Single-dose pharmacokinetics of amprenavir coadministered with grapefruit juice.

In this crossover study in 12 healthy volunteers, coadministration of amprenavir (1,200 mg; single dose) with grapefruit juice slightly reduced the maximum concentration of drug in serum (Cmax) compared to administration with water (7.11 versus 9.10 microg/ml), slightly increased the time to Cmax (1.13 versus 0.75 h), and did not affect the area under the concentration-time curve from 0 to 12 h (AUC(0-12)), the AUC(0-infinity), or the concentration at 12 h. Therefore, grapefruit juice does not clinically significantly affect amprenavir pharmacokinetics.

Pharmacokinetic study of human immunodeficiency virus protease inhibitors used in combination with amprenavir.

In an open-label, randomized, multicenter, multiple-dose pharmacokinetic study, we determined the steady-state pharmacokinetics of amprenavir with and without coadministration of indinavir, nelfinavir, or saquinavir soft gel formulation in 31 human immunodeficiency virus type 1-infected subjects. The results indicated that amprenavir plasma concentrations were decreased by saquinavir soft gel capsule (by 32% for area under the concentration-time curve at steady state [AUC(ss)] and 37% for peak plasma concentration at steady state [C(max,ss)]) and increased by indinavir (33% for AUC(ss)). Nelfinavir significantly increased amprenavir minimum drug concentration at steady state (by 189%) but did not affect amprenavir AUC(ss) or C(max,ss). Nelfinavir and saquinavir steady-state pharmacokinetics were unchanged by coadministration with amprenavir compared with the historical monotherapy data. Concentrations of indinavir, coadministered with amprenavir, in plasma decreased in both single-dose and steady-state evaluations. The changes in amprenavir steady-state pharmacokinetic parameters, relative to those for amprenavir alone, were not consistent among protease inhibitors, nor were the changes consistent with potential interactions in CYP3A4 metabolism or P-glycoprotein transport. No dose adjustment of either protease inhibitor in any of the combinations studied is needed.

The pharmacokinetics of cisatracurium in patients with acute respiratory distress syndrome.

UNLABELLED: Continuous neuromuscular blockade is often necessary in patients being treated for acute respiratory distress syndrome (ARDS) to optimize oxygenation. In this study, neuromuscular blockade (no response to two responses at the train-of-four stimulation at the orbicularis oculi muscle) was achieved in six patients with ARDS by a continuous infusion of cisatracurium. The plasma concentration of cisatracurium during the infusion averaged 1.00 (0.25-1.45) microg/mL, expressed as median (range). The clearance and half-life were 6.5 (3.3-7.6) mL. min(-1). kg(-1) and 25 (16-48) min, respectively. The laudanosine plasma concentrations were 0.70 (0.12-1.20) microg/mL. The pharmacokinetic variables of cisatracurium are similar to those of patients without organ failure undergoing elective surgery. Plasma laudanosine levels always remained well less that those associated with seizure activity in animal models. Long-term infusion of cisatracurium was not associated with any side effects. Cisatracurium is a suitable muscle relaxant when deep and continuous levels of muscle relaxation are required in patients treated for ARDS. IMPLICATIONS: We studied the pharmacokinetics of cisatracurium in six patients treated for respiratory distress syndrome by continuous muscle relaxation. A deep degree of neuromuscular blockade corresponding to abolition of two responses at the orbicularis oculi to train-of-four stimulation was obtained in all patients. The pharmacokinetic variables observed in these severely ill patients were similar to those of anesthetized patients. No accumulation of laudanosine was seen. Cisatracurium appears to be suitable when continuous muscle relaxation is required in critically ill patients.

A comparison of the steady-state pharmacokinetics and safety of abacavir, lamivudine, and zidovudine taken as a triple combination tablet and as abacavir plus a lamivudine-zidovudine double combination tablet by HIV-1-infected adults.

