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Biomedical subjects

S Laufer

Publications and source records attributed to S Laufer.

At least 37 records · Page 2Linked to original sources
PubMed1998

Brain insulin and insulin receptors in aging and sporadic Alzheimer's disease.

The search for the causes of neurodegenerative disorders is a major theme in brain research. Acquired disturbances of several aspects of cellular metabolism appear pathologically important in sporadic Alzheimer's disease (SDAT). Among these brain glucose utilisation is reduced in the early stages of the disease and the regulatory enzymes important for glucose metabolism are reduced. In the brain, insulin, insulin-like growth factors and their receptors regulate glucose metabolism and promote neuronal growth. To detect changes in the functional activity of the brain insulin neuromodulatory system of SDAT patients, we determined the concentrations of insulin and c-peptide as well as insulin receptor binding and IGF-I receptor binding in several regions of postmortem brain cortex during aging and Alzheimer's disease. Additionally, we performed immunohistochemical staining with antibodies against insulin in neocortical brain areas in SDAT and controls. We show for the first time that insulin and c-peptide concentration in the brain are correlated and decrease with aging, as do brain insulin receptor densities. Weak insulin-immunoreactivity could be demonstrated histochemically in pyramidal neurons of controls, whereas in SDAT a stronger insulin-immunoreactivity was found. On a biochemical level, insulin and c-peptide levels were reduced compared to middle-aged controls, but were unchanged compared to age-matched controls. Brain insulin receptor densities in SDAT were decreased compared to middle-aged controls, but increased in comparison to age-matched controls. IGF-I receptor densities were unchanged in aging and in SDAT. Tyrosine kinase activity, a signal transduction mechanism common to both receptor systems, was reduced in SDAT in comparison to middle-aged and age-matched control groups. These data are consistent with a neurotrophic role of insulin in the human brain and a disturbance of insulin signal transduction in SDAT brain and favor the hypothesis that insulin dependent functions may be of pathogenetic relevance in sporadic SDAT.

Adult↗
PubMed1997

Synthesis and evaluation of a novel series of pyrrolizine derivatives as dual cyclooxygenase-1 and 5-lipoxygenase inhibitors.

The aim of our study was to investigate structure activity relationship following the replacement of the 6-phenyl substituent at the 6,7-diaryl-2,3-dihydropyrrolizine template by various heteroaromatic residues. In this context we developed a new, efficient, and highly sensitive test method for the screening of dual cyclooxygenase-1 (COX-1) and 5-lipoxygenase (5-LOX) inhibitors. We used human platelets as a source of COX-1 and human PMNLs as a source of 5-LOX. Both cell types were isolated from the same volume of blood. PGE2 and LTB4 respectively were determined by highly selective and sensitive ELISA kits, using monoclonal antibodies. For a single determination at most 0.5 mL whole blood is needed.

Arachidonate 5-Lipoxygenase↗
PubMed1997

The effects of ML 3000 on antigen-induced responses in sheep.

ML 3000 is a dual inhibitor of cyclooxygenase (COX) and 5-lipoxygenase (5-LO), two enzymes that contribute to the airway inflammation in asthma. When administered as an aerosol at a dose of 100 mg, 0.5 h before antigen challenge in allergic sheep, ML 3000 provided significant inhibition against the early bronchial response (EAR, mean 33% protection, P<0.05), completely blocked the late antigen-induced bronchoconstriction (LAR, mean 81% protection, P<0. 05) and the airway hyperresponsiveness (AHR, P<0.05) to aerosolized carbachol that occurs 24 h after antigen challenge in this model. Consistent with this functional protection was a small but significant reduction in the percentage of neutrophils recovered in bronchoalveolar lavage (BAL) at 8 h and 24 h after challenge. These findings are similar to previous data obtained in this animal model with other 5-LO inhibitors (blockade of the LAR and AHR) and COX inhibitors (blockade of AHR). These results suggest that aerosol administration of a dual inhibitor of COX and 5-LO may have beneficial effects in the treatment of allergic airway disease.

Acetates↗
PubMed1997

Bioequivalence evaluation of two flutamide preparations in healthy female subjects.

