Showing papers in "Methods and Findings in Experimental and Clinical Pharmacology in 1989"

Acceptability of visual analogue scales in the clinical setting: a comparison with verbal rating scales in postoperative pain.

Abstract: Pain is the clinical symptom most difficult to evaluate. Although clinical trials methodology have permitted assessment of pain objectively through rating scales, these strategies have not been used in clinical setting. The present study was undertaken to determine if visual analogue scales could be useful in the measurement of postoperative pain in usual medical practice. The study comprised 212 patients with abdominal, orthopedic or gynecological surgical procedures within the previous 24 h. Patients evaluated their pain using a verbal rating scale (VRS) of five points or a visual analogue scale (VAS) of 10 cm. The investigators also evaluated patient pain through a VAS. The results obtained showed that a high correlation between VRS and VAS could be established in all patients (p less than 0.001). The VAS of patients and researchers were also found to be highly correlated (p less than 0.001). When values of each group were compared by pain intensity a total agreement of VAS scores at low pain level could be established, but differences were found at high pain intensity levels, suggesting that physicians scored lower than patients when pain was severe to unbearable. It is concluded that VAS could be a reliable method to assess pain in clinical setting.

Brain histamine in Alzheimer's disease.

Abstract: The concentration of histamine (HA) has been determined by high-performance liquid chromatography (HPLC) with fluorometric detection in 21 different regions of brains from patients with senile dementia of the Alzheimer type (SDAT) and subjects (CB) whose causes of death were not related to neuropsychiatric, neurological and/or neurodegenerative diseases. The highest levels of HA in the central nervous system (CNS) of both control (CB) and SDAT samples were found in the posterior hypothalamus (CB = 3.13 +/- 0.63 pmol/mg; SDAT = 7.75 +/- 1.43 pmol/mg, p less than 0.005), where the HA neurons are located, and in the anterior hypothalamus (CB = 1.77 +/- 0.33 pmol/mg; SDAT = 2.82 +/- 0.45 pmol/mg, p less than 0.005). The lowest HA levels were detected in the cerebellum (CB = 0.12 +/- 0.04 pmol/mg; SDAT = 0.24 +/- 0.09 pmol/mg, p less than 0.01) and medulla oblongata. HA levels were significantly higher in SDAT than in CB in the following areas: motor cortex (Brodmann's area 4) (A4), premotor cortex (A6), postcentral gyrus (A1,2), posterior parietal cortex (A5,7), superior temporal gyrus (A41,42), temporal pole (A38), primary and secondary visual cortices (A17,18), anterior and posterior regions of the hypothalamus, putamen, caudate nucleus, nucleus accumbens, thalamus, hippocampus, pons, medulla oblongata and cerebellum. No changes were seen in globus pallidus and corpus callosum. Since the origin of HA in the brain is dependent upon three main compartments (neuronal, mast cell, vascular smooth muscle), with approximately 60-80% of the total HA belonging to the neuronal pool, on the basis of neurochemical data we postulate that the increase in the levels of HA in SDAT might account for or be associated with alterations in neuroendocrine, cognitive, neurovascular and sleep-wakefulness functions.

Effectiveness of a transdermal nicotine system in smoking cessation studies.

