bluuebunny/crossref_metadata_2025 huggingface dataset:
PHARMACOKINETICS OF VALPROIC ACID AFTER ORAL AND INTRAVENOUS ADMINISTRATION
Authors: PERUCCA E. , GATTI G. , FRIGO G.M. , CREMA A.
Published: July 2012

The kinetics of sodium valproate (di‐n‐propyl‐acetate, Depakine®) have been studied in six healthy volunteers after administration of single oral and intravenous doses (800 mg).

Kinetic parameters were similar for both routes of administration. In all subjects absorption was rapid and complete. Half‐lives ranged from 11–15 h. Apparent volumes of distribution were relatively low (0.147 ± 0.0041/kg) and showed little variation amongst individuals.

The factors responsible for the poor correlation between dosage and serum levels during chronic treatment and therapeutic implications are discussed.
DOUBLE‐BLIND EVALUATION OF THE SAFETY AND HYPNOTIC EFFICACY OF TEMAZEPAM IN INSOMNIAC OUTPATIENTS
Authors: HEFFRON W.A. , ROTH P.
Published: July 2012

Efficacy of temazepam 30 mg at night as an hypnotic was compared with placebo in 55 out‐patients with insomnia. The study was double blind, with two comparable groups of patients established by random allocation. Placebo and medication were taken for 4 consecutive nights and sleep questionnaires were completed the next day.

Patients reported that temazepam was more effective than placebo in reducing the difficulty of falling asleep and improving sleep maintenance. They also indicated that they awoke less and were less disturbed by early morning awakenings and reported as a group that the average duration of sleep was increased by 1 hour.

The patients receiving temazepam reported being more alert in the morning and for the entire day than with placebo.
Effects of benzodiazepines on psychomotor performance.
Authors: Wittenborn JR
Published: July 2012

1 The literature relating to the effects of benzodiazepines on psychomotor performance is critically reviewed. 2 The multiple and diverse psychomotor tests used are assessed according to their ability to demonstrate differences between drugs. 3 Three general conclusions are: (1) The speed with which simple acts of a repetitive nature are performed may be impaired by benzodiazepines. (2) learning and immediate memory will also be impaired. (3) there is relatively little indication that well established higher mental faculties are adversely involved.
Differential effects of the 1,4 and 1,5 benzodiazepines on performance in healthy man.
Authors: Nicholson AN
Published: July 2012

1 The immediate and residual effects on performance of benzodiazepines differ, and the differences are important in the use of these drugs. 2. Diazepam and its hydroxylated metabolites, temazepam and oxazepam, each possess hypnotic activity, and have effects on performance limited to the sleep period. The demethylated metabolite of diazepam, nordiazepam, and its precursor, potassium clorazepate, which also possess hypnotic activity, have a longer duration of action, although the next day anxiolytic effect is accompanied by only minimal effects on performance. The 1.5 benzodiazepine, clobazam, seems to have minimal immediate effects on performance. 3 Diazepam and its hydroxylated metabolites, temazepam and oxazepam, would be useful in the management of insomnia without psychopathology in those cases in which residual effects on performance must be avoided. Nordiazepam and potassium clorazepate would be appropriate for insomnia secondary to day‐time anxiety, and clobazam may be useful as a day‐time anxiolytic. 4 It is emphasized that more work needs to be carried out on the effects of anxiolytics on performance before one can be certain that ingestion during the day would be without any deleterious effects on skilled work.
Improved physical performance as a therapeutic objective in patients with angina.
Authors: Ling AS , Groel JT
Published: July 2012

1 Improvement in physical performance, based on exercise tolerance, self‐assessed work and physician‐rated functional capacities, is proposed as a measure of efficacy of anti‐anginal therapy in the rehabilitation of the cardiac patient. 2 Improved physical performance parallels changes in frequency of anginal attacks and a nitroglycerin requirements following beta‐blocker therapy. 3 Nadolol (a beta‐ blocker), given once daily is as effective as propranolol, given four times daily as an anti‐anginal agent.
Diuretics as initial treatment for essential hypertension.
Authors: Finnerty FA Jr
Published: July 2012

1 In the United States, the thiazide diuretics are considered the cornerstone of all antihypertensive regimens for four reasons: by themselves, they are capable of controlling the blood pressure in 60‐ 70% of the hypertensive population; they prevent the sodium retention produced by all other antihypertensive agents; they can be given once a day; and they are inexpensive. 2 Despite these advantages, the thiazide do cause hypokalaemia hyperuricaemia and hyperglycaemia. The incidence of hypokalaemia (K less than 3.0 mEq/l) is only 2‐4%; the incidence of hyperuricaemia (uric acid greater than 10 mg per cent is 3‐4%; and the incidence of hyperglycaemia is 1‐2%. 3 The possibility that a beta‐ blocking agent combined with a thiazide diuretic might produce better BP control, prevent thiazide‐induced abnormalities and exert a coronary prevention action with once daily administration would suggest that such a combination should be the ideal initial therapy for most patients with hypertension.
Long‐term treatment of essential hypertension using nadolol and hydrochlorothiazide combined.
Authors: El‐Mehairy MM , Shaker A , Ramadan M , Hamza S , Tadros SS
Published: July 2012

