Dextrophropoxyphene effects on QTc-interval prolongation: Frequency and characteristics in relation to plasma levels.

OBJECTIVE: To evaluate frequency and risk factors for dextropropoxypheneinduced QT-interval prolongation in the clinical setting. DESIGN: Prospective, noninterventional, observational, longitudinal cohort approach. Electrocardiograms were blindly evaluated by independent professionals. SETTING: General ward of a public hospital of metropolitan Buenos Aires. PATIENTS, PARTICIPANTS: Ninety-two patients with indication of receiving dextropropoxyphene for analgesic purposes were included consecutively. All patients finished the study. INTERVENTIONS: All patients were monitored with electrocardiographic controls (previous to drug administration and during steady state) to diagnose and quantify changes in the duration of the QTc interval. MAIN OUTCOME MEASURE: Frequency of drug-induced QTc interval prolongation, QTc interval correlation with plasma drug, and metabolite levels. RESULTS: Ninety-two patients were studied (50 percent males). All patients received a (mean ± SD [range]) dextropropoxyphene dose of 125 ± 25[100-150] mg/d. Dextropropoxyphene and norpropoxyphene concentrations were 112 ± 38[45-199] and 65 ± 33[13-129] ng/mL, respectively. The intra-treatment QTc interval was >450 ms in only one patient (only with the Hodge correction). There were no cases of QTc > 500 ms, and there were no significant differences in the results considering different correction formulas (Bazzet, Fridericia, Framingham, Hodges). Dextropropoxyphene concentrations correlated with QTc (R > 0.45) interval and ΔQTc (R 0.52-0.87), whereas norpropoxyphene correlation was even greater for QTc (R > 0.40-0.64) and ΔQTc (R > 0.47-0.92). Depending on the QTc correction formula, eight patients presented ΔQTc > 30 ms and one patient with ΔQTc > 60 ms. No patient presented arrhythmia during the study. CONCLUSIONS: The authors did not observe a relationship between dextropropoxyphene and QTc interval prolongation at the therapeutic doses used in Argentina.

Simultaneous quantitation of meperidine, normeperidine, tramadol, propoxyphene and norpropoxyphene in human plasma using solid-phase extraction and gas chromatography/mass spectrometry: Method validation and application to cardiovascular safety of therapeutic doses.

RATIONALE: Several opioid analgesics have been related to the prolongation of cardiac repolarization, a condition which can be fatal. In order to establish a correct estimation of the risk/benefit balance of therapeutic doses of meperidine, normeperidine, tramadol, propoxyphene and norpropoxyphene, it was necessary to develop an analytical method to determinate plasma concentrations of these opioids. METHODS: Here we describe a method which incorporates strong alkaline treatment to obtain norpropoxyphene amide followed by a one-elution step solid-phase extraction, and without further derivatization. Separation and quantification were achieved by gas chromatography/electron ionization mass spectrometry (GC/EI-MS) in selected-ion monitoring mode. Quantification was performed with 500 µL of plasma by the addition of deuterated analogues as internal standards. RESULTS: The proposed method has been validated in the linearity range of 25-1000 ng/mL for all the analytes, with correlation coefficients higher than 0.990. The lower limit of quantification was 25 ng/mL. The intra- and inter-day precision, calculated in terms of relative standard deviation, were 2.0-12.0% and 6.0-15.0%, respectively. The accuracy, in terms of relative error, was within a ± 10% interval. The absolute recovery and extraction efficiency ranged from 81.0 to 111.0% and 81.0 to 105.0%, respectively. CONCLUSIONS: A GC/MS method for the rapid and simultaneous determination of meperidine, normeperidine, tramadol, propoxyphene and norpropoxyphene in human plasma was developed, optimized and validated. This procedure was shown to be sensitive and specific using small specimen amounts, suitable for application in routine analysis for forensic purposes and therapeutic monitoring. To our knowledge, this is the first full validation of the simultaneous determination of these opioids and their metabolites in plasma samples.

D-propoxyphene and dipyrone co-administration produces greater antinociception and fewer adverse effects than single treatments in rats.