Abstract: To investigate the effectiveness and tolerability of a transdermal nicotine system (TNS) as an aid towards easing smoking cessation, two double-blind placebo-controlled randomized field studies were performed. The TNS was available in sizes of 10, 20 and 30 cm2, delivering 7, 14 and 21 mg of nicotine per 24 h. A first study was undertaken in general medical practice by a group of 21 doctors (Practitioner Study). This study involved 199 nicotine-dependent cigarette smokers of whom 100 were allocated to the nicotine group and 99 to the placebo group. The second trial was performed in 112 young people, 56 in each treatment group, at the Universities of Basle and Zurich (University Study). The placebo and the nicotine groups were comparable in both studies. Participants smoking more than 20 cigarettes a day were treated with the 30-cm2 system and the others with the 20-cm2 system. When abstinence, as verified by CO measurements, was achieved, the next smaller system was applied. In the Practitioner Study, the double-blind treatment phase lasted for 12 weeks with consultations every month and in the University Study the consultations during the 9-weeks' treatment period took place every 3 weeks. Abstainers in both studies will be followed up until 12 months after treatment was begun. After 1, 2 and 3 months of treatment 41%, 36% and 36% of the participants in the nicotine group of the Practitioner Study were abstinent. The corresponding figures in the placebo group were 19.4%, 20.4% and 22.5%. The differences were statistically significant for all three months (p = 0.001; p = 0.018 and p = 0.043). Body weight did not increase in the TNS group, but did in the placebo group (+ 4.4 kg). The craving for cigarettes and withdrawal symptoms decreased more under nicotine substitution. Abstinence rates in the University Study were initially higher with 51.8% in the nicotine group and 28.6% in the placebo group after 3 weeks of treatment, but then declined to 42.9% after 6 weeks and 39.3% after 9 weeks in the nicotine group and to 25% and 19.6%, respectively, in the placebo group. The differences between the groups were statistically significant on all 3 occasions, with p = 0.012, p = 0.046 and p = 0.023.(ABSTRACT TRUNCATED AT 250 WORDS)

Delivery of anticancer drugs.

Abstract: Chemotherapy is a major therapeutic approach for the treatment of both localized and metastasized cancers. Since anticancer drugs are neither specific nor targeted to the cancer cells, improved delivery of anticancer drugs to tumor tissues in humans appears to be a reasonable and achievable challenge. Scientists are working to increase the availability of drug for tumor uptake by 1) delaying the release preparations for long-lasting actions; 2) using liposome-entrapped drugs for prolonged effect or reduced toxicity; 3) administrating inert, non-toxic prodrugs for specific activation at the tumor site; 4) delivering the antibody-mediated drugs; or 5) conjugating site-specific carriers to direct the drug to the tumor target. The latter depends heavily on pharmacokinetic investigations. Some success has been achieved in enhancing the efficacy and reducing the toxicity of drugs. Pharmacokinetic and pharmacodynamic considerations are two areas which have been focused toward the quantitative pharmacological studies of anticancer drugs in this manuscript. This review covers biodistribution and elimination, furnishing information on body clearance and unveiling sites of major metabolism; administration of anticancer drugs via various routes for optimal utilization; intra-arterial infusion for localized tumors, intrathecal, intraperitoneal and intrapleural injection for regional cavity administration. Conventional delivery routes, doses, pharmacokinetics data and elimination routes of therapeutic anticancer drugs are tabled. General approaches for delivery of anticancer drugs in achieving therapeutic improvements are outlined and correlated. Mechanism of drug resistance, and specific changes affecting the delivery of available chemotherapeutic agents, as well as the drugs to restore the sensitivities to agents of resistant tumor cells, are discussed. This monograph covers the developments and progress in the delivery of anticancer drugs in two approaches: the theoretical approach, including pharmacokinetic and pharmacodynamic considerations, therapeutic implications and mechanism of drug resistance, and the practical approach, including the physical, chemical, biochemical and physiological considerations. Among these, the physical approach for the delivery of anticancer agents to target sites (via microparticulate drug carriers: nanoparticles, liposomes, microspheres and activated carbon as well as the magnetic microcapsules) has shown recognizable improvements in prolonging anticancer effects and reducing toxicities. Implantable pumps and reservoirs for regional chemotherapy provide external control of delivery rate. The implanted systems, in general, yield better results than the traditional treatments in the treatment of liver and brain cancer. Chemical approaches for the improvement of drug delivery use prodrugs, biodegradable polymers and macromolecular matrix techniques.(ABSTRACT TRUNCATED AT 400 WORDS)

High plasma levels of cortisol in patients with senile dementia of the Alzheimer's type.

