bluuebunny/crossref_metadata_2025 huggingface dataset:
Plasma concentrations and central nervous system effects of the new hypnotic agent zopiclone in patients with chronic liver disease.
Authors: Parker G , Roberts CJ
Published: July 2012

Eight healthy individuals and seven cirrhotic patients received 7.5 mg zopiclone orally. Two further cirrhotics received 3.75 mg. Plasma concentrations of zopiclone and psychometric tests including reaction time and critical flicker fusion threshold and electroencephalographic tracings were performed at regular intervals after drug administration. Peak plasma levels of zopiclone were similar in the two groups but the time to peak was delayed in the cirrhotics. Plasma zopiclone half‐life was 8.53 +/‐ 0.83 h in the cirrhotics and 3.50 +/‐ 0.33 h in the healthy individuals. In the group of cirrhotics there was a negative correlation between zopiclone half‐life and serum albumin concentration (r = ‐0.87). Zopiclone caused sedation in both groups. Reaction time was prolonged and critical flicker fusion threshold reduced in both groups. Recovery was delayed in the cirrhotics compared to the healthy subjects but was complete by 8 h. The size of the changes was somewhat greater in the cirrhotics but baseline observations differed between the groups. The mean dominant frequency was lower in the cirrhotics and fell slightly in that group after zopiclone administration. The response to zopiclone is delayed and exaggerated in cirrhosis. Precautions are therefore required when using this drug in patients with chronic liver disease.
Drug utilization studies: a tool for determining the effectiveness of drug use.
Authors: Laporte JR , Porta M , Capella D
Published: July 2012

To evaluate the quality of the consumption of medicines in Spain, its potential efficacy, and its evolution during the last years, an assessment of the ‘intrinsic value’ of the most sold pharmaceutical specialities (amounting to more than 50% of total pharmaceutical market) was carried out. A panel of five clinical pharmacologist classified medicines, according to their intrinsic value, in four groups: (i) ‘high value’ (41% of analyzed medicines in 1980); (ii) ‘relative value’ (12% in 1980); (iii) ‘doubtful value’ (3%); (iv) ‘no value’ (23%), and (v) ‘unacceptable value’ (21%). Drugs were also classified according to their expected potential of use; and three groups were formed: (i) ‘high’ (32%); (ii) ‘relatively high’ (14%), and (iii) ‘reduced’ (10%). A fourth group of ‘not applicable’ (44%) in this classification was formed with pharmaceuticals considered unvaluable or unacceptable in the first classification. The results of this study suggest that this kind of analysis may be a useful tool to evaluate the efficacy of drugs in the community, and to identify priorities and guidelines in the selection of drugs in each country.
Effect of treatment with chlorthalidone and atenolol on response to dilator agents in the forearm resistance vessels of men with primary hypertension.
Authors: Robinson BF , Dobbs RJ , Phillips RJ
Published: July 2012

The forearm resistance vessels of men with primary hypertension respond to verapamil with a greater than normal dilatation relative to that induced by sodium nitroprusside. We have examined the effect on this functional abnormality of treatment with chlorthalidone (50 mg daily in 16 patients) and atenolol (100 mg daily in eight patients and 200 mg daily in two). The responsiveness of the forearm resistance vessels to local intra‐arterial infusion of verapamil and sodium nitroprusside was assessed before treatment and again after a minimum of 1 month of drug therapy. Forearm blood flow was measured by venous occlusion plethysmography. Chlorthalidone induced significant reductions in calculated mean arterial pressure, which fell from 135 +/‐ 4 to 117 +/‐ 4 mm Hg, and the dilator response to verapamil at 5 micrograms/min, which was reduced from 2.4 +/‐ 0.2 to 1.5 +/‐ 0.2 ml min‐1 100 ml‐1 forearm; the response to sodium nitroprusside at 3.2 micrograms/min was not significantly changed. Atenolol induced significant reductions in mean arterial pressure, which fell from 134 +/‐ 6 to 123 +/‐ 6 mm Hg, heart rate which fell from 72 +/‐ 3 to 55 +/‐ 2 beats/min, and response to verapamil at 5 micrograms/min which fell from 2.7 +/‐ 0.2 to 2.1 +/‐ 0.2 ml min‐1 100 ml‐1 forearm; the response to sodium nitroprusside was not significantly changed. Both drugs caused reversion towards normal of the relative enhancement of responsiveness to verapamil that was present before treatment.(ABSTRACT TRUNCATED AT 250 WORDS)
The pharmacokinetics of frusemide are influenced by age.
Authors: Andreasen F , Hansen U , Husted SE , Jansen JA
Published: July 2012

After a 24 h control period 80 mg frusemide was given intravenously over 2 min to a group of young and a group of elderly healthy male volunteers. The serum concentration of frusemide and the excretion in urine of the drug and a glucuronidated metabolite were followed for 24 h. The elimination of the drug from serum was described by an open two compartment model. The serum clearance (CLs) was 170 +/‐ 19 ml min‐1 in the young and 129 +/‐ 11 ml min‐1 in the elderly (P less than 0.01) and the average renal clearance (CLr) was 67% of CLs in the young and 58% of CLs in the elderly (NS). The average amount of unchanged frusemide in the urine during the first 30 min was 30 +/‐ 6 mg in the young but only 20 +/‐ 4 mg in the elderly (P less than 0.01). The albumin concentration in serum was 15% lower in the elderly but on the average the protein bound fraction of frusemide was 98.6% in both groups. The Vd ss did not differ between the two age groups (0.130 1 kg‐1) but the elimination half‐life was 70 +/‐ 20 min in the young and 102 +/‐ 33 min in the elderly (P less than 0.05). In the young 11.4 +/‐ 5.0 mg frusemide was excreted as a glucuronidated compound whereas this figure was only 5.4 +/‐ 2.9 mg in the elderly (P less than 0.01). It is concluded that the age‐related changes in the fate of unchanged frusemide in the organism mainly can be explained by a reduction in the tubular secretion of the drug which in turn may be caused by a reduction in renal plasma flow.
Antihypertensive and renal haemodynamic effects of atenolol and nadolol in elderly hypertensive patients.
Authors: O'Callaghan WG , Laher MS , McGarry K , O'Brien E , O'Malley K
Published: July 2012

