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OBJECTIVES: Because of the extensive variability in paracetamol clearance in young women, published data were pooled with newly collected observations in search of covariates of paracetamol pharmacokinetics (PK) within this specific population. SUBJECTS AND METHODS: PK estimates and clinical characteristics [pregnant, weight, exposure to oral contraceptives (OC)] in young women following IV loading dose (2 g paracetamol) were pooled, using a non-compartmental linear disposition model in individual time-concentration profiles. Data were reported by median and range. Rank correlation was used to link clearance (l/h) to weight, Mann Whitney U test to compare clearance (l/h.m-2) between subgroups (pregnant, OC exposure). Finally, a multiple regression model with clearance (l/h) in all women and all non-pregnant women was performed. RESULTS: Based on 73 paracetamol PK estimates, a 8-fold variability in clearance (range 7.1-62.2 l/h) was documented, in part explained by a correlation (r2=0.36) between clearance (l/h) and weight. Clearance (l/h and l/h.m-2) and distribution volume (l) at delivery (n=36) were higher compared to non-pregnant observations. In nonpregnant women, women on OC (n=20) had a higher paracetamol clearance (l/h.m-2) compared to women (n=17) not on OC (p = 0.023).Weight (p = 0.0043) and pregnancy (p = 0.02) were independent variables (r=0.56) of paracetamol clearance (l/h). In non-pregnant women, weight (p = 0.009) and OC exposure (p = 0.03) were independent variables (r=0.51). CONCLUSIONS:Weight, pregnancy and OC result in higher clearance of IV paracetamol in young women. Besides compound specific relevance, these findings also unveil covariates of drug metabolism in young women. [ABSTRACT FROM AUTHOR]

In the accompanying paper we describe how MRK-409 unexpectedly produced sedation in man at relatively low levels of GABAA receptor occupancy (∼10%). Since it was not clear whether this sedation was mediated via the α2/α3 or α1 GABAA subtype(s), we characterized the properties of TPA023B, a high-affinity imidazotriazine which, like MRK-409, has partial agonist efficacy at the α2 and α3 subtype but is an antagonist at the α1 subtype, at which MRK-409 has weak partial agonism. TPA023B gave dose- and time-dependent occupancy of rat brain GABAA receptors as measured using an in vivo [3H]flumazenil binding assay, with 50% occupancy corresponding to a respective dose and plasma drug concentration of 0.09 mg/kg and 19 ng/mL, the latter of which was similar to that observed in mice (25 ng/mL) and comparable to values obtained in baboon and man using [11C]flumazenil PET (10 and 5.8 ng/mL, respectively). TPA023B was anxiolytic in rodent and primate (squirrel monkey) models of anxiety (elevated plus maze, fear-potentiated startle, conditioned suppression of drinking, conditioned emotional response) yet had no significant effects in rodent or primate assays of ataxia and/or myorelaxation (rotarod, chain-pulling, lever pressing), up to doses (10 mg/kg) corresponding to occupancy of greater than 99%. In man, TPA023B was well tolerated at a dose (1.5 mg) that produced occupancy of >50%, suggesting that the sedation previously seen with MRK-409 is due to the partial agonist efficacy of that compound at the α1 subtype, and highlighting the importance of antagonist efficacy at this particular GABAA receptor population for avoiding sedation in man. [ABSTRACT FROM PUBLISHER]