Abstract: Plasma cortisol levels and other factors including thyroid hormone in patients with Alzheimer's type (n = 10), vascular type (n = 10) or mixed type (n = 10) senile dementia were compared with those in non-demented senile controls (n = 10). Plasma cortisol levels at 8:00 a.m. in Alzheimer's type dementia and mixed type dementia were 17.3 +/- 4.3 micrograms/dl (mean +/- SD) and 15.6 +/- 2.3 micrograms/dl, respectively. These values were significantly higher (p less than 0.005 and p less than 0.01) than those found in the control subjects (12.0 +/- 3.1 micrograms/dl). Plasma cortisol levels in vascular-type dementia (14.4 +/- 6.3 micrograms/dl) did not differ significantly from those in the controls. Plasma ACTH in senile dementia of the Alzheimer's type was lower, but not significant as compared with that in normal controls. In three subgroups of senile dementia and normal controls, plasma cortisol levels inversely correlated significantly with the degree of cognitive function. Plasma levels in TSH-thyroid system and blood pressure did not show any significant change in three types of senile dementia. These data suggest that senile dementia of the Alzheimer's type accompanies relatively and primarily high plasma cortisol levels and this may associate with cognitive dysfunction in Alzheimer's type senile dementia.

Pharmacokinetics and bioavailability of nicotine in healthy volunteers following single and repeated administration of different doses of transdermal nicotine systems.

Abstract: Healthy nicotine-dependent smokers were applied different doses of transdermal nicotine systems (TNS) during single and repeated administrations. Plasma and urine nicotine and cotinine concentrations were determined by high performance liquid chromatography (HPLC). After single application of TNS, the maximal concentration (Cmax) and area under curve (AUC) of nicotine in plasma as well as the amount of nicotine excreted in urine were linearly related to the dose. The stable urinary cotinine excretion was not influenced by the amount of nicotine delivered by the TNS. The relevant 24 h plasma nicotine concentration reached after TNS application compares well with the plasma nicotine footpoints--not the peaks--observed in moderate to heavy cigarette smokers. A comparison between different nicotine doses from different TNS allowed to conclude to the functionality of the systems as regards pharmacokinetics and bioavailability. One or two hours after removal of the systems, there was a very slow decline of the nicotine concentrations. After repeated application of TNS, there was evidence for only a very limited nicotine accumulation in plasma (+14%) or in urine (+9%) over 10 days. The steady-state of nicotine was reached within 4 days. The continuous delivery of nicotine over 24 h resulted in an early morning plasma concentration which probably decreases or prevents the craving for the first cigarette.

Percutaneous absorption of rosmarinic acid in the rat.

Abstract: Rosmarinic acid (RA) is a nonsteroidal anti-inflammatory agent. The purpose of the study was to investigate the transdermal absorption of RA, its tissue distribution and absolute bioavailability. In ex vivo experiments, permeation of RA across excised rat skin was about 8 times higher from alcoholic solution than from water, indicating that ethanol may act as sorption promoter. The flux from water or alcoholic solution was 4.4 or 10 micrograms/cm2/h, and the tleg was 7.8 or 3.7 h, respectively. After I.V. administration, RA is best described by a 2-compartment open model; t1/2 = 1.8 h, t1/2 alpha = 0.07 h, V tau = 2.3 L/kg, V beta = 15.3 L/kg. Upon topical administration of RA in form of a W/O ointment (25 mg/kg, 50 cm2), the absolute bioavailability was 60%. 0.5 hours after I.V. administration, RA was detected and measured in brain, heart, liver, lung, muscle, spleen and bone tissue, showing the highest concentration in lung tissue (13 times the blood concentration), followed by spleen, heart and liver tissue. 4.5 hours (peak time) after topical administration of about 3 mg on the hind leg over 20 cm2, RA was measured in blood, skin, muscle and bone tissue. The percutaneous route of administration seems to be a promising one for the therapeutic use of RA as nonsteroidal anti-inflammatory agent.

Opiate-induced pupillary effects in humans.

Abstract: The pupillary effects of several opiates were assessed in human volunteers (N = 6) by means of a newly developed hand-held pupilometer, Pupilscan. Static (diameter) and dynamic (light reflex) responses after morphine, heroin, codeine, oxycodone, oxymorphone and hydrocodone were recorded. The opiates caused dose-related decreases in pupillary size and in the velocity of constriction to a light stimulus. The velocity of redilation after a light stimulus was also decreased. These data indicate that opiates cause systematic changes in dynamic pupillary responses in humans and that measures of these changes may be useful in the quantitative estimation of drug-induced impairment.