1 The stepped care approach for the treatment of hypertension was adopted in a study at Ain Shams Hospital using hydrochlorothiazide (HCT) and a new beta‐blocker, nadolol. Sixty mild to moderately hypertensive patients were studied for 20 weeks (2 weeks no antihypertendive the therapy, 3 weeks placebo, 3 weeks HCT, 4 weeks nadolol + HCT dose titration and 8 weeks nadolol + HCT maintenance). The dose of HCT was 50 mg once daily throughout the study except for six patients who had their HCT dose increased to 100 mg daily during maintenance. The dose of nadolol ranged from 40‐240 mg daily. 2 No patient on HCT monotherapy achieved full control of his supine diastolic blood pressure (SDBP less than 90 mm Hg). On combined therapy, 55 patients (91.7%) showed a full response, whereas the remaining five patients a good or adequate response. 3 Thirty‐two of these patients agreed to continue in the study for a further 21 months (totalling 2 yr of therapy). To date, 15 of them have completed a total of 10 months, 7 have completed 11 months and 10 have completed 12 months. The delta percentage decrease in supine BP continued to be 28.0 and 19.5 for systolic and diastolic BPs respectively. 4 No significant changes in funduscopies, chest X‐rays, ECGs, or full laboratory investigations were noted. A few side‐effects of mild nature occurred. None necessitated discontinuation of therapy. 5 Combined therapy with nadolol and HCT is a safe and effective method of controlling hypertension over extended periods.
Orally active angiotensin‐converting enzyme inhibitor (SO 14,225) as a treatment for essential hypertension.
Authors: Brunner HR , Gavras H , Waeber B , Turini GA , McKinstry DN , Vukovich RA , Gavras I
Published: July 2012

1 Captopril (SQ14,225), an orally active inhibitor of angiotensin‐ converting enzyme, was administered to nine patients with essential hypertension. Plasma renin activity (PRA) was low in four, 'normal' in three and high in two patients. 2 In the hospital, captopril alone induced a significant drop in BP from 165 +/‐ 6/106 +/‐ 2 to 140 +/‐ 5/90 +/‐ 1 mmHb (P less than 0.001). PRA increased concomitantly (P less than 0.05), whereas plasma‐converting enzyme activity (P less than 0.005) and plasma aldosterone (P less than 0.05) were reduced. 3 Six patients underwent chronic ambulatory therapy with captopril for a mean of 16 +/‐ 3 weeks. After discharge from the hospital, BP remained normalized but in five out of six patients this required additional diuretic therapy. 4 The results suggest that captopril alone or combined with diuretic therapy provides a new, efficient and well tolerated tool to treat patients with essential hypertension independently of their PRA level. It may turn out to be more effective in lowering BP than beta‐adrenoceptor‐blocking agents.
Effect of treatment of hypertension in the primary preventive trial, Goteborg, Sweden.
Authors: Wilhelmsen L , Berglund G , Sannerstedt R , Hansson L , Andersson O , Sievertsson R , Wikstrand J
Published: July 2012

1 A treatment group comprising 635 hypertensive men (casual SBP greater than 175 or DBP greater than 115 twice) was compared with a reference group (n = 391 men; casual SBP greater than 175 or DBP greater than 115 only at screening). All men belonged to the same population sample of 7,455 men aged 47‐54 yr. 2 The two groups did not differ with respect to age, smoking habits or cholesterol values, but screening BPs were higher in the treatment group. 3 During 4.3 years' follow‐up there was a significantly lower total death rate in the treatment group compared with reference group. 4 There was also a strong tendency towards lower incidence of non‐fatal myocardial infarction (P = 0.06). The pooled incidence of non‐fatal myocardial infarction and fatal CHD was lower in the treatment group than in the reference group (P less than 0.03).
Human pharmacology of narcotic antagonists.
Authors: Jasinski DR
Published: July 2012

1 Human studies at the Addiction Research Center enable narcotic antagonists to be classified into three subgroups: (1) nalorphine‐like agents; (2) pure antagonists; and (3) morphine‐like agents. 2 Six narcotic antagonists (pentazocine, nalbuphine, cyclazocine, butorphanol, propiram and buprenorphine) developed in recent years seem to have a lesser abuse potential than codeine or propoxyphene. 3 When adjusted for relative availability of the agents, epidemiological data shows that pentazocine is abused less than codeine or propoxyphene in the US. 4 Recent studies with buprenorphine indicate that this agent would find application both as an analgesic of low abuse potential and as a new type of drug for the treatment of addiction.
Environmental factors affecting paracetamol metabolism in London factory and office workers.
Authors: Mucklow JC , Fraser HS , Bulpitt CJ , Kahn C , Mould G , Dollery CT
Published: July 2012

A Paracetamol elimination was measured, using serial saliva samples, in 114 London factory and office workers, 76 Whites and 38 Asian immigrants. 2. Use of social drugs such as alcohol, tobacco and the oral contraceptive varied considerably within the sample, being appreciably greater in White subjects. 3. Paracetamol clearance was 21% slower in Asians than in Whites and half‐life 18% longer. The total range of clearance was 1.86–6.78 ml min‐1 kg‐1. 4. Clearance was slower in women than in men, increased with increasing alcohol intake and cigarett consumption, and was more rapid in those women using the oral contraceptive. The effects of alcohol and the oral contraceptive were also found in White subjects alone. 5 The variables found to correlate independently with paracetamol clearance accounted for only 27% of the total sample variance, however, and are unlikely to be the major determinants of paracetamol elimination in man.
The effect on paracetamol absorption of stimulation and blockade of beta‐adrenoceptors.
Authors: Clark RA , Holdsworth CD , Rees MR , Howlett PJ
Published: July 2012

