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At least 55 records · Page 3Linked to original sources
PubMed1975

Radioimmunoassay for anileridine, meperidine and other N-substituted phenylpiperidine carboxylic acid esters.

Antibodies that bind an 125I-tyramyl derivative of N-succinylanileridine have been produced in animals immunized with N-succinylanileridine-hemocyanin conjugate. Several congeners and metabolites have been tested as competitors of this antigen-antibody reaction. The concentrations (in picomoles) required for 50% inhibition have been found to be: anileridine (0.2), meperidine (3.5), piminodine (3.8), diphenoxylate (20.5), normeperidine (20.0), meperidine acid (45,000) and anileridine acid (3,400). Although ester hydrolysis results in changes in inhibiting capacities on the order of 10(4), major structural changes in the substituent on the nitrogen of the piperidine ring are not readily recognized by the antibody. This radioimmunoassay can be used to study a variety of N-substituted phenylpiperidine carboxylic acid esters by relating the results to the standard curve obtained for the drug under investigation. For all practical purposes, alphaprodine, morphine and methadone do not interfere with the assay.

Animals↗
PubMed2003

Insurmountable antagonism of AT-1015, a 5-HT2 antagonist, on serotonin-induced endothelium-dependent relaxation in porcine coronary artery.

The purpose of this study was to examine the inhibitory effects of AT-1015, a newly synthesized 5-HT(2) receptor antagonist, on serotonin-induced endothelium-dependent relaxation in U 46619 (5 x 10(-9)M)-precontracted porcine coronary artery pre-incubated with ketanserin (3 x 10(-6)M), and then compare its effects with another potent 5-HT(2) antagonist, ritanserin. The investigation showed that AT-1015 (10(-8)-10(-6)M) caused rightward shift with significant inhibition of maximum relaxation response induced by serotonin in porcine coronary artery with endothelium. Ritanserin caused a rightward shift of serotonin-induced relaxation without decreasing maximum response at 10(-9) and 10(-8)M, but it inhibited the maximum relaxation response at 10(-7)M. The study showed that AT-1015 and ritanserin had no inhibitory effect on bradykinin-induced relaxation in porcine coronary artery with endothelium. Thus, these findings suggested that AT-1015 at concentrations of 10(-8)-10(-6)M caused noncompetitive blockade of serotonin-induced endothelium-dependent relaxation in porcine coronary artery. The antagonistic effects of AT-1015 on serotonin-induced relaxation were different from that of ritanserin, except at 10(-7)M ritanserin. The variation of inhibitory effects between these two 5-HT(2) antagonists may be due to the different chemical structure and/or interaction sites at the receptor.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1976

[Anesthesia using piritramide and chlorpromazine in dogs].

Piritramide with chlorpromazine in doses of 3 mg kg-1 of live weight causes total anesthesia the intensity of which differs according to the breed and condition of the individual. Anesthesia sets in in 30 to 45 minutes and lasts for 3/4 to 1 1/2 hour. During the anesthesia somatic temperature and frequency of pulse decrease, and even after 24 hours they do not reach the original values. In a majority of cases breathing frequency rises insignificantly, and after 2 to 3 hours it returns to the normal. In single cases there occurs an extreme increase of the number of respirations. The per minute breath volume in the various cases and measurings differs considerably. In the course of anesthesia there occurs an increase of glucose, a decrease of the total protein, an increase of the activity of GPT and GOT, a decrease of the numbers of erythrocytes, of haematocrit and haemoglobin, an increase of pCO2 of the blood, and a decrease of the actual pH of the blood. In the number of leucocytes no changes occurred. The changes in the BE were insignificant. All deviations, except the deviations of the pulse and of the temperature, return to the original values within 24 hours. In the ECG there occurred a fluctuation in the forming of emotions and changes of the amplitude values of the QRS group and of the T wave. In the EEG striking periodical complexes of slow waves were found or combinations of slow and rapid frequencies.

Acid-Base Equilibrium↗
PubMed1987

The evaluation and application of a radioimmunoassay for the measurement of diphenoxylic acid, the major metabolite of diphenoxylate hydrochloride (Lomotil), in human plasma.