STUDY OBJECTIVE: To investigate the steady-state pharmacokinetics of a triple combination tablet containing abacavir (ABC) 300 mg, lamivudine (3TC) 150 mg, and zidovudine (ZDV) 300 mg taken twice/day, and those of ABC 300 mg twice/day plus a double combination tablet containing 3TC 150 mg and ZDV 300 mg twice/day (ABC-COM). DESIGN: Open-label, crossover study. SETTING: Two hospital-based clinical research units. PATIENTS: Twelve men infected with human immunodeficiency virus-1. INTERVENTION: Steady-state pharmacokinetics of ABC, 3TC, and ZDV were assessed after dosing with ABC-COM and the triple combination tablet. MEASUREMENTS AND MAIN RESULTS: Steady-state pharmacokinetics of ABC, 3TC, and ZDV were similar for the triple combination tablet versus ABC-COM for the following: geometric mean (GM) area under the serum concentration-time curve, ABC 6.08 versus 5.87, 3TC 5.51 versus 5.53, and ZDV 1.38 versus 1.46 microg x hr/ml; GM maximum serum concentration (Cmax-ss), ABC 3.09 versus 3.19, 3TC 1.26 versus 1.40, and ZDV 1.19 versus 1.15 microg/ml; median time to Cmax-ss, ABC 0.75 versus 0.75, 3TC 1.50 versus 1.24, and ZDV 0.75 versus 0.75 hours; and GM oral clearance, ABC 51 versus 49, 3TC 27 versus 27, and ZDV 217 versus 206 L/hour. The GM half-lives of ABC and ZDV were similar for both treatments, 1.69 versus 1.58 and 2.30 versus 2.08 hours, respectively. CONCLUSION: Steady-state pharmacokinetics of ABC, 3TC, and ZDV were similar in patients who took them as ABC-COM or as a triple combination tablet.

In vivo effect of alpha(1)-acid glycoprotein on pharmacokinetics of amprenavir, a human immunodeficiency virus protease inhibitor.

Observations from early clinical pharmacology studies of amprenavir, an inhibitor of human immunodeficiency virus type 1 (HIV-1) protease that is highly bound to human plasma proteins (approximately 90%), showed the single-dose pharmacokinetics of amprenavir to be variable between and within individuals. A cross-study analysis of various demographic, laboratory, and clinical covariates was therefore performed. Differences in amprenavir pharmacokinetics could be due to variable concentrations in alpha(1)-acid glycoprotein (AAG), the predominant plasma protein to which amprenavir binds. Therefore, AAG was considered an important factor to study since the literature suggested that AAG levels vary by race, age, and weight and following trauma or infection, including HIV disease. Pooled data from three single-dose studies analyzed by stepwise linear regression indicated that AAG concentrations significantly correlated with age and race and that only AAG concentrations were a significant predictor of amprenavir apparent total clearance (CL/F). A significant inverse linear relationship was found between AAG and amprenavir CL/F. Compared to white subjects, black subjects had significantly lower AAG concentrations and therefore significantly higher amprenavir CL/F. Although AAG has a significant influence on the variability of total drug pharmacokinetics, unbound, or free, drug concentrations are not affected by AAG concentrations. Incorrect conclusions could be drawn on the pharmacokinetics of highly protein-bound drugs if AAG concentration is not included in the analysis.

Pharmacokinetic and pharmacodynamic study of the human immunodeficiency virus protease inhibitor amprenavir after multiple oral dosing.

