Showing papers in "Methods and Findings in Experimental and Clinical Pharmacology in 1983"

Acetic acid and phenylquinone writhing test: a critical study in mice.

Abstract: Studies were planned to establish the dose-effect relationship with both acetic acid and phenylquinone and to find out suitable concentrations for these two chemicals for pre- and post screening. The LD50 of acetic acid and phenylquinone were found to be 3.16% and 0.23%, respectively. Based on the studies conducted, the prescreening and postscreening concentrations of 0.5% is recommended for acetic acid, while for phenylquinone, prescreening concentration of 0.005% and postscreening concentration of 0.02% is advocated. Using this criterion in the acetic acid writhing test, analgin was the most potent analgesic while aspirin was the least. However, suprofen was most potent and paracetamol least among analgesics employed against phenylquinone induced writhing.

A sensitive method to evaluate effects of analgesics in man.

Abstract: In recent papers (8, 12, 13) it has been shown that the analysis of event related brain potentials has become a powerful tool in attempts to quantify pain experience in man. However, the following conditions have to be fulfilled when cerebral potentials are used to measure experimentally induced pain, as well as pain relief under pharmacological treatments: 1) randomization of stimulus intensities to minimize effects of habituation within and between sessions (3), 2) randomization of interstimulus intervals with a minimum distance of about 15 seconds to avoid overlapping effects, and 3) control of the power spectral density of brain activity immediately before the stimulus is applied. In searching for pain related cerebral potentials a principal component analysis was utilized. The grand mean of all evoked potentials (analysis period 500 ms) was built, and the brain potentials were decomposed into basic waveforms for the different experimental conditions (painful-nonpainful; different kinds of skin stimuli). Two components were found as correlates of the painfulness in a sample of 8 healthy untreated subjects (4). In order to demonstrate the usefulness and sensitivity of the here described methods to quantify analgesic effects in man, the opioide tilidine and the opiate antagonist naloxone were orally administered in different combinations. In detail, the 5 treatments: tilidine (100 mg), naloxone (32 mg), tilidine (100 mg) + naloxone (8 mg), tilidine (100 mg) + naloxone (32 mg), and placebo, were given double blind (3 replications of 5 X 5 Latin squares) in 15 healthy subjects, each participating in 5 sessions with exactly 3 days intervals.(ABSTRACT TRUNCATED AT 250 WORDS)

Ethanol-cephalosporin antibiotic interactions: an animal model for the detection of disulfiram (Antabuse)-like effects.

Abstract: Disulfiram (Antabuse)-like reactions occurring in patients undergoing antibacterial therapy with certain cephalosporin antibiotics, and after ingestion of ethanol, are well documented. A murine model is described which may prove useful in the detection of compounds likely to produce this effect. Eight cephem compounds (moxalactam, cefamandole, cefmetazole, cefonicid, cefmenoxime, cefoperazone, cefotiam, ceforanide) each carrying an N-methyltetrazolethiol substituent in the 3-position of the dihydrothiazine ring of the parent antibiotic were capable of inducing a disulfiram-like reaction in the test animals. Evidence is presented which strongly suggests a direct relationship between N-methyltetrazolethiol and related heterocyclic thiols and the ability to induce this reaction.

Evaluation of gastric mucus in man by means of the "mucoprotective index": a review of a five-year experience with this method.

Abstract: measurement of a "mucoprotective index" on the basis of the mucoprotein content of human gastric juice proved a reliable method to evaluate the protective properties of gastric mucus in man in pathological conditions and under the effect of drugs. The results of five years' investigations with that method are reported and commented upon.

The effect of coumarin and 7-hydroxycoumarin on in vitro macrophage phagocytosis of latex particles.

Abstract: The influence of various concentrations of coumarin (C) and 7-Hydroxycoumarin (7HC) upon in vitro macrophage phagocytosis of latex particles was investigated. A C dose of 20 micrograms/ml was indicated to have the greatest stimulating effect of all doses used with a percent effect of 25.6. A C dose of 80 micrograms/ml showed no apparent activity. C doses of 40, 10 and 1 microgram/ml had only a slight positive effect on phagocytosis compared to the control. 7HC concentrations of 80, 40, 20, 10 and 1 microgram/ml did not show any influence on the phagocytotic activity compared to the control. These preliminary data indicate a direct effect of C on macrophage function as has been suggested and refutes the hypothesis that 7HC is the pharmacologically active agent in reduction of high protein edemas.

