz JC. In vivo occupation of cerebral histamine H1 receptors evaluated with 3H-mepyramine may predict sedative J Pharmacol 1979; 60: 391-92. properties of psychotropic drugs. Eur 6. Uzan A, Le Fur G, Malgouris C. Are antihistamines sedative via a blockade ofbrain H, receptors? J Pharm Pharmacol 1979; 31: 701-02. 7. Bye CE, Claridge R, Peck AW, Plowman F. Evidence for tolerance to the central nervous system effects of the histamine antagonist, triprolidine, in man. Eur J Clin
Pharmacol 1977; 12: 181-86. 8. Nicholson AN. Effect of the antihistamines,
triprolidine hydrochloride,
on
performance in
From
to
difficulty in crossing the blood-brain barrier, though specificity of action may well be a contributory factor. It is rapidly absorbed (peak plasma concentrations 1-2 h after a single oral dose), extensively biotransformed by the liver, and
The
Round the World
brompheniramine maleate and Br J Clin Pharmacol 1979; 8:
our
Correspondents
United States DISTURBED SCIENTIFIC EXCHANGES
SOME scientists are saying that Stanford University in California dismissed Steven W. Mosher, an anthropologist, from its doctoral programme because he offended the People’s Republic of China. That’s wrong, reply Stanford officials. They say the dismissal was based on a finding that he had used unethical methods in gathering data in China in 1979 and 1980. A central feature of Mr Mosher’s evidence, accumulated while living in a village near Canton, was that Chinese officials were forcing many women to submit to abortions as part of a national birth control campaign. What particularly angered the Chinese Government was that he published an article in a magazine in anti-Communist Taiwan. Stanford has declined to make public an investigating committee’s report stating what he is supposed to have done to warrant dismissal. Donald Kennedy, Stanford’s president, states that the material could injure innocent parties. Mr Mosher told the New York Times that his Chinese wife, Maggie So, gave the school inaccurate derogatory information about his activities in the village because he insisted on divorcing her. The Mosher case comes at a time of a decline in scientific exchange by US scientists with both of the major Communist powers. China has banned all further field research by Americans; Soviet scientists still visit the United States but in reduced numbers. The reason is that President Reagan, as a sanction after the imposition of martial law in Poland, refused to renew three programmes: science and technology, space, and energy. Eight other exchange programmes continue. Some scientists-particularly some dissident Soviet emigresbelieve the Soviet visits hold no benefits for the United States anyway. Michael Taksar, a Soviet mathematician now at Stanford, maintains that most Soviet scientists coming here are ideologically reliable bureaucrats or spies on the alert for technological secrets. That does not accord with the experience of Walter Gilbert, a molecular biologist and Nobel laureate from Harvard, who recalls that Andrei Mirzabekof, a Soviet scientist, helped him immensely. "He got me involved in the line of research that led to the chemical the Nobel prize." Another sequency methods that molecular biologist, Max Gottesman, of the National Cancer Institute, tells a different story. The scientist he saw, while fairly competent, was argumentative. "He’d have a little vodka and start telling me how mighty the Soviet Union was and how it could wipe us out... I asked him what impressed him most about Chicago and he said people searching through garbage cans for food." , A middle-of-the-road view comes from Gordon Scher, an official at the National Science Foundation, who has been much involved in Soviet exchanges. In the early years of the programme, about a decade ago, some of the Soviet visitors lacked convincing scientific credentials, but the situation had improved. "With time," Scher observes, "the proportion has shifted towards substantive
eventually won
"
scientists."
man.
321-24.
Young GC A sustained release antihistamine. Practitioner 1964; 193: 664-67. 10. Fowle ASE, Hughes DTD, Knight GJ. The evaluation of histamine antagonists in man. Eur J Clin Pharmacol 1971; 3: 215-20. 11. Chapman PH, Rawlins MD. A randomized single blind study of astemizole and chlorpheniramine in normal volunteers. Br J Clin Pharmacol 1983; 13: 593P. 12. Nicholson AN, Stone BM. Performance studies with the H,-histamine receptor antagonists, astemizole and terfenadine Br J Clin Pharmacol 1982; 13: 199-202. 13. Nicholson AN, Smith PA, Spencer MB Antihistamines and visual function: studies on dynamic visual acuity and the pupillary response to light. Br J Clin Pharmacol 1982; 9.