MRK-409 binds to α1-, α2-, α3- and α5-containing human recombinant GABAA receptors with comparable high affinity (0.21—0.40 nM). However, MRK-409 has greater agonist efficacy at the α3 compared with α1 subtypes (respective efficacies relative to the full agonist chlordiazepoxide of 0.45 and 0.18). This compound readily penetrates the brain in rats and occupies the benzodiazepine site of GABAA receptors, measured using an in vivo [3H]flumazenil binding assay, with an Occ50 of 2.2 mg/kg p.o. and a corresponding plasma EC50 of 115 ng/mL. Behaviourally, the α3-preferring agonist efficacy profile of MRK-409 produced anxiolytic-like activity in rodent and primate unconditioned and conditioned models of anxiety with minimum effective doses corresponding to occupancies, depending on the particular model, ranging from ∼35% to 65% yet there were minimal overt signs of sedation at occupancies greater than 90%. In humans, however, safety and tolerability studies showed that there was pronounced sedation at a dose of 2 mg, resulting in a maximal tolerated dose of 1 mg. This 2 mg dose corresponded to a Cmax plasma concentration of 28 ng/mL, which, based on the rodent plasma EC50 for occupancy of 115 ng/mL, suggested that sedation in humans occurs at low levels of occupancy. This was confirmed in human positron emission tomography studies, in which [11C]flumazenil uptake following a single dose of 1 mg MRK-409 was comparable to that of placebo, indicating that occupancy of GABAA receptor benzodiazepine binding sites by MRK-409 was below the limits of detection (i.e. <10%). Taken together, these data show that MRK-409 causes sedation in humans at a dose (2 mg) corresponding to levels of occupancy considerably less than those predicted from rodent models to be required for anxiolytic efficacy (∼35—65%). Thus, the preclinical non-sedating anxiolytic profile of MRK-409 did not translate into humans and further development of this compound was halted. [ABSTRACT FROM PUBLISHER]

Laropiprant is a selective antagonist of the prostaglandin D2 (PGD2) receptor subtype 1 (DP1). Three double-blind, randomized, placebo-controlled studies evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of single and multiple oral doses of laropiprant in healthy male volunteers. Single doses up to 900 mg and multiple doses up to 450 mg were generally well tolerated. Laropiprant exhibited dose-proportional pharmacokinetics. Oral absorption is rapid (Tmax=0.8–2.0 h) and the terminal half-life is approximately 12–18 h. The pharmacokinetics of laropiprant was not affected by food. Single doses of 6 mg and higher were effective in suppressing PGD2-induced cyclic AMP accumulation in platelets, demonstrating laropiprant target engagement with DP1. Laropiprant has detectable off-target antagonist effects at the thromboxane A2 receptor but no clinically significant effect on collagen-induced platelet aggregation or bleeding times with multiple doses up to 200 mg.Clinical Pharmacology & Therapeutics (2008); 83, 6, 840–847 doi:10.1038/sj.clpt.6100345 [ABSTRACT FROM AUTHOR]

The forearm vascular response to nitric oxide (NO) and calcitonin gene-related peptide (CGRP) was investigated in 10 migraine patients and 10 matched control subjects. Changes in forearm blood flow (FBF) during intrabrachial infusion of: (i) serotonin (releasing endogenous NO), (ii) sodium nitroprusside (SNP, exogenous NO-donor), and (iii) CGRP were measured using venous occlusion plethysmography. Flow-mediated dilation (FMD) of the brachial artery, a measure for the endogenous release of NO reactive to occlusion, was measured using ultrasound and expressed as percentage change vs. baseline diameter. FBF ratio (i.e. FBF in the infused over the control arm) at baseline (1.1 ± 0.1) did not differ between both populations. Serotonin, SNP and CGRP induced a dose-dependent increase ( P < 0.001) in FBF ratio in controls (to 2.8 ± 0.3, 6.7 ± 1.4 and 6.9 ± 1.2 at the highest dose, respectively) and migraineurs (2.5 ± 0.4, 5.6 ± 0.8 and 6.5 ± 1.3, respectively); these ratios did not differ between both groups. FMD was comparable in control subjects (5.8 ± 1%) and migraine patients (5.2 ± 1%). Based on the forearm vascular response to NO and CGRP, migraine patients do not display generalized changes in vascular function. [ABSTRACT FROM AUTHOR]

