Hepatic and renal effects of propoxyphene napsylate on pregnant rats

El uso del napsilato de propoxifeno (NP), fármaco analgésico opioide y depresor del SNC, involucra riesgo potencial de abuso y sus consecuencias, particularmente durante el embarazo. Como en la literatura hay datos indicando la posibilidad de serios efectos colaterales del NP sobre el hígado, el objetivo de este trabajo fue examinar los efectos del NP en ratas preñadas y sus fetos. Ratas hembras tratadas durante toda la preñez (desde el día 0 hasta el día 20) con 5, 15 ó 45 mg/kg de NP, una vez al día, por gavage. Grupos controles recibieron el líquido usado como vehículo (aceite de acacia). Al término, muestras de hígado y riñón de las ratas preñadas y sus fetos extraídos. Las muestras fueron procesadas para microscopías óptica y electrónica. No se detectaron alteraciones morfológicas en hígados de ratas preñadas o fetos con ninguna dosis de NP empleada. Los riñones de estos animales mostraron signos de toxicidad, paticularmente, con la dosis más alta del fármaco y, especialmente, en las células de los túbolos contorneados proximales. Nuestros resultados sugieren que, en la rata, las alteraciones fisiológicas propias de la gravidez parecen cambiar el órgano-blamco de la toxidad del NP, es decir, los efectos se manifiestan en el riñón y no en el hígado. Los mecanismo involucrados en este cambio no son aún conocidos

Interaction between ethanol and opioids in a protozoan assay.

Ethanol excess combined with opioids can be fatal due to their toxic interaction, yet the nature of the interaction is little documented. Since ethanol and some opioids have membrane stabilizing activity, the present study used a protozoan motility model to test the possibility that ethanol may interact with some opioids on this basis. The EC50 in motility reduction for ethanol, dextropropoxyphene, methadone and pethidine was 522.0 +/- 36.7 mM, 0.59 +/- 0.08 mM, 0.40 +/- 0.09 mM and 4.57 +/- 0.36 mM, respectively. When ethanol was combined with one of the three drugs in equitoxic doses at a ratio of 0.5:0.5, the predicted/observed EC50 values for ethanol-dextropropoxyphene, ethanol-methadone and ethanol-pethidine were 1.37, 1.11 and 1.00, each being close to unity, indicating an additive interaction. The interaction between ethanol and dextropropoxyphene was further explored at 0.25:0.75 and 0.75:0.25 equitoxic dose ratios, with the predicted/observed EC50 values of 0.98 and 0.97, also showing an additive interaction. This suggests that a non-specific interaction between ethanol and opioids may also take place in vivo, which could cause increased toxicity over and above the involvement of opioid receptors. Information from this study should aid understanding of the mechanism of interactions in human poisoning by agents with membrane stabilizing activity.

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.

[Toxicity of anti-tumor preparations after intracranial, subarachnoid and suboccipital administration (experimental study)]. / Toksichnost' protivoopukholevykh preparatov pri vnutrimozgovom, subarakhnoidal'nom i suboktsipital'nom vvedenii (éksperimental'noe issledovanie.

Experiments were conducted on animals to study intrathecal injection of agents differing in the mechanism of action: variamycin, mitramycin, reumycin, proxyphein, and prospidin. Their acute toxicity in a single intracerebral injection and chronic toxicity in repeated suboccipital injection were studied. The brains of animals who died or were killed were studied pathomorphologically in different periods. Intracerebrally and suboccipitally injected variamycin and mitramycin induced marked toxic reactions, even the death of animals, and cannot be recommended for the neurooncological clinic. The antineoplastic reumycin, proxyphein, and prospidin cause no toxic reactions of the brain and meninges on injection by the above mentioned methods; they are recommended for approbation in the neurooncological clinic for the treatment of patients with malignant tumors of the brain by injection into the system of the cerebrospinal fluid.

The effects of dopamine on central hemodynamics and myocardial metabolism in experimental propoxyphene-induced shock.

The hemodynamic and cardiometabolic effects of dopamine were evaluated in propoxyphene-induced circulatory shock in eight pentobarbital anesthetized pigs. Circulatory shock was induced by an infusion of propoxyphene chloride 15 mg . min-1 i.v. At shock, i.e. CI less than or equal to 2.0 l . min-1 . m-2 and/or MAP less than or equal to 60 mmHg, dopamine was infused at 10, 20, 40, 80 and 160 micrograms . kg-1 . min-1 with an interval between increments of 8 min. After 30 min at 160 micrograms . kg-1 . min-1, the infusion rate was reversibly decreased. The propoxyphene infusion of 15 mg . min-1 was continued throughout the study. Dopamine improved the circulation in seven animals; one animal died in refractory shock during dopamine infusion. Dopamine infusion at shock level resulted in an increase of the following variables (% of baseline value): MAP (69%), HR (109%), CI (138%) and SVI (129%). Normalisation was seen in MRAP (120%) and in MPAOP (100%). A profound decrease in systemic vascular resistance was unchanged. Increases were seen in left and right ventricular stroke work index, to 88% and 176% of baseline, respectively. Left ventricular dP/dt increased (170%). In the coronary circulation myocardial blood flow increased (133%) as did myocardial oxygen consumption (65%) concomitant with a decrease in myocardial oxygen uptake (41%), but coronary vascular resistance progressively decreased (38%). The myocardial propoxyphene extraction changed from +54% to -86% during peak dopamine infusion. In conclusion, dopamine reversed cardiac failure in propoxyphene overdose by a marked positive inotropic stimulation restoring contractility. A marked positive chronotropic stimulation maintained a sufficient cardiac index and a normal blood pressure in spite of a profound vasodilatation which was unresponsive to dopamine.