Study on the anti-hypoxic effect of some drugs used in the pharmacotherapy of cerebrovascular disease.

Abstract: The anti-hypoxic effect of some agents used in the pharmacotherapy of cerebrovascular disease was studied using the following methods: incomplete ischemia by bilateral carotid ligation in rats, anoxic hypoxia by inhalation of argon in mice, and hemic hypoxia induced by injection of sodium nitrite (120 mg/kg s.c.) in rats. The following drugs were studied: piracetam, orotic acid, centrophenoxine, pentobarbital, vincamine, vinpocetine, cinnarizine, aligeron, xanthinol nicotinate and papaverine. The most pronounced anti-hypoxic effect was shown primarily with the metabolic acting drugs, such as orotic acid, centrophenoxine, piracetam and pentobarbital, followed by the preparations with combined metabolic and vasoactive properties (vincamine and vinpocetine). The predominantly vasoactive drugs were less effective in anoxic hypoxia, but showed more pronounced effect in incomplete ischemia.

The hypotensive effect of captopril in hypertensive patients is age-related

Abstract: The hypotensive action of the angiotensin-converting enzyme inhibitor captopril was investigated in 13 hypertensive patients in relation to their age, body weight, the pretreatment level of plasma renin activity (PRA), serum creatinine concentration and suppression of angiotensin II (PA II) by captopril. Captopril was administered in biweekly doubling doses (15 mg, 50 mg and finally 100 mg t.i.d.). The change in systolic blood pressure produced by captopril was significantly (p less than or equal to 0.05 or less) related to age (r = 0.67), to weight (r = 0.55), to the initial PRA levels (r = -0.63) and to the drop in PA II (r = 0.67) but not to the serum creatinine concentration. The change in diastolic blood pressure was also (p less than or equal to 0.05 or less) related to age (r = 0.59), to the pretreatment PRA level (r = -0.71) and to the fall in PA II (r = 0.70) but not to weight or to serum creatinine concentration. Our data suggest that the hypotensive action of captopril is more pronounced in younger hypertensive patients.

Studies of rhenium carboxylates as antitumor agents. Part II. Antitumor studies of bis (mu-propionato) diaquotetrabromodirhenium (III) in tumor-bearing mice.

Abstract: The neutral, dimeric complexes of rhenium, bis (mu-carboxalato)-diaquotetrahalodirhenium (III) (carboxalato = acetato, propionato, or butyrato and halo = chloro or bromo), were synthesized and survival studies were done on mice bearing P-388 leukemia or B-16 melanoma. The complex bis (mu-propionato) diaquotetrabromodirhenium (III) proved to be the most effective in increasing the life span of the mice. The complex showed some activity against B-16, but virtually none against P-388. The complexes are all quite non-toxic.

Effect of silymarin (Carsil) on the microsomal glycoprotein and protein biosynthesis in liver of rats with experimental galactosamine hepatitis.

Abstract: The effect of the hepatoprotective drug silymarin (Carsil) on the incorporation rate of 14C-leucine into total proteins and on the biosynthesis of UDP-N-acetylhexosamine and microsomal glycoproteins using 14C-glucose of rat liver with D-galactosamine hepatitis was studied. It was found that i.p. treatment with Carsil in a dose of 140 mg/kg applied for 4 consecutive days partly abolishes the inhibitory effect of galactosamine on protein and glycoprotein biosynthesis. The specific activity of 14C-labelled UDP-N-acetylhexosamine is higher in the liver of D-galactosamine treated rats, compared with the specific activity of the nucleotide from liver pretreated with Carsil and then injected with galactosamine. This fact supports the suggestion that Carsil probably activates the metabolic conversion of UDP-hexosamine to the acetylated metabolite-UDP-N-acetylhexosamine, which is the normal liver cell metabolite, in liver cells.

