Showing papers in "Methods and Findings in Experimental and Clinical Pharmacology in 1986"

NONLIN84/PCNONLIN: software for the statistical analysis of nonlinear models.

Abstract: A new software package, NONLIN84, has been developed for the analysis of general nonlinear models including pharmacokinetic models NONLIN84 is easier to use than the older NONLIN77, and can handle a wider class of estimation problems, such as maximum likelihood estimation involving iterative reweighting Two large libraries of pharmacokinetic models are distributed with NONLIN84 and can be accessed by simply specifying a model number A companion program, PCNONLIN, runs on DOS based microcomputers and retains most of the features of NONLIN84

AUC-RPP: BASIC computer program for compartment model independent pharmacokinetic analysis.

Abstract: A computer program in BASIC for compartment model independent analysis (AUC-RPP) is presented. The program is based on regression analysis of the terminal phase, the area under the curve and the area under the first moment curve. It is designed for i.v. constant rate infusion, i.v. push and extravascular administration. For the latter route a simple estimate on the absorption rate constant is performed.

Immunomodulation by some oligopeptides.

Abstract: The influence of bradykinin, some of its analogues, substance P and different partial sequences on lymphoid cells was studied under in vitro conditions. The oligopeptides bradykinin and substance P were found to be able to induce the secretion of charge-changing and chemokinetic lymphokines in very low concentrations. In each case, bell-shaped dose-response curves were registered in a concentration range from 10(-12) to 10(-6) M. An analysis of the lymphokine patterns suggests that T cells are the producer cells of charge-changing lymphokines. Comparing the structure-activity relationships of the peptides, the amino acid sequence Arg-Pro at the N-terminal region of bradykinin and substance P or Pro-Arg at the C-terminal part of tuftsin and rigin appear to be responsible for the lymphokine secretion.

Effects of meclofenoxate and Extr. Rhodiolae roseae L. on electroconvulsive shock-impaired learning and memory in rats.

Abstract: In experiments on albino rats, the authors studied the effects of meclofenoxate and Extr Rhodiolae roseae on the memory-impairing action of convulsant electroshock "Step-down" passive avoidance training with negative reinforcement was used to trace the changes in memory Meclofenoxate administered ip in a dose of 100 mg/kg body weight for five days prevented the retrograde amnesia observed after convulsant electroshock upon retention testing on the 3rd and 24th hr after the end of the training session The Rhodiola extract administered orally in a dose of 010 ml/rat for 10 days, which in other experimental approaches improved learning and memory, remained ineffective here The role of biogenic monoamines in the learning- and memory-improving effects of meclofenoxate is considered on the basis of earlier studies by the authors

Assessment of the hemodynamic response to single passive head up tilt by non-invasive methods in normotensive subjects.

Abstract: The hemodynamic response to passive upright tilt in thirty-five normal subjects was assessed by combined electrocardiography, differentiated electrical impedance cardiography, phonocardiography and non-invasive blood pressure measurement. The increase in transthoracic impedance and decrease in estimated stroke volume were accompanied by a cardio-acceleratory and vasopressor response. The increase in heart rate did not compensate for the decrease in estimated stroke volume and the estimated cardiac output decreased. Diastolic and mean blood pressure, however, increased. The relative systolic time interval was largely increased. Most of these changes returned to base-line on resuming the supine position. This test procedure and the non-invasive methods used offered a suitable setting for the within-subject assessment of postural changes in cardiovascular function. Certain methodological aspects were found to affect the interpretation of the impedance cardiographic data. Pre-systolic low amplitude-high velocity changes in transthoracic impedance, especially when occurring in conditions where strict respiratory control cannot be sustained, can complicate the delineation of the systolic time intervals and the correction of respiration-related fluctuations in the signal's base-line. One further subject is presented with imminent syncope on tilting, in order to highlight this intrinsic but unpredictable morbidity as a limiting factor in the application of this study procedure.

Dynamic characteristics of dopamine, norepinephrine and serotonin metabolism in axonal endings of the rat hypothalamus and striatum during hypoxia: a study using HPLC with electrochemical detection.