Contact allergies induced by TTS-treatment.

Abstract: The efficiency of a nicotine-containing transdermal therapeutic system (TTS) was investigated in a clinical study, the purpose of which was to help 183 heavy smokers give up their addiction by systematic and continuous nicotine application and simultaneous behavioral therapy. During the treatment period, 53% of the patients complained of pruritus and 39% developed erythemas that were almost exclusively confined to those areas where the patches had been applied. However, most symptoms appeared only in slight or moderate forms. In contrast to irritative cutireactions, 6 patients developed a genuine contact allergy (type IV, delayed type reaction) which proved in 5 cases to be induced by the nicotine contained in the patches. Presumably TTS-treatment may induce contact allergies to pharmaceutic agents, as has already been described in other observations on allergies to haptens.

Percutaneous absorption of coumarin, griseofulvin and propranolol across human scalp and abdominal skin.

Abstract: The objective of this study was to investigate the role of the transfollicular pathway in the diffusion process of chemicals through excised human skin in vitro Skin was obtained from 5 cadavers (3 males, 3 females) within 24 h of death The age of the subjects varied between 18-77 years Three radiolabelled drugs, namely 14C-coumarin, 3H-propranolol and 3H-griseofulvin, were studied The permeation parameters such as flux, lag time, diffusion coefficient and permeability constant were determined across scalp and abdominal skin using the Thomas Diffusion Cell For all tested substances the flux through scalp skin was higher than across abdominal skin and the lag time was decreased The differences were statistically significant at p less than 005 for coumarin and propranolol These data suggest that the transfollicular pathway in permeation might have a significant impact on the diffusion parameters for some drugs Also, in the case of coumarin, permeability seems to be epidermis/dermis-controlled, whereas for griseofulvin and propranolol the Stratum corneum apparently is the permeability limiting barrier

Computerized rotometer apparatus for recording circling behavior.

Abstract: A computerized rotometer for recording rotational behavior in rats is described. The digital pulses derived from the infrared photocell detector induced by animal rotations were input directly to a 20-megabyte microcomputer for on-line recording and were processed further to the Digital Equipment Corporation's VAX computer with the SAS software system for statistical and graphical analysis. The typical results obtained with drugs (apomorphine and amphetamine) eliciting contralateral and ipsilateral rotation in rats with unilateral 6-hydroxydopamine (6-OHDA)-induced lesions of the nigrostriatal dopamine pathway were presented. The effect of catechol-O-methyltransferase (COMT) inhibitor, OR-611, on the potentiation of L-dopa-induced contralateral rotation in 6-OHDA-lesioned rats was also studied. The automation of rotometer apparatus and the speed of data analysis facilitate screening novel antiparkinsonian drugs in rats with unilateral lesions of 6-OHDA.

Psychophysiological research in psychiatry and neuropsychopharmacology. II. The investigation of antihypoxidotic/nootropic drugs (tenilsetam and co-dergocrine-mesylate) in elderlies with the Viennese Psychophysiological Test-System (VPTS).

Abstract: In a double-blind placebo-controlled study, the effects of tenilsetam, a novel antihypoxidotic/nootropic agent, on spontaneous and event-related activity of the central and autonomous nervous system were studied in 15 elderly subjects of both sexes aged 58-77 years by means of the Viennese Psychophysiological Test-System (VPTS). The VPTS includes a special selection and combination of experimental situations, physiological measurements, behavioral measurements and data analysis. At weekly intervals, the subjects received randomized single oral doses of placebo, 150 mg, 300 mg and 900 mg tenilsetam (TEN) and 5 mg co-dergocrine-mesylate (CDM) as reference drug. Psychophysiological testings were carried out before and 2 h after drug administration. Evaluation of the spontaneous EEG-activity demonstrated no significant drug effects as compared to placebo. In contrast, TEN showed a dose-dependent augmentation of the N1-P2 and N2-P300 amplitudes of the event-related potentials (ERPs) in specific experimental conditions. In reference to placebo, the increase of N2-P300 amplitude after the highest dosage of TEN, as well as after CDM, amounted to approximately 5 microV, which confirms the hypothesis that nootropic drugs may influence the P300 amplitude in the sense of an improved availability of cognitive processing resources. There was no effect on ERP latencies, on mean amplitudes of contingent negative variation and of post-imperative negative variation, on autonomous nervous system, on psychological measurements, nor on reaction time. However, specific improvements were observed in psychomotor measures, such as synchronization accuracy and rhythmicity. These findings highlight the importance of using EEG and ERP measures in different experimental situations in conjunction with behavioral, psychological and autonomous nervous system measures to study nootropic drug effects.