Comparative study of aztreonam and cefamandole in the treatment of serious urinary tract infections

Abstract: In a single blind study we compared the efficacy of aztreonam (Az), a novel monocyclic beta-lactam antibiotic, to that of cefamandole (Cef) in the treatment of serious urinary tract infections (UTIs). Twenty-one patients were studied (6 men and 15 women, 18-75 years old), 12 suffering from an upper and 9 from a lower UTI; 14 of them received Az and 7 Cef (2:1 ratio), according to a prospective randomization schedule. Az or Cef were administered intramuscularly (1 g every 8 hours) for 5 to 10 days. Patients were followed up for 28 to 42 days after end of treatment. The following bacteria were isolated in the urine cultures: E. coli (in 14 cases), Proteus sp. (4), Klebsiella sp. (2) and Pseudomonas sp. (in 1 case). All 21 bacterial isolates were susceptible to Az while 19 of them were susceptible to Cef (the Pseudomonas strain was sensitive to Az but resistant to Cef). During the entire period of observation, we had 13 cures and 1 relapse in Az-group and 5 cures and 2 relapses in the Cef-group. Aztreonam was as equally well tolerated as cefamandole and no major side effects were observed in either group. In 4 Az- and 3 Cef-patients a rise of SGOT and SGPT (up to 2 1/2 times the upper normal limits) was observed, but it subsided a few days after the end of treatment. Our study shows that aztreonam is at least as effective, safe and well tolerated an antimicrobial agent for the treatment of serious urinary tract infections as cefamandole; In the future aztreonam deserves a large scale, systematic trial in all infections caused by gram-negative bacteria.

Cimetidine-theophylline complex formation.

Abstract: Cimetidine forms a complex with theophylline in vitro in both pH 7.4 buffer and human plasma. The increase in the amount of theophylline in solution is about 20% in the buffer system and about 36% in plasma. It is hypothesized that this complex formation may contribute to and be part of the mechanism of the clinically observed decreased theophylline clearance in man in presence of cimetidine.

The clinical significance of the effects of cigarette smoking on drug disposition.

Abstract: Cigarette smoking is one of a number of environmental factors that contribute to interindividual variations in response to an administered drug. Polycyclic aromatic hydrocarbons present in cigarette smoke induce hepatic aryl hydrocarbon hydroxylase and cytochrome P448 and increased levels of these enzymes are responsible for a higher metabolic clearance of drugs which are substrates for these enzymes. The clinical significance of this induction is greatest for those drugs with a low therapeutic index such as theophylline. In some cases a modification of the normal therapeutic dose is justified to maintain adequate control. The magnitude of the effect of cigarette smoking on the induction of hepatic metabolic activity has been linked with age for a number of drugs including theophylline, some benzodiazepines and propranolol. Generally, the inductive effect is smaller in the elderly but, as there is no direct correlation between chronological age and physiological age, it is imperative that age and smoking habits be treated as individual sources of intersubject variation in pharmacokinetics and that this be borne in mind in the evaluation of new drugs and the safe clinical use of existing ones.

Effects of parenteral treatment by nicergoline on the development of hypertension of S.H.R.

Abstract: Six consanguine monogamous SHR couples (G 1) were treated from 5 weeks of age on with an alpha blocker, nicergoline, 100 mcg. kg-1 day-1 i.p. Male rats were treated without interruption; treatment was withheld in female rats from delivery to weaning. They were compared with six similar SHR couples who were only daily i.p. injected with the same volume of solvent in the same conditions, as controls. Second (G 2) and third (G 3) generation rats (untreated) were studied. In G 1 rats, systolic blood pressure (SBP) was decreased, and no change was found in heart rate (H R), heart weight to body weight ratio (HW/BW), hypothalamic and bulbar noradrenaline content (HNA,BNA). In G 2 rats, SBP, BNA and plasma renin activity were significantly decreased, all other parameters being unchanged. No parameter change was observed in G 3 rats. We think that such long acting effects after antenatal treatment could only be due to an action on the origin of the SHR hypertension.

In vitro activity of norfloxacin in synthetic media and human urine compared to that of cinnoxacin, nalidixic acid and pipemidic acid.

Abstract: Activity of norfloxacin was compared to that of cinnoxacin, nalidixic acid and pipemidi acid in DST-agar and human urine solidified by adding 1.2% agar. Norfloxacin was the most active compound when tested on DST-agar but the MIC values increased from 64 to 128 fold when tested in urine. Other compounds also showed an increase in MIC in urine-agar, but the increase was less marked. MICs for norfloxacin in DST-agar and Muller-Hinton-Agar were similar. Higher concentrations were required in Muller-Hinton-Broth than in Muller-Hinton-Agar.