Abstract: The metabolism of dopamine, norepinephrine and serotonin was studied in normoxic or hypobaric hypoxic rats, using HPLC with electrochemical detection. The changes in serotonin and its metabolite 5 hydroxy indolacetic acid (5 HIAA) levels in the hypoxic striatum and hypothalamus suggest an inhibition of 5 HIAA formation and a complex interaction between synthesis, release and uptake. Hypoxia caused a decrease of the striatal levels of homovanillic acid (HVA), dihydroxy 3-4 phenylacetic acid (DOPAC) [inhibition of tyrosine hydroxylase (TH) and monoamine oxidase (MAO)] and 3-methoxytyramine (3 MT) (inhibition of release). Striatal dopamine levels were increased, suggesting an increase in granular dopamine storage, with an impaired release. Hypothalamic levels of norepinephrine were decreased during hypoxia [(inhibition of TH, MAO, and dopamine beta-hydroxylase (DBH)].

Glucan-induced hemopoietic and immune stimulation: therapeutic effects in sublethally and lethally irradiated mice.

Abstract: The hemopoietic effects of glucan, a beta 1,3 polyglycan biological response modifier, were assayed in normal and irradiated mice. In normal mice, glucan administration increased the content of bone marrow and splenic transplantable pluripotent hemopoietic stem cells (CFU-s), committed granulocyte-macrophage progenitor cells (GM-CFC), and pure macrophage progenitor cells (M-CFC). In mice partially hemopoietic depleted by exposure to 6.5 Gy of 60Co irradiation glucan increased the number of endogenous pluripotent hemopoietic stem cells (E-CFU). The most pronounced effects were observed when glucan was administered 1 day before irradiation. In addition, the administration of glucan 1 day before lethal (9.0 Gy) irradiation-enhanced survival. The enhanced survival in glucan-treated mice in part appeared to be mediated by an enhanced resistance to the surgence of enteric opportunistic pathogens that occurs following radiation-induced hemopoietic and immune depression.

Enhancement of serum antibody production in mice by oral administration of lipophilic derivatives of muramylpeptides and bacterial lipopolysaccharides with bovine serum albumin.

Abstract: Lipophilic derivatives of muramyl peptides, namely N alpha-(N-acetylmuramyl-L-alanyl-D-isoglutaminyl)-N epsilon-stearoyl-L-lysine [MDP-Lys (L18)] and 6-O-(2-tetradecylhexadecanoyl) -MDP (B30-MDP) were demonstrated to significantly enhance anti-bovine serum albumin (BSA) antibody production when they were incorporated in liposomes with BSA and administered by gastric intubation to BALB/c mice on days 0 and 1 (the primary immunization) and on days 27 and 28 (booster). N-acetylmuramyl-L-alanyl-D-isoglutamine (MDP) itself showed negligible activity under the same experimental conditions. A stearoyl derivative of sodium beta-N-acetylglucosaminyl-(1-4)-N-acetylmuramyl-L-alanyl-D-isoglutaminyl (D)-meso-diaminopimelic acid-(D)-amide-D-alanine (GM-53) that was isolated by enzymatic degradation of L. plantarum cell wall peptidoglycans also showed a powerful adjuvant effect by oral administration in liposomes with BSA. Similar or stronger adjuvant effects were observed by oral administration of bacterial lipopolysaccharide (LPS) preparations, KO3 LPS isolated from K. pneumoniae (a noncapsulated mutant, LEN-1), Bacto lipopolysaccharide W derived from. E. coli (O127:B8) and BIOSTIM F1 fraction derived from K. pneumoniae (O1:K2) Liposomes as a vehicle for oral administration were not always required for the manifestation of the adjuvant effects of MDP-Lys (L18) and BIOSTIM F1. These compounds, but not B30-MDP, showed a powerful adjuvant effect when orally administered with BSA in phosphate buffered saline.

Modulatory effect of glucans on the functional and biochemical activities of guinea-pig macrophages.

Abstract: The particulate and soluble glucan preparations isolated from Saccharomyces cerevisiae and Candida albicans affected various activities of guinea-pig macrophages. The stimulation of INT reduction and superoxide production were observed in the presence of all insoluble and some soluble glucans in vitro, but most of the preparations under study had an inhibitory effect on phagocytic activity. On the other hand, the stimulation of both metabolic and functional activities was obtained in vivo. Macrophages from guinea-pigs treated with glucans exerted an increased ability to reduce INT and to produce superoxide. Their candidacidal capacity was rapidly elevated, and peritoneal macrophages had raised phagocytic activity as well. A more pronounced stimulatory effect was observed in the presence of insoluble rather than soluble glucans, and this was more expressive in vitro than in vivo.