1 The effect of drugs acting on beta‐adrenoceptors on the absorption and excretion of paracetamol was studied in 26 volunteers and nine patients with mild hypertension, each subject acting as his/her own control. 2 Isoprenaline given 30 min before paracetamol significantly slowed absorption, the effect being dose related, and blocked by prior administration of propranolol. 3 When isoprenaline was given immediately before the paracetamol, absorption was not altered, although a cardiovascular response was seen. 4 Oral salbutamol also delayed paracetamol absorption. 5 Propranolol given alone increased the rate of paracetamol absorption. 6 These results with the changes in the rate of gastric emptying produced by these agents.
'MacDope': a simulation of drug disposition in the human body: applications in clinical pharmacokinetics.
Authors: Bloch R , Sweeney G , Ahmed K , Dickinson CJ , Ingram D
Published: July 2012

1 We have described a novel approach to absorption, distribution, metabolism and elimination of drugs in which the patient is described using 23 Patient Factors and drugs by up to 50 Drug Factors. Kinetic behavior of a drug results from the interaction of patient and drug factors according to equations describing an eight compartment model. In this model non‐linear processes (protein binding, hepatic drug metabolism and renal tubular transport) are handled by derivations of the law of mass action which have been generalised to permit the consequences of multiple drugs interacting at single macromolecular sites to be correctly calculated. 2 The mathematical description of this model is provided in a companion paper and solution of the equations is only possible using a digital computer. The computer programme is provided with an interactional format which makes operation independent of mathematical skills. Patients are defined by age, sex, height and weight with, or without, organ dysfunction; the programme then generates appropriate factors. Drug enters the system when a prescription is type on the keyboard and required Drug Factors are then retrieved from the disc flies. Drug concentrations in plasma or body fluids are given as simple graphs as a function of time, or in tabular form. 3 Any of the Patient or Drug Factors may be altered before, or during a run and up to three drugs may be simulated at one time thus permitting certain kinetic interactions to be examined. The scope of the simulator is illustrated using aspirin: pH dependent gastric absorption, first‐order conversion of aspirin to salicylate, partly first order and partly saturable hepatic metabolism of salicylate, and the complex renal handling of this drug are all represented. Interaction of phenytoin with salicylate has been examined quantitatively to suggest limited clinical relevance for the observed displacement of phenytoin from serum albumin. The use of the simulator in a short course of pharmacokinetics is briefly described.
Metabolism of an oral tryptophan load. I: Effects of dose and pretreatment with tryptophan.
Authors: Green AR , Aronson JK , Curzon G , Woods HF
Published: July 2012

1 The metabolism of three oral doses of L‐tryptophan (50, 25 and 10 mg/kg) in healthy young males has been investigated. 2 There was a linear relationship between both peak and area under curve of the total plasma tryptophan concentrations whilst the relationship between these parameters and plasma free tryptophan was hyperbolic. 3 Before the tryptophan load about 85% of plasma tryptophan was bound to albumin. As plasma tryptophan concentrations increased there was a hyperbolic increase in free tryptophan. Scatchard analysis revealed 1.4 binding sites/molecule albumin with a dissociation constant (Kd) of 57.9 microM. Following administration of L‐tryptophan (50 mg/kg) twice daily for 7 days there was no alteration in the number of binding sites but the dissociation constant (Kd) had decreased to 30.9 microM. 4 L‐ Tryptophan (50 mg/kg twice daily for 7 days) markedly increased both basal plasma total and free tryptophan. However following a further load the total tryptophan curve was comparable to that seen after acute administration. The plasma free tryptophan curve was lowered relative to that seen after an acute dose. 5 Increasing the tryptophan dose shortened the plasma half‐life and decreased the volume of distribution and the rate of clearance. Longer term tryptophan administration had no significant effect on plasma half‐life or volume of distribution but did decrease the rate of plasma clearance. 6 The plasma kynurenine concentration increased with increasing tryptophan dose and basal concentrations increased markedly after longer term tryptophan administration. 7 Tryptophan administration either acutely or chronically produced little change in urinary tryptophan or 5‐ hydroxyindole acetic acid excretion. Urinary kynurenine and indole acetic acid excretion increased with increasing doses of tryptophan. 8 Data are discussed in relation to the administration of L‐tryptophan for the treatment of depression.
The pharmacokinetics of metoclopramide in man with observations in the dog.
Authors: Bateman DN , Kahn C , Davies DS
Published: July 2012

1 The pharmacokinetics of metoclopramide have been studied in eight normal male volunteers. 2 The mean plasma beta half‐life was 156.7 min after i.v. administration of 10 mg metoclopramide. 3 After oral dosing of 10 mg the mean half‐life was 196.6 min and after 20 mg 317.5 min (P less than 0.05). 4 Bioavailability of a 10 mg oral dose of metoclopramide varied between 32 and 97%. 5 A major urinary metabolite was metoclopramide‐N‐4‐sulphate and the amounts of conjugates appearing in urine to 24 h correlated significantly with the bioavailability. 6 In the dog the metabolic fate of metoclopramide is different to man with conjugation being a minor metabolic pathway. The half‐life in the dog does not appear to be dose dependent. 7 The wide differences in bioavailability of metoclopramide in man may contribute to the unpredictable occurrence of side effects.
Pharmacokinetics of atenolol in patients with terminal renal failure and influence of haemodialysis.
Authors: Flouvat B , Decourt S , Aubert P , Potaux L , Domart M , Goupil A , Baglin A
Published: July 2012

