bluuebunny/crossref_metadata_2025 huggingface dataset:
Kinetics of metoprine, a lipid‐soluble antifolate.
Authors: Jones BR , Gordon CS , Umans J , Reidenberg MM , Young CW
Published: July 2012

1 Using a dihydrofolate reductase inhibition assay, we have conducted either pharmacokinetic studies in six patients receiving metoprine. 2 The serum level v time‐curve for metoprine equivalents was irregular; first‐order elimination was not observed during the study period of 0‐ 120 h. A model‐independent analysis was therefore performed, employing the area under the curve during the first 120 h (AUC). 3 At an oral dose of 65 mg/m2 without leucovorin, a peak level of 0.6 microgram/ml and an AUC of 52 micrograms ml‐1 h produced significant leukopenia and thrombocytopenia. 4 At doses ranging from 100 mg/m2 to 175 mg/m2 orally, with leucovorin administration 40 mg/m2 intravenously at 24 and 96 h, haematologic toxicity was seen in only 1 patient who received 175 mg/m2. This patient also had the highest peak serum level (2.8 micrograms/ml) and AUC (228 micrograms ml‐1 h). 5 One partial response and one minor regression were observed in the studied patients; these two patients had the 175 mg/m2 dose, highest peak levels (2.4 and 2.8 micrograms/ml) and highest AUCs (197 and 228 micrograms ml‐1 h). The other patients had lower peak levels and AUCs and had neither therapeutic response nor hematologic toxicity. 6 The AUC and peak serum levels were linearly related to each other (P less than 0.001). 7 Total urinary excretion of dihydrofolate reductase inhibitors (as metoprine equivalents) in the first 120 h ranged from 5 to 17% of the administered dose.
The seed and the soil: effect of dosage, personality and starting state on the response to delta 9 tetrahydrocannabinol in man.
Authors: Ashton H , Golding J , Marsh VR , Millman JE , Thompson JW
Published: July 2012

1 The effects of two doses of delta 9THC (2.5 and 10 mg), delivered by paced smoking of herbal cigarettes, on CNV magnitude, subjective mood ratings and heart rate were studied in 20 subjects. 2 There were highly significant interactions between drug dosage and Extraversion and Neuroticism scores, so that the direction and degree of response to the different doses of delta 9THC depended on the personality characteristics of the subjects. 3 The effects of 9 mg delta 9THC and placebo, delivered in herbal cigarettes smoked naturally, on smoking behaviour, subjective mood ratings, measures of autonomic activity and auditory and visual cortical evoked responses were compared in 12 subjects. 4 Smoking behaviour, subjective ‘high’ rating and elevation of heart rates were the most significant discriminators between drug and placebo. The latency of some of the components of the visual evoked responses was also increased by delta 9THC. 5 There was a significant correlation between the effects of delta 9THC on skin conductance reactivity and the basal (pre‐drug) level, reactivity increasing after drug in subjects with low basal reactivity and decreasing in those with high basal levels. 6 Both experiments provided clear evidence of dose‐ dependent biphasic stimulant and depressant actions of delta 9THC on both subjective and objective measures, and these effects were influenced by the personality and the starting state of the subjects.
Quantitative comparison of aldosterone antagonists in normal human subjects: prediction of therapeutic potency.
Authors: McInnes GT , Harrison IR , Shelton JR , Perkins RM
Published: July 2012

1 The potency of single doses of the aldosterone antagonist SC8109 relative to spironolactone in reversing the urinary electrolyte effects of fludrocortisone was examined in a double‐blind, balanced, crossover study in six healthy volunteers. 2 For the urinary ratio log10 10Na/K, the relative potency of SC8109; spironolactone on a weight basis was 0.08:1 (95% confidence limits 0.04–0.13:1). 3 The potency of SC8109 relative to spironolactone for natriuresis and antikaliuresis was 0.10:1 and 0.05:1, respectively. 4 The results show excellent agreement with clinical experience where SC8109 was considered to have one tenth the potency of spironolactone. We suggest that the human bioassay employed in this study provides quantitative information which should be predictive of the therapeutic potency of aldosterone antagonists.
Sodium valproate and cognitive functioning in normal volunteers.
Authors: Thompson PJ , Trimble MR
Published: July 2012

1 The effects of sodium valproate on the performance of a series of psychological tests and mood was studied. 2 Ten healthy male volunteers received sodium valproate and placebo, each for a period of 2 weeks, in a double‐blind cross‐over design. Dosage of sodium valproate was increased to 800 mg/day in the first week and to 1 g/day in the second week of treatment. 3 Psychological testing took place on three occasions, before and on completion of each of the two treatment periods. 4 The few significant differences between drug and placebo conditions indicated impairment on sodium valproate. 5 The findings are discussed in relation to those from a similarly designed study of the anticonvulsant phenytoin. Implications for epilepsy are also considered.
Serum phenytoin concentration and clinical response in patients with epilepsy.
Authors: Gannaway DJ , Mawer GE
Published: July 2012

