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At least 73 records · Page 4Linked to original sources
PubMed1983

Simultaneous determination of ketobemidone and its N-demethylated metabolite in patient plasma samples by gas chromatography mass spectrometry with selected ion monitoring.

An analytical procedure has been developed for the simultaneous determination of ketobemidone and its N-demethylated metabolite, norketobemidone. After isolation from plasma and re-extraction to acidic aqueous phase, the two aminophenols were extracted as ions pairs with tetrabutylammonium to dichloromethane, where derivatization with ethyl chloroformate took place. Determination was performed by gas chromatography mass spectrometry with selected ion monitoring. Ketobemidone and norketobemidone could be detected in plasma in a concentration of 1 ng ml-1 and 3 ng ml-1, respectively. Determinations were performed down to 5 ng ml-1. The relative standard deviation of the method in the analysis of 10 ng ml-1 of ketobemidone and norketobemidone, respectively, was 8% and 9% (n=10). The absolute recovery of unconjugated ketobemidone and norketobemidone through the method at the 100 ng ml-1 level was 91% and 85%, respectively. The method was applied to the determination of ketobemidone and norketobemidone in plasma from patients given ketobemidone. The concentrations of unconjugated norketobemidone was too small to be detected.

Analgesics, Opioid↗
PubMed1997

Dose-finding study of oral metopimazine.

A few studies indicate a dose-response effect of the antiemetic metopimazine. The aim of this study was therefore to investigate the tolerability of increasing doses of metopimazine given orally every 4 h for eleven doses. The dose levels 20 mg, 30 mg, 40 mg, 50 mg and 60 mg were studied in 36 patients completing 46 cycles of chemotherapy. Serum concentrations of metopimazine and the acid metabolite AMPZ were measured by HPLC in 13 patients (15 cycles). The dose-limiting toxicity was moderate to severe dizziness caused by orthostatic hypotension as seen in 0, 0, 17%, 42% and 50% of patients at the respective dose levels. Other side effects were few and mild, and only a single possible extrapyramidal adverse event was observed in a patient at the 60-mg dose. High serum concentrations were not predictive for toxicity, as found on comparison of patients with and without symptoms, but in individual patients symptoms were seen at the time of Cmax. We found that metopimazine was safe with a dosage of 30 mg x 6. This dose is four times higher than that previously recommended for antiemetic use.

Administration, Oral↗
PubMed1998

Effects of amidinopiperidine-4-carboxylic acid 4-tert-butylphenyl ester, a specific trypsin inhibitor, on the growth of HL-60 cells.

Previous results showed that the synthetic compound amidinopiperidine-4-carboxylic acid 4-tert-butylphenyl ester (APCA-OPhBut), a trypsin inhibitor, could specifically inhibit the activity of proteinase In and lead to growth arrest of Hela cells in early S phase. In this study, APCA-OPhBut exhibited inhibitory effects on the growth of HL-60 cells. Apoptotic cells were observed when the cells were cultured with APCA-OPhBut above 50 microM. Time course studies demonstrated that apoptotic cells were increased in a dose- and time-dependent manner. Flowcytometric assays demonstrated that HL-60 cells underwent slight G1 growth arrest after treatment with APCA-OPhBut. No change of Bcl-2 protein level was detected. The findings suggest that the intracellular trypsin-like protease inhibited by APCA-OPhBut not only plays a key role in DNA synthesis initiation but is also necessary for survival of certain cell lines.

Apoptosis↗
PubMed1993

Amidinopiperidine-4-carboxylic acid 4-tert-butylphenyl ester, a trypsin inhibitor, suppresses the onset of DNA synthesis in HeLa cells synchronized by a double-thymidine block.

Release of HeLa cells arrested at the G1/S boundary by double-thymidine block caused abrupt uptake of [methyl-3H]thymidine into DNA after 5 min, and two sharp high activity peaks, peak I and peak II, were observed 8 and 23 min after removal of the thymidine block and this was followed by a gradual uptake of [3H]thymidine. The duration of the cell cycle was 23 h, and definite changes in cell density were observed between 12 and 13 h and also between 35 and 36 h after removal of the thymidine. Addition of amidinopiperidine-4-carboxylic acid 4-tert-butylphenyl ester (APCA-OPh'Bu), a trypsin inhibitor, immediately after removal of the arrest strongly suppressed DNA synthesis and mitosis. In contrast, addition of APCA-OPh'Bu 10 min after removal of the arrest, and hence also after the appearance of peak I, had no effect on peak II nor on the uptake of thymidine occurring during the remainder of the first cell cycle, nor on mitosis. However, it strongly suppressed the second DNA synthesis and mitosis. These results suggest participation of a trypsin-like proteinase at the onset of DNA synthesis. Removal of thymidine from the arrested cells at a cell density of 2% (4 x 10(3) cells/cm2) induced an immediate and rapid rise in trypsin-like proteinase activity. However, the activity decreased with increasing cell density. No clear increase in the activity was seen at a cell density of 20% (4 x 10(4) cells/cm2). However, both trypsin-like proteinases obtained at cell densities of 2% and 20% were strongly inhibited by APCA-OPh'Bu and these inhibitory effects were similar.(ABSTRACT TRUNCATED AT 250 WORDS)

Cell Cycle↗
PubMed1975

In vitro adsorption of diphenoxylate hydrochloride on activated charcoal and its relationship to pharmacological effects of drug in vivo. I.