1 The pharmacokinetics of atenolol, after 200 mg orally, were studied in 18 patients with terminal renal insufficiency (creatinine clearance less than 5 ml/min), of whom twelve were being treated by chronic dialysis. 2 The peak plasma level, 1.59 +/‐ 0.43 mg/l, was reached in 4.7 +/‐ 2.1 h. 3 Without dialysis treatment, the apparent plasma half‐ life of atenolol was greatly increased (73.4 +/‐ 28.8 /). During dialysis, it dropped to 7.5 +/‐ 3.7 h but returned to 51.2 +/‐ 17.3 h after dialysis. The plasma atenolol plot was a rising slope for a few hours after the end of dialysis. 4 Renal clearance of atenolol was very low (4.6 +/‐ 1.5 ml/min). 5 Plasma clearance during dialysis was 42.6 +/‐ 21.3 ml/min for a mean blood flow‐rate of 236 +/‐ 25 ml/min through a cuprophane membrane dialyser. 6 These results suggest that dosage should be modified for these patients.
Comparative trial of labetalol and acebutolol, alone or associated with dihydralazine, in treatment of essential hypertension.
Authors: Thibonnier M , Lardoux MD , Corvol P
Published: July 2012

1 Labetalol, an alpha‐ and beta‐ adrenoceptor blocking drug, was compared with acebutolol, alone or associated with dihydralazine in forty patients with moderate essential hypertension. 2 Labetalol (400‐ 800 mg daily) seemed to have a slightly higher potency than acebutolol alone (400–800 mg daily). 3 Labetalol (1200–1600 mg daily) had the same potency as the combination of acebutolol (400–800 mg daily) and dihydralazine (50–100 mg daily). 4 Contrarily to acebutolol, the drop in blood pressure with labetalol was not correlated with initial plasma renin activity. 5 Labetalol side effects were minor and did not lead to drug withdrawal.
Elimination of oral cimetidine in chronic renal failure and during haemodialysis.
Authors: Bjaeldager PA , Jensen JB , Larsen NE , Hvidberg EF
Published: July 2012

1 The absorption and elimination of a single oral dose of 400 mg cimetidine was studied in fourteen fasting patients with impaired renal function. In addition, the dialysance of cimetidine was studied in five patients on haemodialysis. 2 The absorption was somewhat, but clinically insignificantly delayed. A second unexplained peak in the absorption curve was found. 3 First order elimination kinetics were confirmed and the length of time of a cimetidine concentration over 0.5 mg/l could be correlated with creatinine clearance. 4 The magnitude of extra renal elimination was estimated to be approximately one fourth of total cimetidine elimination in normal patients and seemed unaffected by impaired renal function. 5 A dose schedule based on AUC found in the patients in renal failure is suggested. The recommendations for daily oral dose range from 300 mg (at borderline dialysis) to 1000 mg in mild renal failure. The suggested doses will give an average plasma concentration of the same order as seen in patients with normal renal function.
Flurbiprofen in the treatment of primary dysmenorrhoea.
Authors: Krishna UR , Naik S , Mandlekar A , Gupta KC , Kulkarni VN , Sheth UK
Published: July 2012

1 In a double‐blind crossover study, flurbiprofen produced marked relief of pain which was significantly more than with aspirin and placebo in patients suffering from primary dysmenorrhoea. In contrast, there was no significant difference between the relief of pain obtained with aspirin and placebo. 2 The clinician's overall assessment of efficacy also indicated that flurbiprofen produced better response as compared to aspirin and placebo in these patients with dysmenorrhoea. 3 Both flurbiprofen and aspirin did not produce any apparent adverse effects on blood loss during the menstrual period. 4 In conclusion, the analgesic effect of flurbiprofen seen in this trial establishes the therapeutic usefulness of the drug in the treatment of primary dysmenorrhoea.
The effects of clobazam and lorazepam on aspects of psychomotor performance and car handling ability.
Authors: Hindmarch I , Gudgeon AC
Published: July 2012

1 Laboratory tests of psychomotor performance and ‘on road’ assessments of car handling ability were made following repeated doses of clobazam 10 mg three times daily, lorazepam 1 mg three times daily and matching placebo 1 capsule three times daily. 2 Both active compounds produced on impairment, compared to placebo, in some mental arithmetic and letter cancellation tasks, but these effects were neither widespread nor consistent. 3 Lorazepam produced a significant impairment of car driving tasks and analogue rating scales of subjective alertness. The pronounced sedative activity of the drug was also shown in the verbal reports of side effects and in indices of early morning sedation derived from the Leeds Sleep Evaluation Questionnaire. 4 Clobazam did not produce either the objective, or the subjective impairment of performance and alertness found with lorazepam. 5 The results taken as a whole show important differences between the 1,4 benzodiazepine, lorazepam, and the 1,5 benzodiazepine, clobazam, in their effects on the integrity of psychomotor performance related to car driving ability.
Effect of histamine and histamine antagonists on portal blood pressure in patients with hepatosplenic schistosomiasis.
Authors: El‐Gendi MA , Nassar SH
Published: July 2012

1 Histamine injection via the cannulated portal vein significantly raised the portal pressure in normal volunteers. This elevation was reversed by an H1‐receptor blocker but not an H2‐receptor blocker. When an H1‐receptor blocker was injected first followed by histamine, no significant change in portal pressure was obtained. On the other hand, an H2‐receptor blocker failed to antagonize the effect of histamine. 2 Histamine injection induced a non‐significant increase in the portal pressure in patients with schistosomal portal hypertension, but when an H1‐receptor blocker was injected a significant drop in the portal pressure was obtained. No similar effect was found after an H2‐receptor blocker injection. 3 Angiographic study showed that histamine induced intrahepatic portal vasoconstriction in the normal controls. A similar change was obtained in the schistosomal group, particularly on the periportal neovascular formation. 4 In the light of the present study, it is suggested that histamine may contribute in part to the physiopathologic changes that lead to portal hypertension in hepatosplenic schistosomiasis. H1‐receptor antagonists may have a role in the treatment of portal hypertension, particularly in bleeding varices.
Assay of thioinosinic acid, an active metabolite of azathioprine, in human lymphocytes.
Authors: Fletcher L , Maddocks JL
Published: July 2012