1 Patients with poorly controlled epilepsy were cautiously transferred from multiple drug therapy to treatment with phenytoin sodium alone. One patient suffered more severe seizures and the initial treatment was restarted. The remainder showed no deterioration. 2 The daily dose of phenytoin was then increased by a small increment at intervals of 2 or more months. The serum phenytoin concentration (total and free) was measured regularly and response was assessed by records of seizure frequency and tests of speech, handwriting, short‐term memory and coordination. 3 Patients (n = 11) with partial seizures showed no consistent improvement with increased phenytoin concentration within the range 15 mg/l (60 mumol/l) to the individual threshold for intoxication, greater than or equal to 35 mg/l (140 mumol/l). Patients (n = 4) with generalized seizures however were consistently improved at higher concentrations. 4 Tolerance to phenytoin varied, the threshold for symptomatic intoxication ranging from 35‐60 mg/l (140‐240 mumol/l) total and 2.7‐5.2 mg/l (10.8‐20.8 mumol/l) free. Ataxia was the commonest symptom and in some cases this was manifest by worsening of performance on the test of coordination (pursuit rotor). Even at lower phenytoin concentrations the patients performed less well on this test than control subjects. Other tests of performance showed no evidence of impairment at higher phenytoin concentrations. 5 The same daily dose of phenytoin tended to give higher serum drug concentrations after intoxication than before.
Pharmacokinetics of diazepam in epileptic patients and normal volunteers following intravenous administration.
Authors: Dhillon S , Richens A
Published: July 2012

1 The pharmacokinetics of diazepam following intravenous administration have been investigated in six normal volunteers and nine epileptic patients receiving chronic antiepileptic drug therapy. 2 After intravenous administration, serum diazepam levels declined biexponentially in all subjects. The elimination half‐life was significantly shorter and the plasma clearance significantly higher in the patients than in the normal volunteers. 3 Serum N‐desmethyldiazepam levels were higher and the time to peak serum concentration was earlier in the epileptic patients than in the controls. 4 It is suggested that the metabolism of diazepam is induced in patients treated with enzyme inducing antiepileptic drugs, although a protein binding interaction between valproic acid and diazepam may contribute to the higher plasma clearance in the epileptic patients taking sodium valproate.
Ethosuximide in human milk and in plasma of a mother and her nursed infant.
Authors: Rane A , Tunell R
Published: July 2012

1 The concentrations of ethosuximide were measured in the milk and in the plasma of a nursing mother and her infant during a period of 4.5 months after delivery. 2 The maternal and the infant's plasma concentrations rose after delivery. 3 The milk concentration ethosuximide was similar to that in maternal plasma on the third day after delivery. During the following 2 months the average milk/maternal plasma concentration ratio was 0.80. The rise in ethosuximide concentration in milk during the first month was steeper than that in infant's plasma, which may be due to an increase in the infant's clearance of the drug. 4 Even if the infant has subtherapeutic plasma concentrations it is recommended to control the levels in infants that are nursed by ethosuximide‐treated mothers when nursing has been established.
Indapamide and bendrofluazide: a comparison in the management of essential hypertension.
Authors: Bing RF , Russell GI , Swales JD , Thurston H
Published: July 2012

1 To compare the efficacy of indapamide with that of bendrofluazide a randomised trial was carried out in twenty patients with essential hypertension. 2 Indapamide (2.5 mg a day) and bendrofluazide (5 mg a day) produced a significant but equivalent fall in blood pressure. 3 Both drugs caused a reduction in body weight and serum potassium with a rise in plasma renin activity but there were no other major side effects. 4 In twelve patients treated with a combination of indapamide and bendrofluazide there was no additional fall in mean blood pressure or serum potassium compared to treatment with bendrofluazide or indapamide alone.
Pharmacokinetics, bioavailability and ECG response of verapamil in patients with liver cirrhosis.
Authors: Somogyi A , Albrecht M , Kliems G , Schafer K , Eichelbaum M
Published: July 2012

1 The pharmacokinetics, bioavailability and ECG response of verapamil was investigated in seven patients with liver cirrhosis and compared with six normal subjects, using stable labelled techniques whereby both the intravenous and oral dose are given simultaneously. 2 After intravenous administration, plasma concentrations were much higher in the patient group such that the total plasma clearance was reduced from a mean of 1258 ml/min in normals to 616 ml/min in the patient group (P less than 0.0025). The apparent volume of distribution nearly doubled (6.76 v 12.05 l/kg, P less than 0.025) and the terminal half‐life was prolonged four fold (3.7 v 14.2 h, P less than 0.001). 3 Given orally, the peak plasma concentration was higher and occurred earlier in the liver cirrhotic patients. The absolute bioavailability more than doubled (22.0% normals v 52.3% liver cirrhotics, P less than 0.001) and apparent oral clearance was reduced to only 20% of normal (6.38 v 1.30 l/min, P less than 0.001). 4 The delta P‐R interval in the patient group lagged behind the plasma concentration, in contrast to normal subjects. The maximum effect was much greater in the patients (15.4 v 41.6% increase, P less than 0.005) and persisted for a longer period of time. The slope of the plasma concentration‐response curve was the same as in normals after intravenous administration. Plasma protein binding remained unchanged. 5 It is recommended that in liver cirrhotic patients the intravenous dose of verapamil be halved and the oral dose decreased by a factor of five in order to prevent untoward effects. As well as a steady‐state plasma concentration will not be reached until approximately 2 days after the beginning of therapy.
Increased levels of 6‐oxo‐PGF1 alpha in human skin following ultraviolet B irradiation.
Authors: Black AK , Hensby CN , Greaves MW
Published: July 2012