Mean residence time.

Abstract: The definition of mean residence time in the strict sense of mathematical statistics is deduced. It is demonstrated that the area-normalized concentration time curve is an estimate of the probability density function for residence times of drug molecules in the pharmacokinetic system, provided that the area under the concentration-time profile is proportional to the total amount eliminated from the system. Criticisms (8) on the determination of the mean residence time are refuted. The linearity of pharmacokinetic systems is defined, based on the statistical interpretation of these systems.

Intracellular sodium, potassium and magnesium concentration, ouabain-sensitive 86rubidium-uptake and sodium-efflux and Na+, K+-cotransport activity in erythrocytes of normal male subjects studied on two occasions.

Abstract: The red cell Na+,K+-ATPase pump activity estimated by the ouabain-sensitive 86Rb-uptake or Na+-efflux, the Na+,K+-cotransport activity measured either by the furosemide-sensitive K+- or Na+- efflux or by the ethacrynic acid-sensitive 86Rb-uptake as well as the intraerythrocyte concentration of sodium, potassium and magnesium were studied in 29 normal male subjects with one to three weeks interval between the first and second blood sampling. Both the red cell sodium and potassium concentration, the erythrocyte ouabain-sensitive 86Rb-uptake and Na+-efflux, the furosemide-sensitive Na+- and K+-efflux and the ethacrynic acid-sensitive 86Rb-uptake are stable over time in the same individual. The furosemide-sensitive Na+-and K+-efflux is significantly related to the ethacrynic acid-sensitive 86Rb-uptake. The intraerythrocyte Na+ concentration was negatively related to the ouabain-sensitive 86Rb-uptake, but not to the ouabain-sensitive Na+-efflux; it was, however, negatively related to the rate constant for the ouabain-sensitive Na+-efflux.

Prediction of apparent volume of distribution in obesity.

Abstract: A standard height-weight table permits the separation of the obese body into two compartments: a lean and a fat Depending upon the physicochemical properties of a drug, such as pKa, apparent partition coefficient and extent of protein binding, the distribution of a drug could either be in the lean compartment or in the whole body Based on this thesis, several equations, either published in the literature or developed for this report, all based on the physico-chemical properties of a drug and the physiological changes in the obese subject, were used to compare the apparent volume of distribution, Vz as predicted by these equations with the Vz values of several drugs reported in the literature for obese subjects Duncan's multiple range test was used for testing literature values vs predicted data Examples from the literature are reported and discussed The validity of these equations needs to be verified as more information on pharmacokinetic parameters in obesity becomes available

Rodent whole-embryo culture as a teratogen screening method.

Abstract: Postimplantation embryo techniques can sensitively detect compounds with adverse biological activity. The versatility of the in vitro embryo toxicity/teratogenicity screening assay has been augmented by the addition of adult hepatic metabolic activation systems, which influence the results for some compounds in the embryo culture system. In this assay, cyclophosphamide produces negative results without metabolic activation and positive results with activation; metabolic activation changes the results for cytochalasin D from positive to negative. Another improvement has been the evaluation of the embryo toxicity/teratogenicity of various water-immiscible solvents. As these studies revealed that sonicated corn oil/serum preparations were nontoxic at concentrations of up to 10% of the culture medium, these solvents can now be used to expose cultured embryos to water-insoluble compounds (e.g., chlorinated pesticides). This in vitro rodent whole-embryo culture makes it possible to investigate extremely rapid cell division and specific time-related morphogenic events. Because in vitro development so closely parallels that occurring in vivo, the in vitro embryo culture system appears to be particularly relevant for the detection of teratogenic and embryotoxic compounds. A variety of compounds have been assayed in vitro via a combination of metabolic activation system and/or water-insoluble chemical delivery systems. Correlation between the published results of the in vitro screening assay and the published results of in vivo embryo toxicology and teratology studies has been very good. However, most of the compounds used in in vitro testing have been strongly teratogenic, and little information is available on compounds that are not teratogenic in in vivo tests. There is also a good correlation between the concentrations of teratogenic agents that cause adverse effects in vitro and the in vivo teratogenic doses of these compounds.