1 A specific assay for the measurement of thioinosinic acid, in human lymphocytes, has been developed with a sensitivity of 50 ng of thioinosinic acid per 5 × 10(6) lymphocytes. 2 Thioinosinic acid is precipitated from purified lymphocytes as the lanthanum salt. Acid hydrolysis results in the formation of 6‐mercaptopurine which, when converted into its phenyl mercury derivative, can be easily extracted into toluene. Back‐extraction of the toluene layer with 0.1N HCl regenerates 6‐mercaptopurine which is then assayed fluorometrically. 3 Blood samples were taken from renal transplant recipients 3 h after an oral dose of 50 mg azathioprine. The results from 5 patients gave a range of 54 to 173 ng of thioinosinic acid per 5 × 10(6) lymphocytes, with a mean of 110 ng. 4 In an in vitro incubation of azathioprine, 1mM with fresh human blood, 160 and 180 ng of thioinosinic acid per 5 × 10(6) lymphocytes was formed after 0.5 h and 5 h respectively. 5 The assay is suitable for the study of the kinetics of thioinosinic acid formation in lymphocytes of patients with kidney transplants. It could also prove useful in the study of thioinosinic acid formation in leukaemia patients undergoing 6‐mercaptopurine treatment.
Tachyphylaxis to beta‐adrenoceptor agonists in human bronchial smooth muscle: studies in vitro.
Authors: Davis C , Conolly ME
Published: July 2012

In studies on human isolated peripheral airway smooth muscle; 1 A concentration dependent beta‐adrenoceptor tachyphylaxis was observed to isoprenaline. 2 Cross desensitization to other beta‐adrenoceptor agonists was demonstrated. 3 The desensitization was reversible with time. Hydrocortisone appeared to accelerate the recovery from the desensitized state. Low concentration isoprenaline (10(‐9) mol l‐1) prevented recovery whereas cyclohexamide 1.8 × 10(‐4) mol l‐1 had no noticeable effect on recovery. Continued occupancy of the receptor appears to prevent recovery. The recovery from the desensitized state does not apparently require synthesis of new proteins. 4 Bronchial wall cyclic AMP response to isoprenaline was attenuated after isoprenaline induced desensitization whereas total phosphodiesterase activity of bronchial wall was not altered by desensitization. Thus by exclusion the adenylate cyclase receptor complex may be altered in human peripheral airway smooth muscle beta‐adrenoceptor tachyphylaxis.
Blood concentrations and pharmacodynamic effects of betaxolol (SL 75212) a new beta‐adrenoceptor antagonist after oral and intravenous administration.
Authors: Warrington SJ , Turner P , Kilborn JR , Bianchetti G , Morselli PL
Published: July 2012

1 In normal subjects, intravenous betaxolol given in doses which inhibited the tachycardia of exercise failed to affect the peak expiratory flow rate. 2 From 2 to 48 h after administration of 150 micrograms/kg in four normal subjects, there was no significant difference between the blood levels, whether given orally or intravenously. 3 At all times, heart rate and blood pressure, at rest and during exercise, were reduced equally after administration by both routes, but the area under the curve of exercise heart rate against time was significantly smaller (P < 0.05) after intravenous drug. 4 The absolute bioavailability of betaxolol was 89 +/‐ 5%.
Wakefullness and reduced rapid eye movement sleep: studies with prolintane and pemoline.
Authors: Nicholson AN , Stone BM , Jones MM
Published: July 2012

1 Effects of prolintane (15 and 30 mg) and pemoline (60 and 100 mg) on sleep were studied in six healthy adult males. Sleep was assessed by electroencephalography and by analogue scales. 2 Prolintane (15 and 30 mg) reduced rapid eye movement (REM) sleep both by delaying the first period (P < 0.05 and < 0.001 respectively) and by reducing total REM sleep (P < 0.05 and < 0.001 respectively). In some subjects there were increased awakenings during the early part of the night, and in two subjects long periods of wakefulness occurred. 3 With pemoline (60 and 100 mg) sleep duration was marked reduced (P < 0.001). There was evidence in some subjects of delay to the first REM period, and reduced percentage REM sleep (P < 0.01). Shortened and fragmented sleep with 60 and 100 mg were associated with reduced sleep efficiency indices (P < 0.001), and shorter sleep period times led to reduced REM/NREM ratios. Absence of an effect on REM latency for the subjects as a group may be related to relatively slow absorption. 4 The heterocyclic amphetamine derivatives have variable effects on sleep. The differences may be dose related, and wakefulness and reduced REM sleep may be seen together or separately. Alterations in sleep occur with doses of pemoline and prolintane which also modify performance.
A comparison of the efficacy of ketotifen (HC 20‐511) with sodium cromoglycate (SCG) in skin test positive asthma.
Authors: Clarke CW , May CS
Published: July 2012

1 Ketotifen (HC 20‐511 Sandoz) 1 mg twice daily for 12 weeks was found to be equivalent to sodium cromoglycate (SCG) 20 mg four times daily for 12 weeks in 35 skin test positive asthmatic patients in a randomised double‐blind cross‐over study. 2 No statistically significant difference between the two drugs in mean values for daily peak flow rates, diary card scores and spirometry at monthly visits was demonstrated. 3 Treatment failures as judged by severe asthma requiring withdrawal from the trial or addition of short courses of prednisone occurred in three patients on each drug. 4 Sedation was noted by 10 patients onHC 20‐511 and 5 on SCG. 5 Weight loss was noted in those patients on SCG, but not those on HC 20‐511.
Pharmacokinetics and protein binding interactions of dapsone and pyrimethamine.
Authors: Ahmad RA , Rogers HJ
Published: July 2012