Objective. To compare the sensitivity of three non-invasive techniques for detecting serotonin (5-HT)1B/1D-receptor agonist-induced peripheral vascular effects in humans: the measurement of (1) systolic (SBP) and diastolic (DBP) blood pressures, (2) dorsal hand vein (DHV) diameter and (3) toe–arm systolic blood pressure gradient (ΔSBPtoe–arm). Methods. A double-blind, placebo-controlled, three-way, cross-over study was performed in 12 healthy male volunteers. According to a randomly assigned allocation schedule, subjects were administered sumatriptan 3 mg, sumatriptan 6 mg or placebo subcutaneously. Measurements were performed at baseline, every 5 min for 30 min and at 40 min and 60 min after drug administration. SBP and DBP were recorded using a semi-automated oscillometric device. DHV diameter was measured using a linear variable differential transformer. ΔSBPtoe–arm was calculated after measuring toe and arm SBP with a strain-gauge technique. Sensitivity was evaluated with responsiveness statistics. Results. Based on weighted mean and compared with placebo, sumatriptan 3 mg and 6 mg increased SBP by 3.3 mmHg (P=0.023) and 6.4 mmHg (P<0.001) and DBP by 5.0 mmHg (P=0.006) and 7.5 mmHg (P<0.001), respectively. Sumatriptan 3 mg and 6 mg decreased DHV diameter by 36% (P=0.015) and 40% (P=0.005), respectively. ΔSBPtoe–arm did not change. Peak changes were observed within 10–15 min after drug administration. The rank order of responsiveness was: BP > DHV diameter > ΔSBPtoe–arm. Conclusions. Clinically relevant doses of subcutaneous sumatriptan increased blood pressure and decreased DHV diameter without affecting ΔSBPtoe–arm. The increase in blood pressure appeared to be dose dependent. Compared with DHV diameter and ΔSBPtoe–arm, blood pressure measurement appeared to be the most sensitive technique for detecting selective 5-HT1B/1D-receptor agonist-induced peripheral vascular effects in humans. [ABSTRACT FROM AUTHOR]

Objectives: To compare quality of life with the selective β[SUB1]-blocker bisoprolol and the thiazide diuretic bendrofluazide in patients with mild to moderate hypertension. Design and setting: Multi centric, randomised, double-blind, two-way crossover study carried out at six general practice centres. Subjects: Eighty-one patients with newly diagnosed or previously treated hypertension, who had a mean diastolic blood pressure (BP) of 95-120 mm Hg after receiving placebo for 4-6 weeks. Interventions: In random order, patients received bisoprolol (5 mg once daily) or bendrofluazide (2.5 mg once daily) for 8 weeks. Main outcome measures: Quality of life and antihypertensive effect. Results: Decrease in systolic/diastolic BP did not differ between bisoprolol (10 ± 2/13 ± 1 mm Hg) and bendrofluazide (9 ± 2/11 ± 1 mm Hg). Between bisoprolol and bendrofluazide neither in the intention-to-treat nor in the efficacy analysis any difference was found in quality of life variables, such as Health Status Index, somatic symptoms, anxiety, depression, total psychiatric morbidity, cognitive symptoms and hostility score. Compared to baseline the Health Status Index improved (P < 0.05) during bisoprolol. None of the other investigated quality of life variables changed compared to baseline. No patients dropped out during bisoprolol or bendrofluazide treatment. Although, the total number of reported adverse events appeared lower during bendrofluazide than during bisoprolol treatment, it is unclear whether drug related adverse events also differ between the two drugs. Conclusions: At equipotent antihypertensive dosages, the effect of an 8-week treatment on quality of life does not differ between the selective β[SUB1]-blocker bisoprolol and the thiazide diuretic bendrofluazide. [ABSTRACT FROM AUTHOR]