The bioavailability of Tamoplex (tamoxifen). Part 1. A pilot study.

Abstract: Tamoxifen and N-desmethyltamoxifen plasma concentrations were found to be similar after a first single dose and during two months therapy with Tamoplex or Nolvadex in groups of 6 and 8 patients, respectively. Single dose absorption results in 10 healthy male volunteers demonstrated bioequivalence of Tamoplex and Nolvadex 10 mg tablets. A large interindividual variation in tamoxifen absorption data was observed, probably related to the dominating metabolic clearance of tamoxifen.

Pharmacological properties of droxicam, a new non-steroidal anti-inflammatory agent.

Abstract: Droxicam showed high antiinflammatory activity in carrageenin-induced edema in rat. At doses of 0.25 and 0.5 mg/kg, droxicam was as active as piroxicam and more active than phenylbutazone given at 2.5 and 5 mg/kg. Against nystatin-induced edema, droxicam (ED50, p.o., 5, 6, 7, 8 h: 7.5, 12.9, 4.8, 8.4 mg/kg) was 4-11 times more active than phenylbutazone and more than 12 times more active than isoxicam. In cotton pellet-induced granuloma in rats, title compound was as active as suprofen. In U.V. light-induced erythema in guinea pigs, droxicam (ED50, p.o., 1, 2, 3, 4 h: 0.51, 0.94, 1.56, 4.88 mg/kg) was 5-9 times more active than phenylbutazone. At doses of 0.1, 0.33 and 1.0 mg/kg/day, droxicam, similar to piroxicam, showed good antiarthritic activity in rats injected with Mycobacterium butyricum against primary and secondary lesions. Droxicam demonstrated strong analgesic activity in protecting against writhings: induced by phenylbenzoquinone in mice: ED50: droxicam = 5.3, phenylbutazone = 61.5, acetylsalicylic acid = 90.7, dipyrone = 83.6, isoxicam = 88.3 mg/kg, p.o.; induced by acetylcholine bromide in mice: ED50: droxicam = 1.1, phenylbutazone = 32.1, acetylsalicylic acid = 32.2, isoxicam = 32.7 mg/kg, p.o.; induced by acetic acid in rat: ED50: droxicam = 0.94, acetylsalicylic acid = 8.72, isoxicam = 4.70 mg/kg, p.o. Antipyretic activity of title compound was demonstrated in rats with pyresis induced by brewer's yeast, being 4-13 times more active than dipyrone. In pyresis induced by Salmonella typhi, droxicam was more active than acetylsalicylic acid and 4-aminoantipyrine at all times and doses. In a study of protection against diarrhea induced by castor oil in rats, droxicam and piroxicam showed equal activity (ED50 = 0.081 and 0.079 mg/kg, p.o., respectively) and were 3.9 and 15.6 times more active than isoxicam and phenylbutazone, respectively. Droxicam significantly inhibited peritoneal capillary permeability in mice at a dose of 5 mg/kg, p.o., while isoxicam and phenylbutazone required 100 and 200 mg/kg, p.o., respectively. Droxicam did not exhibit uricosuric activity in rats. It did not show cardiovascular or respiratory effects in anesthetized cats, nor modify their response to administration of acetylcholine, norepinephrine and histamine. In the Irwin's test, droxicam did not alter rat behavior (80 mg/kg, i.p.) nor that of mice (160 mg/kg, p.o.). Induction of gastrointestinal injuries in rats by droxicam was 10 times less than by piroxicam (UD50: droxicam, 57 mg/kg, p.o.; piroxicam, 5.6 mg/kg, p.o.). The potentiation of gastric injuries induced by stress through cold in rats was also studied.(ABSTRACT TRUNCATED AT 400 WORDS)

Neurobehavioral screening in rats: validation study.

Abstract: The usefulness of a neurobehavioral check-list for the detection and characterization of neurotoxic effects of chemical compounds was evaluated in rats. The animals were given single doses of the test compounds, and higher or lower doses of the substances were administered in subsequent weeks, depending on the outcome of the experiments. The testing procedure proved to be useful for detecting the neurobehavioral hazards of psychotherapeutics and other drugs with known neurobehavioral side-effects. However, the investigational technique was less satisfactory for evaluating alcohols and various neurotoxic agents. With these compounds, even repeated dosing did not improve the predictability of the testing scheme. Swimming performance was also investigated and was found to be impaired only in rats treated with neuroleptic drugs. Based on this validation study, the advantages and pitfalls of the neurobehavioral check-list approach are discussed.

