Showing papers in "Methods and Findings in Experimental and Clinical Pharmacology in 1980"

Prostaglandins and inflammatory reactions in the eye.

Abstract: Evidence for the biosynthesis and release of prostaglandins and related substances in pathophysiological states of ocular tissues is reviewed and their participation in ocular injury and acute inflammation discussed. Ocular tissues are capable of generating prostaglandins from the endogenous or exogenous precursor, arachidonic acid. Prostaglandins are released into the aqueous humour in response to paracentesis, mechanical or laser injury to the iris, and in experimental immunogenic and non-immunogenic ocular inflammation. Antidromic stimulation of the trigeminal nerve, formaldehyde or nitrogen mustard-induced irritation of the eye do not cause the release of prostaglandins, nor are the responses to these stimuli inhibited by prostaglandin synthetase inhibitors. Prostaglandins in small doses administered topically or intraocularly produce some of the responses of injury and inflammation, such as hyperaemia, miosis, breakdown of the blood-aqueous barrier and rise in intraocular pressure. Also, E-type prostaglandins administered topically together with histamine (but not the individual components) cause cellular infiltration and produce oedema in conjunctival tissues. Non-steroidal aspirin-like drugs at concentrations which inhibit prostaglandin biosynthesis markedly block injury responses but have only a moderate inhibitory effect on acute inflammatory reactions of the eye. The present evidence suggests that prostaglandins are involved in some of the injury and inflammatory responses. However, recent studies indicate that the intermediates of arachidonic acid metabolism, especially hydroxy fatty acids, may play a greater role in inflammatory responses.

Quantitative EEG and psychometric analyses in assessing CNS-activity of Ro 13-5057--a cerebral insufficiency improver.

Abstract: In a double-blind, placebo-controlled cross-over study, the encephalotropic, psychotropic and pharmacodynamic properties of Ro 13-5057/001, a new 2-pyrrolidinone derivative, were investigated in 10 geriatric subjects. They received in randomized order at weekly intervals, single oral doses of placebo, 250 mg, 500 mg and 1000 mg Ro 13-5057, as well as 2000 mg pirazetam as reference drug. EEG recordings, psychometric testing and evaluation of blood pressure, pulse rate and side effects were carried out at the hours 0, 2, 4, 6, 8 and 24. Power spectral density analysis of the EEG demonstrated Ro 13-5057 to be an encephalotropic drug, as statistically significant CNS changes occurred in comparison to placebo, which were characterized by a decrease of delta activity, increase of alpha activity and slow beta activity and acceleration of dominant frequency. The reference drug 2000 mg pirazetam induced similar changes. Such alterations were previously described by us as typical for certain antihypoxidotic/nootropic drugs and are indicative of improvement in vigilance. Psychometric data confirmed this interpretation of neurophysiological alterations as shortening of reaction time, acceleration of tapping speed, CNS activation as measured by the Archimedean spiral, improvement in mood as well as improvement in qualitative but deterioration of quantitative aspects of attention were observed at various times after the active substances as compared with placebo. Regarding time-efficacy, the peak effect in CNS changes was noted in the 2nd hour after Ro 13-5057, but interestingly there were also alterations as late as 24 hours after oral administration. Dose-efficacy curves suggested 1000 mg Ro 13-5057 as the most effective compound of the study. The lack of side effects and clinically relevant changes in blood pressure and pulse rate indicates that the drug is well tolerated in man.

An improved method to study antibacterial activity of antibiotics in an in vitro model simulating serum levels.

Abstract: The bacterial activity of cefoxitin was studied in an improved in vitro model simulating serum levels. The peak concentration of cefoxitin was 110 mcg/ml as achieved after 1 g i.v. Half-life time was adjusted to 50 minutes. The time at which the viable count reached the mark 1% of the original inoculum after the lowest count was determined (regrowth period) ranged from one to 10 hours from the beginning of the experiments.

The simultaneous monitoring of plasma levels of neostigmine and pyridostigmine in man.