The pharmacokinetics (PK) and pharmacodynamics (PD) of omarigliptin, a novel once-weekly DPP-4 inhibitor, were assessed following single and multiple doses in healthy subjects. Absorption was rapid, and food did not influence single-dose PK. Accumulation was minimal, and steady state was reached after 2 to 3 weeks. Weekly (area under the curve) AUC and C max displayed dose proportionality within the dose range studied at steady state. The average renal clearance of omarigliptin was ∼2 L/h. DPP-4 inhibition ranged from ∼77% to 89% at 168 hours following the last of 3 once-weekly doses over the dose range studied. Omarigliptin resulted in ∼2-fold increases in weighted average postprandial active GLP-1. Omarigliptin acts by stabilizing active GLP-1, which is consistent with its mechanism of action as a DPP-4 inhibitor. Administration of omarigliptin was generally well tolerated in healthy subjects, and both the PK and PD profiles support once-weekly dosing. A model-based assessment of QTc interval risk from the single ascending dose study predicted a low risk of QTc prolongation within the likely clinical dose range, a finding later confirmed in a thorough QT trial., (© 2016, The Authors. The Journal of Clinical Pharmacology Published by Wiley Periodicals, Inc. on behalf of American College of Clinical Pharmacology.)

In the accompanying paper we describe how MRK-409 unexpectedly produced sedation in man at relatively low levels of GABA(A) receptor occupancy (∼10%). Since it was not clear whether this sedation was mediated via the α2/α3 or α1 GABA(A) subtype(s), we characterized the properties of TPA023B, a high-affinity imidazotriazine which, like MRK-409, has partial agonist efficacy at the α2 and α3 subtype but is an antagonist at the α1 subtype, at which MRK-409 has weak partial agonism. TPA023B gave dose- and time-dependent occupancy of rat brain GABA(A) receptors as measured using an in vivo [(3)H]flumazenil binding assay, with 50% occupancy corresponding to a respective dose and plasma drug concentration of 0.09 mg/kg and 19 ng/mL, the latter of which was similar to that observed in mice (25 ng/mL) and comparable to values obtained in baboon and man using [(11)C]flumazenil PET (10 and 5.8 ng/mL, respectively). TPA023B was anxiolytic in rodent and primate (squirrel monkey) models of anxiety (elevated plus maze, fear-potentiated startle, conditioned suppression of drinking, conditioned emotional response) yet had no significant effects in rodent or primate assays of ataxia and/or myorelaxation (rotarod, chain-pulling, lever pressing), up to doses (10 mg/kg) corresponding to occupancy of greater than 99%. In man, TPA023B was well tolerated at a dose (1.5 mg) that produced occupancy of >50%, suggesting that the sedation previously seen with MRK-409 is due to the partial agonist efficacy of that compound at the α1 subtype, and highlighting the importance of antagonist efficacy at this particular GABA(A) receptor population for avoiding sedation in man.

Background: Data on contributors to between-individual variability in overall tramadol clearance and O-demethyl tramadol (M1) formation in preterm neonates and young infants are limited., Methods: A population pharmacokinetic analysis of tramadol and M1 was undertaken using non-linear mixed effects model. Covariate analysis included weight, postmenstrual age (PMA), postnatal age (PNA), creatinaemia, (cardiac) surgery, cardiac defect, and cytochrome (CYP)2D6 polymorphisms, classified by CYP2D6 activity score., Results: In 57 patients (25-54 weeks PMA), 593 observations were collected. Tramadol clearance was described using a two-compartment, zero-order input, first-order elimination linear model. An additional compartment was used to characterize M1. Tramadol clearance at term age was 17.1 litre h(-1) (70 kg)(-1) (CV, 37.2%). Size (37.8%) and PMA (27.3%) contribute to this variability. M1 formation clearance (CL2M1, i.e. the contribution of M1 synthesis to M clearance) was 4.11 litre h(-1) (70 kg)(-1) (CV, 110.9%) at term age. Size and PMA were the major contributors to the variability (52.7%); the CYP2D6 activity score contributes 6.4% to this variability., Conclusions: Overall tramadol clearance estimates confirm earlier reports while CL2M1 variability is explained by size, PMA, and CYP2D6 polymorphisms. The CL2M1 is very low in preterm neonates, irrespective of the CYP2D6 polymorphism with subsequent rapid maturation. The slope of this increase depends on the CYP2D6 activity score. The current pharmacokinetic observations suggest a limited micro-opioid receptor-mediated analgesic effect of M1 in preterm neonates and a potential CYP2D6 polymorphism-dependent effect beyond term age.