Inosiplex treatment of acquired immunodeficiencies: a clinical model for effective immunomodulation.

Abstract: Patients with various conditions associated with immunologic deficiency (cancer, radiotherapy, surgery, burns, aging, prodromal Acquired Immunodeficiency Syndrome, were treated with inosiplex (INPX) at a dose of 3-4 g/day for periods of time ranging from 1 week to several months. Patients were evaluated clinically, and immunologically with the following assays; natural killer (NK) cytotoxicity, T-lymphocyte count, mitogen-induced proliferation, E rosettes, and skin test reactivity. The data resulting from this large and varied population were quite consistent and reproducible, and indicated that INPX treatment was effective in simultaneously reducing the incidence of complications, infections and mortality while enhancing the immune status of the patient. It has therefore been concluded that an immunopharmacologically active agent such as INPX can elicit important clinical benefits in patients with disorders of diverse etiology, perhaps through modulation of an immunologic defect that is common to a variety of seemingly unrelated conditions.

A protocol for the evaluation of new psychoactive drugs in man.

Abstract: A protocol is presented that has proven effective in the determination, in man, of the psychotomimetic potency and qualitative nature of action of a new drug. It involves a minimum of animal screening, but relies heavily upon the use of experienced human subjects. This procedure has been successful in the discovery of over 200 novel CNS-active agents.

Muramyl dipeptide and carbon tetrachloride hepatotoxicity in rats: involvement of plasma membrane and calcium homeostasis in protective effect.

Abstract: The present study was carried out to investigate the effect of single and multiple doses of N-acetylmuramyl-L-alanyl-D-isoglutamine (MDP) on CCl4-induced hepatotoxicity, and hence some of the mechanisms involved. MDP (8.26 mumol/kg i.v.) was administered to rats according to different protocols followed by a single dose of CCl4 (5.2 mmol/kg i.p.), and either the hepatocytes were subsequently isolated and tested for viability and lipid peroxides formation or the level of serum aminotransferases and lactate dehydrogenase (LD) was measured. The results clearly indicate that MDP pretreatment in a single dose reduced CCl4 hepatotoxicity as judged from viability tests as well as reduction of elevated lipid peroxides induced by CCl4 administration. The level of lactate dehydrogenase was also brought to normal value by single MDP administration. MDP also decreased significantly the CCl4-elevated Ca2+ content of isolated hepatocytes and postmicrosomal supernatant Ca2+. 14C-palmitic acid incorporation was increased significantly for neutral lipids and/or phospholipids in hepatocytes and certain subcellular fractions under MDP treatment in vivo. A different effect was seen after multiple MDP administration which further increased CCl4-induced elevation of aminotransferases. Even the repeated administration of MDP without CCl4 increased the level of the latter enzymes. It may be concluded that a single administration of MDP can protect liver cells from CCl4 injury by a mechanism affecting the plasma membrane.

Clinical characterization of imuthiol.

Abstract: Imuthiol is a nontoxic agent recruting and regulating T cells. Phase III studies in chronic bronchitis and bronchiectasis showed that immune functions were restored to normal, or near normal values. Cure was obtained in rheumatoid arthritis, tuberculosis and chronic infections in the elderly. Imuthiol is an effective agent for the treatment of syndromes and disease states where the underlying defect is a T-cell deficiency or dysfunction.

In vivo immunopharmacological properties of tuftsin (Thr-Lys-Pro-Arg) and some analogues.