In the present study two different preparations containing 250 mg flutamide (3'-trifluoromethyl-4'-nitro-2-methyl-propionylanilide, CAS 13311-84-7) were compared in 20 female subjects. The trial was performed in a randomized two-way cross-over design. Each subject received one tablet with 250 mg flutamide in each period. The two treatment periods were separated by a wash-out phase of 7 days. Blood samples were obtained just before dosing and 18 times during the subsequent 36 h. The plasma concentrations of flutamide, 2-hydroxyflutamide and trifluoromethylnitroaniline were determined by HPLC with UV-detection. Due to the low plasma levels of the parent drug flutamide, the data of the pharmacologically active metabolite 2-hydroxyflutamide (CAS 52806-53-8) were used for bioequivalence assessment. The following mean values were obtained after administration of the test and reference preparation respectively: Flutamide: AUC0-36 = 95.82 ng.h/ml vs 93.33 ng.h/ml, Cmax = 44.78 ng/ml vs 38.73 ng/ml, tmax = 1.71 h vs 1.66 h, 2-hydroxyflutamide: AUC0-infinity = 6090.73 ng.h/ml vs 6068.83 ng. h/ml, Cmax = 772.74 ng/ml vs 779.84 ng/ml, tmax = 2.21 h vs 2.17 h, t1/2 = 8.21 h vs 8.32 h, trifluoromethylnitroaniline: AUC0-infinity = 1771.87 ng.h/ml vs 1701.44 ng.h/ml, Cmax = 173.36 ng/ml vs 171.32 ng/ml, tmax = 2.74 h vs 2.63 h, t1/2 = 10.75 h vs 9.83 h. The two preparations proved to be bioequivalent.

Adult↗
PubMed1995

Regioisomeric 5(3)-aminomethyl-3(5)-phenylisoxazoles: synthesis, spectroscopic discrimination, and muscarinic activity.

The regioselective synthesis of isomeric 5(3)-aminomethyl-3(5)-phenyl isoxazoles using different methods is described. Spectroscopic data, especially mass spectrometric fragmentation, were used to identify and characterize the regioisomers. The muscarinic activity of these isoxazoles was assayed on isolated guinea-pig ileum and atria as well as on isolated rabbit vas deferens.

Animals↗
PubMed1995

General pharmacology of [2,2-dimethyl-6-(4-chlorophenyl)-7-phenyl-2,3- dihydro-1H-pyrrolizine-5-yl]-acetic acid in experimental animals.

[2,2-Dimethyl-6-(4-chlorophenyl)-7-phenyl-2,3-dihydro-1H-pyrrolizine-5- yl]-acetic acid (ML 3000) is a newly synthesized compound with analgesic, antipyretic and anti-inflammatory activity. The general pharmacological effects of ML 3000 following oral administration were investigated in experimental animals. The results showed that with regard to the CNS, ML 3000 did not affect behaviour in the Irwin test, locomotor activity or hexobarbital-induced sleep at doses of 30, 100 and 300 mg/kg. ML 3000, at a single dose of 100 mg/kg administered intraduodenally, had no notable effect on the cardiovascular system or respiration in anaesthestised rats and dogs nor on neuromuscular function in anaesthetised cats. No evidence of gastric damage or disturbance of peristalsis was observed following oral administration of ML 3000. In vitro, ML 3000 evoked a weak spasmogenic response in the guinea-pig ileum with a dose-related inhibition of acetylcholine, histamine and barium chloride-induced responses. A small transient reduction in urine volume was observed after the highest dose accompanied by decreases in electrolyte excretion at doses of 100 and 300 mg/kg in rats. The results demonstrate that ML 3000 has no notable general pharmacological effects under the experimental conditions reported.

Acetates↗
PubMed1995

Distribution and excretion of [14C]-labelled [2,2-dimethyl-6-(4-chlorophenyl)-7-phenyl-2,3-dihydro-1H-pyrrolizine-5- yl]- [2'-14C]-acetic acid in rats.

A non-redox dual inhibitor of both cyclooxygenase and 5-lipoxygenase, [2,2-dimethyl-6-(4-chlorophenyl)-7-phenyl-2,3-dihydro-1H-pyrrolizine-5- yl]-[2'-14C]-acetic acid (3, ML 3000), was synthesized as [14C]-labelled compound and administered orally to rats. Distribution of radioactivity was examined by use of whole-body autoradiography after administration of doses in the range 13.7-26.6 mg/kg. Highest tissue levels were detected in the lung, liver, kidney, heart and large and small intestine. 48 h after administration, 58.3% of the total radioactivity was found in the feces and 7.9% in the urine. The distribution of radioactivity in the tissue, time course of plasma concentration, urinary and fecal excretion as well as hydrolysis experiments with beta-glucuronidase suggest an enterohepatic circulation and metabolization to glucuronides.

Acetates↗
PubMed1995

Studies on the in vitro and in vivo genotoxicity of [2,2-dimethyl-6- (4-chlorophenyl)-7-phenyl-2,3-dihydro-1H-pyrrolizine-5-yl]-acetic acid.