Background: To document covariates which contribute to inter-individual variability in propofol pharmacokinetics in preterm and term neonates., Methods: Population pharmacokinetics were estimated (non-linear mixed effect modelling) based on the arterial blood samples collected in (pre)term neonates after i.v. bolus administration of propofol (3 mg kg(-1), 10 s). Covariate analysis included postmenstrual age (PMA), postnatal age (PNA), gestational age, weight, and serum creatinine., Results: Two hundred and thirty-five arterial concentration-time points were collected in 25 neonates. Median weight was 2930 (range 680-4030) g, PMA 38 (27-43) weeks, and PNA 8 (1-25) days. In a three-compartment model, PMA was the most predictive covariate for clearance (P<0.001) when parameterized as [CL(std).(PMA/38)(11.5)]. Standardized propofol clearance (CL(std)) at 38 weeks PMA was 0.029 litre min(-1). The addition of a fixed value in neonates with a PNA of >/=10 days further improved the model (P<0.001) and resulted in the equation [CL(std).(PMA/38)(11.5) +0.03] for neonates >/=10 days. Values for central volume (1.32 litre), peripheral volume 1 (15.4 litre), and peripheral volume 2 (1.29 litre) were not significantly influenced by any of the covariates (P>0.001)., Conclusions: PMA and PNA contribute to the inter-individual variability of propofol clearance with very fast maturation of clearance in neonatal life. This implicates that preterm neonates and neonates in the first week of postnatal life are at an increased risk for accumulation during either intermittent bolus or continuous administration of propofol.

As migraine is associated with an increased risk for ischaemic stroke and peripheral vasospastic disorders, it was hypothesized that interictal vascular changes may be present in migraine patients. Using ultrasound and applanation tonometry, the cardiovascular properties of migraine patients were compared with those of matched control subjects. Vascular parameters of the carotid arteries, cardiac output and systemic vascular resistance did not differ between both groups. Right temporal artery diameter was larger in migraine patients (mean difference 101 micro m; 95% confidence interval (CI) 9/194 micro m; P = 0.033). At the brachial artery, migraine patients displayed a smaller distension (difference -24 micro m; 95% CI -45/-4 micro m; P = 0.021) and a decreased compliance (difference -0.025 mm2/kPa; 95% CI -0.047/-0.003 mm2/kPa; P = 0.024). Thus, migraine patients display an increased peripheral arterial stiffness. The presence of these interictal vascular changes suggests that migraine might be part of a more generalized vascular disorder.

Objective: To compare the sensitivity of three non-invasive techniques for detecting serotonin (5-HT)(1B/1D)-receptor agonist-induced peripheral vascular effects in humans: the measurement of (1) systolic (SBP) and diastolic (DBP) blood pressures, (2) dorsal hand vein (DHV) diameter and (3) toe-arm systolic blood pressure gradient (DeltaSBP(toe-arm))., Methods: A double-blind, placebo-controlled, three-way, cross-over study was performed in 12 healthy male volunteers. According to a randomly assigned allocation schedule, subjects were administered sumatriptan 3 mg, sumatriptan 6 mg or placebo subcutaneously. Measurements were performed at baseline, every 5 min for 30 min and at 40 min and 60 min after drug administration. SBP and DBP were recorded using a semi-automated oscillometric device. DHV diameter was measured using a linear variable differential transformer. DeltaSBP(toe-arm) was calculated after measuring toe and arm SBP with a strain-gauge technique. Sensitivity was evaluated with responsiveness statistics., Results: Based on weighted mean and compared with placebo, sumatriptan 3 mg and 6 mg increased SBP by 3.3 mmHg ( P=0.023) and 6.4 mmHg ( P<0.001) and DBP by 5.0 mmHg ( P=0.006) and 7.5 mmHg ( P<0.001), respectively. Sumatriptan 3 mg and 6 mg decreased DHV diameter by 36% ( P=0.015) and 40% ( P=0.005), respectively. DeltaSBP(toe-arm) did not change. Peak changes were observed within 10-15 min after drug administration. The rank order of responsiveness was: BP > DHV diameter > DeltaSBP(toe-arm.), Conclusions: Clinically relevant doses of subcutaneous sumatriptan increased blood pressure and decreased DHV diameter without affecting DeltaSBP(toe-arm). The increase in blood pressure appeared to be dose dependent. Compared with DHV diameter and DeltaSBP(toe-arm), blood pressure measurement appeared to be the most sensitive technique for detecting selective 5-HT(1B/1D)-receptor agonist-induced peripheral vascular effects in humans.