Abstract: Tuftsin (Thr-Lys-Pro-Arg) is part of the Fc fragment of a leukophilic IgG and is a stimulator of the phagocytic activity of macrophages and polymorphonuclear cells (PMN) when cleaved from its carrier molecule. Tuftsin was shown to stimulate in vitro all PMN and macrophage functions examined through binding to specific cell surface receptors. In the present work, we provide further evidence that synthetic tuftsin administered to mice may act as an immunomodulator and that its effects on immune functions may result from a primary action on macrophages. After i.v. injection at a dosage of 25 micrograms/mouse, tuftsin stimulated effector (phagocytosis) and regulatory (IL1 production) functions of macrophages and potentiated DTH reaction. Lymphocyte functions (proliferative response to mitogens, T cell-mediated cytotoxicity, IL2 and gamma IFN production) were depressed at times at which macrophage activities were maximally enhanced, suggesting that negative regulatory functions of these latter cells were also stimulated. Tuftsin analogues were synthetized representing substitution or derivatization of the threonyl residue. The relative potencies of these analogues in augmenting phagocytosis-induced chemiluminescence of macrophages were tuftsin greater than or equal to (Gly1)-tuftsin greater than for-tuftsin greater than (for-Met1)-tuftsin greater than (Met1)-tuftsin. Concerning potentiation of DTH reaction the order was (Gly1)-tuftsin greater than or equal to (for-Met1)tuftsin greater than tuftsin greater than (Met1)-tuftsin greater than for-tuftsin. In contrast to tuftsin, none of the analogues induced depression of spleen cell reactivity to mitogens. In addition, (for Met1)-tuftsin administration resulted in an increased production of IL2 and IFN by ConA-stimulated spleen cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Rifampicin concentrations in cerebrospinal fluid and plasma of the rabbit by high performance liquid chromatography.

Abstract: A high performance liquid chromatographic (HPLC) assay has been developed for the measurement of rifampicin in cerebrospinal fluid and plasma samples in the rabbit. The method involved a preliminary organic solvent extraction of the drug and p-dimethylaminobenzoic acid (internal standard) from biological samples and subsequent concentration and analysis by HPLC. An aliquot (25 microliters) of the concentrate was injected into the liquid chromatograph and eluted with acetonitrile-10 mM phosphate buffer of pH 3.5 (48: 52, v/v) on a 30 microns C8 reversed phase column linked to a 5 microns C8 analytical column at ambient temperature (25 +/- 1 degrees C). The eluate was detected at 215 nm. The method has been used to investigate the disposition of rifampicin in plasma and CSF in rabbits.

Pharmacokinetics of droxicam in rat and dog.

Abstract: A study was made of the oral absorption of droxicam in the rat. Five minutes after administration of 1 mg/kg droxicam, only piroxicam levels (its active metabolite) were detected at the portal vein and caudal vena cava. The transformation of droxicam into piroxicam takes place in the gastrointestional tract. A pharmacokinetic test to compare the plasma levels of piroxicam obtained in rat and dog was then made after oral administration of droxicam and piroxicam. In both animal species the oral absorption of droxicam was not dose-related. However, droxicam given at therapeutic doses (0.2-0.3 mg/kg) was bioequivalent to piroxicam. The elimination half-life of piroxicam after oral administration of droxicam and piroxicam was 8 +/- 2 h in the male rat, 27 +/- 12 h in the female rat and 38 +/- 18 h in the male dog, whilst the half-life of oral absorption of piroxicam did not vary from one animal species to another. In the case of droxicam, however, this value was higher than that after oral administration of piroxicam, as a consequence of the process of transformation of droxicam into piroxicam. It is concluded that droxicam is a prodrug of piroxicam with a slower rate of absorption, but with the same bioavailability within the range of therapeutic doses.

In vitro teratogenicity of acetylsalicylic acid on rat embryos: studies with various culture conditions.

Abstract: Rat embryos taken at day 9.5 of gestation were exposed in vitro to acetylsalicylic acid (aspirin) using various culture conditions. It was observed that embryos were sensitive to aspirin emulsified in olive oil at concentrations greater than or equal to 150 micrograms/ml. Between 43% and 66% of the embryos exhibited multiple malformations depending on the culture medium, 100% homologous rat serum or Waymouth medium supplemented with 50% rat serum, respectively. At concentrations greater than or equal to 400 micrograms/ml aspirin induced further toxic effects on embryo growth and differentiation. When gelatin was used as the drug-delivery system, aspirin at concentrations of greater than or equal to 150 micrograms/ml induced some malformations (mainly irregular somite shapes) in 57% of the embryos cultured in Waymouth medium, but in only 13% of the embryos grown in 100% serum. At concentrations which were greater than or equal to 400 micrograms/ml aspirin induced dysmorphogenic effects in all embryos, without any concomittant toxicity.