1 Seven normal volunteers received oral doses of 100 mg dapsone (DDS), 25 mg pyrimethamine (PYR) singly or in combination in random order. 2 Plasma and salivary DDS and plasma monoacetyldapone (MADDS) and PYR were estimated simultaneously by a hitherto unpublished quantitative absorption thin layer chromatographic method. This assay was shown to be satisfactory for pharmacokinetic studies. 3 The half‐life of DDS was unaltered by PYR but the apparent volume of distribution was significantly increased from a mean of 1.53 1 kg‐1 to 1.93 1 kg‐1 and the peak DDS plasma levels measured fell by 17%. 4 The pharmacokinetic parameters of PYR were unchanged by DDS. 5 The half‐life of MADDS was unchanged by PYR and was not affected by the acetylator status of the subject. 6 Salivary DDS excretion reflects the free plasma DDS concentration. Administration of PYR with DDS significantly alters the mean saliva/plasma DDS ratio from 0.265 to 0.358 suggesting an increase in free DDS with PYR therapy. 7 In vitro studies of plasma protein DDS binding indicate that DDS binds to a single class of binding sites on human plasma protein and PYR competitively displaces DDS from these sites. 8 The usefulness of salivary drug measurements in detecting increases of free drug in plasma in man is demonstrated.
Non‐migrainous headache for the evaluation of oral analgesics.
Authors: Von Graffenried B , Nuesch E
Published: July 2012

1 Eight double‐blind, randomized, placebo‐controlled, single‐dose, cross‐over studies were carried out to evaluate the usefulness of testing the acute analgesic effect of drugs in out‐patients with non‐ migrainous headache. 2 The reference compounds were either (1) aspirin, (2) a combination of aminopyrine, caffeine and butalbarbital (Optalidon), and (3) a combination of (2) with dihydroergotamine (Tonopan). 3 The test compounds were (1) proquazone, (2) fluproquazone and (3) and (4), new formulations of Optalidon and Tonopan in which the aminopyrine was replaced by propyphenazone. They were all found to be active. 4 A significant, dose‐response relationship was established for aspirin (250, 500 and 1000 mg). 5 It is concluded that the non‐ migrainous headache model is a practical, reproducible and sensitive method for the investigation of the acute efficacy of analgesics.
Analgesic and anti‐inflammatory effects of paracetamol evaluated by bilateral oral surgery.
Authors: Lokken P , Skjelbred P
Published: July 2012

1 In a double‐blind crossover study, essentially the same operation was performed on two separate occasions in 24 healthy patients. 2 On one occasion they were given paracetamol (Panadol) 1 g four times daily for 2 d, then 0.5 g four times daily for the next 2 d; on the other, they were given placebo tablets. 3 Several objective and subjective assessments were recorded for a paired comparison of the postoperative courses. 4 Significantly less swelling was measured after the operation when paracetamol was given; on day 3 it averaged 71% of that with placebo. This reduction in postoperative swelling was greater than the reduction previously obtained with ibuprofen and oxyphenbutazone using the same clinical model. 5 With paracetamol, a tendency was noted towards reduced local inflammatory temperature increase and less postoperative bleeding. 6 The results of this clinical trial agree with recent findings in animals studies which show paracetamol to be anti‐ inflammatory. 7 The pain and preference scores were clearly in favour of paracetamol. Adequate pain relief with paracetamol may require doses as high as 1 g three to four times daily. 8 The results obtained in this model with bilateral oral surgery suggest that in situations in which there are tissue lesions caused by surgery or injury, paracetamol may be preferable to acetylsalicylic acid if swelling and bleeding are to be prevented or reduced.
Comparison of intravenous acetylsalicylic acid and dipyrone in postoperative pain: an interim report.
Authors: Blendinger I , Eberlein HJ
Published: July 2012

1 In 17 gynaecological patients with postoperative pain the analgesic efficacy of intravenous lysine salicylate 1.8 g (corresponding to acetylsalicylic acid (ASA) 1.0 g) and dipyrone 1.0 g were compared in a double‐blind randomized study. 2 In the ASA group, mean pain relief and pain intensity difference scores reached a maximum 30 min after drug administration and remained at this level for the next 90 minutes. 3 In the dipyrone group, these scores reached their peak 60 min after drug administration and seemed to fall off during the next hour. 4 The mean pain relief and intensity difference scores were greater following aspirin than dipyrone. However, firm conclusions cannot be drawn from the results of this small study.
Management of pain after abdominal surgery: dipyrone compared with pethidine.
Authors: Patel CV , Koppikar MG , Patel MS , Parulkar GB , Pereira Pinto LM
Published: July 2012

1 Dipyrone 2.5 g was compared with pethidine 100 mg in a double‐blind parallel group study. 2 Patients with moderate or severe postoperative pain following abdominal surgery received one of the two drugs intramuscularly. 3 The two treatment groups were homogeneous when analyzed by age, weight, height, sex, and initial severity of pain. 4 The onset degree and duration of pain relief afforded by both drugs was similar when the groups were compared as a whole or according to initial pain level. 5 No side‐effects were attributed to either drug in this study.
Hepatotoxicity of mild analgesics.
Authors: Prescott LF
Published: July 2012