14: 683-90. 14. Uzan A, Le Fur G. Mequitazine et vigilance. Allergic Immunol 1979; 11: 27-30. 15. Le Fur G, Malgouris C, Uzan A. Effect of mequitazine, anon sedative antihistamine on brain H1 receptors Life Sci 1981; 29: 547-52. 16. Nicholson AN, Stone BM. The H1-antagonist mequitazine: studies on performance and visual function. Eur J Clin Pharmacol (in press). 17 Reinberg A, Bicakova-Rocher A, Peiffer C, Levi F, Nicolai A. Effets de la mequitazine sur les rythmes circadiens des resultats de tests psychometriques et de la temperature orale Eur J Clin Pharmacol (in press).
18. Rose
C, Quach TT, Llorens C, Schwartz JC. Relationship between occupation of H1-receptors and sedative properties of antihistamines. Arzneim-Forsch
cerebral
1982; 32: 1171-73.
activity and central effects of terfenadine. A review of European studies. Arzneim-Forsch 1982; 32: 1191-93. Reinberg A, Levi F, Guillet P, Burke JT, Nicolai A. Chronopharmacological study of antihistamines in man with special reference to terfenadine. Eur J Clin Pharmacol
19. Nicholson AN. Antihistaminic 20.
1978; 14: 245-52. 21. Kulshrestha VK, Gupta PP, Turner P, Wadsworth J. Some clinical pharmacological studies with terfenadine, a new antihistaminic drug. Br J Clin Pharmacol 1978; 6: 25-30. 22. Lockhart JDF, Maneksha S. Terfenadine suspension in children with allergies Practitioner (in press). 23. Reinberg A, Sidi E, Ghata J. Circadian reactivity rhythms of human skin to histamine or allergen and the adrenal cycle. J Allergy 1965; 36: 273-83. 24. Reinberg A, Levi F, Fourtillan JP, Peiffer C, Bicakova-Rocher A. Both pharmacokinetics and antihistamine effects of mequitazine vary between morning and evening administration. Eur J Clin Pharmacol (in press).
persist to the next day, despite continuing peripheral activity. This possibility has been studied with triprolidine hydrochloride (10 mg) and brompheniramine maleate (12 mg). After ingestion of brompheniramine or triprolidine, performance is impaired for up to 5 and 7 h, respectively,though drowsiness may last longer. If they are given in the early evening, performance during the next working day is unlikely to be affected, though the question remains whether antihistaminic cover will then be adequate. sedation may
Therapeutics ANTIHISTAMINES AND SEDATION ANTHONY N. NICHOLSON
Royal Air Force Institute of Aviation Medicine, Farnborough, Hampshire With careful use of antihistamines central effects may be minimised or even largely while avoided adequate peripheral antihistaminic activity is to central effects may develop quickly Tolerance preserved. so that sedation is no longer troublesome with some drugs, after a few days. With sustained-release antihistamines, earlyevening dosage may provide sufficient activity, without sedation, the next day. For patients in whom daytime sedation is troublesome three drugs, astemizole, mequitazine, and terfenadine, are likely to prove useful. However, the response of the individual patient cannot be predicted, and the possibility of sedation can never be completely excluded.