In a dose-ranging study of amprenavir (formerly 141W94), an inhibitor of the protease enzyme of human immunodeficiency virus (HIV) type 1, single-dose and steady-state pharmacokinetic parameters were estimated from plasma samples collected on day 1 and during week 3, respectively. Amprenavir was administered on either a twice-daily (b.i.d.) or three-times-daily dosage schedule to 62 HIV-infected adults, 59 of whom had pharmacokinetic data. Log-log regression analysis (the power model) revealed that the steady-state area under the curve (AUC(ss)) and the maximum, minimum, and average concentrations at steady state (C(max,ss), C(min,ss), and C(avg,ss), respectively) increased in a dose-proportional manner over the 300- to 1,200-mg dose range. Steady-state clearance was dose independent. AUC(ss)/AUC(0-->infinity) decreased linearly with dose and correlated significantly with treatment-associated decreases in alpha(1)-acid glycoprotein. After 3 weeks, the dose of 1,200 mg b.i. d. provided a median amprenavir C(min,ss) (0.280 microg/ml) that was higher than the median in vitro 50% inhibitory concentration for clinical HIV isolates (0.023 microg/ml), even after adjustment for protein binding. The median amprenavir C(min,ss) was also greater than the estimated in vivo trough concentration calculated to yield 90% of the maximum antiviral effect (0.228 microg/ml) over 4 weeks. A pharmacodynamic analysis of the relationship between steady-state pharmacokinetic parameters and safety revealed headache and oral numbness to be the only side effects significantly associated with C(max). The pharmacodynamic relationship defined in this study supports the use of 1,200 mg b.i.d. as the approved dose of amprenavir.

Single-dose pharmacokinetics of amprenavir, a human immunodeficiency virus type 1 protease inhibitor, in subjects with normal or impaired hepatic function.

Amprenavir (141W94) is extensively metabolized by P450 cytochromes, specifically, CYP3A4. Because hepatic insufficiency reduces P450-mediated metabolism, the concentrations in plasma of drugs metabolized through this pathway are often increased in subjects with liver disease. Following administration of a single, oral dose of 600 mg of amprenavir, pharmacokinetic parameters were determined for 10 subjects with severe cirrhosis, 10 subjects with moderate cirrhosis, and 10 healthy volunteers. Model-independent methods for determining the area under the plasma concentration-time curve (AUC) from time zero to infinity (AUC(0-infinity)) showed an increase in amprenavir AUC(0-infinity) of 2.5-fold in the group with moderate cirrhosis and 4.5-fold in the group with severe cirrhosis compared with that in the control group of healthy volunteers (P < 0.05). AUC(0-infinity) was linearly related to the severity of liver disease, as assessed by the Child-Pugh score. Of the laboratory data used to calculate the Child-Pugh score, only the mean total bilirubin concentration showed a significant relationship with AUC(0-infinity). The relationship between the total bilirubin concentration and the AUC(0-infinity) of amprenavir was well characterized by a simple E(max) model, suggesting that the total bilirubin concentration may be a useful parameter for predicting the amprenavir AUC in subjects with hepatic insufficiency. Finally, the sera of cirrhotic subjects showed significant decreases in the levels of alpha(1)-acid glycoprotein, the primary plasma binding protein for amprenavir. On the basis of the results of this study, for an exposure equivalent to a clinical dose of 1,200 mg twice daily in subjects without cirrhosis, subjects with Child-Pugh scores of 5 to 8 should receive a twice-daily 450-mg dose of amprenavir, and subjects with Child-Pugh scores of 9 to 15 should receive a twice-daily 300-mg dose of amprenavir.

Pharmacokinetic interaction between amprenavir and clarithromycin in healthy male volunteers.

The P450 enzyme, CYP3A4, extensively metabolizes both amprenavir and clarithromycin. To determine if an interaction exists when these two drugs are coadministered, the pharmacokinetics of amprenavir and clarithromycin were investigated in healthy adult male volunteers. This was a Phase I, open-label, randomized, balanced, multiple-dose, three-period crossover study. Fourteen subjects received the following three regimens: amprenavir, 1,200 mg twice daily over 4 days (seven doses); clarithromycin, 500 mg twice daily over 4 days (seven doses); and the combination of the above regimens over 4 days (seven doses of each drug). Twelve subjects completed all treatments and the follow-up period. The erythromycin breath test (ERMBT) was administered at baseline, 2 h after the final dose of each of the three regimens and at the first follow-up visit. Coadministration of clarithromycin and amprenavir significantly increased the mean amprenavir AUC(ss), C(max,ss), and C(min,ss) by 18, 15, and 39%, respectively. Amprenavir had no significant effect on the AUC(ss) of clarithromycin, but the median T(max,ss)for clarithromycin increased by 2.0 h, renal clearance increased by 34%, and the AUC(ss) for 14-(R)-hydroxyclarithromycin decreased by 35% when it was given with amprenavir. Amprenavir and clarithromycin reduced the ERMBT result by 85 and 67%, respectively, and by 87% when the two drugs were coadministered. The baseline ERMBT value did not correlate with clearance of amprenavir or clarithromycin. A pharmacokinetic interaction occurs when amprenavir and clarithromycin are coadministered, but the effects are not likely to be clinically important, and coadministration does not require a dosage adjustment for either drug.