[2,2-Dimethyl-6-(4-chlorophenyl)-7-phenyl-2,3-dihydro-1H-pyrrolizine-5- yl]-acetic acid (CAS 156897-06-2, ML 3000) was examined for genotoxic activity in bacteria and mammalian cells in vitro as well as in vivo. The substance did not increase gene mutation frequencies either in a bacterial system or in a cultured V79 cell line of the Chinese hamster. Both in vitro tests were conducted in the presence and absence of S9-mix. In the unscheduled DNA synthesis assay in vitro with primary rat hepatocytes, negative results were also obtained. A cytogenetic analysis of the bone marrow of male and female Wistar rats was performed. After oral application ML 3000 did not increase the number of cells with structural chromosomal aberrations. The results suggest that ML 3000 has no genotoxic potential in vitro and in vivo.

Acetates↗
PubMed1995

Acute and chronic anti-inflammatory properties of [2,2-dimethyl-6-(4- chlorophenyl)-7-phenyl-2,3-dihydro-1H-pyrrolizine-5-yl]-acetic acid.

The carrageenan-induced paw oedema in the rat was chosen as the experimental model for acute antiphlogistic activity. ED50 values of 3 mg/kg p.o. for indometacin and of 17 mg/kg p.o. for [2,2-dimethyl-6-(4-chlorophenyl)-7-phenyl-2, 3-dihydro-1H-pyrrolizine-5-yl]-acetic acid (ML 3000) at calculated plasma levels (micrograms/ml) of approximately 5.0 and 20.0 were recorded for indometacin and ML 3000, respectively. The activity ratio of indometacin: ML 3000 is therefore about 1:6 with regard to the oral dose and about 1:4 with regard to the calculated plasma level. Indometacin is more potent than ML 3000 on the one hand, but on the other hand ML 3000 is better tolerated by the stomach in this experimental study: the ulcerogenic dose UD50 (indometacin) is 7 mg/kg p.o., whereas ML 3000 is tolerated well up to the highest tested dose of 100 mg/kg p.o. The adjuvant arthritis in the rat served as the model for chronic antiphlogistic activity. ML 3000 at doses of 20 mg/kg/d p.o. and higher, and indometacin at a dosage of 2 mg/kg/d p.o. produced a similar rate of reduction of the adjuvant-induced secondary lesions and paw swelling of the injected and uninjected paws, following prophylactic as well as therapeutic treatment with the compounds.

Acetates↗
PubMed1994

ML 3000 reduces gastric prostaglandin synthesis without causing mucosal injury.

In this study we characterized the effects of a novel anti-inflammatory drug, ML 3000 ([2,2-dimethyl-6-(4-chlorophenyl)-7-phenyl-2,3-dihydro-1H-pyrrolizine- 5-yl]-acetic acid), on the gastric mucosa and attempted to determine the mechanism responsible for its apparent stomach-sparing properties. Acute gastric damaging properties of ML 3000 versus indomethacin were examined in the rat, while chronic-type gastric ulcer was examined in the rabbit. At doses of up to 100 mg/kg p.o., ML 3000 did not produce significant acute gastric injury, while indomethacin at 5-20 mg/kg p.o. caused mucosal necrosis and bleeding. ML 3000 significantly inhibited gastric and blood prostaglandin E2 synthesis, with the higher doses tested (30 and 100 mg/kg) producing comparable effects to that seen with indomethacin at 10 or 20 mg/kg. Gastric and blood leukotriene B4 synthesis were not significantly affected by either drug. While indomethacin caused a significant increase in leukocyte adherence to mesenteric venules, ML 3000 did not. When administered repeatedly to rabbits, diclofenac caused penetrating ulcer formation in the gastric antrum of the majority of the animals. ML 3000 did not produce any detectable damage at doses of 10 or 30 mg/kg, but an ulcer was observed in one of five rabbits given the 100 mg/kg dose. Prior administration of ML 3000 (10-100 mg/kg) did not significantly affect the extent of gastric damage induced by subsequent oral administration of ethanol. These studies demonstrate that ML 3000 spares the gastric mucosa despite significantly suppressing gastric prostaglandin synthesis.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetates↗
PubMed1994

Tuberculosis in adolescents. A case commentary.

The resurgence of tuberculosis (TB) in the United States has placed a substantial segment of the adolescent population at high risk, particularly those adolescents residing in metropolitan areas. Physicians providing health care to adolescents must be aware of the risk factors for TB and of the epidemiology of this insidious disease. Active alliances must be established among health-care professionals in the community to ensure effective screening, diagnosis, and treatment programs.

Adolescent↗
PubMed1994

Gastrointestinal tolerance of [2,2-dimethyl-6-(4-chlorophenyl-7-phenyl- 2,3-dihydro-1H-pyrrolizine-5-yl]-acetic acid in the rat.