Summary
INTRODUCTION
THE use of H1-antihistamines is likely to be associated with impairment of central nervous function, though severity and persistence vary between drugs and between patients, and may even vary from day to day with the same drug in the same individual. With some, such as chlorpheniramine, impairment appears shortly after ingestion and is of limited severity and duration, whereas with others, such as clemastine and promethazine, impairment may be delayed and much more obvious.] Clearly, antihistamines free from central effects would be a useful advance, and there has been increasing interest in their development. Histamine may well prove to be a neurotransmitter with an important role in sedation and wakefulness. Indeed, drowsiness with antihistamines has been attributed to inhibition of histamine N-methyltransferase3 and blockade of central histaminergic receptors.4-6 However, serotonergic antagonism, anticholinergic activity, and blockade of alpha adrenoreceptors must also be borne in mind since antihistamines are rarely pure Hl-antagonists. Anticholinergic activity is particularly relevant, and, though alpha blockade and sedation may not correlate well for the antihistamines, such a mechanism probably contributes to the sedation seen with promethazine. Whatever may be the mechanism of sedation, it depends on the drug crossing the blood-brain barrier: most antihistamines are highly liposoluble and do so with ease. Apart from a trial-and-error search for an antihistamine that in a particular patient does not induce drowsinesswhich may be successful-there are several ways of avoiding daytime sedation. Some drugs may be useful even in low doses; and with others tolerance to the central-nervoussystem effects may readily develop. For instance, even with triprolidine-a potent inhibitor with obvious sedative effects-tolerance seems to develop with twice daily ingestion,’ and sustained-release preparations can provide useful antihistaminic activity beyond the period of impaired
performance.88
SUSTAINED RELEASE
The particular advantage of sustained-release preparations is that, when they are ingested during the early evening,
not
In this context, measurements of weal-and-flare responses to intradermal histamine suggest a persistent antihistaminic effect of triprolidine for up to 24 h after ingestion, 10 and there is pharmacokinetic evidence of maintained plasma levels with brompheniramine. Clinical data are scarce, and the use in this
way of sustained-release
preparations
must
depend
on
experience. ANTIHISTAMINES WITHOUT SEDATION
More recently there has been interest in antihistamines which for various reasons are likely to be free of central effects. In animals some H] -antagonists, even at high doses, cause little, if any, sedation. Such agents are believed to have a higher affinity for peripheral than for central receptors-a property enhanced if the drug has difficulty in crossing the blood-brain barrier. Activity of drugs with poor central access may be restricted to antagonism of the HI-receptor; in the absence of, say, anticholinergic activity, impaired performance would be even less likely. At the moment there are three drugs which are claimed to provide antihistaminic therapy without sedation. However, even with these drugs the possibility of sedation cannot be excluded, and so trial and error may still be a useful approach to attain therapy free of sedation. Astemizole In practical terms the activity of astemizole is restricted to antagonism of H] -receptors. It has no affinity for acetylcholine receptors, and is devoid of beta-adrenergic activity. At high doses there is some evidence of serotonin antagonism and affinity for alpha-adrenergic receptors but, since it crosses the blood-brain barrier with difficulty, interactions are highly unlikely. It is rapidly absorbed and distributed with peak plasma levels around 1 h, but it
is slowly eliminated with an estimated half-life of 104 h. The slow elimination of the drug is shown not only by pharmacokinetic but also by pharmacodynamic studies. Indeed, dermal responses to histamine are modified for several days after a single 10 mg oral dose. Studies on the effects of astemizole on vision and on performance suggest that the drug is likely to be free of impairment in doses up to 20 mag. 12,13 The dose currently for adults is 10 mg once daily. The long duration of action should maintain protection if a dose is missed, but in view of the slow elimination more studies are needed on the most appropriate dose.
Mequitazine Mequitazine possesses in man a greater affinity for peripheral and this, together with difficulty than for central in crossing the blood-brain barrier, is believed to explain the absence of sedative effects at doses providing optimum peripheral activity. It has some anticholinergic activity, but there is no evidence of central effects at the recommended dose of 5 mg twice daily. With mequitazine peak plasma concentrations are reached around 6 h after ingestion, and the elimination half-life is around 38 h. Several centres’have examined effects on performance and on vision in man. ]6,]7 The recommended single dose of 5 mg (adults) does not impair performance, whereas 10 mg does have central effects. Mequitazine seems to have a useful therapeutic window around 5 mg, with well-established clinical efficacy.