The adsorption of diphenoxylate hydrochloride, a potent antidiarrheal agent, on activated charcoal powder was studied in vitro. Langmuir adsorption isotherms were established at pH 4 and 7, and the maximum adsorption capacity of charcoal for this drug was estimated using these values. Activated charcoal modified the bioavailability of diphenoxylate hydrochloride in vivo. The antipropulsive action of diphenoxylate in the mouse was strongly inhibited in the presence of activated charcoal. A comparative evaluation of charcoal and chromium oxide used as inert, nonabsorbable markers revealed that chromium oxide may be the marker of choic in GI transit studies in laboratory animals since it does not influence the bioavailability of diphenoxylate hydrochloride.

Adsorption↗
PubMed1977

Determination of diphenoxylate hydrochloride and atropine sulfate in solutions and tablets.

Methods for the determination of diphenoxylate hydrochloride and atropine sulfate combinations in solutions and powdered tablet composites are presented. A semiautomated assay for diphenoxylate hydrochloride in individual tablets (content uniformity) also is presented. The USP XIX assays for these products are cumbersome and, in the case of solutions, inaccurate due to spectral interferences; the proposed methods offer substantial improvements in sensitivity, specificity, and speed. Results obtained by the USP and proposed methods are compared for several lots of commercial products. The accuracy and precision of the proposed methods are shown by standard recovery studies.

Atropine↗
PubMed1994

Clinical application of nebulized opioids for treatment of dyspnoea in patients with malignant disease.

This article describes our experience in the clinical use of nebulized opioids for the management of dyspnoea in patients with terminal cancer by reviewing three specific patient case studies in which this treatment was found to be both safe and effective in controlling breathlessness. The patients were treated with morphine, hydromorphone or anileridine in various doses according to their prior use of opioids. Additional formal studies are being initiated at this Centre.

Administration, Inhalation↗
PubMed1976

Intracranial self-stimulation in rats as a function of various stimulus parameters. VI. Influence of fentanyl, piritramide, and morphine on medial forebrain bundle stimulation with monopolar electrodes.

The effects of different subcutaneous doses of fentanyl (0.02, 0.04, 0.08, and 0.16 mg/kg), piritramide (0.63, 2.50, 10.0 and 40.0 mg/kg), and morphine (2.50, 5.00, 10.0 and 20.0 mg/kg) on self-stimulation in rats were studied. Different stimulus parameter combinations (SPC) inducing low, high or intermediate control response rates (CRR) were applied during the same experimental sessions. The three narcotic analgesics induced response depression (RD) and response stimulation (RS). RS was mostly observed at low dose levels; RD was dose-related. SPC's inducing low CRR were more sensitive than those inducing high CRR. Fentanyl was more potent than piritramide and than morphine. The RD is related to motor incapacitation, as the doses needed to effectively reduce self-stimulation also induced obvious catatonia. The RS probably is a more specific effect reflecting sensitization of structures involved in reinforcement of behavior.

Analgesics, Opioid↗
PubMed1978

Toward the development of a potent, nonsedating, oral analgesic.

The separate and combined analgesic effects of 10 mg of oral amphetamine sulfate and 25 mg of oral anileridine dihydrochloride were studied in 24 healthy, adult, male volunteers. Tolerance of progressively increasing pain produced by the Submaximum Effort Tourniquet Technique was tested four times in each subject: after amphetamine, after anileridine, after the combination, and after a matching placebo. Treatments were administered double blind and in counterbalanced order. Elapsed time to report of slight, moderately distressing, very distressing, and unbearable pain was recorded on each trial. The four oral treatments differed significantly for very distressing and for unbearable pain. At each of the three upper pain levels, the mean tolerance times for anileridine and amphetamine were similar; each was longer than placebo but shorter than the combination; and the effect of the combination was approximately the sum of the effects of the two components.

Administration, Oral↗
PubMed1993

Interaction of the antiemetic metopimazine and anticancer agents with brain dopamine D2, 5-hydroxytryptamine3, histamine H1, muscarine cholinergic and alpha 1-adrenergic receptors.

The interactions of the antiemetic metopimazine (MPZ) and of the chemotherapeutic agents, cisplatin, carboplatin, doxorubicin, etoposide and vincristine were investigated at five neurotransmitter receptor binding sites. MPZ had nanomolar affinity for alpha 1, dopamine D2 and histamine H1 receptors, weak affinity for muscarinic cholinergic receptors, but no affinity for 5-hydroxytryptamine3 (5-HT3) receptors. Except for vincristine, which showed nanomolar affinity of muscarinic cholinergic receptors, none of the chemotherapeutic agents showed affinity for any of the receptors investigated at concentrations ranging between 10(-5) and 10(-7) M. Accordingly, chemotherapy-induced nausea and vomiting seems to be mediated by mechanisms other than the direct interaction of cytostatics with the neurotransmitter receptors investigated. Our finding that MPZ is without affinity for 5-HT3 receptors and therefore seems to mediate its antiemetic effect predominantly by dopamine D2 receptor blockade makes it an interesting drug for use in combinations with the new class of antiemetics, the 5-HT3 receptor antagonists. Data obtained in a recent clinical trial support this observation.

Animals↗