[Pupillometry: a non-invasive pharmacokinetic and pharmacodynamic method to study the action of trospium chloride (Spasmo-lyt) on smooth muscle].

Abstract: The basic principle of pupillometry is to measure the changes of pupillar++ diameter versus time. We used a special device: split lam stand, black and white television camera with monitor fixed to a Polaroid. Trospium chloride is a compound with anticholinergic efficacy. The injection of 0.8 mg of trospium chloride followed by oral administrations of 10, 20, and 40 mg showed increasing effects on the mydriatic reaction. Comparing the area under the curves made it possible to estimate the bioavailability of the compound.

A method for induction of cold, indomethacin and restraint ulcers in rats.

Abstract: A new method has been developed for producing gastric ulcers in rats. The rapid induction of gastric lesions was achieved by a combination of the administration of indomethacin in addition to cold and restraint stressors. Ulcer indices were easily reproducible and remained constant. In addition, atropine, cimetidine and an antacid were tested for their antiulcerogenic effects with the same model. All three drugs inhibited ulcer development in a dose-dependent manner.

Maturational aspects of the dopaminergic system: ontogenesis of high affinity dopamine binding to neural membrane fragments of the rat brain.

Abstract: High affinity binding of [3H]-dopamine was measured in membrane fractions prepared from cerebral cortex, amygdala, hypothalamus, thalamus and reticular formation of female rats aged 1 to 260 days old. [3H]-dopamine bound with approximately 30 x 10(-9) M affinity to neural membrane fractions of female brains of any age. [3H]-dopamine binding increased with age either in a sigmoid fashion, as was the case in the amygdala, hypothalamus and reticular formation, or in a parabolic fashion, as was the case in the cerebral cortex and thalamus, the adult levels being reached on the 30th and 70th day of life respectively.

Effect of Kalmegh extract on rat liver and serum enzymes.

Abstract: Oral administration of Kalmegh extract under acute (single dosage) and sub-acute (for 7 and 15 consecutive days) conditions at a dosage of 0.5 g dry leaf/kg/day to adult rats produced no change in the activities of glutamate oxaloacetic transaminase (GOT) and glutamate pyruvic transaminase (GPT) in liver and rerum. Administration of ethyl alcohol at a dosage of 0.2 g/kg/day (oral) for 7 and 15 consecutive days produced an appreciable increase in liver GOT and GPT activities. No appreciable change in serum GOT and GPT activities was observed under similar condition of treatment. Oral administration of a high dosage of ethyl alcohol (3 g/kg/day) produced significant increase in the activities of serum enzymes only. This alcohol-induced increase in serum transaminase activity became normal with pre- and post-treatment of Kalmegh extract (0.5 g/kg/day). This result suggests that Kalmegh extract protects alcohol-induced toxic-effect in liver tissue.

Are local tolerance tests in animals always necessary

Abstract: The Draize test was introduced in 1944 as a toxicological standardization method to study irritation and toxicity of substances applied to the eye (and the skin). It has been considered, from that time on, as a routine toxicological protocol by most regulatory agencies to test eye-tolerance of chemicals. The authors think that for ethical and scientific reasons, this test is obsolete and should be changed or eliminated. They suggest the use of cell cultures or an in vitro technique for ocular safety assessment. The described technique uses a bovine cornea clamped in vitro between two chambers and kept alive in physiological conditions during six hours. This in vitro corneal perfusion system replaces in vivo irritation tests and enables quantitation of corneal drug uptake at the same time. This system provides reproducible results and can be used in ocular toxicological studies as well as in pharmacokinetic modeling.

Favorable effects of the lipid-lowering and platelet antiaggregant Plafibride on the aging process of mice of the C57bl/6J strain.