Ethanol does not increase lethality due to propoxyphene in rats.

Male Wistar rats (210-330 g) were used as test animals. Propoxyphene (175 mg/kg) and ethanol (2 g/kg) were administered by gastric intubation, naloxone (2 mg/kg) by subcutaneous injection. Four groups, each consisting of 19 rats received either of the following drug treatments: Propoxyphene; ethanol + propoxyphene; naloxone + propoxyphene; and naloxone + ethanol + propoxyphene. The drugs were given in the sequence mentioned at the beginning of the experiment. Naloxone was also given 45 and 90 min later. Mortality was reduced to 42% in the group that received ethanol and propoxyphene as compared to 73% in the group that received propoxyphene only. Naloxone protected against lethality in both groups. A rise in the propoxyphene/norpropoxyphene (P/N) ratio due to an increase in the absolute concentrations of propoxyphene and a decrease in the absolute levels of norpropoxyphene in blood, brain and heart tissues was observed in the ethanol + propoxyphene group, compared to the propoxyphene group. Although these pharmacokinetic data indicate impaired propoxyphene metabolism in the presence of ethanol, ethanol did not enhance propoxyphene induced lethality. This is also contrary to suggestions from previous studies. Our results demonstrate that at least in one species and at one dose ratio (ethanol/propoxyphene) ethanol might reduce the lethality caused by propoxyphene alone. This suggests antagonism between the two drugs, probably in the central nervous system.

Lack of evidence of increased lethality due to propoxyphene overdose in the presence of ethanol in male Wistar rats.

The primary purpose of the present investigation was to evaluate if the presence of ethanol increased lethality induced by propoxyphene. A secondary aim was to study the effect of naloxone on propoxyphene lethality alone, and on the concomitant administration of propoxyphene and ethanol. Male Wistar rats (210-330 g) were used as test animals. Propoxyphene (175 mg/kg) and ethanol (2 g/kg) were administered by gastric intubation, naloxone (2 mg/kg) by subcutaneous injection. Four groups, each consisting of 19 rats, received either of the following drug treatments: Propoxyphene, ethanol + propoxyphene, naloxone + propoxyphene, and naloxone + ethanol + propoxyphene respectively. The drugs were given in the sequence mentioned at the beginning of the experiment. Naloxone was also given 45 and 90 min later. Mortality was reduced to 42% in the group that received ethanol and propoxyphene compared to 73% in the group that received propoxyphene only. Naloxone protected against lethality in both groups. Some animals died despite naloxone administration, possibly due to a nonopioid cardiotoxic effect of propoxyphene or its metabolite. An increase in the propoxyphene/norpropoxyphene (P/N) ratio due to an increase in the absolute concentrations of propoxyphene and a decrease in the absolute levels of norpropoxyphene in blood, brain, and heart tissues was observed in the ethanol + propoxyphene group, compared to the propoxyphene group. In the animals which died, the highest P/N ratio was observed in brain tissue and the lowest in heart muscle. Despite the pharmacokinetic data obtained in this investigation indicating impaired propoxyphene metabolism in the presence of ethanol, ethanol did not enhance propoxyphene-induced lethality.(ABSTRACT TRUNCATED AT 250 WORDS)

How toxic are propoxyphene and ethanol in combination?

Ethanol has been claimed to potentiate greatly the lethality of propoxyphene, although published clinical data suggest only an additive effect. Mice were treated intraperitoneally with various doses of propoxyphene hydrochloride and ethanol. Isobolograms of the data show the combination to be less-than-additive for lethality and loss of motor coordination and, at worst, simply additive for sedation.

Pre- and postnatal development of rats following concomitant intrauterine exposure to propoxyphene and chlordiazepoxide.