1 Clinically normal human abdominal skin in 11 subjects, was irradiated with three times the minimal‐erythema dose of ultraviolet B (u.v. B) irradiation. 2 Erythema was assessed visually, and exudate was recovered by a suction bulla technique from normal skin, and from skin at 6, 24 and 48 h after irradiation. 3 Erythema was moderate at 6 h, but increased to a maximum at 24 h, which was maintained at 48 h. 4 6‐ oxo‐PGF1 alpha was markedly raised at 6 h, moderately raised at 24 h, but had returned to control levels at 48 h, when the erythema was still maximal. 5 Prostaglandin I2, the precursor of 6‐oxo‐PGF1 alpha and 6‐ oxo‐PGF1 alpha may, therefore, play a part in the early inflammatory process after u.v. B irradiation, but is unlikely to be responsible for the erythema still present at 48 h.
Differential effects of enzyme induction on antipyrine metabolite formation.
Authors: Danhof M , Verbeek RM , Van Boxtel CJ , Boeijinga JK , Breimer DD
Published: July 2012

1 The influence of enzyme induction with antipyrine and pentobarbitone was studied on the rates of formation of the major metabolites of antipyrine: 4‐hydroxyantipyrine, norantipyrine and 3‐hydroxymethyl‐ antipyrine + 3‐carboxy‐antipyrine. The inducing drugs were given to panels of healthy volunteers for 8 days and prior to and after this period antipyrine total elimination clearance was determined in plasma, whereas the partial clearances for production of the individual metabolites were assessed on the basis of urinary excretion data. 2 Antipyrine total clearance had significantly increased by 16% following treatment with antipyrine, which could almost entirely be attributed to a selective increase in the rate of production of norantipyrine. 3 With pentobarbitone total clearance of antipyrine had increased by 60%, which was associated with a significant increase in the clearance of production of all three metabolites. However, the increase in norantipyrine formation was significantly higher than the increase in 4‐ hydroxyantipyrine and 3‐hydroxymethyl‐antipyrine formation. 4 The most likely explanation for these differences in the degree of induction of the different metabolic routes of antipyrine, is that different enzymes are involved in the different routes. Apparently the enzyme involved in norantipyrine formation is most sensitive to induction by antipyrine and pentobarbitone. By measuring rates of antipyrine metabolite formation it may be possible to study the degree of selectivity of enzyme inducers on oxidative drug metabolism.
Effect of rifampicin on metoprolol and antipyrine kinetics.
Authors: Bennett PN , John VA , Whitmarsh VB
Published: July 2012

1 Effects of rifampicin on the pharmacokinetics of single oral doses of metoprolol and antipyrine are reported. 2 Rifampicin, administered daily for 15 days, reduced the area under the plasma concentration‐time curve (AUC) of metoprolol but the rate constant for elimination (beta) of metoprolol from plasma did not alter significantly. 3 Administration of rifampicin for 13 days reduced AUC and increased beta of antipyrine. Thirteen days after discontinuing rifampicin. AUC and beta of antipyrine remained significantly different from the initial values. 4 Some loss of beta‐adrenoceptor blockade should be anticipated if rifampicin is administered to patients who are receiving metoprolol.
Comparison of the pharmacodynamic and pharmacokinetic profiles of single and multiple doses of a commercial slow‐release metoprolol formulation with a new Oros delivery system.
Authors: Kendall MJ , Jack DB , Woods KL , Laugher SJ , Quarterman CP , John VA
Published: July 2012

1 A new osmotic pressure mediated delivery system for metoprolol (Lopresor Oros) has been evaluated by measuring the haemodynamic effects and pharmacokinetics after single and multiple oral dosing in young healthy volunteers. 2 Similar studies have been carried out in the same group using equivalent single and multiple oral doses of the commercial slow‐release preparation (Slow Lopresor). 3 The new osmotic delivery system produces a more uniform haemodynamic response: a plateau metoprolol concentration in plasma is reached about 6 h after dosing and is maintained for 10 h.
Clindamycin passage into human milk.
Authors: Steen B , Rane A
Published: July 2012

1 The clindamycin bioactivity was measured during the dosage interval in the plasma of women with puerperal infections and in their breast milk. 2 There was a marked interindividual variation in the peak levels. The clindamycin bioactivity in the milk ranged from 1/10 to several times the corresponding bioactivity in the plasma that was collected at the same time. 3 The concentration of clindamycin in the milk (bioactivity) at the end of the dosage interval correlated with the area under the plasma concentration v time curve. 4 Clindamycin is thus transferred into human breast milk. Although the actual amounts secreted are small, the wellknown side effects and the lack of knowledge about the disposition and effects of clindamycin in newborn infants are strong arguments against nursing during treatment with this drug.
Sublingual buprenorphine used postoperatively: ten hour plasma drug concentration analysis.
Authors: Bullingham RE , McQuay HJ , Porter EJ , Allen MC , Moore RA
Published: July 2012

1 A 10 h study of plasma drug concentrations of the opiate buprenorphine after use was designed because a previous 3 h study had shown that peak plasma drug concentrations in some patients had not occurred by 3 h after the sublingual dose. 2 Fifteen postoperative patients were studied: at 3 h after a 0.3 mg intravenous dose five patients received a sublingual preparation of 0.4 mg of buprenorphine, five 0.8 mg of buprenorphine and five placebo. Plasma drug concentrations of buprenorphine were measured by specific radioimmuno‐ assay. 3 Plasma drug concentrations after sublingual buprenorphine were significantly higher than those in the placebo group by 1 h. They remained significantly higher over the succeeding nine hours. The mean time to peak plasma drug concentration was about 200 min in both the 0.4 mg and 0.8 mg groups (range 90‐360 min). The plasma drug concentrations in the 0.8 mg group were approximately twice those in the 0.4 mg group; the ratio of the relative systemic availabilities was similarly 1.8:1. The absolute systemic availability was estimated at about 55% for both groups. Uptake of buprenorphine from the sublingual site was essentially complete by 5 h after the dose was given. 4 The implications for the timing of sublingual doses in clinical use are discussed.
Effect of long‐term cimetidine treatment on left ventricular function in haemodialysis patients with active hyperparathyroidism.
Authors: Lai KN , Fassett RG , Mathew TH
Published: July 2012