Naloxone prevents hyperthermia induced convulsions in the immature rat.

Abstract: There is increasing evidence suggesting that endogenous opioid peptides play a role both in temperature regulation and in the etiopathology of seizures. We have studied the effects of the opioid antagonist naloxone on hyperthermia-induced seizures in unrestrained 15 day old rat pups. Saline injected control animals exposed to an ambient temperature of 40 degrees C for one hr showed a gradual increase in body temperature reaching a maximum of 42 degrees C at 50 min of exposure; at this time, all animals had convulsions and 86% died. Animals pre-treated with 10 mg/kg naloxone reached a maximum core temperature of 41 degrees C after 60 min at 40 degrees C and no convulsions or deaths were observed. When animals were exposed for 60 min to a 27 degrees C environment, saline controls maintained their normal body temperature throughout the experiment, while 5 mg/kg naloxone produced a marked hyperthermic effect. These experiments suggest that endogenous opioids may play a role in both temperature adaptation and hyperthermia-induced seizures in the rat pup.

Monoamines as immunomodulators: importance of suppressors and helpers of the bone marrow.

Abstract: The intraimmune pathways and mechanisms of action of the serotoninergic and dopaminergic systems in exerting a modulating effect upon immunogenesis are presented. Experiments were carried out in mice immunized with sheep red blood cells (1 X 10(7); 5 X 10(6)). Participation of the hypothalamic-pituitary complex in the monoaminergic mechanisms of stimulation and inhibition of rosette formation was revealed. Dissection of the pituitary stalk prevented stimulation of rosette formation by apomorphine (1 mg/kg i.p) and bupropion (20 mg/kg) and the reduction of the immune response by haloperidol (1 mg/kg), 5-hydroxytryptophan (300 mg/kg) and serotonin (50 mg/kg). The results of syngeneic cellular transfer of different immunocompetent organs showed that serotonin injection induced an increase in B-suppressor activity of bone marrow cells, reaching maximal value in the inductive period (day 3 of the immune response). B-Lymphocyte suppression in donors not treated with serotonin peaked on day 5 of the immune response. Stimulation of the immune response under activation of the dopaminergic system after apomorphine administration was provided by an increase in T-helper activity in the bone marrow cells, mainly with respect to IgM-response. The suppressive activity of bone marrow T cells on IgM- and IgG-immune responses was increased in nonimmunized donors treated with serotonin or haloperidol. The mechanisms of neurochemical multichannel immunomodulation by means of redistribution of cellular populations resulting in an increase in suppressors or helpers in bone marrow are discussed.

Model-free evaluation and mean-time concept in pharmacokinetics.

Abstract: Pharmacokinetic characteristics may be separated into three classes: firstly, those which are truly independent of pharmacokinetic modelling - curve characteristics for instance, such as Cmax or tmax, but also organic clearance values; secondly, those which can be evaluated without an explicit pharmacokinetic model but under basic assumptions - characteristics such as total clearance, mean and variance of residence times or total volume of distribution; and thirdly, those which are bound to elaborate pharmacokinetic models, such as hybrid constants, micro-constants or partial volumes of distribution. It can be demonstrated that the second class - the model-independent evaluated characteristic - and the third are mutually transferrable; examples of this transcription are given. However, these purely theoretical considerations can only demonstrate that the second class is consistent with classic pharmacokinetic modelling. The usefulness of the model-independent evaluated characteristic is underlined by results of clinical pharmacological investigations in which this technique was applied. The topics addressed by these studies cover the problems of deep compartments, differences in absorption, influence of disease, drug interaction, and first-pass metabolization. Since the mean-time concept in particular is still controversial in the literature, some general theoretical explanations seem to be necessary.

Clinical trials with C 1740, an immunomodulator compound proposed for prevention of acute infectious exacerbations in chronic bronchitis.

Abstract: C 1740 is an immunmodulating agent of biological origin proposed for the prevention of infectious exacerbations in chronic bronchopathy. The first placebo-controlled double-blind randomized clinical trials have led to opposite conclusions regarding the utility of C 1740. The rate of infectious exacerbations in the placebo group and a large Type II error could explain the "negative clinical trials". However, two out of four "positive clinical trials" were associated with high risk of falsely positive results. The activity of C 1740 is discussed here.