The defensive role played by the gastric microcirculation.

Abstract: Microcirculation plays an important role in the maintenance of functional integrity of the stomach and in the provision of its defense mechanisms against damage. Changes in blood flow in the gastro-duodenal mucosa, brought about by the local release of vasoactive or cytotoxic mediators, including free-radicals, the eicosanoids thromboxanes and leukotrienes, and the related phospholipid, PAF, have been implicated in the pathogenesis of various forms of peptic ulceration and erosive gastritis. Damage to microvessels and vascular endothelium leading to disruption of microcirculation is considered to be an initial event in the development of such lesions. Furthermore, preservation of microcirculation by prostaglandins is likely to make an important contribution to the overall protection of the gastric mucosa by these agents. Studies on the hemostatic mechanisms in the gastric mucosa indicate that bleeding is initially arrested by a coagulation process that is independent of platelet aggregation. Thus, the identification and characterization of microcirculatory events is of major importance in the understanding of pathophysiological processes in the gastric mucosa.

Circulatory counter-regulations induced by continuous administration of nitroglycerin.

Abstract: In a placebo-controlled, double-blind, cross-over study in seven healthy volunteers, continuous transdermal administration of nitroglycerin over 48 h by means of Nitroderm TTS 10 evoked counter-regulations that interfered with the nitrate effects. These counter-regulations comprised an increase in sympathico-adrenal activity, manifested in elevated plasma levels of adrenaline and noradrenaline, and an internal hemodilution, readily perceptible from the decrease in the hematocrit readings. As a result, several of the circulatory effects of nitroglycerin were no longer in evidence, or much weaker on the second day of the study. The effects concerned were the reduction of systolic and diastolic blood pressure, the increase in heart rate, the prolongation of PEPc, and shortening of LVETc, and the change in digital-pulse morphology (increase in the a/b quotient). On the other hand, the increase in venous distensibility and the decrease in hematocrit were unaltered throughout the observation period. The attenuation of the action of nitroglycerin noticeable 24 h after application of the patches is, therefore, not indicative of any loss of effect of the substance per se, but due to the circulatory counter-regulations, which were largely confined to the arterial side of the circulation and scarcely affected the venous system. One or two hours after removal of the patches, counter-regulations had practically ceased.

Human pharmacological investigations of a transdermal nicotine system.

Abstract: To define the pharmacological properties of a newly developed transdermal nicotine system (TNS) designed to facilitate abstention from smoking, three human pharmacology studies were performed in healthy, nicotine-dependent smokers. The first study, in which cigarette smoking served as the standard mode of nicotine intake, was carried out to evaluate the most suitable non-invasive methods for detecting the pharmacodynamic effects of nicotine and to provide a baseline for comparisons with the results of the subsequent studies to assess the effects of single and repeated applications of the TNS. The pharmacodynamic changes induced by smoking were generally most pronounced after the first cigarette following 10 hours' abstinence. The most sensitive parameters were heart rate, which increased, stroke volume measured by impedance cardiography, which decreased, cutaneous blood flow measured by Laser Doppler flowmetry and skin temperature, which diminished to a statistically significant extent after each cigarette. Increases in blood pressure were not very pronounced. Plasma catecholamines were consistently elevated after each cigarette, but the changes were not statistically significant. Compared with those induced by cigarette smoking, the cardiovascular effect seen after either a single application of the TNS (10, 20 and 40 mg/24 h) or repeated application of a TNS delivering 14 mg nicotine/24 h were minor. A slight increase in blood pressure was detectable only on the first day of application and had disappeared after 10 days' repetitive application, suggesting the development of partial tolerance. Heart rate was slightly increased by 3-7% and stroke volume decreased by 5-12% on the tenth day of TNS application.(ABSTRACT TRUNCATED AT 250 WORDS)

Psychophysiological research in psychiatry and neuropsychopharmacology. I. Methodological aspects of the Viennese Psychophysiological Test-System (VPTS).