Abacavir: absolute bioavailability, bioequivalence of three oral formulations, and effect of food.

STUDY OBJECTIVES: Study A: to determine the absolute bioavailability of a single 300-mg abacavir hemisulfate tablet. Study B: to determine the bioequivalence of two oral abacavir formulations (300-mg hemisulfate tablet, 100-mg succinate caplet), the effect of food on the bioavailability of the 300-mg hemisulfate tablet, and the bioavailability of the hemisulfate tablet relative to the hemisulfate solution. DESIGN: Phase I, randomized, open-label, balanced two- (study A) and three- or four-period (study B), crossover studies. SETTING: Two clinical research centers. SUBJECTS: Six men infected with the human immunodeficiency virus (HIV), aged 27-39 years (study A), and 18 HIV-infected men and women, aged 21-50 years (study B). INTERVENTIONS: In study A, all subjects received a single, oral 300-mg tablet of abacavir hemisulfate or a single, intravenous infusion of abacavir hemisulfate 150 mg over 60 minutes. In study B, all subjects received each of three single-dose treatments: three 100-mg abacavir succinate caplets in a fasted state, one 300-mg abacavir hemisulfate tablet in a fasted state, and one 300-mg abacavir hemisulfate tablet with a high-fat breakfast. Twelve subjects in study B also received a fourth treatment of abacavir hemisulfate 300 mg as an oral solution in a fasted state. Plasma samples collected for 24 hours (study A) or 12 hours (study B), and urine samples collected for 12 hours (study A) were analyzed by validated high-performance liquid chromatographic methods. MEASUREMENTS AND MAIN RESULTS: Abacavir pharmacokinetic parameters were calculated using standard, noncompartmental methods. In study A, the geometric least square (GLS) mean absolute bioavailability of oral abacavir was 83% (range 65-107%). In study B, the hemisulfate tablet was bioequivalent to the succinate caplet, but its time to maximum concentration (Tmax) occurred 30 minutes earlier. Administration of the abacavir hemisulfate tablet with food had no effect on area under the curve from time zero to infinity (AUC0-infinity), decreased maximum concentration (Cmax) by 26%, and delayed Tmax by 38 minutes. The relative bioavailability (GLS mean AUC0-infinity ratio) of the 300-mg abacavir hemisulfate tablet to solution was 101%, Cmax was 11% lower, and Tmax was unchanged. The most common drug-related adverse events associated with abacavir were nausea, vomiting, abdominal pain, and headache, all of which were mild. CONCLUSION: Based on our results, abacavir is safe and well tolerated and can be administered with or without meals.

Lack of a pharmacokinetic interaction between atovaquone and proguanil.