1 The effect of long‐term oral cimetidine on left ventricular function was evaluated in chronic haemodialysis patients with active hyperparathyroidism. 2 Radionuclide ventriculography (seven patients) and echocardiography (five patients) revealed a significant increase in ejection fraction and mean velocity of circumferential fibre shortening six months after treatment. 3 The improved cardiac performance was associated with improvement of bone histology. C‐terminal parathyroid hormone, serum calcium, and mean arterial pressure changed little after treatment. 4 The improved cardiac performance is thought to be related to the suppression of uraemic hyperparathyroidism by cimetidine. 5 The present study suggests that uraemic hyperparathyroidism may play an important role in “uraemic cardiomyopathy”.
The effect of the beta‐adrenoceptor antagonist pindolol on exercise performance.
Authors: Dhatariya RC , Blowers AJ
Published: July 2012

1 Fifty‐two patients who had been treated for essential hypertension for at least 5 years with once‐a‐day pindolol alone or in combination with a diuretic participated in a strenuous exercise programme. The 24 h antihypertensive efficacy of once‐a‐day pindolol was shown in blood pressure readings made before the intake of the day's dose. 2 During the first stage of the study before interruption of therapy, pindolol maintained effective blood pressure control and prevented an excessive rise in blood pressure and heart rate following strenuous exercise. 3 Following a 6 week period of interruption of pindolol therapy, higher blood pressure and heart rate levels were reached following exercise. 4 After reintroduction of a single dose of pindolol, improvement in blood pressure control and lower heart rate levels were again seen following exercise. 5 Compared with the period without drug systolic and diastolic blood pressures were lowered to about the same extent at rest and during exercise after maintenance pindolol and after a single dose of pindolol following a 6 week interruption period, but pre‐exercise levels rose considerably during the period when therapy was discontinued.
Bioavailability of dihydroergotamine in man.
Authors: Little PJ , Jennings GL , Skews H , Bobik A
Published: July 2012

1 The pharmacokinetics of dihydroergotamine (DHE) in plasma were examined in six normotensive subjects after single acute doses of dihydroergotamine, 10 micrograms/kg i.v. and 10, 20 and 30 mg orally. 2 The mean apparent half‐time of elimination was 2.37 +/‐ 0.29 h and plasma clearance of dHE was 1002 +/‐ 169 ml/min. 3 Mean apparent absorption of DHE determined from the 10 mg dose was 26.6 +/‐ 10% and ranged from 8.9 to 60.3%. The oral bioavailability after the 10, 20 and 30 mg doses averaged 0.47 +/‐ 0.07%, 0.59 +/‐ 0.13% and 0.52 +/‐ 0.14% respectively. Inter‐patient variability in bioavailability was 6‐fold. 4 The results indicate that pre‐systemic 'first‐pass' extraction of DHE is the main determinant of its oral bioavailability. Oral doses of the drug up to 30 mg do not saturate this extraction process resulting in apparently linear kinetics for the drug.
Efficacy and pharmacokinetics of aspirin in post‐operative dental pain.
Authors: Seymour RA , Rawlins MD
Published: July 2012

1 Soluble aspirin, 600 mg and 1200 mg, and placebo were compared in a double‐blind, cross‐over study in 12 patients with post‐operative pain following removal of impacted lower third molars. 2 Significant analgesia after 600 mg aspirin occurred only at 45 min after administration, whereas significant analgesia after 1200 mg aspirin occurred from 45 to 240 min. The 1200 mg dose produced greater analgesia than the 600 mg dose and is to be recommended in clinical practice. 3 Plasma concentrations of salicylate and acetylsalicylate were measured after both doses. A significant correlation (rs = 0.876, P less than 0.01) was observed between analgesia and plasma salicylate concentration after 1200 mg aspirin.
Comparison between atenolol and nadolol in essential hypertension at rest and on exercise.
Authors: Wilcox RG , Hampton JR
Published: July 2012

1 The effects of 4 week treatment periods of once‐daily atenolol 100 mg, nadolol 80 mg, nadolol 160 mg and placebo on resting and exercise heart rate and blood pressure were compared in a single‐blind crossover trial in fifteen patients with essential hypertension. 2 Both atenolol and nadolol, irrespective of dose, reduced resting and exercise blood pressures to the same extent. 3 Nadolol caused a greater bradycardia both at rest and during exercise than did atenolol, thereby effecting a greater reduction in double‐product. 4 During progressive treadmill exercise neither atenolol nor nadolol prevented a linear increase in heart rate and blood pressure which were parallel to, but at a lower level than, that produced by placebo. 5 In each individual patient the magnitude of the hypotensive effect produced by one drug was similar to that produced by the other. 6 All the treatment periods resulted in the same linear increase in the patients' perceived exertion scores during exercise despite marked differences in haemodynamic responses evoked by the beta‐adrenoceptor blockers compared with placebo. 7 Neither atenolol or nadolol produced any significant change in peak expiratory flow rate compared with placebo.
Captopril treatment: inter‐dose variations in renin, angiotensins I and II, aldosterone and blood pressure.
Authors: Atkinson AB , Cumming AM , Brown JJ , Fraser R , Leckie B , Lever AF , Morton JJ , Robertson JI
Published: July 2012