As little is known of the antihypertensive efficacy or renal haemodynamic effects of beta‐adrenoceptor blocking drugs in the elderly we studied two such drugs, atenolol and nadolol, in elderly hypertensive patients. Ten patients took part in a placebo‐controlled double‐blind study of atenolol and 10 received nadolol in a single‐ blind placebo‐controlled study. Treatment phases lasted 12 weeks for atenolol or 10 weeks for nadolol. Blood pressure, effective renal blood flow and glomerular filtration rate data obtained at the end of each treatment phase were analysed. Atenolol lowered mean arterial pressure (mean +/‐ s.e. mean) from 129.9 +/‐ 1.5 to 108.2 +/‐ 2.3 mm Hg (P less than 0.01) while it increased mean effective renal blood flow 512.5 +/‐ 86.6 to 646.0 +/‐ 116.1 ml min‐1 1.73 m‐2 (P less than 0.05). Nadolol reduced mean arterial pressure from 133.2 +/‐ 2.0 to 113.5 +/‐ 3 mm Hg (P less than 0.001) but reduced mean effective renal blood flow from 558.8 +/‐ 32.2 to 446.0 +/‐ 26.9 ml min‐1 1.73 m‐2 (P less than 0.05). Glomerular filtration did not alter significantly with either drug. We conclude that beta‐adrenoceptor blocking drugs are effective antihypertensive agents in the elderly but have disparate effects on effective renal blood flow perhaps because of differences in cardioselectivity. These data suggest that comparative studies with thiazide diuretics and beta‐adrenoceptor blocking drugs are warranted in elderly hypertensives.
Oxazepam pharmacokinetics in patients with epilepsy treated long‐term with phenytoin alone or in combination with phenobarbitone.
Authors: Scott AK , Khir AS , Steele WH , Hawksworth GM , Petrie JC
Published: July 2012

The pharmacokinetics and serum protein binding of oxazepam, a drug mainly eliminated by a single step glucuronidation reaction, were studied in nine epileptic patients treated long‐term with phenytoin or phenytoin with phenobarbitone, and in nine healthy control subjects. Oxazepam elimination half‐life was shorter and apparent oral clearance higher in treated patients than in age and sex matched control subjects. Serum bilirubin concentration was lower in treated patients. There was no significant correlation between serum bilirubin concentrations and oxazepam elimination. Serum alpha 1‐acid glycoprotein concentration was higher in the treated patients than in the control group. Oxazepam was more than 93% bound to serum proteins, but the extent of binding was not significantly different between the two groups. These results show that oxazepam glucuronyl transferase activity is increased by treatment with phenytoin alone or in combination with phenobarbitone in epileptic patients.
Plasma digoxin: assay anomalies in Fab‐treated patients.
Authors: Gibb I , Adams PC , Parnham AJ , Jennings K
Published: July 2012

Using a variety of radioimmunoassay methods, plasma digoxin concentrations were measured in two patients before and after the administration of ovine Fab antibody fragments to remove the effects of digoxin. Gross method‐dependent anomalies in the results due to in vitro drug interaction were observed. More widespread use of immunotherapy may invalidate data obtained by direct immunoassay techniques.
Prolactin secretion in man: a useful tool to evaluate the activity of drugs on central 5‐hydroxytryptaminergic neurones. Studies with fenfluramine.
Authors: Quattrone A , Tedeschi G , Aguglia U , Scopacasa F , Direnzo GF , Annunziato L
Published: July 2012

Acute oral administration of various doses of fenfluramine, a 5‐HT releaser, induced a dose‐related increase of PRL secretion in nine healthy volunteers. Fenfluramine reached the maximum effect on PRL secretion at 4 h after its administration. This effect was already significant at 2 h and lasted till 8 h. Metergoline, a 5‐HT receptor blocker, when administered alone, decreased serum PRL levels in six healthy subjects. The pretreatment with this drug significantly antagonized the PRL‐releasing action of fenfluramine (60 mg) suggesting that the effect of fenfluramine on PRL release may be mediated through a 5‐HT mechanism in the brain. These findings suggest the possibility that serum PRL levels in humans may represent a useful tool to evaluate, in vivo, the activity of drugs possessing putative 5‐ hydroxytryptaminergic properties.
The analgesic effect of the GABA‐agonist THIP in patients with chronic pain of malignant origin. A phase‐1‐2 study.
Authors: Kjaer M , Nielsen H
Published: July 2012

Fourteen patients with chronic pain of malignant origin were treated with escalating doses of THIP intramuscularly 5‐30 mg in an open phase 1 study. Analgesic activity was demonstrated in 60% of the patients at the level of 20 mg THIP and a dose response relation was present. Side effects, sedation, dizziness, euphoria, nausea, and blurred vision were present in up to 80% of the patients and were dose limiting. The maximum serum concentration was reached within 1 h after dosing in 87% of all administrations. Mean t1/2 was 1.52 +/‐ 0.63 h and the clearance was 0.49 +/‐ 0.181 min. Significant correlations were demonstrated between serum concentration, dose of THIP, analgesic effect and side effects. It is concluded that THIP cannot be used for the treatment of chronic cancer pain, not because of insufficient analgesic effect but because of unacceptable side effects.
Mitochondrial respiration inhibitors and human sperm motility: implication in the development of spermicides.
Authors: Hong CY , Chiang BN , Wei YH
Published: July 2012