Abstract: In order to find a psychophysiological paradigm for clinical application we have developed the Viennese Psychophysiological Test-System (VPTS), which includes a special selection and combination of experimental situations, physiological measurements, behavioral measurements and data analysis. This study presents detailed information concerning these four aspects. Experimental situations are related to the human model of information processing, where short changes of stimulus-reaction-correlated processes are selected: resting conditions (eyes open, eyes closed), habituation-orienting test, psychomotor-performance test, signal-detection test and reaction-time test. Physiological measures include central and peripheral activity of the cerebrospinal and autonomic nervous system: cortical activity (spontaneous electroencephalogram, auditory evoked potentials, late positive components, slow potentials), ocular activity (eye and eyelid movements), electrodermal activity (skin conductance), cardiac activity (heart rate measurement), respiratory activity (rate of respiration) and peripheral vascular activity (finger pulse volume). Behavioral measurements extend from micro behavior to complex diagnostic systems: psychomotor measurements, self-reported mood, arousal and visceral perception, psychological and psychiatric interviews. The application of this test system in 15 elderly subjects of both sexes aged 58-77 years gives information which exceeds the sum of the singular constructing elements of the VPTS.

Study on the peroral absorption of the endekapeptide cyclosporine A.

Abstract: The beagle dog was found to be a suitable model for pharmacokinetic and bioavailability studies of cyclosporine A (CsA). All pharmacokinetic parameters studied were in the same order of magnitude as those found in man. Three CsA peroral formulations in the form of capsules were compared with a commercially available P.O. solution (to be diluted for administration) and a solution for intravenous administration. Of the three experimental capsule formulations, one based on a microemulsion resulted in an extent of absolute and relative bioavailability not different from that of the available P.O. solution. The advantage, however, is that it is a capsule preparation, ready to swallow, and does not need any manipulation by the patient to dilute the solution. The other two capsule preparations, based on a Gelucire gel with sorption promoters and a microemulsion containing Azone, resulted in a lesser bioavailability than the solution.

Histamine and its actions on isolated tissues of lower vertebrates.

Abstract: The response to histamine (Hi) of isolated organs such as the intestinal tract and heart, obtained from certain lower vertebrates, was investigated phylogenetically and compared with the response to acetylcholine (ACh), 5-hydroxytryptamine and epinephrine (Ep). Contractions induced by Hi (10(-4) M) were not noticeable in any of the intestinal strips of fish and amphibians tested, although ACh produced marked contractions in all preparations even at 10(-6) M. Contractile responses of intestinal preparations to Hi were elicited from reptiles, and seemed to be associated with the H1 receptor in many species but not with the H2 receptor. In isolated fish auricles, neither inotropic nor chronotropic responses were produced by Hi. In bullfrogs and in the majority of species, including reptiles and higher classes, a marked positive inotropic response was elicited via H1 or H2 receptors, but in some animals chronotropic effect was less impressive. The effects of ACh and Ep on heart preparations were remarkable in almost all species tested. When the Hi contents in various tissues were studied comparatively, a determinant stage of Hi appearance in the tissue coincided with the stage in which a definite Hi response emerged in isolated organs.

Mode of action of razoxane: inhibition of basement membrane collagen-degradation by a malignant tumor enzyme.

Abstract: Razoxane is an antitumor agent structurally related to EDTA. Its cytotoxic mechanism of action has been shown to involve interference with cell division and reduction of the gross rate of DNA synthesis. In this study we present evidence that razoxane, at therapeutically attainable concentrations, inhibits type IV collagen and basement membrane degradation by an enzyme isolated from malignant tumors. This effect is attributed to the chelating properties of razoxane and may explain the antimetastatic properties, by means of stabilization of tumor blood vessels, which have been associated with the action of the antitumor drug.