1 Hepatotoxicity is rare when mild analgesics are used in normal therapeutic doses. 2 The potential of aspirin and salicylates to cause hepatotoxicity has been only recently recognized. 3 Salicylate hepatitis is often asymptomatic, and may only be revealed by finding elevated levels of aminotransferases. 4 Most cases have occurred in children or young adults with connective tissue diseases, who take high doses of salicylates for long periods. 5 Hepatic injury is not recognized as a complication of acute aspirin poisoning. 6 Following overdosage of paracetamol, a toxic intermediate metabolite causes acute hepatic necrosis which may be fatal. 7 Cysteamine, methionine and N‐ acetylcysteine confer protection against this severe liver damage, but the time between overdosage and treatment is critical. 8 The chronic therapeutic use of paracetamol should be considered a potential but very rare cause of active chronic hepatitis. 9 There is no clear evidence of phenacetin hepatotoxicity in man. 10 Phenylbutazone may cause liver injury and other analgesics can cause hypersensitivity reactions in which the liver is involved.
Monooxygenase activity of human liver in microsomal fractions of needle biopsy specimens.
Authors: Boobis AR , Brodie MJ , Kahn GC , Fletcher DR , Saunders JH , Davies DS
Published: July 2012

1 Methods are described for the determination of mixed function oxidase activity in microsomal fractions from percutaneous needle biopsies of human liver. 2 Activities of needle biopsy samples were comparable with those of wedge biopsy sample obtained at laparotomy from different subjects. 3 Although cytochrome P‐450 content of liver from rat and man was similar, human AHH activity was only 10% of that in the rat. 4 In biopsies with preserved hepatic architecture, AHH activity and cytochrome P‐450 content showed a significant positive correlation. 5 Cigarette smoking significantly increased both AHH activity and turnover number, but not cytochrome P‐450 content, of biopsies with normal architecture. 6 The presence of liver disease caused a significant decrease in AHH activity and cytochrome P‐450 content.
The effects of bromocriptine in methyldopa treated hypertension.
Authors: Lewis MJ , Henderson AH
Published: July 2012

1. The effects of treatment with the dopaminergic agonist bromocriptine were studied in nine patients with essential hypertension receiving methyldopa as sole therapy. 2. In Phase 1 of the study, the addition of bromocriptine on a single‐blind basis caused a significant fall in lying and standing blood pressures. Plasma prolactin fell significantly but there was no significant change in the other biochemical parameters measured. All patients volunteered that they felt a sense of well‐being after starting bromocriptine treatment. 3. In Phase 2 of the study the substitution of placebo for bromocriptine in a randomized double‐blind trial significantly increased lying and standing blood pressures and plasma prolactin. No consistent or significant changes were observed in methyldopa‐induced side‐effects following the substitution of placebo for bromocriptine. 4. In Phase 3 of the study, a gradual increase in blood pressure was observed in all patients over a few months after stopping bromocriptine therapy. 5. The significance of these findings in relation to the role played by plasma prolactin and central dopaminergic activity in blood pressure regulation is discussed.
Assay of 6‐thioguanine in human plasma.
Authors: Dooley T , Maddocks JL
Published: July 2012

1. A fluorimetric method has been developed for measuring therapeutic concentrations of 6‐thioguanine in human plasma. The drug was measured as an oxidized derivative, guanine 6‐sulphonate. 2. 6‐thioguanine was extracted from plasma by a novel procedure which isolated the drug from an interfering plasma components. This method involved the formation of the thioguanine phenyl mercury derivative in alkaline plasma and its extraction into toluene. The free drug was released by back‐extraction into hydrochloric acid. 3. The assay is specific and shows a limit of sensitivity of 5 ng/ml. This was shown to be adequate for measuring plasma concentrations of 6‐thioguanine after the administration of a 160 mg dose in a patient with leukaemia.
Comparison of labetalol and propranolol in hypertension.
Authors: Nicholls DP , Husaini MH , Bulpitt CJ , Stephens MD , Butler AG
Published: July 2012

1 Labetalol has been compared with propranolol in a double‐blind, double‐dummy study of 24 patients with mild or moderate essential hypertension. 2 Two patients were unable to tolerate propranolol and five labetalol, because of symptom side effects; this difference was not significant (P greater than 0.1). 3 On a self‐administered questionnaire, labetalol was associated with a greater number of side effects per patient than propranolol, but no individual side effect was significantly more common with either drug. 4 There was no difference in the number of spontaneously reported side effects between the two drugs. 5 Both drugs impaired pulmonary function, but propranolol caused a greater reduction than labetalol after 8 weeks of treatment. 6 We conclude that labetalol and propranolol are similarly effective and acceptable to the patient.
Pharmacology of guanfacine.
Authors: Scholtysik G.
Published: July 2012

1. The pharmacological effects of the centrally acting antihypertensive drug guanfacine are reviewed. 2. The drug lowers systemic blood pressure in hypertensive rats dose‐dependently after oral application of 0.3‐5 mg/kg. 3. Evidence is presented that guanfacine produces its antihypertensive action by a specific stimulation of central alpha‐ adrenoceptors. 4. Certain pharmacological differences between clonidine and guanfacine are discussed.
Acute and chronic renal effects of guanfacine in essential and renal hypertension.
Authors: Roeckel A. , Heidland 2d A.
Published: July 2012

1. Antihypertensive drugs may influence renal function, due to haemodynamic effects and altered release of hormones. 2. Acute and chronic renal effects (glomerular filtration rate (GFR) renal plasma flow (CPAH); diuresis; electrolyte clearances (CNa+, CK+, CCa++, CPO4 3‐) of guanfacine have been investigated. 3. Acute intravenous injection induced a marked decrease in GFR, renal blood flow, diuresis and electrolyte clearances. These effects were less pronounced after oral administration. 4. In long‐term antihypertensive treatment these effects are less prominent. 5. EFfects of guanfacine on blood pressure and heart rate are similar to those of clonidine (initial pressor response and bradycardia after intravenous injection).
Central effects of guanfacine and clonidine during wakefulness and sleep in healthy subjects.
Authors: Spiegel R. , DeVos JE
Published: July 2012