OBJECTIVE: To assess the magnitude of the putative effect of atovaquone on the pharmacokinetics of proguanil and to determine whether the pharmacokinetics of atovaquone are affected by concomitant administration of proguanil, with both drugs administered for 3 days to healthy adult volunteers. METHODS: This was an open-label, randomized, three-way cross-over study, in which 18 healthy volunteers received 400 mg proguanil, 1000 mg atovaquone and 1000 mg atovaquone + 400 mg proguanil. Each treatment was given once daily for 3 days with a 3-week wash-out period between each occasion. For the assay of proguanil, cycloguanil and atovaquone, blood was sampled before dosing and at regular intervals over 8 days when proguanil was given, and over 17 days when atovaquone was given. RESULTS: The geometric mean of the area under the atovaquone plasma concentration-time curve calculated from 0 to 24 h after the last dose (AUC0->24h) was 180 microg x ml(-1) h following administration of atovaquone alone and 193 microg x ml(-1) h following atovaquone with proguanil. The geometric mean AUC0->24h for proguanil was 6296 ng x ml(-1) x h after proguanil alone and 5819 ng x ml(-1) x h following proguanil with atovaquone. The corresponding values for the metabolite cycloguanil were 1297 ng x ml(-1) x h and 1187 ng x ml(-1) x h, respectively. The geometric mean elimination half-life (t1/2) of atovaquone was 57.1 h when given alone and 59.0 h when administered together with proguanil. The corresponding geometric mean values of t1/2 for proguanil were 13.7 h and 14.5 h. Exploratory statistical analysis showed no important gender effects on the pharmacokinetics of atovaquone, proguanil, or cycloguanil. CONCLUSION: The pharmacokinetics of atovaquone and proguanil and its metabolite, cycloguanil, were not different when atovaquone and proguanil were given alone or in combination.

No need to adjust the dose of 311C90 (zolmitriptan), a novel anti-migraine treatment, in patients with renal failure not requiring dialysis.

311C90 ("Zomig", zolmitriptan), is a novel and selective, centrally and peripherally acting 5 HT1B/1D receptor agonist in development for the acute, oral treatment of migraine. We have conducted a parallel group study in patients with moderate/severe renal impairment (creatinine clearance < or = 40 ml/min) and age- and sex-matched healthy volunteers (creatinine clearance > or = 60 ml/min). All subjects received a single, 10 mg dose of 311C90. Mean peak concentrations of 311C90 and its pharmacologically active N-desmethyl metabolite (183C91) were similar in both groups although AUC0-infinity for 183C91 was increased by 35% in the renally impaired patients. Other pharmacokinetic parameters were little changed apart from the expected reduction in CLR and urinary recovery and a small increase of 0.9 and 1.0 h, respectively, in the mean half-lives of 311C90 and 183C91. For the 2 inactive metabolites, the N-oxide (1652W92) and the indolacetic acid (2161W92), mean peak concentrations were approximately 3 times higher in renally impaired patients than in healthy volunteers and AUC0-infinity was 6-7.5 times higher. CLR for these metabolites was approximately 90% lower in renal impairment and half-life of both was increased approximately 3-fold. Baseline blood pressures were higher in the renally impaired group. After 311C90 there was a transient, small increase in blood pressure in both groups. There was little difference in the increase in diastolic blood pressure between the groups (16 mmHg in both) but the rise in systolic blood pressure was greater in the renally impaired group (23 mmHg vs 16 mmHg in healthy subjects). The lack of substantial changes in the plasma concentrations of both parent compound and 183C91, and the similarity of the changes in blood pressure, in renally impaired subjects compared to healthy volunteers suggest that there is no reason to adjust the dose of 311C90 in patients with renal impairment.

The pharmacokinetics and effects on blood pressure of multiple doses of the novel anti-migraine drug zolmitriptan (311C90) in healthy volunteers.