1 The ability of captopril, 150 mg three times daily by mouth, to effect sustained reduction in plasma angiotensin II, with converse increases in circulating angiotensin I, and in active, inactive and total renin concentrations, has been assessed. 2 During prolonged treatment with captopril alone, and 12 h after the last dose of the drug, plasma angiotensin II remained approximately one‐sixth of basal concentrations, while angiotensin I and renin concentrations were proportionately increased. However, further increases in angiotensin I, and in active, inactive and total renin concentrations, were seen 2 and 6 h after the morning dose of 150 mg captopril. 3 Inter‐dose variations in plasma aldosterone and blood pressure were not closely related to concurrent variations in the renin‐angiotensin system. 4 Arguments are presented for relying on measurements of plasma renin and angiotensin concentrations rather than of renin activity or aldosterone in assessing the effectiveness of converting enzyme inhibition.
The use of labetalol in Japan: results of multicentre clinical trials.
Authors: Takeda T , Kaneko Y , Omae T , Yoshinaga K , Masuyama Y , Nukada T , Shigiya R
Published: July 2012

1 The anti‐hypertensive effects and safety of labetalol have been evaluated in multicentre clinical trials in Japan based on unified study protocols. The results of three studies are reported. 2 A total of 178 patients with essential hypertension were treated with labetalol for 12 weeks, 127 of them with labetalol alone (monotherapy) and the other 51 with labetalol plus diuretics (combined therapy). 3 Satisfactory antihypertensive effects were achieved in 76 of the 119 assessable patients in the monotherapy group and 25 of the 49 in the combined therapy group. The mean daily doses of labetalol were 329 mg in the monotherapy group and 374 mg in the combined therapy group. Seven patients (six in the monotherapy group; one in the combined therapy group) were withdrawn from the trials due to side‐effects. 4 Sixty‐one patients with hypertension were treated with labetalol alone or combined with diuretics for 6 months or longer. In most of these patients, good blood pressure control was achieved. No patients had to discontinue the treatment due to side‐effects. The mean daily doses of labetalol were stabilised in and after week 8 of the treatment at an average of 260 mg in the monotherapy and 450 mg in the combined therapy. Tolerance to the anti‐hypertensive effect did not develop. 5 Thirty patients with phaeochromocytoma were treated with labetalol and good blood pressure control was achieved in 21 of them. The effects of labetalol were better in patients with predominantly adrenaline‐ secreting tumours, and better in patients with sustained hypertensive type than in those with paroxysmal hypertensive type.
Beta‐adrenoceptor blockade and atrio‐ventricular conduction in dogs. Role of intrinsic sympathomimetic activity.
Authors: Giudicelli JF , Lhoste F
Published: July 2012

1 Atrio‐ventricular conduction and its modifications induced by six beta‐adrenoceptor blocking agents and isoprenaline have been investigated in the anaesthetized dog using the extrastimulus technique and measuring atrial (AERP), nodal (NERP), global (GERP) effective refractory periods as well as global functional refractory period (GFRP). 2 When beta‐adrenoceptor blockade was produced by (+/‐)‐ propranolol (beta 1 + beta 2‐adrenoceptor blockade) which is devoid of intrinsic sympathomimetic activity (ISA) but has membrane stabilizing effects (MSE), sotalol (beta 1 + beta 2‐adrenoceptor blockade, no ISA, no MSE) and atenolol (beta 1‐adrenoceptor blockade, no ISA, no MSE), all parameters were significantly increased. When beta‐adrenoceptor blockade was achieved with pindolol (beta 1 + beta 2‐adrenoceptor blockade) and practolol (beta 1‐adrenoceptor blockade) which have ISA but no MSE, all parameters remained unchanged, as was also the case with (+)‐propranolol, which has MSE but neither ISA nor beta‐ adrenolytic properties. 3 Isoprenaline at high doses significantly reduced the refractory periods but when infusion was stopped, marked but reversible conduction depression was observed. 4 It thus appears that beta‐adrenoceptor blockade but not MSE is responsible for the onset of atrial and AV‐conduction impairment and that ISA affords protection against this impairment.
The effect of intrinsic sympathomimetic activity of beta‐adrenoceptor blockers on circadian heart rate.
Authors: Fitscha P , Tiso B , Meisner W , Spitzer D
Published: July 2012

1 The effect of a beta‐adrenoceptor blocker without intrinsic sympathomimetic activity (propranolol) and a beta‐adrenoceptor blocker with ISA (pindolol) on circadian heart rate was studied in 10 patients (3 women and 7 men) with an average age of 55 years and the following diagnoses: coronary heart disease (n = 7) and hypertension (n = 3). The therapy was carried out in a randomized, cross‐over study, with 3 × 40 mg propranolol and 3 × 5 mg pindolol. 2 Propranolol lowered the averaged circadian heart rate significantly (P less than 0.001) from 78 to 68 beats/min. The rate decreased both during the day and at night and the reduction was greater the higher the control value. The minimal hourly heart rate also decreased significantly (P less than 0.005) from 65 to 69 beats/min. 3 After pindolol the averaged circadian heart rate was not markedly changed. It reached a stable rate of around 70 beats/min. At a heart rate of below 70 beats/min an increase in rate was observed, whereas above 70 beats/min a reduction was found. The mean heart rate during the day remained unchanged. There was a significant relationship between the level of the control heart rate and the decrease in rate (r = 0.85, P less than 0.005). 4 In a bicycle exercise test of 1 Watt/kg body weight over a period of 6 min, both beta‐adrenoceptor blockers lowered blood pressure and heart rate to the same extent.
Renal function during acute and long term pindolol treatment in hypertensive patients with normal and decreased glomerular filtration.
Authors: Rosenfeld J , Boner G , Wainer E
Published: July 2012