Abstract: It is known that an excessive intake of lipids and raised lipid levels in the blood accelerate many of the age-dependent pathologies Therefore, it is probable that the administration of hypolipidemic agents delays to a certain degree the rate of aging This concept has been experimentally tested in mice of the C57BL/6J strain treated with N-(2-p-chlorophenoxy) methylpropionil)-N'-morfolinomethylurea (Plafibride) The chemical was given in diet pellets at a dose of approximately 180 mg/kg body weight/day There were no manifestations of toxicity despite the fact that treatment lasted 8 months On the contrary, it seems that the aging process was favorably influenced since vigor and neuromuscular coordination were somewhat preserved in the treated mice in comparison to the controls Moreover, old mice treated with Plafibride showed values for body and liver weights that were more similar to those of younger mice These effects were especially evident in animals fed an hypercaloric diet enriched with fat and sucrose The present experimental results suggest performing clinical studies for investigation of the effects of long-term treatment with Plafibride on the physiological and pathological manifestations of human aging

Inosine effect on high-energy phosphate content, mechanical activity of glycerinated fiber bundles, morphology and microcirculation in myocardium in toxi-allergic and allergic myocarditis.

Abstract: It has been shown in experiments on rabbits on rabbits that in AM and TAM 80 mg/kg of inosine increase the total content of adenylic system nucleotides to the normal level and 160 mg/kg of inosine exceeds it. At the same time in the case of 80 mg/kg, ATP content is considerably increased and ADP is normalized while with 160 mg/kg ATP content becomes normal and ADP exceeds the normal level significantly. MGFB contractility returns to normal. Myocardial blood supply becomes more active both by increasing coronary circulation and probably through the Thebesian veins of the heart. It has been shown that on the one hand, inosine inhibits the development of an inflammatory process and on the other hand it considerably accelerates elimination and resolution of inflammatory foci.

Effect of combined treatment of diphenylhydantoin with clonazepam and chlordiazepoxide on the threshold for maximal electroconvulsions in mice.

Abstract: The anticonvulsant effect of either clonazepam (0.2-6.4 mg/kg) or chlordiazepoxide (2.5-40 mg/kg) alone or in combination with diphenylhydantoin (4-16 mg/kg) was studied against electroconvulsions in mice. All drugs were injected intraperitoneally, diphenylhydantoin - 75 min and the benzodiazepines - 60 min before the test. Adding either clonazepam or chlordiazepoxide (in doses moderately increasing the convulsive threshold) was more effective than doubling the dose of diphenylhydantoin. Both the interaction between benzodiazepines and diphenylhydantoin at the level of the receptor for picrotoxin-barbiturates and benzodiazepine-induced potentiation of specific diphenylhydantoin binding are likely to contribute to the observed phenomenon. On the other hand, a diphenylhydantoin-induced increase in the total number of specific benzodiazepine binding sites seems of minor importance since clonazepam (with a high affinity for these sites) and chlordiazepoxide (with a low affinity) were equipotent in the enhancement of the combined treatment efficacy.

Laboratory methods for ten hepatic toxification/detoxification parameters

Abstract: This article is a summary of laboratory methods for the hepatic drug metabolizing enzymes which are reliable, sensitive, and reasonably straightforward to perform. Assay conditions are given for which the enzyme rate determinations are linear with respect to time and protein concentration for hepatic tissue preparations from Charles River Sprague Dawley CD male rats. In selecting these particular assay methods, factors such as disposal of radioactive wastes, safety of laboratory personnel, and cost of required equipment were considered. Thus 9 of the 10 hepatic parameters utilize simple spectrophotometric techniques; the remaining assay (ethoxyresorufin O-deethylase) requires a spectrophotofluorometer. The hepatic toxification/detoxification assays are cytochrome P-450 and reduced glutathione content, NADPH-cytochrome C reductase, aminopyrine N-demethylase, ethoxyresorufin O-deethylase, glutathione S-transferase (3 substrates) and UDP-glucuronyltransferase (2 substrates).

Sorbent therapy of the porphyrias. II. Experimental plasma or hemoperfusion with a commercial charcoal cartridge