D-propoxyphene is a commonly prescribed opiate analgesic. Its use is limited by unwanted side effects at high doses and tolerance development after chronic administration. Dipyrone (also known as metamizol) is a non-steroidal anti-inflammatory drug extensively used in Latin America and Europe. The objective of this work was to evaluate the antinociceptive efficacy of a dipyrone/D-propoxyphene combination and the development of tolerance to its repeated administration in the tail flick test in rats. Male Wistar rats (200+/-20 g) were i.v. injected twice daily (8 h apart) with 0.31 mg/kg D-propoxyphene, 400 mg/kg dipyrone, or the combination of these drugs, at the same doses, until complete tolerance was observed. A time course of the effects for each administration was determined. At the doses tested, D-propoxyphene and dipyrone produced mild antinociception per se. Repeated administration resulted in complete tolerance to their antinociceptive effects by the sixth dose. The D-propoxyphene/dipyrone combination produced more antinociception than expected by the sum of individual drug effects. With this treatment, tolerance developed at the 15th administration. In animals already tolerant to D-propoxyphene or dipyrone alone, subsequent administration of the combination partially restored the antinociceptive effect. These results suggest that the use of this combination provides advantages over single drug therapies.

Titanium pigment in tissues of drug addicts: report of 5 necropsied cases.

The aim of this report is to describe the anatomic-pathologic findings from necropsies of 5 drug addicts with titanium pigment in several organs after chronic intravenous injection of crushed propoxyphene hydrochloride tablets. Samples from liver, spleen, lungs, lymph nodes, and bone marrow were obtained, and after being grossly studied, they were submitted to evaluation using common light and polarized microscopy. In all 5 cases, a pigment with characteristics of titanium dioxide was found within tissue samples of the organs studied. Our findings suggest that research concerning titanium pigment within body tissues should be enhanced, considering the potential contribution of this morphologic data to forensic pathology.

Titanium pigment in tissues of drug addicts: report of 5 necropsied cases

O objetivo deste relato é descrever os achados anatomopatológicos de cinco casos de toxicômanos com pigmento de titânio em vários órgãos, após injeção de comprimidos esmagados de cloridrato de propoxifeno. Foram obtidos fragmentos do fígado, baço, pulmões, linfonodos e medula óssea e, após a avaliação macroscópica, amostras foram submetidas à microscopia de luz comum e de luz polarizada. Em todos os cinco casos, foi encontrado um pigmento com características de dióxido de titânio nas amostras dos órgãos estudados. Nossos achados sugerem que a pesquisa sobre pigmento de titânio em tecidos corporais deva ser complementada, considerando-se a contribuição de dados morfológicos em Patologia Forense.

Adicciones de medicamentos en el personal de enfermeria / Medicine adiction in the nurse staff

Este trabajo describe las situaciones que facilitan, la adicción por medicamentos al uso indebido de Nubaina, klosidol, benzodiazepinas, por parte del personal de enfemeria en los servicios de terapia intensiva y emergencias

Adicciones de medicamentos en el personal de enfermeria / Medicine adiction in the nurse staff

Este trabajo describe las situaciones que facilitan, la adicción por medicamentos al uso indebido de Nubaina, klosidol, benzodiazepinas, por parte del personal de enfemeria en los servicios de terapia intensiva y emergencias

Adicciones de medicamentos en el personal de enfermeria / Medicine adiction in the nurse staff

Este trabajo describe las situaciones que facilitan, la adicción por medicamentos al uso indebido de Nubaina, klosidol, benzodiazepinas, por parte del personal de enfemeria en los servicios de terapia intensiva y emergencias

Açäo do napsilato de propoxifeno sobre o fígado e rins maternos e fetais de ratas albinas, durante toda a prenhez: aspectos morfológicos / Hepatic and renal effects of propoxyphene napsylate on pregnancy rats

O uso do napsilato de propoxifeno (NP), um fármaco analgésico opióide e depressor do Sistema Nervoso Central, está envolvido com risco potencial de abuso e suas conseqüências, particularmente durante a gravidez. Como na literatura há dados indicando a possibilidade de sérios efeitos colaterais do NP sobre o fígado, o objetivo deste trabalho foi examinar os efeitos do NP em ratas prenhes e seus fetos. Ratas prenhas foram tratadas durante toda a gravidez (desde o dia zero ao 200 dia) com 5, 15 e 45 mglkg de peso corporal/dia de NP, uma vez ao dia, por gavage. Grupos controles receberam o veículo (solução de Acácia). Ao término, amostras de fígados e rins foram retiradas das matrizes e de seus conceptos, submetidos a exames de microscopia de luz e eletrônica. Nenhuma alteração morfológica foi detectada nos fígados maternos e fetais com qualquer dose do NP empregado, na microscopia óptica; porém, nos rins, tanto nas matrizes quanto nos conceptos mostraram sinais de toxicidade, particularmente com as doses máximas do fármaco, e especialmente nas células dos túbulos contorcidos proximais. Nossos resultados sugerem que, na rata, as alterações fisiológicas próprias da gravidez parecem atingir o órgão alvo de toxicidade do napsilato de propoxifeno, ou seja, os efeitos passam a exercer alterações sobre os rins e não sobre o fígado. Os mecanismos envolvidos ainda não são conhecidos