Three inhibitors of the mitochondrial respiratory chain, rotenone, antimycin A, potassium cyanide and the uncoupler of oxidative phosphorylation, 2,4‐dinitrophenol, were tested for their sperm immobilizing effects with a trans‐membrane migration method. None of these drugs inhibited human sperm motility at the concentrations of 10(‐ 6), 10(‐5), 10(‐4) and 10(‐3) M. The suggestion to develop spermicidal contraceptives from mitochondrial respiration inhibitors could not be substantiated; and the theory that motility inhibiting drugs act primarily on the sperm membrane was reconfirmed.
Phase 1 tolerability and antiamoebic activity studies with 1‐ methylsulphonyl‐3‐(1‐methyl‐5‐nitro‐2‐imidazolyl)‐2‐imidazolidinone (Go.10213): a new antiprotozoal agent.
Authors: Vaidya AB , Ray DK , Mankodi NA , Paul T , Sheth UK
Published: July 2012

Go.10213, a new nitroimidazole, was studied in 12 male volunteers for tolerability and in 20 patients with intestinal amoebiasis for antiamoebic activity. Go.10213 was well‐tolerated by volunteers up to a dose of 400 mg X 3. Patients also tolerated well the dose of 100‐150 mg X 3 for 7 days. In two patients, there were mild and transient side‐ effects like headache, dizziness, fatigue, etc. No neurological side‐ effects were observed. There were no significant changes in blood pressure, pulse rate and ECG. The organ function tests did not show any adverse effects of Go.10213 on bone‐marrow, kidney, liver, etc. Go.10213, at a dose of 150 mg X 3, showed potent antiamoebic activity in 10 patients with intestinal amoebiasis, as judged by the clinical relief, the eradication of the trophozoites and cysts of Entamoeba histolytica from stools and the healing of colonic ulcers. Go.10213, a novel nitroimidazole, may prove to be the most potent and safe agent against the protozoal infections, e.g. amoebiasis, giardiasis and trichomoniasis.
Haemodynamic dose‐response effects of i.v. penbutolol in angina pectoris.
Authors: Silke B , Verma SP , Hussain M , Nelson GI , Okoli RC , Taylor SH
Published: July 2012

The haemodynamic dose‐response effects of intravenous penbutolol, a newer beta‐adrenoceptor antagonist with intrinsic sympathomimetic activity but without cardioselectivity, were evaluated in 10 patients with angiographically documented coronary artery disease. Following four logarithmetically cumulative i.v. boluses (0.5‐4 mg dosage range) there was a log linear increase in plasma penbutolol concentration; the levels achieved (51 +/‐ 8 to 219 +/‐ 19 ng/ml) were in the therapeutic range (12 to 250 ng/ml). Penbutolol resulted in a linear decrease in heart rate (maximum delta HR ‐ 4 beats/min; P less than 0.01); there was a small increase in pulmonary artery occluded pressure which reached its maximum at the lower doses (maximum delta PAOP + 1 mm Hg; P less than 0.01). The resting cardiac output, blood pressure and calculated systemic vascular resistance were unchanged. During 4 min steady‐state supine bicycle exercise there was attenuation of exercise cardiac output (delta C.I. ‐ 0.6 1 min‐1 m‐2; P less than 0.01) and systolic pressor response (delta SBP ‐ 13 mm Hg; P less than 0.01) compared with control observations without change in other measured or derived variables. The haemodynamic profile of penbutolol compared favourably with other beta‐adrenoceptor antagonists previously evaluated under similar conditions in patients with ischaemic heart disease. Over the i.v. dose‐range evaluated penbutolol attenuated exercise‐induced angina with a relatively modest depression of cardiac performance; the small change induced in resting haemodynamic variables may, in part, have been contributed to by the intrinsic sympathomimetic activity of penbutolol.
Induction of propranolol metabolism by rifampicin.
Authors: Herman RJ , Nakamura K , Wilkinson GR , Wood AJ
Published: July 2012

The effect of rifampicin on the blood concentration‐time curve of propranolol at steady‐state following oral administration of 120 mg every 8 h was investigated in six normal, young, male subjects. After an initial 2 week dosing period, all individuals additionally received 600 mg rifampicin daily for 3 weeks followed by a 4 week period during which again only the propranolol was given. In four of the subjects the effects of 900 and 1200 mg rifampicin daily was also studied. Changes in disposition were assessed by estimation of propranolol's oral clearance and elimination half‐life during the dosage interval. Rifampicin (600 mg/day) caused a large increase in propranolol's oral clearance (35.7 +/‐ 16.3 vs 96.1 +/‐ 26.9 ml min‐1 kg‐1, mean +/‐ s.d.), but neither the elimination half‐life nor extent of plasma binding were affected. Increasing the daily dosage to 900 and 1200 mg did not cause any additional changes in oral clearance. Four weeks after discontinuing rifampicin, propranolol's oral clearance had essentially returned to its pre‐induction level. The oral clearance of propranolol was significantly smaller (89.5 +/‐ 14.4%) during the dosage interval immediately after administration of the last rifampicin dose than the value measured 24 h later. The findings are consistent with rifampicin causing induction of the drug metabolizing enzymes responsible for propranolol's biotransformation. The marked reduction in the steady‐state propranolol blood concentration that results from chronic rifampicin administration would be expected to result in a significant change in clinical effectiveness of the beta‐adrenoceptor blocker when the two drugs are used concurrently.
The action of salicylates on bile flow in man.
Authors: Cooper MJ , Williamson RC
Published: July 2012