Abstract: Summary The synthesis of a series of pyridostigmine analogues was reported. From these analogues N,N - dipropylcarbamoyloxy - | -methylpyridinium bromide was considered the most suitable com' pound for use as a common internal marker for the simultaneous determination of neostigmine and pyridostigmine in human plasma. The assay involved a preliminary ion-pair extraction of the drugs and the internal marker from plasma using potassium-iodide glycine buffer. The extract was analysed by a GC system (10%OV-17 on chromosorb W-AW, 100-120 mesh) linked to a nitrogen' sensitive detector. The calibration graphs of neostigmine and pyridostigmine were linear and reproducible over the range 5 ng to | 00 ng per ml in 3 ml plasma samples. This assay procedure has been used to monitor simultaneously the plasma levels of neostigmine (4.7 to 33 ng per ml) and pyridostigmine (2.7 to 18.6 ng per ml) of a myasthenic patient over a period of twelve hours with repeated dosing of neostigmine bromide (30 mg) and pyridostigmine bromide (60 mg).

Inhibition of steroidogenesis in isolated rat adrenal cells by glutethimide congeners.

Abstract: A series of glutethimide congeners produce concentration-dependent inhibition of corticosterone production by a suspension of isolated rat adrenal cells. The dextro-rotatory antipode of aminoglutethimide is more potent than its levo enantiomer in inhibiting corticosterone production in this system. Glutethimide, its metabolite glutaconimide, and congeners including those with anti-convulsant activity, 4-hydroxyglutaconimide and 4-aminoglutethimide, have all demonstrated concentration-dependent inhibition of corticosterone production by isolated rat adrenal cells.

The effects of extremes of age on drug action.

Abstract: Many examples of age-related differences in the response of individuals to a particular drug have been documented. In many cases these differences can be related to modified distribution, metabolism or excretion of the drug. There is evidence that in neonates and the elderly, the extent and rate of these processes are less than those in older children and young adults. However, in a given age group there is no consistent trend for all drugs. In some cases the increased plasma concentration of the drug would be regarded as an advantage as it prolongs the response, but it is certainly not true for drugs such as streptomycin, warfarin and the hypoglycemic agents. Two points which emerge from the results of many studies with neonates and the elderly are that interindividual variations in plasma half-lives, metabolite and drug excretion and protein binding are significantly larger than those in young adults and that in the case of the elderly, chronological age does not necessarily reflect biological age. In combination these factors emphasise the importance of individual drug monitoring of plasma levels and hence of knowing the pharmacokinetic constants of the drug in the individual patient. In clinical practice, the dose of a drug is most commonly calculated on the basis of body weight or surface area. This is generally perfectly acceptable for older children and adults, but is not always a reliable formula for neonates and the very old. Simple changes in such parameters as urine pH can override calculations based upon body size.(ABSTRACT TRUNCATED AT 250 WORDS)

Endocrine profile of topterone, a topical antiandrogen, in three species of laboratory animals.

Abstract: Topterone, 17 alpha-propyltestosterone, was administered parenterally or topically to rats, rabbits or hamsters to determine its endocrine profile. Systemic administration demonstrated that topterone was both antiandrogenic and progestational. Topical application failed to elicit a systemic antiandrogenic response at 1 g/kg/day and only a minimal progestational response was seen at 32 mg/kg/day. No other endocrine activities were detected.

Acute changes in the renin-angiotensin-aldosterone system, catecholamines and prostaglandins during captopril in man.

Abstract: The acute hypotensive effect of 25 mg captopril was investigated in 26 hypertensive patients (11 essential and 15 with renal arterial disease). Intra-arterial blood pressure was recorded continuously and arterial blood was sampled for renin, angiotensin I and II, aldosterone, kininase II, catecholamines and prostaglandins. Captopril provoked increases in plasma renin activity, active and total plasma renin concentration and angiotensin I; decreases in plasma kininase II activity, angiotensin II, aldosterone, prostaglandins E2 and F2 alpha and no changes in plasma (nor)adrenaline, dopamine and inactive renin concentration.

Plasmid determined drug resistance in clinically isolated Escherichia coli.

Abstract: The results of a survey for the presence of R plasmids in 100 clinically isolated strains of Escherichia coli are presented. Sixty-nine per cent of the strains were resistant to at least one of the antimicrobial agents tested and 63.7% of the resistant strains transferred all or part of their resistance genes to Escherichia coli k 12.