Antibodies to diphenoxylic acid, the pharmacologically active metabolite of Lomotil, were successfully used to develop a precise and specific radioimmunoassay for the measurement of diphenoxylic acid in human plasma. The observed cross-reaction of the antiserum with Lomotil (23.5%) and p-hydroxy diphenoxylic acid (2.9%) was not considered to affect significantly the accuracy of the direct determination of diphenoxylic acid in plasma from human volunteers after ingestion of Lomotil tablets. Within-day and between-day coefficients of variation were better than 3 and 6%, respectively, over the concentration range of 3.4 to 255 ng ml-1. Comparable precision could be achieved at 2 ng ml-1 by doubling the volume of sample analyzed. The assay was used to measure plasma concentrations of diphenoxylic acid in 12 human volunteers for up to 24 hr after ingestion of Lomotil (10mg) tablets. Plasma diphenoxyllic acid levels rose to a mean (SE) maximum level of 87.8 (2.7) ng ml-1 3.3 (0.3) hr after dosing. By 24 hr after dosing plasma levls had decreased to 14.26 (1.67) ng ml-1. The appearance and elimination of plasma diphenoxylic acid could be described by a biexponential function. The appearance half-life was calculated to be 0.82 (0.09) hr, and the elimination half-life was 7.24 (0.73) hr.

Diphenoxylate↗
PubMed1996

Bioavailability of the antiemetic metopimazine given as a microenema.

The absorption of the antiemetic metopimazine (MPZ) given as a single dose of (a) 40 mg microenema, (b) 40 mg orally and (c) 10 mg as a 60 min i.v. continuous infusion was investigated in six healthy volunteers. Blood samples were drawn and the serum concentrations of MPZ and its acid metabolite were measured. The bioavailability of MPZ given orally and as enemas was 22.3 and 19.5% respectively. Partial avoidance of hepatic first pass metabolism was seen with the enemas, which in contrast to suppositories, seems to represent a reliable form of rectal administration.

Administration, Oral↗
PubMed1990

The effect of food on serum concentrations of metopimazine.

1. Six healthy volunteers were given single oral doses of the antiemetic metopimazine (MPZ), starting with trial (a) 20 mg preprandially and followed by trial (b) 50 mg preprandially. In trials (c) and (d) the doses were similar to those in trials (a) and (b), but MPZ was given postprandially. To evaluate intra-individual variation in serum concentrations, trial (a) was repeated three times in four of the volunteers (trial (e)). 2. Blood samples were drawn and the serum concentrations of MPZ and its acid metabolite (AMPZ) were measured by h.p.l.c. 3. There was no evidence of dose-dependent kinetics at the dose levels studied. 4. Median AUC values were 22.6, 16.2, 52.4 and 35.2 (trials (a), (b), (c) and (d), ng ml-1 h). Food intake decreased the serum concentrations of MPZ, suggesting that MPZ should be taken preprandially.

Adult↗
PubMed1977

Carcinogenesis tests of nitroso-N-methylpiperazine, 2,3,5,6-tetramethyldinitrosopiperazine, nitrosoisonipecotic acid and nitrosomethoxymethylamine in rats.

Four nitrosamines; nitroso-N-methylpiperazine, 2,3,5,6-tetramethyldinitrosopiperazine, nitrosoisonipecotic acid and nitrosomethoxymethylamine, closely related in structure to potent carcinogens, were fed chronically to rats in drinking water for one year. No toxic effects leading to life shortening were observed. There was no significant incidence of any malignant tumor other than the endocrine tumors normally found in untreated animals of our colony. This indicated that the small changes in structure represented by these compounds were sufficient to reduce greatly, or eliminate, the carcinogenic action.

Adrenal Gland Neoplasms↗
PubMed1976

[On the mode of action of difenoxin (R 15 403). Part 2: Studies on the perfused isolated colonic loop of the rat (author's transl)].

The effect of 1-(3-cyano-3,3-diphenylpropyl)-4-phenyl-isonipecotinic acid hydrochloride (difenoxin, R 15 403), a new antidiarrhoic agent, was studied in vivo in rats with an isolated colonic loop. Difenoxin had no effect on transport or absorption of fluid during perfusion experiments. When given i.p. it inhibited the motility of the coecum but not that of the colon. Difenoxin has apparently no effect on normal rat colon, although an effect may have been masked by the wide variation of parameters measured under identical conditions.