Following oral administration of 1.5 g of sodium salicylate or acetylsalicylate to five patients with indwelling T‐tubes there was an approximately 50% increase in bile flow. The increase appeared to be in the bile‐acid independent fraction of canalicular flow and was not accompanied by a change in lithogenicity. Neither agent would be of use in the medical treatment of cholesterol gallstones.
The QT interval and cycle length: the influence of atropine, hyoscine and exercise.
Authors: Staniforth DH
Published: July 2012

Twenty‐seven healthy male subjects of mean age 24.3 +/‐ 4.0 years and mean weight 74.9 +/‐ 9.1 kg took part in an investigation to assess the most suitable correction for the QT interval as a function of cardiac cycle length. 547 sets of data points were generated. Atropine 0.6, 1.2 and 1.8 mg, and hyoscine 0.4 and 0.8 mg, and exercise on a bicycle ergometer at power levels of 50‐250 watts together with post‐exercise values were employed to obtain a range of heart rates. Simultaneous measurement of cardiac output and total peripheral resistance were made. It was found that the traditional square root formula gave an unsatisfactory correction for the QT for supine subjects following atropine and hyoscine. The formula K = QT/RRN was linearized and fitted to the data by the least squares method and gave a best fit correction with N = 0.35, which is close to the cube root correction of Fridericia (1920). Neither stroke volume nor total peripheral resistance were found to provide a further enhancement of the correction. The relationship between QT and cycle length following the exercise protocol was found to be best represented by Bazett's correction but the complex changes in the QT produced by exercise were noted. These findings support the suggestion that either the cube root correction or the best fit correction with N = 0.35 provides a better correction factor than the traditional square root correction for the QT interval in clinical pharmacology experiments for data generated in resting patients.
A method for predicting the phototoxicity of non‐steroidal anti‐ inflammatory drugs.
Authors: Diffey BL , Brown S
Published: July 2012

The photosensitisation potential of several non‐steroidal anti‐ inflammatory drugs (NSAIDs) has been investigated in vivo using an irradiation monochromator. Evidence of abnormal, immediate photosensitivity was obtained in 13 of the 38 patients taking one of four out of seven different NSAIDs. A simple mathematical model was developed to predict the likelihood of photosensitivity occurring with a given drug by considering the mass of drug normally ingested, the spectral absorption characteristics of the drug, and the quantity and spectral quality of the radiation (e.g. sunlight) to which the patient may be exposed.
Evidence for an effect of sodium cromoglycate on sensory nerves in man.
Authors: Collier JG , Fuller RW
Published: July 2012

Sodium cromoglycate was given by both intravenous injection and local intra‐arterial infusion to healthy volunteers. Intravenous injection of a dose of 4 mg in four subjects caused a statistically significant rise in blood pressure and pulse rate associated with a feeling of warmth in the perineum and blush areas of the face and chest. Brachial artery infusion of sodium cromoglycate at doses of 100‐1000 microgram/min caused a feeling of warmth in the limb during 26 out of 30 infusions and this sensation was subject to tachyphylaxis. During eight infusions in which there was a sensation of warmth there was no change in local blood flow as measured by strain‐gauge plethysmography. In a further six studies involving 12 infusions of sodium cromoglycate the feeling of warmth was not accompanied by a rise in local skin temperature. The results suggest that sodium cromoglycate may stimulate afferent nerves in man.
Atenolol elimination in the neonate.
Authors: Rubin PC , Butters L , Reynolds B , Evans J , Sumner D , Low RA , Reid JL
Published: July 2012

The elimination of the cardioselective beta‐adrenoceptor antagonist atenolol has been studied in 35 neonates by measuring drug concentration in cord blood and in blood obtained at 24 h by heel stab. Elimination rate was assessed by calculating the slopes of lines joining these two concentration points. The slopes had a mean of 0.043 h‐1 (equivalent to a half‐life of 16 h) and were normally distributed with 95% of values being in the range 0.02‐0.066. There was no relationship between slope and neonatal weight or skinfold thickness, but most babies were at term and the range of these indices was narrow. Babies who developed a bradycardia had cord atenolol concentrations and slopes which did not differ significantly from those in babies without bradycardia. We conclude that atenolol elimination in the neonate is reduced when compared to adults. This prolonged elimination is consistent with the physiological characteristics of this age group and with previous observations on drugs eliminated by renal excretion.
Cyclic interconversion of vitamin K1 and vitamin K1 2,3‐epoxide in man.
Authors: Bechtold H , Trenk D , Meinertz T , Rowland M , Jahnchen E
Published: July 2012

The disposition of a single intravenous bolus dose of 10 mg vitamin K1 and vitamin K1‐2,3‐epoxide were studied in two healthy subjects without and with 12 h pretreatment dose of phenprocoumon (0.4 mg/kg). For each compound administered alone the plasma concentration‐time profile was adequately fitted by a biexponential equation, with an average terminal half‐life of 2.0 and 1.15 h for the administered vitamin K and its 2,3‐ epoxide respectively. While vitamin K1 was measurable in plasma following administration of vitamin K1‐2,3‐epoxide, the epoxide was not detectable following administration of vitamin K1. Following pretreatment with phenprocoumon and after intravenous administration of vitamin K1, both the average half‐life and area under the plasma concentration‐time profile of vitamin K1 were marginally reduced to 1.5 h and 1.76 mg l‐1 h respectively, while the plasma concentration of vitamin K1‐2,3‐epoxide was readily measurable and its half‐life markedly prolonged to 14.7 h. Following pretreatment with phenprocoumon and after oral administration of vitamin K1‐2,3‐epoxide, no vitamin K1 was detectable in plasma and the half‐life of the epoxide was 13.8 h. Based on area considerations the data suggest that either phenprocoumon does more than just inhibit the reduction of vitamin K1‐2,3‐epoxide to vitamin K1, or that the simple model describing the interconversion between vitamin K1 and its epoxide is inadequate. The same conclusion is drawn from the analysis of comparable data in dogs, obtained by Carlisle & Blaschke (1981).
Low bioavailability of ergotamine tartrate after oral and rectal administration in migraine sufferers.
Authors: Ibraheem JJ , Paalzow L , Tfelt‐Hansen P
Published: July 2012