AIMS: Zolmitriptan (311C90), a novel, selective, centrally and peripherally acting 5-HT1D-receptor agonist is under development as an acute treatment for migraine. The tolerability, pharmacokinetics and effects on blood pressure and heart rate of multiple doses of 5 or 10 mg (5 doses administered over 24 h) were compared, in healthy adult volunteers, with those after placebo and single doses of zolmitriptan. METHODS: Twelve subjects participated in a randomized, balanced, crossover comparison. Plasma and urine concentrations of zolmitriptan and its metabolites, pulse rate and blood pressure were measured at intervals after drug. Ten volunteers completed the study. RESULTS: Zolmitriptan was well tolerated after single and multiple doses throughout the study. There was no evidence of significant changes in the pharmacokinetic parameters of zomitriptan or its metabolites after the last dose compared to the first, except for an expected rise in peak concentrations and a small, apparent increase in the amount of drug excreted in urine and hence in CLR. After the last 10 mg dose, mean dosing interval zolmitriptan AUC was 80.3 ng ml-1 h compared with 86.5 ng ml-1 h after the single 10 mg dose (95% CI for ratio 0.76-1.13). There was no evidence of changes in the pharmacokinetic parameters of zolmitriptan and its metabolites after 10 mg compared with 5 mg, except a small increase in zolmitriptan CLR. There were no statistically significant increases in peak systolic or diastolic blood pressure after the last doses of zolmitriptan compared to placebo or in peak blood pressure after the last dose compared to the first. There were no significant differences between blood pressure immediately before the first and last doses of each multiple dose regimen. Peak erect systolic blood pressure after the last 10 mg dose (137 mmHg) was significantly lower than that after placebo (147 mmHg, 95% CI for difference -18, -2) and that after the last 5 mg dose (148 mmHg, 95% CI -19, -3). CONCLUSIONS: Repeated doses of 5 or 10 mg zolmitriptan are well tolerated despite higher plasma concentrations than expected from single doses.

The interaction between propranolol and the novel antimigraine agent zolmitriptan (311C90).

AIMS: Zolmitriptan (Zomig, formerly known as 311C90), a selective 5HT1B/1D agonist is under development as an acute oral treatment for migraine. Despite the use of prophylactic medication, such as propranolol, breakthrough attacks often occur in patients. Consequently we investigated the effects of propranolol on the pharmacokinetics of, and cardiovascular responses to, zolmitriptan. METHODS: A double-blind, randomized, crossover study of the effects of pre-treatment with propranolol 160 mg daily for 7 days or placebo on the pharmacokinetics and effects on blood pressure of a single 10 mg dose of zolmitriptan in 12 healthy volunteers. RESULTS: Propranolol increased mean zolmitriptan Cmax and AUC by 56% and 37% respectively; mean t1/2 was prolonged from 3.1 to 4.0 h. Mean Cmax and AUC of the pharmacologically active N-desmethyl metabolite were reduced by 24% and 11% respectively and the metabolite:parent AUC ratio (AUCm/AUCp) fell from 0.46 to 0.26. Mean Cmax and AUC for the inactive indole acetic acid metabolite were both reduced by 13% and AUCm/AUCp from 1.04 to 0.59. A small pressor effect of short duration was observed following zolmitriptan with mean peak rises of 13 and 11 mmHg in systolic and diastolic pressures respectively; propranolol had no effect on the pressor response. CONCLUSIONS: The results suggest that propranolol inhibits biotransformation of zolmitriptan but with no change in the small pressor response to zolmitriptan. It is therefore unlikely that the pharmacokinetic changes will lead to clinically important changes in pharmacological effects and dosage adjustment of zolmitriptan is not required in patients taking propranolol for migraine prophylaxis.

Pharmacokinetics of netivudine, a potent anti-varicella zoster virus drug, in patients with renal impairment.

The pharmacokinetics of a single oral 200 mg dose of netivudine (1-(beta-D-arabinofuranosyl)-5-(1-propynyl)uracil), a nucleoside analogue under development for use in varicella zoster virus infections, were studied in 12 renal failure (RF) subjects (creatinine clearance 15 +/- 7 mL/min) and 12 age-matched healthy subjects with normal creatinine clearance. Blood and urine samples were collected up to nine days after drug administration. Concentrations of netivudine and of its main metabolite, the pyrimidine base 5-(1-propynyl)uracil (5 PU), were determined by a specific high performance liquid chromatography assay. The mean peak plasma concentrations of netivudine, Tmax, and volume of distribution were not significantly affected by RF. The elimination half-life of netivudine was approximately 15 h in subjects with normal renal function and 60 h in RF patients. Plasma and renal clearances of netivudine were significantly reduced in RF patients and AUC was three to four times higher in these patients. Cmax and AUC of 5 PU were higher in RF patients, and the half-life was also significantly longer. However, the half-life of this metabolite was much lower than that of the parent compound. Tmax and the lag time were similar in the two groups. There were highly significant correlations for netivudine and 5 PU between half-life and creatinine clearance and between renal clearance and creatinine clearance. These findings suggest that netivudine dosage may need to be reduced in patients with severe renal failure, and confirm that formation of the 5 PU is independent of the elimination of netivudine from plasma.