H] -receptors, 14,15
212
Terfenadine This antagonist is highly specific. It is without alpha or beta adrenergic receptor activity, and is free of serotonin or acetylcholine antagonism. Terfenadine has equal affinity for peripheral and central
HI-receptors, 18
and absence of central effects is due
excreted in the urine and faeces. The elimination half-life is between 16 and 23 h. Performance, studiesl9 show that 60 mg is without adverse effects on the central nervous system-indeed, there may be an alerting effect. 1,]2,13,20 (Performance was unaffected by 3 days of the recommended regimen-60 mg twice
daily.21)
Antihistamines, like most medications, should not be used in pregnancy, and adequate contraceptive precautions should be taken with women of childbearing potential. At the moment the use of these drugs in children (6-12 years) is uncertain. Astemizole and mequitazine have not been studied in children and so are not recommended. However studies have not been carried out with terfenadine. 22 It is available in an oral suspension, and half the adult dose (ie, 30 mg) is recommended twice daily. CHRONOPHARMACOLOGY
of the human skin to histamine varies time the according of day, 23 and an interesting aspect of the of antihistamines is that their duration of effect may activity differ with morning and evening dosage. The activity of terfenadine has been studied in this way. 20 Antihistamine protection can be provided’for 24 h by 60 mg given at 0700 h and 30 mg given at 1900 h-the smaller dose in the evening allowing for the drug’s possible alerting effect. Whether a regimen based on chronological principles would also be appropriate for mequitazine is now being investigated. 17,24 It is possible that optimum therapy with antihistamines could involve different doses at different times of the day, though at the moment two equal doses a day are being recommended for both terfenadine (60 mg) and mequitazine (5 mg).
response to
REFERENCES 1. Clarke
CH, Nicholson AN. Performance studies with antihistamines. Br J Clin Pharmacol 1978; 6: 31-36. 2. Schwartz J-C, Garbarg M, Quach TT. Histamine receptors in brain as targets for tricyclic antidepressants. Trends Pharmacol Sci 1981; 2: 12-125. 3. Netter KJ, Bodenschatz K. Inhibition of histamine-N-methylation by some antihistamines Biochem Pharmacol 1967; 16: 1627-31. 4. Krnjevic KJ; Phyllis JW Actions of certain amines on cerebral cortical neurones. Br J Pharmacol 1963; 20: 471-90. 5. Quach TT, Duchemin AM, Rose C, Schwartz JC. In vivo occupation of cerebral histamine H1 receptors evaluated with 3H-mepyramine may predict sedative J Pharmacol 1979; 60: 391-92. properties of psychotropic drugs. Eur 6. Uzan A, Le Fur G, Malgouris C. Are antihistamines sedative via a blockade ofbrain H, receptors? J Pharm Pharmacol 1979; 31: 701-02. 7. Bye CE, Claridge R, Peck AW, Plowman F. Evidence for tolerance to the central nervous system effects of the histamine antagonist, triprolidine, in man. Eur J Clin
Pharmacol 1977; 12: 181-86. 8. Nicholson AN. Effect of the antihistamines,
triprolidine hydrochloride,
on
performance in
From
to
difficulty in crossing the blood-brain barrier, though specificity of action may well be a contributory factor. It is rapidly absorbed (peak plasma concentrations 1-2 h after a single oral dose), extensively biotransformed by the liver, and
The
Round the World
brompheniramine maleate and Br J Clin Pharmacol 1979; 8:
our
Correspondents
United States DISTURBED SCIENTIFIC EXCHANGES
SOME scientists are saying that Stanford University in California dismissed Steven W. Mosher, an anthropologist, from its doctoral programme because he offended the People’s Republic of China. That’s wrong, reply Stanford officials. They say the dismissal was based on a finding that he had used unethical methods in gathering data in China in 1979 and 1980. A central feature of Mr Mosher’s evidence, accumulated while living in a village near Canton, was that Chinese officials were forcing many women to submit to abortions as part of a national birth control campaign. What particularly angered the Chinese Government was that he published an article in a magazine in anti-Communist Taiwan. Stanford has declined to make public an investigating committee’s report stating what he is supposed to have done to warrant dismissal. Donald Kennedy, Stanford’s president, states that the material could injure innocent parties. Mr Mosher told the New York Times that his Chinese