1 In an acute study in hypertensive patients with normal and decreased renal function the i.v. administration of pindolol (0.1 mg/kg) caused a decrease in inulin clearance and a concomitant but not significant decrease in PAH clearance with a constant filtration fraction. 2 The long‐term administration of pindolol (5–20 mg/day) to hypertensive patients with normal renal function was not associated with changes in renal function but in patients with a decreased renal function, pindolol caused an increase in PAH clearance but no change in inulin clearance.
Haemodynamic differences in untreated hypertension and hypertension treated with various beta‐adrenoceptor antagonists.
Authors: Weil C , Waite R
Published: July 2012

1 As a rule, hypertension progresses from an early stage with a high cardiac output (CO) and an inappropriately normal total peripheral resistance (TPR) to later stages with a normal or decreased CO and a high TPR. 2 Low CO and high TPR can be considered detrimental to the blood perfusion in the tissues and organs and thus to their functional and structural integrity. 3 Among beta‐adrenoceptor antagonists, some lower blood pressure by reducing CO, thus bringing about a reactive increase in TPR. The result is that, even though blood pressure is reduced, the haemodynamic conditions commanding regional blood flow are qualitatively similar to those in untreated hypertension. To what extent these circumstances may curtail the benefit expected from blood‐ pressure reduction deserves careful investigation. 4 Pindolol, a beta‐ adrenoceptor antagonist with an appropriate degree of intrinsic sympathomimetic activity (ISA), lowers blood pressure while lowering TPR and not unduly reducing cardiac performance. These features should on theoretical grounds lead to a greater improvement in the prognosis of hypertension.
Electrophysiological effects of cardioselective and non‐cardioselective beta‐adrenoceptor blockers with and without ISA at rest and during exercise.
Authors: Hombach V , Braun V , Hopp HW , Gil‐Sanchez D , Behrenbeck DW , Tauchert M , Hilger HH
Published: July 2012

1 In 46 patients (16 female and 30 male), aged between 18 and 73 years and effect of acute beta‐adrenoceptor blockade with i.v. pindolol, acebutolol and atenolol has been studied at rest and during ergometric exercise, during routine intracardiac His bundle investigations. 2 At rest the functional parameters of the sinus node were impaired most markedly by atenolol. A‐V nodal conduction was more depressed with acebutolol and atenolol than with pindolol. The His‐Purkinje system conduction remained unaffected by all three beta‐adrenoceptor blocking agents. 3 During ergometric exercise the depressant action of beta‐ adrenoceptor blockade on sinus nodal function with lower heart rates and on A‐V nodal conduction with slower conduction velocities was equieffective with pindolol, acebutolol and atenolol. His‐Purkinje system conduction again remained unchanged with one exception that after administration of pindolol, conduction rate during exercise was faster than before beta‐adrenoceptor blockade. 4 It may be concluded that, in patients with low heart rates, an antagonist such as pindolol with relatively pronounced intrinsic sympathomimetic activity can be considered to be the drug of choice. In contrast, patients with higher heart rates at rest should be treated with a cardioselective betablocker without ISA. Patients with overt Sick Sinus Syndrome should not be given beta‐adrenoceptor blockers at all. 5 Physical activity may change (improve or impair) the antiarrhythmic potency of beta‐ adrenoceptor blockers used in the treatment of supraventricular tachycardias or tachyarrhythmias.
The influence of beta‐adrenoceptor blockade on left ventricular function.
Authors: Hahn B , Strauer BE
Published: July 2012

1 This study was designed to compare in a randomized cross‐over trial pindolol, a beta‐adrenoceptor blocking agent with intrinsic sympathomimetic activity and metoprolol, a cardioselective beta‐ adrenoceptor blocker lacking sympathomimetic activity in hypertensives with incipient heart failure. Cardiac function was investigated by M‐ Mode and 2D‐echo‐cardiography. 2 Both pindolol and metoprolol in equipotent doses lowered blood pressure to the same extent. 3 There was no difference in overall left ventricular function in ventricular geometry or in wall dynamics after either drug. 4 In comparison to metoprolol, pindolol produced less reduction in resting heart rate, cardiac index and ejection velocity reflecting the intrinsic sympathomimetic activity of the drug.
Comparison of withdrawal phenomena after propranolol, metoprolol and pindolol.
Authors: Rangno RE , Langlois S
Published: July 2012

1 After abrupt propranolol withdrawal a rebound increase in cardiac sensitivity to isoprenaline occurred in 9/9 patients and persisted up to 14 days. A mild brief rebound in resting heart rate occurred in 4/9 patients and a rebound in blood pressure occurred in 6/9 patients. These withdrawal phenomena were prevented by gradual withdrawal on a prolonged small dose of propranolol. 2 After abrupt metoprolol withdrawal a rebound increase in cardiac sensitivity to isoprenaline occurred in 8/8 patients but had resolved by 8 days. A marked persistent rebound in resting heart rate occurred in 8/8 patients while a small brief rebound in blood pressure occurred in only one patient. These withdrawal phenomena were largely prevented by gradual withdrawal on a prolonged small dose of metoprolol. 3 After abrupt pindolol withdrawal there was no rebound in isoprenaline sensitivity but a mild brief rebound in resting heart rate occurred in 9/10 patients. There was no rebound in blood pressure. 4 The type, magnitude and frequency of withdrawal phenomena after various beta‐adrenergic receptor blockers probably reflects substantial differences in their basic pharmacological characteristics. 5 Caution must be exercised when withdrawing any patient from any beta‐adrenoceptor blocker since an adverse cardiac event is unpredictable.
Influence of lipid solubility on the sperm immobilizing effect of beta‐ adrenoceptor blocking drugs.
Authors: Hong CY , Turner P
Published: July 2012