Fifteen migraine patients were administered 2 mg ergotamine tartrate in a partial cross‐over design as a single, oral tablet, rectal suppository and rectal solution. Eight of these patients were in a previous investigation given 0.5 mg ergotamine tartrate intravenously. The blood samples were taken up to 54 h after oral and suppository while it was followed for only 3 h after rectal solution. The chemical analysis was performed by applying h.p.l.c. method with a limit of sensitivity of 0.1 ng/ml ergotamine base in plasma. No ergotamine was detected in the blood samples after the oral route, whereas small and very variable quantities was found in blood after the rectal route. Regular calculation of bioavailability could therefore not be performed. An estimate of the maximal possible bioavailability was found to yield a mean value of 2% (tablets); 5% (suppositories) and 6% (rectal solution). Rectal solution elicited faster absorption and the extent of absorption was significantly higher (P less than 0.05) than for the suppository.
Plasma chloroquine and desethylchloroquine concentrations in children during and after chloroquine treatment for malaria.
Authors: Walker O , Dawodu AH , Adeyokunnu AA , Salako LA , Alvan G
Published: July 2012

Twelve children with acute falciparum malaria were treated with 25 mg/kg chloroquine orally in three divided doses at 24 h intervals. Concentrations of chloroquine and its metabolite, desethylchloroquine, were measured in plasma from the beginning of treatment for up to 7 days using a high pressure liquid chromatography (h.p.l.c.) technique. Chloroquine was detectable in plasma within 30 min of giving the drug. Peak level was reached in 1‐8 h after the first dose of 10 mg/kg and the peak concentrations ranged between 65 and 263 ng/ml. Chloroquine concentration declined slowly in plasma after stopping drug administration so that the concentration at the seventh day was 37.5% of the concentration on the third day. The apparent half‐life was 3‐4 days. Desethylchloroquine was detectable in plasma within 30 min of giving chloroquine and peak levels were reached in 2‐12 h. Peak concentration after the first dose of chloroquine ranged between 9 and 62 ng/ml. Desethylchloroquine was also slowly cleared from plasma and mean concentration at the end of 7 days was 49% of the mean concentration at the end of 3 days.
Release of LPL activity after intravenous injection of a low molecular weight heparin.
Authors: Etienne J , Millot F , Pieron R , Laruelle P
Published: July 2012

A low molecular weight heparin (MW 4000‐6000), PK 10169 (Pharmuka), with much reduced anticoagulant in vitro capacity, retains the properties of the standard heparin in releasing lipoprotein lipase and hepatic lipase activity after being injected intravenously.
Depression of theophylline elimination following BCG vaccination.
Authors: Gray JD , Renton KW , Hung OR
Published: July 2012

This study investigated the effects of BCG vaccination on the elimination of a single dose of theophylline in twelve healthy female volunteers. Two weeks following BCG vaccination the mean serum theophylline half‐life was increased significantly in subjects with a positive Mantoux test compared to the mean half‐life determined prior to vaccination. The mean volume of distribution for theophylline was unchanged following vaccination. In two subjects with negative Mantoux tests theophylline half‐life was unchanged after vaccination. It is therefore suggested that immunostimulation following BCG vaccination may impair the capacity of the liver to eliminate theophylline.
Kinetics of 5‐aminosalicylic acid after jejunal instillation in man.
Authors: Nielsen Haagen O , Bondesen S
Published: July 2012

The human pharmacokinetics of 5‐aminosalicylic acid (5‐ASA), the active moiety of salazosulphapyridine (SASP), is only known from studies in which rapid absorption has been deliberately avoided. The present investigation demonstrates that pure 5‐ASA is absorbed extremely quickly when given as an instillation in the proximal part of the small bowel, and acetylation follows immediately. The metabolite is excreted very rapidly by the liver in small amounts, while the major part is eliminated renally.
Effects of oral and intravenous midazolam, triazolam and flunitrazepam on the sleep‐wakefulness cycle of rabbits.
Authors: Scherschlicht R , Marias J
Published: July 2012

The effect of the new, short‐acting benzodiazepine, midazolam as well as that of triazolam and flunitrazepam on the sleep of rabbits was recorded for 6 h. Midazolam at 1 mg kg‐1 i.v. augmented both rapid eye movement sleep (REMS) and non‐REM sleep (NREMS) only in the first half of the observation period. At 10 mg kg‐1 i.v., NREMS was further increased in the first and, to a lesser degree, in the second 3‐h period, while REMS was suppressed. Both doses were less effective orally than intravenously. Qualitatively, the effect of triazolam 0.01 and 0.1 mg kg‐1 i.v. was very similar to that of the corresponding low and high intravenous doses of midazolam, except that the high dose of triazolam had a prolonged effect on total sleep time. Like midazolam, triazolam was substantially less effective orally than intravenously. Flunitrazepam at 0.1 and 1 mg kg‐1 i.v. produced almost the same effects as midazolam and triazolam at the respective low and high intravenous doses, but had a longer duration of action. In contrast to midazolam and triazolam, flunitrazepam was almost as active orally as intravenously.
Pharmacokinetics and bioavailability of midazolam in man.
Authors: Heizmann P , Eckert M , Ziegler WH
Published: July 2012