1. Three double‐blind studies in young normotensive male volunteers were carried out: a study in ten awake subjects, comparing guanfacine 2.0 and 4.0 mg with clonidie 0.15 and 0.30 mg and placebo; and two polygraphic sleep studies each with six subjects, comparing guanfacine 1.0 and 2.0 mg with placebo, and clonidine 0.15 and 0.30 mg with placebo, respectively. 2. In awake subjects, both drugs reduced systolic blood pressure without significantly altering diastolic blood pressure, pulse rate and objective performance parameters. 'Side‐ effects' such as tiredness, decreased inclination to work, and dryness of the mouth were somewhat more frequent after the higher clonidine dose than after both doses of guanfacine, and peaked 2 h after clonidine but only 4‐6 h after guanfacine. 3. Clonidine 0.15 and 0.30 mg given in the evening was followed by a substantial and dose‐ dependent reduction in rapid eye movement (REM) sleep. Guanfacine 1.0 mg did not alter REM sleep and 2.0 mg of guanfacine had less effect than both doses of clonidine in this respect. Clonidine's effect on REM sleep began after about 2 h, whereas guanfacine's action on REM sleep began 5 h after the dose. 4. Guanfacine and clonidine possess a qualitatively similar pattern of activity with regard to the parameters studied; but the central effects are less pronounced and occur later after guanfacine than after clonidine in equiactive doses.
Effect of cimetidine on the absorption of orally administered tetracycline.
Authors: Fisher P. , House F. , Inns P. , Morrison PJ , Rogers HJ , Bradbrook ID
Published: July 2012

1 Six healthy female subjects received orally two 250 mg tetracycline tablets either with 400 mg cimetidine or placebo. In a separate experiment six healthy female volunteers received 500 mg tetracycline as a suspension on the fifth day of a 6 day regime of 400 mg cimetidine or placebo, 8 hourly and at bedtime. 500 mg tetracycline as tablets was also given with cimetidine only. 2 Following a single dose of cimetidine the mean peak tetracycline plasma concentration was significantly reduced by 1.2 microgram/ml and the area under the plasma concentration, time curve was decreased by 40%. The 72 h urinary tetracycline excretion was diminished by approximately 30%. 3 Tetracycline had no effect on the plasma concentration, time profile of cimetidine. 4 Administration of 400 mg cimetidine 8 hourly and at night for 6 days and dosing with 500 mg tetracycline as tablets or suspension on the fifth day produced no alteration in tetracycline kinetics. 5 It was concluded that under clinical circumstances it is unlikely that cimetidine produces a clinically significant alteration in tetracycline absorption or disposition. 6 The bioavailability of tetracycline from tablets and suspension was found to be similar (31.2% and 36.9% of the dose excreted in the urine over 72 h). 7 The mean renal clearance of tetracycline was 83.8 ml/min (95% confidence interval +/‐ 9.2 ml/min) and was unaltered by cimetidine treatment.
A sex difference in the effects of oral codeine and promethazine on the ventilatory response to carbon dioxide in human volunteers.
Authors: Pleuvry BJ , Maddison SE
Published: July 2012

1 Interactions between codeine and promethazine have been studied in male and female volunteers, measuring ventilation, end tidal PCO2, ventilatory response to CO2, pulse and blood pressure. 2 The effects of codeine on the above measurements have been compared in subjects who habitually smoke cigarettes and non smoking subjects. 3 Codeine displaced the ventilatory response to CO2 to the right and increased end tidal PCO2 in female subjects but not in males. 4 Promethazine plus codeine displaced the ventilatory response to CO2 to the right in male subjects but tended to reduce the response to codeine in females. 5 The slope of the ventilatory response to CO2 was significantly steeper in smokers and codeine caused significant reductions in slope in these subjects.
Effect of heparin administration on plasma binding of benzodiazepines.
Authors: Desmond PV , Roberts RK , Wood AJ , Dunn GD , Wilkinson GR , Schenker S.
Published: July 2012

1 The effect of intravenous administration of 100 units of heparin on plasma of diazepam, chlordiazepoxide, oxazepam and lorazepam was examined in fourteen normal subjects and five patients with cirrhosis. 2 In normal non‐fasted subjects heparin caused a rapid 150–250% rise in the free fraction of diazepam, chlordiazepoxide and oxazepam but no change of lorazepam. The changes in free fraction were slightly smaller, but still significant, when the subjects were fasted. 3 These change in free fraction occurred within 90 s of administration of heparin and binding had returned to baseline by 30 to 45 min. 4 In the cirrhotic subjects the response to heparin was variable. 5 The use of heparin during drug disposition studies may affect the estimation of pharmacokinetic parameters and possibly pharmacological effects which are dependent on the circulating unbound drug level.
Homoeopathic therapy in rheumatoid arthritis: evaluation by double‐ blind clinical therapeutic trial.
Authors: Gibson RG , Gibson SL , MacNeill AD , Buchanan WW
Published: July 2012

Twenty‐three patients with rheumatoid arthritis on orthodox first‐line anti‐inflammatory treatment plus homeopathy were compared wtih a similar group of twenty‐three patients on orthodox first‐line treatment plus an inert preparation. There was a significant improvement in subjective pain, articular index, stiffness and grip strength in those patients receiving homoeopathic remedies whereas there was no significant change in the patients who received placebo. Two physicians were involved in prescribing for the patients and there were no significant differences in the results which they obtained. No side effects were observed with the homoeopathic remedies.