Animals↗
PubMed1975

An X-ray study on the acute action of diphenoxylate on the intestinal motility in volunteers.

The intestinal inhibitory activity of 1-(3-cyano-3,3-diphenylpropyl)-4-phenyl-4-piperidine-carboxylic acid ethyl ester (diphenoxylate) after a single oral dose of 5 mg was studied in 10 volunteers with X-ray diagnostic methods. The diphenoxylate treatment lengthened the transit time of the barium sulphate to caecum from 3.2 to 4.3 h. The X-ray cinematography showed the slower duodenal emptying in 5/10 of the subjects, but only in 1 of these the velocity of the peristaltic wave was clearly decreased. The results demonstrate directly the acute inhibitory action of diphenoxylate on intestinal motility with the dose used generally 3--4 times daily for the symptomatic treatment of diarrhoea.

Adult↗
PubMed2006

Engineering cyclic tetrapeptides containing chimeric amino acids as preferred reverse-turn scaffolds.

Four residues making almost a complete 180 degrees turn in the direction of the peptide chain define a reverse turn, a common motif and recognition site in proteins. Cyclization between residues i and i + 3 and incorporation of heterochiral dipeptides (such as d-Pro-l-Pro) in the i + 1 and i + 2 positions are used to constrain a peptide to a reverse-turn conformation. A combined approach, cyclic tetrapeptides (CTPs) based on heterochiral dipeptides of chimeric amino acids, is evaluated as minimalist scaffolds for reverse-turn conformations. Cyclo-(d-Pro-l-Pro-d-Pro-l-Pro) has been studied with density functional theory (DFT) calculations and molecular dynamics simulations. The all-trans amide conformer was the most stable in vacuo, while the cis-trans-cis-trans (ctct) or trans-cis-trans-cis (tctc) amide conformer was more favored in water due to its large dipole moment. Different conformations could be selectively stabilized by different substitutions on the proline rings. Due to the small 12-membered ring and exocyclic constraints, conformational interconversions could only occur at high temperature. The presence of seven hydrogens on each ring that could be functionalized offers an overwhelming diversity to design molecules to probe receptors. The spatial relationships of C(alpha)-C(beta) vectors of reverse turns in proteins were subjected to principal component analysis for determination of the relative orientation of the C(alpha)-C(beta) vectors. Most reverse-turn structures could be mimicked effectively with a subset of CTP scaffolds with an root-mean-square displacement (RMSD) of approximately 0.5 A. Structural diversity of CTP scaffolds could be enhanced by the incorporation of proline analogues, such as azaproline (azPro) or pipecolic (Pip), azapipecolic (azPip), nipecotic (Nip), and isonipecotic (Inp) acids.

Amino Acids↗
PubMed1977

Radioimmunoassay for normeperidine: studies on the N-dealkylation of meperidine and anileridine.

A sensitive and specific radioimmunoassay for normeperidine has been developed that can detect as little as 100 pg of this metabolite. In competitive binding experiments with [125I]O-tyramyl-normeperidinic acid and an antiserum produced in rabbits immunized with a bovine serum albumin-normeperidinic acid conjugate, meperidine is only 0.01% as effective an inhibitor as normeperidine. Therefore, normeperidine can be determined in physiological fluids and in tissue extracts when relatively large amounts of meperidine or other N-phenylpiperidine esters are present. High pressure liquid chromatography can be used to confirm the results obtained by radioimmunoassay during the in vitro N-dealkylations of meperidine and anileridine to normeperidine. The normeperidine isolated by high pressure liquid chromatography accounts for all of the inhibitory reactivity determined in the enzymatic digests by the radioimmunoassay. Kinetic parameters (Km and Vmax) can be determined for the N-dealkylation of meperidine and anileridine. The formation of normeperidine with time can be followed in rabbits injected with meperidine or anileridine. Plasma levels may also be determined when meperidine is administered as an obsteric analgesic.

Animals↗