The pharmacokinetic behaviour and the bioavailability of midazolam were investigated in six volunteers after intravenous (0.15 mg/kg) and oral administration (10, 20 and 40 mg). Following rapid intravenous injection of midazolam, the plasma concentration of the substance decreased to approximately 10% within 2 h owing to a rapid rate of distribution. A two compartment model adequately described the kinetics of midazolam in plasma. The following average values were found: elimination half‐life, 2.3 h; total clearance, 323 ml/min, and apparent volume of distribution at steady‐state (VSS), 50.21. After oral administration, the drug is rapidly absorbed. Maximum plasma levels are reached within 30 min and the drug is rapidly eliminated from plasma with practically the same half‐life as determined after i.v. administration. The bioavailability after the ingestion of 10, 20 and 40 mg midazolam in the form of tablets ranged from 31 to 72%, due to the high liver extraction quota of midazolam.
Comparison of the effects of intravenously administered midazolam, triazolam and their hydroxy metabolites.
Authors: Ziegler WH , Schalch E , Leishman B , Eckert M
Published: July 2012

The aim of the study was to compare the pharmacological activity and clinical effect after i.v. administration of midazolam, triazolam and their hydroxy metabolites, and, secondly, to compare the clinical effects of midazolam and triazolam in doses yielding the same duration of action (15 mg and 0.25 mg, respectively). In a randomized, cross‐ over procedure, six healthy volunteers received one of the following in the morning at approximately weekly intervals: 15 mg midazolam; 9 mg alpha‐hydroxy midazolam; 1 mg triazolam; 1 mg alpha‐hydroxy triazolam; 1 mg 4‐hydroxy triazolam. Tests of drug effect (investigator's assessment, psychometric testing, and self‐rating by subjects) were carried out at different times in the 24‐h period following administration. Triazolam 0.25 mg was also studied in four of these six subjects to supplement the findings in the cross‐over study. Triazolam 1 mg was shown to have the strongest, most long‐lasting effect. Midazolam 15 mg had almost the same intensity of effect but this was shorter lasting, i.e. 5 h as against 10 h for 1 mg triazolam. The alpha‐ hydroxy metabolites had a duration of action about half that of the parent compounds and a less potent effect, and 4‐hydroxy triazolam was virtually devoid of effect. The lower 0.25‐mg dose of triazolam had about the same duration of action as 15 mg midazolam but did not achieve the same degree of maximum effect as measured by psychometric tests and self‐assessment by subjects. The findings of this study indicate that midazolam would be suitable for use in situations in which a brief but intense hypnotic sedative effect is desired.
Midazolam and oxazepam in the treatment of insomnia in hospitalized patients.
Authors: Gallais H , Casanova P , Fabregat H
Published: July 2012

Fifty‐nine hospitalized patients participated in a double‐blind study: 19 received 15 mg midazolam, 20 received 50 mg oxazepam, and 20 placebo. The three groups were comparable with regard to age, sex, height, weight, and degree and type of insomnia. The sleep‐onset latency was shorter with midazolam than with placebo or oxazepam (Mann‐ Whitney test, alpha less than 0.05). With regard to total sleep duration and the number of nocturnal awakenings, there was no difference between the midazolam and oxazepam groups, whereas there was a difference between these two groups and placebo. More subjects of the midazolam group felt calm and refreshed on awakening. Safety, assessed by clinical examination and laboratory tests, was excellent. This study confirms the usefulness of midazolam in treating ‘early’ insomnia, i.e. difficulty in falling asleep.
Chemical structure and biological activity of the diazepines.
Authors: Danneberg P , Weber KH
Published: July 2012

Since the introduction of chlordiazepoxide and diazepam many diazepines have been developed. Use of these drugs is increasing and considerable knowledge has accumulated about their mechanisms of action. The structural and pharmacological properties of these drugs are surveyed briefly.
Hypnotics and the control of breathing: a review.
Authors: Cohn MA
Published: July 2012

Hypnotics are central depressants. In sufficient doses, they suppress respiration, and so their effects on respiration are important considerations in their safety. The paper reviews mechanisms of respiratory control and methods of assessment, the effects of hypnotics on control of breathing and new methods of non‐invasive respiratory monitoring.
Quantitative pharmaco‐EEG and performance after administration of brotizolam to healthy volunteers.
Authors: Saletu B , Grunberger J , Linzmayer L
Published: July 2012

The activity of brotizolam (0.1, 0.3 and 0.5 mg) was studied in normal subjects using quantitative pharmaco‐EEG, psychometric and clinical evaluation. Power spectral density analysis showed no changes after placebo, while brotizolam increased beta‐activity, decreased alpha‐ activity and increased the average frequency (anxiolytic pharmaco‐EEG profile). In addition, 0.3 and 0.5 mg brotizolam augmented delta‐ activity indicating hypnotic activity. The highest dose (0.5 mg) of brotizolam decreased attention, concentration, psychomotor performance and affectivity, and increased reaction time. The lower doses of brotizolam also caused a decrease in attention and concentration, but tended to improve psychomotor performance, shorten reaction time, and did not influence mood or affectivity. Brotizolam (0.1 mg) is the minimal effective psychoactive dose with a tranquillizing effect, while 0.5 mg and to some extent 0.3 mg induce a sedative effect and may be regarded as hypnotic doses.
Effects of brotizolam, flurazepam and placebo upon nocturnal auditory arousal thresholds.
Authors: Hartse KM , Thornby JI , Karacan I , Williams RL
Published: July 2012