1 Sperm immobilizing effects of five beta‐adrenoceptor blockers were measured on six human semen samples with a trans‐membrane migration method. 2 The concentrations which decreased sperm motility to 50% of control (ED50) were 0.8, 4.2, 6.2, 11.0 and 33.0 mM for propranolol, oxprenolol, metoprolol, acebutolol and sotalol respectively. 3 There was a linear correlation between the log values of ED50 and the log partition coefficients of these beta‐adrenoceptor blockers. 4 Because the lipid solubility determines the sperm immobilizing potencies of beta‐adrenoceptor blockers, we support the theory that beta‐ adrenoceptor blockers inhibit sperm motility by stabilizing the cellular membrane. 5 The clinical implication of this finding is that more lipid soluble drugs are likely to have more interference on sperm function, at least when they are used locally.
Potassium supplements during long‐term thiazide therapy for essential hypertension.
Authors: Wilkinson PR , Tait C , Hesp R , Raftery EB
Published: July 2012

Increasing doses of a slow‐release potassium supplement were given to nine hypertensive patients previously treated for at least 18 months with bendrofluazide 10 mg daily. Serum potassium and total body potassium (TBK) were measured after 2 months on each dose. No significant increase in serum potassium or TBK occurred over a 6 month period of supplementation using doses commonly prescribed in clinical practice.
Treatment of children with a single dose a day of sustained release theophylline.
Authors: Pedersen S
Published: July 2012

Six children were given a single dose of theophylline (Nuelin Retard) (median dose 13.2 mg/kg) after a large breakfast, rich in carbohydrates, for 4 days. On 5 serum levels of theophylline were measured over the following 24 h. Absorption of theophylline was slow and acceptable peak to trough differences were demonstrated. However subtherapeutic serum levels of theophylline were recorded in all children at some time during the dose interval.
Plasma protein binding of phenytoin in 100 epileptic patients.
Authors: Peterson GM , McLean S , Aldous S , Von Witt RJ , Millingen KS
Published: July 2012

The plasma protein binding of phenytoin was investigated in 100 epileptic patients, using equilibrium dialysis at 37 degrees C. The unbound fractions of phenytoin in plasma formed a skewed distribution, with a range of 9.7 to 24.7% and a median value of 12.3%. Most (80%) patients appeared to form one group with free phenytoin fractions from 9.7 to 14.5%, while the remainder formed a group with elevated free fractions (greater than 14.5%). Total and unbound plasma concentrations of phenytoin were strongly correlated (r=0.95, P less than 0.0001). There was a weak correlation between increasing age and the unbound phenytoin fraction (r=0.28, P less than 0.01). The results indicate that measurement of the total phenytoin concentration in plasma should usually provide a reliable index of anticonvulsant effect. However, determination of the unbound phenytoin fraction would be beneficial in the management of those patients in whom this fraction may be elevated, due to interacting drugs or biochemical abnormalities.
Bioavailability of labetalol increases with age.
Authors: Kelly JG , McGarry K , O'Malley K , O'Brien ET
Published: July 2012

The antihypertensive drug labetalol was administered orally and intravenously to ten hypertensive patients aged between 28 and 75 years. There was a significant increase with age in both bioavailability and half‐life of labetalol. Clearance tended to be lower in the elderly subjects. First pass metabolism results in variable oral bioavailability of labetalol which is greater in the elderly and this should be borne in mind when using the drug in this age group.
The influence of oral contraceptives on the metabolism of methaqualone in man.
Authors: Oram M , Wilson K , Burnett D
Published: July 2012

1 Oral contraceptives were shown to suppress the mid‐cycle increase in methaqualone metabolism observed in premenopausal women not receiving oral contraceptive therapy. No women were identified in whom this suppression was not observed. 2 Combined oestrogen‐progestogen contraceptives produced the effect in all nine women studied. The effect was also observed in one woman who was receiving progestogen‐ only contraceptives. 3 The effect of the combined contraceptives was observed within one month of the commencement of the contraceptive therapy. 4 The results emphasise the need to monitor the effect of the menstrual cycle in women not receiving oral contraceptive therapy when the effects of such therapy is studied. 5 These effects are more likely to be the consequence of an inhibition of hormonal control of hepatic metabolic activity by the synthetic steroids than they are to simple inhibition of hepatic metabolism.
Enalapril maleate and a lysine analogue (MK‐521): disposition in man.
Authors: Ulm EH , Hichens M , Gomez HJ , Till AE , Hand E , Vassil TC , Biollaz J , Brunner HR , Schelling JL
Published: July 2012