The gastrointestinal tolerance of [2,2-dimethyl-6-(4-chlorophenyl)-7- phenyl-2,3-dihydro-1H-pyrrolizine-5-yl]-acetic acid (ML 3000, CAS 156897-06-2) has been tested in comparison with indometacin, after both single and multiple administrations for 5 and 11 days in an in vivo rat assay. A single oral administration of ML 3000 at doses of 10, 30 and 100 mg/kg produced no gastrointestinal damage. Repeated oral administration of ML 3000 at daily doses of 10, 30 and 100 mg/kg produced slight gastrointestinal damage, but the effect was minimal and was not found to be statistically significant. Indometacin produced highly statistically significant gastric and duodenal damage following one single administration of 10 mg/kg. Repeated oral administration, at 3 mg/kg each day, produced moderate and statistically significant gastric and slight duodenal damage on Day 5 of dosing. However, by Day 11 pronounced duodenal damage was observed which was shown to be statistically highly significant. These results indicate that ML 3000 is clearly better tolerated by the gastrointestinal tract than indometacin after single and multiple administration up to 11 days in rats.

Acetates↗
PubMed1994

Pharmacological profile of a new pyrrolizine derivative inhibiting the enzymes cyclo-oxygenase and 5-lipoxygenase.

2,2-Dimethyl-6-(4-chlorophenyl)-7-phenyl, 2,3-dihydro-1H-pyrrolizine-5-yl)-acetic acid (ML 3000) is a dual inhibitor of the enzymes cyclo-oxygenase and 5-lipoxygenase in bovine and human thrombocytes and granulocytes. In animal experiments the compound has antiphlogistic, analgesic, antipyretic, antiasthmatic and antiaggregative activity at a dosage that causes no gastrointestinal damage.

Acetates↗
PubMed1993

Hypertensive effects and structure-activity relationships of 5-omega-aminoalkyl isoxazoles.

Structure-activity and dose-response relationships of a series of novel 5-omega aminoalkyl and 5-omega-amino-heteroalkyl isoxazoles on blood pressure and heart rate of Sprague-Dawley rats have been investigated. To differentiate between peripheral and central cardiovascular actions of those compounds a pithed rat and anaesthetized rat preparation was used. Most of the compounds investigated exhibit potent hypertensive actions. The hypertensive effects of the tested compounds is depending on the amphiphilic character of the isoxazoles represented by a basic moiety in a definite distance to the phenyl substituents. To achieve high pharmacological activity a fully flexible side chain is requested, too. Possible mechanisms of action are discussed.

Animals↗
PubMed1991

[Hypertensive action of 5-(beta-aminoethyl)aminoisoxazoles: synthesis and screening of isoxazolopyrazines and isoxazolodiazepines].

The 5-aminoisoxazole 1 is converted via the 4-nitro derivative to the 4,5-diamino compound 4, which cyclises with glyoxal to yield the isoxazolo[4,5-b)pyrazine 5. Decomposition of the isoxazole moiety is always observed in experiments to hydrogenate partially the pyrazine ring and to phenylate the N-atom, respectively. Therefore, the corresponding tetrahydro derivative 6 is prepared from 4 and 1,2-ethandiol ditosylate. Starting with benzohydroxamic acid chloride and a cyanoacetic acid amide the tetrahydro isoxazolo[5,4-e]1,4-diazepinone-4 18 is synthesized. All new compounds are characterized by their spectroscopic data, the reaction mechanisms are discussed. Using the model of the pithed and the anaesthetized rat, resp., the pyrazino- and diazepino-isoxazoles (compounds 5, 6, 13, 18) have less or no hypertensive activity as compared to the corresponding derivatives with fully flexible side chains.

Animals↗
PubMed1990

[Hypertensive acting 5-(beta-aminoethyl)aminoisoxazoles: synthesis and screening of derivatives with with partially rigid C-5 side chains and omega-position heterocyclics].

Isoxazoles with a 1,2-diaminoethane side chain at C-5 are synthesized by nucleophilic substitution of 5-chloro derivatives. Using piperazine, imidazolidine and 1,2-diaminocyclohexane, resp., isoxazoles with partially rigid chains at C-5 are formed. The same procedure succeeds in the synthesis of isoxazoles having a heterocycle at the omega-position of the side chain. The hypertensive activity of all new compounds is shown for the pithed and the anaesthetized rat, resp. According to structure activity relationships the hypertensive activity of compounds 7 and 8, resp., is mainly determined by the heterocycle at the omega-position (piperazine greater than piperidine approximately pyrrolidine greater than morpholine). Derivatives 2-5 with partially rigid 5-(beta-aminoethyl)amino side chains show less hypertensive activity than the corresponding compounds without restrictions.

Anesthesia↗