Objectives: Second-generation triptans are believed to have fewer cardiovascular effects than sumatriptan. This was investigated in vivo by comparing the vascular effects of equipotent therapeutic dosages of selective 5-HT1B/1D-receptor agonists., Methods: Sixteen patients with migraine headaches completed a double-blind, placebo-controlled, four-way crossover study. With ultrasonography and applanation tonometry used 1.5 hours after the oral intake of sumatriptan (50 mg), rizatriptan (10 mg), zolmitriptan (2.5 mg), or placebo arterial vessel wall properties, blood flow and pressure waveforms were measured in common carotid, brachial, and temporal arteries. At the brachial artery, flow-induced vasodilation (an endothelium-dependent process) was evaluated, and blood pressures were recorded., Results: Mean arterial pressure, 91 +/- 2 mm Hg after placebo, increased (P < .05) by 4% to 6% after administration of each triptan. Each active treatment decreased (P < .001) both brachial and carotid artery diameter. Isobaric compliance of the brachial artery, 0.077 +/- 0.010 mm2/kPa after placebo, decreased (P < .01) by 11% +/- 8%, 11% +/- 11%, and 23% +/- 7% after administration of sumatriptan, rizatriptan, and zolmitriptan, respectively. Isobaric compliance of the carotid artery was 1.31 +/- 0.10 mm2/kPa after placebo (no change). Zolmitriptan was the only triptan that decreased temporal artery diameter significantly (by 12% +/- 3%, P < .001). The resistance of the temporal artery vascular bed increased after administration of sumatriptan (by 26% +/- 11%, P < .05) and zolmitriptan (by 40% +/- 9%, P = .001). Flow-induced vasodilation was unaffected., Conclusions: Selective 5-HT1B/1D-receptor agonists induce vasoconstriction and decrease compliance of conduit arteries. These effects are more pronounced at muscular (temporal, brachial) compared with elastic (carotid) arteries. Resistance is only increased at the temporal artery vascular bed, suggesting cranioselectivity for resistance vessels. Endothelial function is not differently affected by any of the triptans tested.

Quality of life with the selective beta1-blocker bisoprolol and the calcium channel blocker nifedipine as a retard formulation was compared in patients with essential hypertension. A multicenter randomized, double-blind, two-way, crossover study design was used. After a placebo run-in period (4-6 weeks), during which all antihypertensive therapy was withdrawn, 82 patients were randomized. During the active treatment periods (8 weeks each), patients received either bisoprolol once daily or nifedipine retard twice daily, using the double-dummy technique. A washout period (4-6 weeks) separated the treatment periods. Data at baseline (at randomization) and at the end of each treatment period were compared. Seventy-five patients completed the study. Blood pressure (168 +/- 2/103 +/- 1 mmHg) decreased (p < 0.001) similarly with bisoprolol (153 +/- 2/90 +/- 1 mmHg) and nifedipine (154 +/- 2/90 +/- 1 mmHg). Compared with baseline values, none of the quality of life variables investigated changed during bisoprolol or nifedipine retard use. Neither in the intention-to-treat nor the efficacy analysis were differences between bisoprolol and nifedipine found in quality of life variables, such as the Health Status Index, somatic symptoms, anxiety, depression, total psychiatric morbidity, cognitive symptoms, and hostility score. Only in the efficacy analysis did Health Status Index tend to be better (p = 0.055) during nifedipine intake when compared with bisoprolol. This trend was not present in the intention-to-treat analysis. The number of dropouts during bisoprolol (n = 2) and nifedipine (n = 3) treatment, and the number of patients reporting side effects (21% and 16%, respectively) did not differ (p = 0.64) between both treatments. It can be concluded that at equipotent antihypertensive dosages, an 8-week treatment period with the selective beta1-blocker bisoprolol or the calcium antagonist nifedipine as a retard formulation does not result in any difference in quality of life variables. It is not clear whether the trend of Health Status Index to become better during nifedipine intake, which was only found in the efficacy analysis and not in the intention-to-treat analysis, is of clinical relevance.