1 The disposition of two angiotensin converting‐enzyme inhibitor drugs was studied in normal volunteers. One drug was enalapril maleate (MK‐ 421), which requires in vivo esterolysis to yield active inhibitor (MK‐ 422). The other was a lysine analogue of MK‐422 (MK‐521), which requires no bioactivation. 2 Absorption of enalapril maleate (10 mg, p.o.) was rapid, with peak serum concentrations of enalapril observed 0.5‐1.5 h after administration. Based upon urinary recovery of total drug (enalapril plus MK‐422), absorption was at least 61%. Bioactivation appeared to be largely post‐absorptive. From the ratio of MK‐422 to total drug in urine, the minimum extent of bioactivation was estimated at 0.7. 3 A similar dose of MK‐521 was absorbed more slowly, reaching peak serum concentrations 6‐8 h following drug administration. Minimum absorption, based upon urinary recovery, was 29%. 4 Serum concentration v time profiles for both drugs were polyphasic and exhibited prolonged terminal phases. 5 Recovery in urine and faeces of administered enalapril maleate (intact and as MK‐422) was 94%. Recovery of MK‐521 was 97%. These results indicate lack of significant metabolism of these agents, apart from the bioactivation of enalapril.
Intra‐dose variation in plasma protein binding of sodium valproate in epileptic patients.
Authors: Marty JJ , Kilpatrick CJ , Moulds RF
Published: July 2012

1 The fluctuations in protein binding of sodium valproate during one dosing interval were studied in five patients stabilized on valproate and taking concurrent anticonvulsant therapy. 2 The patients took their usual morning dose of valproate (400‐800 mg) and serial blood samples were collected by venepuncture at 0, 1, 2, 3, 4, and 6 h post‐dose. 3 Free valproate was separated from protein bound drug by plasma ultrafiltration and the ultrafiltrate and total plasma valproate concentrations were measured by a gas chromatographic method. 4 The maximum and minimum concentrations in the ultrafiltrates occurred at the same times as in the plasma. However, the percentage fluctuation was always greater in the ultrafiltrates (range 192‐412%) compared with the plasma (range 153‐374%) due to the concentration‐dependent nature of valproate protein binding. 5 If free valproate levels are to be monitored, knowledge of sampling time and dosage history is important for interpretation of the results.
Interpretation of CO2 exhalation rate data from demethylation of aminopyrine and its metabolite monomethylaminoantipyrine.
Authors: Rhodes JC , Aarons LJ , Houston JB
Published: July 2012

1 Aminopyrine breath tests make use of the commercially available (N‐ dimethyl‐[14C])‐aminopyrine. A pharmacokinetic model has been proposed to relate 14CO2 exhalation rates (CER) to the demethylation of ([14C]‐ methyl)‐aminopyrine (AP) and ‐monomethylaminoantipyrine (MAP). 2 computer simulations based on the model show that the shape of the CER‐ time profile is largely dependent on the ratio of the MAP to AP elimination rate constants. If this ratio equals 0.5 then the CERs decline in the monoexponential fashion. Ratios less than 0.5 result in concave biexponential curves whereas ratios greater than 0.5 result in convex curves. When demethylation is not complete for both compounds the transfer from biexponential to monoexponential behaviour will only occur at ratios greater than 0.5. 3 The resolution of concave biexponential CER‐time profiles to give accurate estimates of AP and MAP elimination rate constants can only be achieved when the length of the experiment is adequate. The commonly employed 2 microCi tracer dose of aminopyrine is insufficient to monitor CER over the necessary time period to detect the proposed biexponential decline.
The pharmacokinetics and bioavailability of mebendazole in man: a pilot study using [3H]‐mebendazole.
Authors: Dawson M , Allan RJ , Watson TR
Published: July 2012

Following the intravenous administration of a tracer dose (1.7 microgram) of [3H]‐mebendazole to a man, an elimination half‐life of 1.16 h was observed and the volume of distribution was calculated to be 2.03 l/kg. After oral administration of the same dose, an elimination half‐life of 0.74 h was observed. The bioavailability of mebendazole from the solution was found to be 17%.
The effect of prolonged treatment with sulphinpyrazone on thromboxane A2 and prostacyclin in man.
Authors: Viinikka L , Toivanen J , Ylikorkala O
Published: July 2012

We studied the effect of 3 weeks' treatment with 4 x 200 mg of sulphinpyrazone daily (six healthy volunteers) on proaggregatory thromboxane A2 (TxA2) and antiaggregatory prostacyclin (PGI2). Platelet TxA2 production was evaluated by measuring its stable metabolite, immunoreactive thromboxane B2, from serum, and vessel wall PGI2 production by measuring its stable metabolite, immunoreactive 6‐keto‐ prostaglandin F1 alpha in plasma. The TxA2 production (initially 209.0 +/‐ 27.1 ng/ml, mean +/‐ s.e. mean) decreased to about 30% from the second day of the treatment onwards, and it recovered in three days after the discontinuation of the treatment. PGI2 (initially 33.6 +/‐ 3.6 pg/ml) did not change. The shift of the balance between TxA2 and PGI2 to the dominance of antiaggregatory PGI2 during sulphinpyrazone treatment may be involved with the efficacy of the drug in the secondary prevention of myocardial infarction.
Cimetidine does not alter morphine disposition in man.
Authors: Mojaverian P , Fedder IL , Vlasses PH , Rotmensch HH , Rocci ML , Swanson BN , Ferguson RK
Published: July 2012

1 The pharmacokinetic parameters of morphine were determined in a crossover fashion following 4 days pretreatment with cimetidine, 300 mg every 6 h, or placebo. 2 Cimetidine had no apparent effect on the mean morphine plasma clearance, volume of distribution, AUC or half‐life (P greater than 0.05; power greater than 0.80). 3 Cimetidine had no apparent effect on the magnitude or duration of morphine induced miosis. 4 The absence of a demonstrable effect on the pharmacokinetics of a drug with a high extraction ratio such as morphine suggests that cimetidine did not significantly reduce hepatic blood flow in ambulant normal volunteers.