Abstract: We studied the ability of a commercial charcoal hemoperfusion cartridge (Hemosorba Hemoperfusion Cartridge, Asahi Medical Company) to adsorb the porphyrin precursors delta-aminolevulinic acid (ALA) and porphobilinogen (PBG) in vitro For measurement of clearances or decreases in concentration of porphyrin precursor, indices of adsorptivity, solutions of porphyrin precursor were circulated from a reservoir through the cartridge and back to the reservoir For determination of change in concentration of porphyrin precursor with time, the concentration of material in the reservoir was determined periodically Clearances of porphyrin precursor were determined from their concentration in both the reservoir (maintained nearly constant by the periodic addition of solute) and the cartridge effluent Clearances were independent of the nature of the medium (saline, 01 M phosphate buffer, pH 74, or human plasma), time (through 2 hr) and initial concentration of porphyrin precursor (30-103 mg/L for ALA, 15-36 mg/L for PBG) ALA clearances (ml/min) were 106 +/- 22, while maximal PBG clearances were never ascertained (greater than or equal to 310) The concentration of porphyrin precursor decreased rapidly during perfusion: about 82% and 98% of ALA and PBG, respectively, were removed in 5 minutes Neither the clearances nor the concentration decreases were affected by the simultaneous presence in the solution of hematin (initial concentration of 50 mg/L), which itself had a clearance of 107 +/- 126 and only a modest concentration change with time (60-68% decrease in 40 min) Hemosorba cartridges adsorbed 650 mg ALA and 85 mg PBG without any appreciable change in adsorptivity Hemoperfusion may be an appropriate adjunctive therapy, in combination with infusions of hematin, of particularly severe or refractory acute porphyric crises

Non-cholinergic, non-adrenergic responses of the rainbow lizard isolated rectum to transmural electrical stimulation.

Abstract: The non-cholinergic, non-adrenergic responses of the rainbow lizard (Agama agama Linn.) isolated rectum to transmural electrical stimulation have been examined in an effort to characterise them. In the presence of atropine (2 microM) and guanethidine (10 microM), tetanic transmural electrical stimulation (at 20 Hz) induced, in most of the preparations examined, a rapid initial relaxation (primary relaxation), which changed during the stimulation period into a contraction (primary contraction) followed by a rebound contraction (secondary contraction), which subsided at the end of the stimulus and was followed, in most preparations, by a relaxation (secondary relaxation) of variable extent and duration. Noradrenaline (1-10 microM) reduced or markedly inhibited the cholinergic muscle twitches, and decreased the various phases of the non-cholinergic, non-adrenergic muscle contractions, especially at low frequencies of stimulation (less than or equal to 10 Hz). At higher frequencies (greater than or equal to 20 Hz), ATP (5-10 microM) increased the primary relaxation, decreased the contractile phases, and inhibited post-tetanic inhibition induced by non-cholinergic, non-adrenergic nerve stimulation. Theophylline (0.1-1.0 microM) increased the primary and rebound contractions with no marked influence on the primary or secondary relaxation. Quinidine (5-50 microM) enhanced the primary relaxation, slightly inhibited the rebound contraction, but inhibited the primary contraction in a concentration-dependent manner. It is concluded that the P1 and P2 purinergic receptors proposed by Burnstock (10) are unlikely to mediate the non-cholinergic, non-adrenergic postsynaptic responses of the rainbow lizard isolated rectum.

Effect of semicarbazide on the perinatal development of the rat: changes in DNA, RNA and protein content.

Abstract: Semicarbazide was injected intraperitoneally to pregnant rats in single doses of 50, 75, 100 or 150 mg/kg. Treatment was administered on days 7, 10 or 13 of pregnancy. Semicarbazide produced abnormalities in 21 day old fetuses, found mainly in liver and kidney and in the skull and sternum, as well as resorptions and fetal deaths throughout gestation. This substance also caused a high postnatal mortality rate during the first month of life, especially with the 100 mg/kg dose. This dose reduced the nucleic acid and protein content in the lung and liver of the rats whether they were adult, pregnant, fetus or newborn. Statistically significant decrease of the nucleic acid level in adult rats appeared 48 hours after treatment. This decrease varied in the two organs studied. The lungs of pregnant rats which received semi-carbazide on day 10 of gestation showed a statistically significant decrease of the nucleic acid and protein levels on day 18 of gestation; there was also a significant decrease of RNA in the liver on this day, while a decrease in the proteins did not appear until day 21. The fetuses of treated mothers showed a significant decrease of DNA and RNA in the lung when they were 21 days old and a continuous decrease of the protein levels lasting up to the end of the first week of life. DNA and RNA in the liver of these offspring decreased when they were 30 days old. As for the protein content, it decreased throughout fetal life and continued to do so during the first month of fetal life.