wife, Maggie So, gave the school inaccurate derogatory information about his activities in the village because he insisted on divorcing her. The Mosher case comes at a time of a decline in scientific exchange by US scientists with both of the major Communist powers. China has banned all further field research by Americans; Soviet scientists still visit the United States but in reduced numbers. The reason is that President Reagan, as a sanction after the imposition of martial law in Poland, refused to renew three programmes: science and technology, space, and energy. Eight other exchange programmes continue. Some scientists-particularly some dissident Soviet emigresbelieve the Soviet visits hold no benefits for the United States anyway. Michael Taksar, a Soviet mathematician now at Stanford, maintains that most Soviet scientists coming here are ideologically reliable bureaucrats or spies on the alert for technological secrets. That does not accord with the experience of Walter Gilbert, a molecular biologist and Nobel laureate from Harvard, who recalls that Andrei Mirzabekof, a Soviet scientist, helped him immensely. "He got me involved in the line of research that led to the chemical the Nobel prize." Another sequency methods that molecular biologist, Max Gottesman, of the National Cancer Institute, tells a different story. The scientist he saw, while fairly competent, was argumentative. "He’d have a little vodka and start telling me how mighty the Soviet Union was and how it could wipe us out... I asked him what impressed him most about Chicago and he said people searching through garbage cans for food." , A middle-of-the-road view comes from Gordon Scher, an official at the National Science Foundation, who has been much involved in Soviet exchanges. In the early years of the programme, about a decade ago, some of the Soviet visitors lacked convincing scientific credentials, but the situation had improved. "With time," Scher observes, "the proportion has shifted towards substantive
eventually won
"
scientists."
man.
321-24.
Young GC A sustained release antihistamine. Practitioner 1964; 193: 664-67. 10. Fowle ASE, Hughes DTD, Knight GJ. The evaluation of histamine antagonists in man. Eur J Clin Pharmacol 1971; 3: 215-20. 11. Chapman PH, Rawlins MD. A randomized single blind study of astemizole and chlorpheniramine in normal volunteers. Br J Clin Pharmacol 1983; 13: 593P. 12. Nicholson AN, Stone BM. Performance studies with the H,-histamine receptor antagonists, astemizole and terfenadine Br J Clin Pharmacol 1982; 13: 199-202. 13. Nicholson AN, Smith PA, Spencer MB Antihistamines and visual function: studies on dynamic visual acuity and the pupillary response to light. Br J Clin Pharmacol 1982; 9.
14: 683-90. 14. Uzan A, Le Fur G. Mequitazine et vigilance. Allergic Immunol 1979; 11: 27-30. 15. Le Fur G, Malgouris C, Uzan A. Effect of mequitazine, anon sedative antihistamine on brain H1 receptors Life Sci 1981; 29: 547-52. 16. Nicholson AN, Stone BM. The H1-antagonist mequitazine: studies on performance and visual function. Eur J Clin Pharmacol (in press). 17 Reinberg A, Bicakova-Rocher A, Peiffer C, Levi F, Nicolai A. Effets de la mequitazine sur les rythmes circadiens des resultats de tests psychometriques et de la temperature orale Eur J Clin Pharmacol (in press).
18. Rose
C, Quach TT, Llorens C, Schwartz JC. Relationship between occupation of H1-receptors and sedative properties of antihistamines. Arzneim-Forsch
cerebral
1982; 32: 1171-73.
activity and central effects of terfenadine. A review of European studies. Arzneim-Forsch 1982; 32: 1191-93. Reinberg A, Levi F, Guillet P, Burke JT, Nicolai A. Chronopharmacological study of antihistamines in man with special reference to terfenadine. Eur J Clin Pharmacol
19. Nicholson AN. Antihistaminic 20.
1978; 14: 245-52. 21. Kulshrestha VK, Gupta PP, Turner P, Wadsworth J. Some clinical pharmacological studies with terfenadine, a new antihistaminic drug. Br J Clin Pharmacol 1978; 6: 25-30. 22. Lockhart JDF, Maneksha S. Terfenadine suspension in children with allergies Practitioner (in press). 23. Reinberg A, Sidi E, Ghata J. Circadian reactivity rhythms of human skin to histamine or allergen and the adrenal cycle. J Allergy 1965; 36: 273-83. 24. Reinberg A, Levi F, Fourtillan JP, Peiffer C, Bicakova-Rocher A. Both pharmacokinetics and antihistamine effects of mequitazine vary between morning and evening administration. Eur J Clin Pharmacol (in press).