Clinical efficacy and pharmacokinetics of micronized halofantrine for the treatment of acute uncomplicated falciparum malaria in nonimmune patients.

Twenty-eight nonimmune patients with acute uncomplicated falciparum malaria returning from subSaharan Africa were treated with a micronized formulation of halofantrine hydrochloride (three doses of 250 mg at 6-hr intervals) to investigate the drug's efficacy, tolerance, and pharmacokinetics. In vitro drug susceptibility patterns were determined by the isotopic semimicrotest. Twenty-four of 28 patients were cured. Two of the four patients experiencing recrudescence were associated with low absorption of the drug and parasites susceptible in vitro to halofantrine. The other two patients had adequate plasma concentrations of halofantrine and its main human metabolite, N-desbutylhalofantrine, but the isolates were also resistant in vitro to the drugs, suggesting drug resistance as the cause of treatment failure. Only mild, transitory side effects were noted. A wide interindividual variation in plasma concentrations of halofantrine and its metabolite was observed. Pharmacokinetic studies suggested that the micronized formulation of halofantrine hydrochloride may not increase drug absorption considerably. Further studies using higher doses or longer treatment periods are needed to ensure that adequate plasma concentrations of the drug are used.

Effects of acrivastine and terfenadine on skin reactivity to histamine.

The response to the histamine hydrochloride prick skin test was studied in 24 healthy volunteers who received, in random order and at least four days apart, acrivastine (8 mg), terfenadine (120 mg), and placebo. The tests were performed on either side of the back before and at the time of administration (single dose), then every 30 minutes for two hours, and every hour for the following four hours. Evaluation was based on the mean of two measurements of the surface area of the wheal-and-flare reaction accompanied by assessment of topical pruritus. The response to histamine was decreased markedly in the two active treatment groups. Although within one hour of injection, the activity of both antihistamines was consistently greater than that of placebo, the kinetics of action of the two products nevertheless differed; indeed acrivastine was active against flare and wheal earlier (within 30 minutes); terfenadine proved to be more active than acrivastine only on flare and only at the later times (four, five, and six hours). The safety study primarily demonstrated drowsiness in one-fourth of the patients receiving placebo and active treatment.

Plasma concentrations of the enantiomers of halofantrine and its main metabolite in malaria patients.

The plasma concentrations of the enantiomers of halofantrine and its N-desbutyl metabolite in six patients with malaria were measured after oral administration of 3 x 750 mg doses of micronised, racemic halofantrine hydrochloride given at 6-hour intervals. Significant differences were observed between the plasma concentrations of the enantiomers both of halofantrine and its N-monodesbutyl metabolite. AUC(0)84h values were higher for (+)halofantrine (9917 micrograms.ml-1.h) than for (-)-halofantrine (6127 micrograms.ml-1.h). The clinical significance of these observations is not known. The isomers have equipotent activity in vitro but their relative toxicity has not yet been assessed.

In vitro activity of the enantiomers of mefloquine, halofantrine and enpiroline against Plasmodium falciparum.

The in vitro activity of the enantiomers of mefloquine, halofantrine and enpiroline was compared against chloroquine-resistant and -susceptible strains of Plasmodium falciparum using a semi-micro drug susceptibility test. For each strain, the corresponding enantiomers exhibited similar activities. The enantiomers of halofantrine were the most active against both susceptible and resistant strains, followed by the enantiomers of mefloquine and enpiroline.