The records of patients in whom Pneumocystis carinii pneumonia (PCP) was diagnosed between January 1989 and December 1991 were reviewed. Thirty-two patients--all immunocompromised--were included in the study: 41% were HIV-positive and 59% HIV-negative. In 23 patients (72%) concomitant pathogens were isolated, most frequently Cytomegalovirus. Presenting symptoms included fever (97%), cough (75%) and dyspnea (63%). All HIV-infected patients had a T4-lymphocyte count below 200/mm3 (or 20%). The majority of patients (80%) treated with trimethoprim-sulfamethoxazole experienced adverse events which were usually well tolerated so that a therapy change was necessary in only 12% of patients. PCP was fatal in 34% of the patients. Respiratory failure requiring mechanical ventilation carries a poor prognosis. The ratio of non-AIDS/AIDS patients infected with PC is increasing. This increase is due to the growing contribution of patients treated with immunosuppressive agents and patients with disease-associated immunodeficiencies other than AIDS. Our study suggests that treatment of PCP is more successful with early diagnosis. In addition, as mortality rate is high in non-AIDS patients, our data suggest that the more frequent use of PCP prophylaxis in patients given immunosuppressive drugs, might reduce the incidence of PCP and PCP related mortality.

Objectives: The aims of the present study were to determine (1) the beta 1-blocking potency and (2) the beta 1-adrenoceptor selectivity of nebivolol in man after repeated dosing (7 days) compared with that after a single oral intake and with that after atenolol for 7 days. In addition, it was investigated whether (3) nebivolol has alpha 1-blocking properties which might at least in part explain the vasodilating property of the compound., Methods: Twelve healthy subjects were randomized in an open, two-way cross-over study. beta 1-Blocking potency and beta 1-adrenoceptor selectivity of nebivolol 5 mg once daily (o.d.) were compared with those of atenolol at three doses (25, 50 and 100 mg) o.d. Measurements were performed after 1 and 7 days of drug intake. beta 1-Adrenoceptor potency was assessed by the percentage decrease in exercise-induced tachycardia (delta EIT) during beta-blockade. beta 1-Selectivity of nebivolol and atenolol were investigated using the heart rate response to isoprenaline at equipotent beta 1-blocking dosages of both drugs. alpha 1-Blockade of nebivolol was measured using the phenylephrine dose-response test., Results: delta EIT after a single oral dose of nebivolol 5 mg (10%) was significantly smaller than after nebivolol 5 mg o.d. for 7 days (15%). After 1 week of treatment no difference was seen in delta EIT between nebivolol 5 mg o.d. and atenolol 25 mg o.d. (16%). At these dosages the suppression in isoprenaline-induced tachycardia by both drugs did not differ (CD20 ratio 1.7). In contrast to atenolol 25 mg, after 1 week of nebivolol 5 mg o.d., blood pressure decreased. This decrease averaged 10% and-like in a study with hypertensive patients-was similar with that after atenolol 100 mg o.d. None of the phenylephrine test parameters changed from pre-study values after nebivolol., Conclusions: beta 1-Blockade of nebivolol 5 mg is larger after repeated dosing than after a single oral intake. After once daily repeated dosing nebivolol 5 mg and atenolol 25 mg are equipotent in beta 1-antagonism. No difference in beta 1-selectivity is observed between the two drugs. Nebivolol has no additional alpha 1-blocking property, which may at least in part explain its vasodilating effect.