Effects of carbamazepine, valproate calcium, clonazepam and piracetam on behavioral test methods for evaluation of memory-enhancing drugs.

Abstract: The effect of three anticonvulsants on several test methods for evaluation of memory-enhancing drugs have been studied in rats and mice. The results were compared to the results obtained from the nootropic piracetam and from imipramine. In an active avoidance test (pole jumping), repeated administration of carbamazepine (5 mg/kg i.p.) and piracetam (300 mg/kg p.o.) protected against impairment of learning rate caused by repeated application of an electroconvulsive shock. Valproate calcium (repeated administration of 30 mg/kg i.p.) was only weakly active, while clonazepam (repeated administration of 0.3 mg/kg i.p.) decreased the learning rate even more. Drugs were given in dosages which have no anticonvulsive activity in this test. The impairment of learning rate caused by repeated application of ethanol was prevented by carbamazepine (5 mg/kg i.p.), valproate calcium (30 and 100 mg/kg i.p.) and piracetam (100 mg/kg i.p.). Clonazepam (0.3 and 1 mg/kg i.p.) had a worsening effect on learning rate. In Porsolt's behavioral despair test, carbamazepine (5, 10 and 30 mg/kg i.p.) and valproate calcium (30 and 100 mg/kg i.p.) shortened the duration of immobility, which indicates an increased psychomotor activity. Clonazepam was ineffective. Results obtained with carbamazepine are similar to those obtained with piracetam. The data are discussed in view of the so-called psychotropic effects of carbamazepine in clinical trials.

High performance liquid chromatographic determination of nicotine and cotinine in plasma and nicotine and cotinine, simultaneously, in urine.

Abstract: Three analytical procedures were developed to determine nicotine in plasma, cotinine in plasma and, simultaneously, nicotine and cotinine in urine. After liquid or solid-phase extraction, the purified aqueous phase is injected into a high performance liquid chromatograph equipped with an ultra-violet detector using a CN Spheri-5 micron cartridge-column with an inner diameter of 4.6 mm and a length of 10 or 22 cm. The limit of quantitation for nicotine in plasma was around 8 to 15 ng/ml, that of cotinine in plasma around 50 ng/ml and that of nicotine and cotinine in urine around 170 ng/ml and 70 ng/ml, respectively. The limit of detection of nicotine in plasma was around 1 ng/ml and that of nicotine and cotinine in urine around 20 ng/ml and 10 ng/ml, respectively. The passive exposure to cigarette smoke by non-smokers and the "resting levels" of nicotine in plasma and urine of smokers were studied. The analytical methods were set up to study the pharmacokinetics and bioavailability of nicotine in healthy volunteers following single and repeated administrations of different doses of transdermal nicotine systems.

GABAergic agents-induced antinociceptive effect in mice.

Abstract: The effect of GABA agonists, namely gamma aminobutyric acid, muscimol, sodium valproate and baclofen was studied on radiant heat-induced nociception in mice. All of the drugs, with the exception of sodium valproate, enhanced the reaction time to radiant heat as effect per se. Concomitant administration of any of these agents with morphine showed a potentiation of morphine-induced analgesia. The GABA antagonists bicuculline and picrotoxin failed to reverse the antinociceptive effect; paradoxically both these agents showed antinociceptive effect per se and also enhanced the response due to morphine.

Transdermal delivery systems.

Abstract: Based on a number of revolutionary ideas in the early seventies the development of transdermal delivery systems (TDS) for systemic therapy has been receiving considerable attention, both in academia and in the pharmaceutical industry. About ten years after a number of products were successfully put on the market, it has become clear that transdermal delivery of drugs not only exhibits appealing therapeutic prospects but may also provide a viable economic basis for future activities of the pharmaceutical industry. The paper will briefly stress some of the fundamentals of transdermal delivery with respect to the skin as absorption site. The main focus will be on transdermal delivery systems, covering design of transdermal systems, manufacturing of transdermal systems, polymers and adhesives, in vitro and in vivo testing of transdermal systems, principles of delivery control, and modelling of transdermal delivery. The final section will describe the fundamental strategies for enhancing drug permeation through the skin by alteration of barrier properties, approaches for thermodynamic activity increase of drug, and the iontophoretic transdermal delivery of drugs.