Vasculitis inducida por medicamentos. Estudio de 13 casos

Se estudiaron trece casos de vasculitis medicamentosa comprobada clínica e histopatológicamente. La mayoría fueron linfomonocíticas (siete casos) y leucocitoclástica (un caso). Clínicamente las lesiones cutáneas eritemato-papulares se observaron en seis casos, la púrpura palpable en cuatro, la urticaria crónica, las lesiones ulcero-necróticas en tres y el prurito generalizado en seis. Algunos tenían más de una manifestación clínica. Dos pacientes presentaron miopatía fibrosa secundaria al uso intramuscular crónico de D-propoxifeno. La patogénesis de las vasculitis por drogas no es conocida completamente. Se cree que en ella están involucrados fenómenos inmunológicos de tipo humoral y celular. La miopatía fibrosa posiblemente es secundaria a un proceso inflamatorio estimulado por la irritación mecánica de la aguja o por algunos medicamentos. Esta es la serie más grande publicada en la literatura de vasculitis medicamentosa y los primeros casos informados de miopatía fibrosa secundaria a D-Propoxifeno.

Necrose peniana secundária à injeçäo de propoxifeno / Penile necrosis secondary injection of propoxyphene

Relata-se um caso de necrose de pele peniana e escrotal secundária à administraçäo acidental de propoxifeno na artéria femoral em paciente dependente a essa droga. O trabalho apresenta aspectos relacionados ao abuso deste fármaco, como efeitos colaterais, complicaçöes locais e risco de dependência ao propoxifeno

Ulcera medicamentosa de ano / Drug-induced ulcer of the anus

Se presenta un caso de úlcera perianal, producto de la administración prolongada de dextropropoxifeno, en forma de supositorios. Se llega al diagnóstico descartando lúes, T.B.C., enfermedad de Crohn, R.C.U.I.m, parasitosis, enfermedades, ginecológicas, enfermedades neurológicas y cáncer. Se detalla su tratamiento quirúrgico y su buena evolución. Se establecen la características de la afección y se hace hincapié en la acción deletérea de la droga. Se llama la atención sobre la indicación de este tipo de drogas en forma de supositorios (AU)

Ulcera medicamentosa de ano / Drug-induced ulcer of the anus

Se presenta un caso de úlcera perianal, producto de la administración prolongada de dextropropoxifeno, en forma de supositorios. Se llega al diagnóstico descartando lúes, T.B.C., enfermedad de Crohn, R.C.U.I.m, parasitosis, enfermedades, ginecológicas, enfermedades neurológicas y cáncer. Se detalla su tratamiento quirúrgico y su buena evolución. Se establecen la características de la afección y se hace hincapié en la acción deletérea de la droga. Se llama la atención sobre la indicación de este tipo de drogas en forma de supositorios

[Myopathy caused by propoxyphene: report of 2 cases with muscle histochemistry]. / Miopatia por propoxifeno: relato de 2 casos com histoquímica de músculos.

The cases of a 43 years old-man with gout and a 24 years-old woman with severe back pain who developed dextro-propoxyphene addiction during pain treatment are reported. They had severe edema and fibrosis of skin, subcutaneous tissue and muscle involving the upper and lower limbs. ESR was elevated, CPK and LDH were normal. EMG in proximal muscles showed decreased duration and voltage of potentials, excess of short polyphasics and increased recruitment (BSAP), with positive waves and fibrillations; distal muscles had fasciculations, fibrillations, positive waves, normal voluntary potentials, decreased recruitment. Lymphography indicate delayed progression of contrast media and obstruction in the thighs. Muscle biopsy on fresh-frozen section and histochemistry showed extensive connective tissue proliferation with intense acid and alkaline phosphatase activity in the perimysial and endomysial area, infiltration of lymphocytes near and around small vessels and capillaries. There were perifascicular and type II fiber atrophy. After discharge the patients returned to propoxyphene addiction and the symptoms who subsided during drug withdrawal come back again. New admission, new drug withdrawal and they were discharged free of symptoms and pathologic changes.