Experimental models of atherosclerosis (the insudative theory).

Abstract: Atherosclerosis, a disease of multifactorial origin, can be promoted or caused experimentally by a wide variety of methods. The leading role of altered endothelial permeability, as well as different experimental techniques for producing changes in permeability, have been discussed by selecting the insudative theory as a working hypothesis. An attempt has been made to prove that by altering the endothelial permeability with different types of injuries, atherosclerotic vascular damage can be provoked with or without hypercholesterolemia.

Neuropharmacological supersensitivity-clinical and experimental correlates and methodological considerations.

Abstract: The effects of chronic neuroleptic treatments on spontaneous and drug-induced locomotor activity and stereotypy is reviewed. The development of tolerance in relation to supersensitivity and its biochemical and clinical correlates are discussed, in addition to central neuropharmacological studies in this area. Proposed mechanisms of supersensitivity development are discussed and suggestions for further research made.

Comparison of metronidazole assay by microbiological and chemical methods.

Abstract: Chemical (thin layer chromatography/fluorescence quenching in situ) and microbiological (agar well, diffusion technique with Clostridium perfringens as indicator strain) methods of assaying metronidazole have been compared. On dummy samples made with pure metronidazole in pooled human serum, both methods had a coefficient of variation ranging from 5.5 to 9.6 per cent of the mean. The microbiological method slightly underestimated the real amounts, and also had lower values than the chemical procedure. Comparison of serum and urine samples taken during the early, middle and late periods after medication to volunteers showed that biotransformation to antibacterially active metabolites contributes significantly to the antibacterial activity, particularly in urine. Biotransformation explains why microbiologically determined concentrations were higher than those determined chemically in samples taken at least 16-20 hours after intake of tablets or suppositories. It is important to be aware of the circumstance that the results of microbiological assay are sensu strictu limited to the particular indicator strain used, since other bacteria may exhibit other patterns of sensitivity to metronidazole and its metabolites.

Intrastriatal kainic acid- a possible model for antidyskinetic/antichoreic agents?

Abstract: Bilateral intrastriatal injection of kainic acid in conscious guinea-pigs induced a spectrum of behaviours comprising: biting, seizures and hyperactivity. Preliminary findings revealed that pharmacological modification of these behaviours was possible. Metoclopramide, haloperidol, reserpine, flurazepam, quipazine, propranolol and aceperone were found to be inactive or very weakly active on the biting behaviours and seizures. Intrastriatal GABA decreased seizure activity but not the biting, whilst RS86, clonazepam, oxiperomide and tiapride decreased biting and seizures. It is suggested that intrastriatal kainate-induced behaviour may be a useful model for delineating agents with antidyskinetic or antichoreic potential. However, the spectrum of behaviour is not always consistent and the mortality rate is high over the subsequent 24 hours.

The pharmacokinetics of cefuroxime lysine in the elderly.

Abstract: Single doses of 750 mg of cefuroxime lysine were given to eight elderly patients. The mean plasma half life was 124 minutes and the mean time to peak was 82 minutes. When compared with previous studies in young healthy volunteers, while peak plasma concentrations are similar, there is prolongation of half life and delay of excretion of the drug in the elderly. In our group studied, no local discomfort was noted following injection.

Effect of prostaglandins F2alpha and E1 on local tissue Po2 and microflow of the brain cortex (cat).

Abstract: The effects of prostaglandin F2 alpha (PGF2 alpha) and E1 (PGE1) on local tissue Po2 and microflow in the cat's brain surface were studied. Local tissue Po2 was polarographically measured with a multiwire surface electrode, and microflow measured by local hydrogen clearance method. The PGs were investigated by intracarotid (i.c.) infusions, single i.c. and intravenous (i.v.) injections. The i.c. infusions were made with dose of 3, 10 and 30 microgram/kg/min of PGF2 alpha and 0.1, 0.4 and 1.0 microgram/kg/min of PGE1. The i.c. application of PGF2 alpha led to a decrease in local tissue Po2 and tissue microflow. With the use of comparatively low doses (3 and 10 microgram) the effect appeared to be more specific, since SAP did not change significantly. Systemic (i.v.) injections of PGF2 alpha caused a significant drop in arterial pressure and decrease in tissue Po2. Studies with PGE1 always demonstrated a decrease in local tissue Po2 and microflow associated with a significant decrease in the SAP. No evidence for a specific effect was found. Suggestions for possible mechanism of action for these PGs are made.