Further evidence for the GABAergic influence on memory. Interaction of GABAergic transmission with angiotensin II on memory processes.

Abstract: In experiments on male Wistar rats trained on active avoidance (shuttle-box) and passive avoidance (step-through) tasks, we found that (-) nipecotic acid, the inhibitor of GABA reuptake, and muscimol, a GABAA-receptor agonist, applied after training either improved or had no effect on retention, depending on the dose used. Angiotensin II (ATII) at a dose of 0.1 microgram/kg injected intracerebroventricularly (i.c.v.) after training facilitated retention. Combinations of ATII and (-) nipecotic acid or muscimol potentiated the memory effects of ATII and GABAergic drugs, respectively. Blockade of GABA receptors (GABAA) by bicuculline or picrotoxin abolished the effects of GABAergic agonists on ATII. It is suggested that GABAergic transmission participates in the consolidation and formation of memory traces and in the retention-facilitating mechanism of action of ATII.

Influence of nootropic drugs on the memory-impairing effect of clonidine in albino rats.

Abstract: The effects of four nootropic drugs (piracetam, aniracetam, meclofenoxate and fipexide) on cognitive functions impaired by the antihypertensive drug clonidine were investigated in albino rats. The changes in learning and memory were studied by two-way active avoidance with punishment reinforcement (shuttle box). Clonidine injected intraperitoneally at a dose of 0.1 mg/kg immediately after a one-day shuttle box training significantly impaired retention. A 5-day treatment before the training session with piracetam 600 mg/kg, aniracetam 50 mg/kg, meclofenoxate 100 mg/kg and fipexide 10 mg/kg completely abolished the memory-impairing effect of clonidine. The role of the NAergic neurotransmitter system in the clonidine-induced disturbances of cognition, as well as in the protective effects of nootropic drugs, was discussed.

PAF-induced platelet aggregation ex vivo as a method for monitoring pharmacological activity in healthy volunteers.

Abstract: Platelet aggregation induced ex vivo by aggregating factors such as adrenaline, ADP, collagen or PAF may be useful as a model for describing drug effects in humans. In the two studies reported here, PAF-induced platelet aggregation ex vivo was used as an indicator of the pharmacological activity in healthy volunteers of the newly developed specific PAF-antagonist WEB 2086. In intravenous and inhalative single rising dose tolerance trials this method proved useful for monitoring the pharmacological action of the compound tested. After administration of placebo no relevant pharmacological activity was observed. In both studies increasing dosages of the test substance showed clear, dose-related inhibition of PAF-induced platelet aggregation. Ex vivo PAF-induced platelet aggregation thus provides a simple and rapid means of assessing functional PAF antagonism during trials of PAF-antagonists in human volunteers.

Differential effect of type I and type II diabetes mellitus on antipyrine elimination.

Abstract: Antipyrine elimination was studied in 11 type I and 10 type II diabetic patients and 2 age-matched control groups. After oral administration of antipyrine (15 mg/kg), salivary concentration of the drug was measured at various time intervals by high performance liquid chromatography method. In type I diabetics the clearance rate (CL) and apparent volume of distribution (V) of the drug were significantly higher when compared to corresponding controls. The elimination half-life (t 1/2) remained unaltered. In type II diabetics, the t 1/2 of the drug was increased due to increase in V. There was no significant difference in CL. It is concluded that antipyrine elimination is enhanced in type I diabetics while in type II patients it is unaltered.

Iloprost-induced writhing in mice and its suppression by morphine.

Abstract: Intraperitoneally (i.p.) administered iloprost produced a writhing response indicating nociception. This effect induced by 4 micrograms/kg iloprost was dose dependently protected by morphine with an ED50 (95% confidence limits) value of 0.039 (0.0018-0.067) mg/kg. On the other hand, indomethacin had no effect on iloprost-induced writhing. Thus, this effect of iloprost seems to be relatively more sensitive than other irritants-induced responses on determining the analgesic potency of narcotic drugs.