Auditory awakening thresholds (AAT) and the back‐to‐sleep latency (BSL) after nocturnal awakenings from Stage 2 sleep were studied in normal male subjects after placebo, brotizolam (0.25, 0.375 and 0.50 mg) and flurazepam (30 mg). AAT (dB) was measured in five trials spaced across the night in a ‘double awakening’ procedure with the second awakening in each trial made from Stage 2 sleep. Each drug condition was associated with elevated mean AAT across the five trials in comparison with placebo. In a trial‐by‐trial analysis only 0.50 mg brotizolam and 30 mg flurazepam were consistently higher in the first three trials compared with placebo. All active drug conditions decreased the mean BSL across all trials in comparison with placebo, but only 30 mg flurazepam and 0.50 mg brotizolam consistently shortened BSL in the first three trials. Brotizolam (0.50 mg) and 30 mg flurazepam are similar in their effects. The subjective improvement reported in insomniac subjects following hypnotic administration may be related to elevation in arousal thresholds and a quick return to sleep after nocturnal sleep disruption.
Effects of acute administration of brotizolam in subjects with disturbed sleep.
Authors: Roehrs T , Zorick F , Koshorek GL , Wittig R , Roth T
Published: July 2012

Effects of ingestion of brotizolam (0.25 and 0.50 mg) over 1‐3 days on polysomnographic measures of sleep were assessed in patients complaining of insomnia. Brotizolam reduced latency to sleep, number of awakenings and wake during sleep, and increased total sleep time. It also increased stage 2 sleep and decreased slow wave and rapid eye movement sleep. Increasing the dose from 0.25 to 0.50 mg increased hypnotic efficacy, and there was a more consistent and reliable effect. Discontinuation of brotizolam had minimal effects on sleep compared with placebo over the 3 nights after acute administration. No side‐ effects or disruption of daytime function was found using questionnaires and objective tests of performance.
Brotizolam as a pre‐operative hypnotic.
Authors: Ahmad F , Rittmeyer P , Goetzke E , Koster J
Published: July 2012

Efficacy of and tolerance to brotizolam when used as a preoperative hypnotic were studied in two double‐blind, randomised parallel group studies. Brotizolam (0.25 and 0.50 mg) was superior to placebo. Efficacy was assessed as good‐to‐satisfactory in 73.0% of patients with 0.25 mg and in 88.0% with 0.5 mg. A similar assessment was reached in 40.0% of patients with placebo. Brotizolam 0.5 mg was superior to 0.25 mg, and with the higher dose subjective assessments of anxiety were reduced. Efficacy of tolerance to 0.5 mg brotizolam and 2.0 mg flunitrazepam were compared, and both drugs were found to be effective and well tolerated. Brotizolam maintained sleep throughout the night more effectively than flunitrazepam. A dose range of 0.25‐0.5 mg brotizolam is recommended as a pre‐operative hypnotic.
Influence of brotizolam on the ventilatory and mouth‐occlusion pressure response to hypercapnia in patients with chronic obstructive pulmonary disease.
Authors: Sybrecht GW
Published: July 2012

Effect of 0.25 mg brotizolam on patients with chronic obstructive lung disease of moderate to severe degree was studied. There was no difference between the slopes of ventilation vs alveolar CO2 for brotizolam and placebo as compared with base line values. Mouth‐ occlusion pressures did not change under the influence of drug or placebo. Brotizolam (0.25 mg) is without adverse side‐effects on respiratory centre output or on mechanics of ventilation.
Ketanserin, a novel 5‐hydroxytryptamine antagonist: monotherapy in essential hypertension.
Authors: Hedner T. , Persson B. , Berglund G.
Published: July 2012

Blood pressure and heart rate, supine and standing, were studied in patients with essential hypertension during 8 weeks of oral therapy with two dosage schedules of ketanserin, 40 mg once and twice daily. Ketanserin caused significant reductions in both supine and standing blood pressure but no significant alterations in heart rate in both groups of patients. Measurements of blood pressure and heart rate over a 24 h period during steady state conditions revealed that maximal blood pressure reduction was correlated with time to peak plasma concentrations. Steady state plasma concentrations of ketanserin were significantly higher in the patients receiving 40 mg twice daily compared to 40 mg once daily. In the group with once daily treatment, tmax was 1.2 +/‐ 0.17 h, Css 13 +/‐ 4.3 ng/ml, Cmax 137 +/‐ 19.6 ng/ml and t1/2, z h. 9.6 +/‐ 1.27 h.
Hepatic enzyme induction and leucocyte delta‐aminolaevulinic acid synthase activity: studies with carbamazepine.
Authors: Rapeport WG , McInnes GT , Thompson GG , Forrest G. , Park BK , Brodie MJ
Published: July 2012

Antipyrine metabolism, daily urinary 6‐beta‐hydroxycortisol excretion, carbamazepine (CBZ) half‐lives and leucocyte delta‐aminolaevulinic acid synthase (ALA.S) activities were measured following 2 weeks' treatment with CBZ 400 mg and 600 mg once daily in eight healthy male volunteers. Dose‐dependent induction of antipyrine metabolism was demonstrated but cortisol hydroxylation appeared maximally induced by the 400 mg dose. CBZ half‐lives fell significantly in both studies (P less than 0.01 in each case) but a greater fall was seen with the higher dose (P less than 0.01). Plasma CBZ concentrations were higher following the eighth doses (P less than 0.01) in both studies. Leucocyte ALA.S activity increased by a mean of 657% following 1 week's treatment with 400 mg CBZ and 1145% on the 600 mg dose. In both studies ALA.S activities fell towards baseline during the second week of treatment. CBZ possesses potent dose‐dependent hetero‐ and auto‐inducing properties. Leucocyte ALA.S activity may represent a novel in vivo index of extrahepatic enzyme induction in man.
Clinical trials: proposal for an international coding system (ICS).
Authors: Bellamy N
Published: July 2012