Contribution to the control of the locomotor activity of the dog.

Abstract: A measuring arrangement was developed for the quantitative determination of the locomotor activity in the dog. The activity is controlled by installing light barriers in the dog kennel. The light-barrier interruptions are counted at given intervals via an electronic system described in this study and the counts are printed by a printer. This allows an automatic control of the locomotor activity continuously even over long periods. The measuring arrangement was tested for its practicability. The locomotion-increasing effect of amphetamine and the locomotion-inhibitory effect of haloperidol were demonstrated in beagles, and dose-dependent differences could be measured quantitatively. The comparison between the control groups of the two investigations, and the values measured prior to treatment, show good reproducibility of the results.

Reproducibility of strain gauge venous occlusion plethysmography in long-run measurements in man.

Abstract: In order to evaluate strain gauge venous occlusion plethysmography as a tool to test the effects of treatment on peripheral blood flow, some biasing effects due to this technique were studied in relation to a long-run session and to cuff and gauge displacement. Arm peripheral blood flow was estimated by a computerized procedure during three successive days in a young male subject. The measurements were arranged as follows: 1) 75 replications under constant conditions, lasting 1.6 hours; 2) 18 triplets with alternative cuff displacement between two forearm positions, lasting 1.5 hours; 3) 40 measurements taken alternatively with a fixed gauge and a displaced one from a proximal to a distal position and vice versa, lasting 2.1 hours. Statistical comparison revealed: 1) a good long-run reproducibility during the first session; 2) a significant difference between the first and third day sessions under the same conditions; 3) a significant difference between the distal and proximal cuff mean flows during the second day session; 4 significant differences among the third day means in dependence of gauge position; 5) no significant dependence on strain gauge tension during the third day session. It is thus concluded that strain gauge plethysmography may be a reliable technique mainly in a longitudinal experimental design when the acute effect of some drug administration is to be evaluated.

Experimental rheoencephalographic and electroencephalographic investigations on piracetam.

Abstract: The influence of piracetam (2-oxo-1-pyrrolidine-acetamide, Pyramem) on the cerebral circulation and brain bioelectrical activity of cortex and mesencephalic reticular formation (RF) was studied in acute experiments on cats which were encephale isole preparations. The methods of local cerebral rheoencephalography (REG) and electroencephalography (EEG) were used. The following REG parameters were assayed: anacrotic section of the curve and its relative part, amplitude and duration of the wave. The arterial blood pressure was followed continuously. The results show that upon piracetam administration (150 mg/kg i.v.) an improvement of the REG parameters of the cortex and RF is observed-an increase of the amplitude and decrease of the values of the anacrotic section of the curve and its relative part. The changes observed indicate a cerebro-vascular resistance decrease and give indirect evidence of cerebral blood volume increase. EEG data are characterized mainly by an increase of alpha-waves, both of cortex and RF. Suggestions for possible mechanism of action of piracetam are made.

The solubility of phenytoin in a physiological salt solution

Abstract: The solubility of phenytoin (PHT) was examined at room temperature (23 degrees C) one hour and 16 hours after solutions were made. PHT was considered to be dissolved if it could be centrifuged at 1500 c g for 30 minutes without loss of supernatant radioactivity produced by 14C-PTH. Radio-labelled PHT dissolved in 50 mM NaOH (pH 12.6) was used as control. One hour after mixing, PHT concentrations greater than 200 microM were incompletely dissolved. Sixteen hours after mixing, concentrations greater than 150 microM were incompletely dissolved. Solutions made with an excess of Na-PHT yielded a supernatant concentration of 105 microM measured 24 hours after mixing. It is concluded that PHT concentrations higher than 105 microM may form supersaturated solutions that remain homogeneous for 16 hours if the total concentration does not exceed 150 microM. The 150 microM solution is considered to be a relatively stable supersaturated solution since the addition of a small amount of Na-PHT caused only a 7% reduction in supernatant radioactivity after 13 hours.