The basic design, measurement and analytical components of clinical trials are frequently difficult to extract from published reports. Precedent indicates that this type of information is amenable to codification. An alphabetical international coding system (ICS) is proposed and its advantages discussed and illustrated.
Haemodynamics and plasma concentrations following sublingual GTN and intravenous, or inhaled, isosorbide dinitrate.
Authors: Culling W , Singh H , Bashir A , Griffiths BE , Dalal JJ , Sheridan DJ
Published: July 2012

We measured plasma nitrate levels and haemodynamics following sublingual glyceryl trinitrate (GTN) (0.5 mg), or isosorbide dinitrate (ISDN) administered intravenously (0.5 mg) or by inhalation (1.25 mg) in 23 patients undergoing cardiac catheterisation for investigation of chest pain. Peak levels were detected at 90 s and 5 min following intravenous and inhaled ISDN respectively and at 3 min following sublingual GTN. Intravenous and inhaled ISDN produced similar plasma levels at 30 s and both were significantly greater than following sublingual GTN. Plasma levels were maintained for longer following inhaled ISDN than intravenous ISDN or sublingual GTN. Haemodynamic responses were qualitatively similar following each treatment; reduction in pulmonary vascular resistance and pressure and left ventricular end diastolic pressure occurred in each group. Heart rate, cardiac output and LV dP/dt.P‐1 remained unchanged. Maximal haemodynamic responses were greater following ISDN than GTN, with little difference between the two preparations of ISDN. Haemodynamic responses were more sustained following inhaled ISDN than following sublingual GTN or intravenous ISDN, the latter two being similar in this respect. These findings suggest that inhaled ISDN may provide more rapid and sustained relief from angina than sublingual GTN.
Does the addition of ketotifen to non‐steroidal anti‐inflammatory drugs confer any additional benefit in rheumatoid arthritis?
Authors: Teh LG , Madhok R , Capell HA
Published: July 2012

Ketotifen (benzocycloheptathiophene) was evaluated in a double‐blind study of patients with active rheumatoid arthritis. Sixty patients were randomly allocated to receive active or matching placebo drug and reviewed 6 weekly for 24 weeks. Conventional NSAIDs were continued throughout. Disease activity was assessed clinically and biochemically at weeks 0, 12 and 24. Nineteen patients remained on active drug for 24 weeks and 11 on placebo. Significant improvement in articular index was seen in both groups but no objective improvement was noted in either group. No undue toxicity was encountered in either group. Use of a drug considered to have selective LTC4 and LTD4 antagonism in combination with conventional cyclo‐oxygenase inhibitors did not confer any additional benefit in rheumatoid arthritis.
Systemic absorption of ketoconazole from vaginal pessaries.
Authors: Ene MD , Williamson PJ , Daneshmend TK , Blatchford NR
Published: July 2012

Eight healthy female subjects were each given (a) ketoconazole 400 mg orally, (b) ketoconazole 400 mg as a single vaginal pessary, (c) ketoconazole 800 mg as two vaginal pessaries, and (d) ketoconazole 1200 mg as three vaginal pessaries. The area under the plasma concentration time curve (AUC) after the oral dose was 51.41 +/‐ 10.99 mg l‐1 h (mean +/‐ s.d.) and the half‐life of ketoconazole was 2.98 +/‐ 1.41 h. The AUCs after vaginal administration were 0.27 +/‐ 0.14, 0.52 +/‐ 0.25, and 0.43 +/‐ 0.22 mg‐1 l h following the 400, 800 and 1200 mg pessaries respectively. Systemic absorption of single doses of vaginally administered ketoconazole appears to be negligible in the absence of vaginal infection. There were no local or systemic side effects related to ketoconazole in these healthy volunteers.
Enalapril (MK421) and its lysine analogue (MK521): a comparison of acute and chronic effects on blood pressure, renin‐angiotensin system and sodium excretion in normal man.
Authors: Hodsman GP , Zabludowski JR , Zoccali C , Fraser R , Morton JJ , Murray GD , Robertson JI
Published: July 2012

The immediate and long‐term effects of enalapril (MK421) and its lysine analogue (MK521) in once‐daily dosage, were compared in a study of 12 normal subjects. Both compounds lowered blood pressure equally throughout 24 h without causing tachycardia. The biochemical changes with MK521 were more sustained than with MK421, but this did not affect the magnitude of blood pressure reduction. Twenty‐four hours after the previous dose, with both active drugs, plasma renin concentration was significantly higher on day 8 than on day 1, though angiotensin I did not increase in proportion; this probably reflects a fall in renin‐ substrate with prolonged converting enzyme inhibition. There was an early natriuresis with each compound but this effect was no longer apparent after 8 days of continuous therapy. Both MK421 and MK521 were well tolerated with no serious side effects.
Comparison of the effects of prizidilol and propranolol on renal haemodynamics at rest and during exercise.
Authors: Malini PL , Strocchi E , Ambrosioni E
Published: July 2012

Effective renal plasma flow and glomerular filtration rate were measured in 22 mild‐to‐moderate, uncomplicated, essential hypertensive patients during placebo and after 3 months of randomly assigned treatment either with prizidilol (n = 10) or propranolol (n = 12). Measurements were performed at rest and during cycloergometer exercise. For a comparable effect on blood pressure effective renal plasma flow was significantly increased at rest by prizidilol (+9%) and decreased by propranolol (‐13.6%); these patterns were maintained during exercise. Glomerular filtration rate was immodified after the treatment with both drugs. It is concluded that prizidilol is an effective hypotensive agent with no deleterious effects on renal haemodynamics.