The pre- and postnatal effects of the combined oral administration of propoxyphene (PPX, 100 mg/kg/day) and chlordiazepoxide (CDX, 25, 50 or 100 mg/kg/day) were evaluated in Wistar rats in separate experiments by dosing on days 6 through 21 of pregnancy. The controls were given either an aqueous gum tragacanth solution or PPX alone. Maternal toxicity, as evident from death or reduction in body weight, was observed in dams given PPX + 100 mg/kg/day CDX, although previous studies with CDX alone showed no maternal toxicity [5]. PPX alone was well tolerated by the mothers and produced neither any detrimental effects on litter size, litter or pup weights, nor any visceral or skeletal anomalies. Treatment with the two largest doses of CDX + PPX was associated with a high incidence of resorptions, a significant reduction in fetal weight, increased incidence of runts, retarded ossification of skull bones, and a variety of sternal defects. In the postnatal study, PPX alone did not affect pup survival or growth, whereas the combined dosing of PPX and CDX resulted in delayed delivery, increase in stillbirths, reduction in birth weight and a high neonatal mortality compared to pups in the control groups. Pentobarbital sleeping time remained unaltered in 11 to 12-week old offspring of dams given PPX alone. However, in 11 to 12-week old progeny exposed in utero to 25 mg/kg CDX + PPX, the pentobarbital sleeping time was significantly prolonged in males but shortened in females, suggesting that prenatal exposure to PPX + CDX caused a sex-related reversal to pentobarbital hypnosis in mature rats.

Effect of repeated oral propoxyphene administration on analgesia, toxicity and microsomal metabolism in the mouse.

Induction of hepatic propoxyphene N-demethylase and aniline hydroxylase activities resulted following repeated oral administration of 25, 50 and 100 mg d-propoxyphene hydrochloride per kg daily in the mouse over a six-day period. A significant elevation in both enzyme activities was noted after a single dose of propoxyphene (100 mg/kg). A dose-related response characterized the observed induction of each microsomal enzyme activity. Pentobarbital sleeping times (a measure of in vivo microsomal activity) also exhibited dose-related decrements in hypnosis with increasing doses of propoxyphene. These effects appeared to correlate with the development of tolerance to both the analgesic and lethal properties of propoxyphene. Pretreatment with SKF-525A, a potent microsomal enzyme inhibitor, abolished this tolerance in each case. Furthermore, a lack of central nervous system cellular tolerance was demonstrated by the finding that intracerebroventricular LD50 values for propoxyphene in propoxyphene- and water-treated mice were identical to the value derived from naive mice. Thus, the observed tolerance seems to be the result of dispositional (metabolic) and not central nervous system tolerance.

Cardio-respiratory toxicity of propoxyphene and norpropoxyphene in conscious rabbits.

The toxic effects of alpha-d-propoxyphene (P) and its primary metabolite alpha-d-norpropoxyphene (NP) were compared to intravenous infusions (100 min.) of equimolar doses of P and NP (80 micronmol/kg equivalent to 30 mg/kg P HCl) in conscious rabbits. During P infusion severe respiratory depression and convulsions were seen in all animals, and six of the nine animals died. During NP infusion, however, only minimal respiratory depression was seen and all the animals survived. Considerable prolongation of the QRS complex and cardiac arrhythmias like intermittent A-V block and ventricular extrasystoles were seen in the ECG during both P and NP infusion, while the arterial blood pressure was unchanged. In P injection experiments (6 mg/kg P HCl), ECG changes preceded reduction in respiratory rate and during NP infusion only minor changes were seen in arterial blood gases, demonstrating that the ECG changes produced by P and NP are independent of respiratory depression. The ECG changes were found to be similar to those reported in quinidine intoxication. The QRS prolongation was markedly correlated with plasma concentrations during and after P and NP infusion. The results of the present investigation favour the hypothesis that the contribution of NP to the toxicity of oral P overdosage in man is ascribed to its cardiotoxic action whereas P is responsible for the CNS toxicity (respiratory depression and convulsions) as well as cardiotoxicity.

Enhancement of propoxyphene-induced analgesia by doxepin.

The activity of the centrally acting analgesic, propoxyphene, either alone or combined with the tricyclic antidepressant, doxepin, has been studied. Doses of doxepin, in themselves lacking any analgesic effect, remarkably enhanced the analgesic activity of propoxyphene, either by the oral or intraperitoneal route. On the other hand, oral toxicity data prove that doxepin does not alter significantly propoxyphene acute toxicity.

Propoxyphene and norpropoxyphene: pharmacologic and toxic effects in animals.

alpha-d-Propoxyphene and its principle metabolite, alpha-d-norpropoxyphene, were compared pharmacologically to establish their relative opioid profiles as defined by naloxone reversal. Propoxyphene exhibited opioid activity in the following tests: mouse abdominal constriction and rat tail heat analgesic tests, inhibition of the twitch of the guinea-pig ileum and acute lethality in rodents. Norpropoxyphene also showed opioid activity in the rat tail heat and guinea-pig ileum tests, but exhibited nonopioid activity in the mouse abdominal constriction and acute toxicity studies. Jumping in mice, precipitated by naloxone, suggests the following order for liability to produce physical dependence after repeated administration: morphine greater than codeine greater than propoxyphene greater than norpropoxyphene approximately saline. Propoxyphene and norpropoxyphene depressed axonal conduction in isolated peripheral nerve and were comparable in potency to standard local anesthetic agents. The nonopioid actions of norpropoxyphene might be due in part to its local anesthetic properties.

Model to study long-term effects of propoxyphene napsylate (darvon-N) on narcotic-dependent mice.

Five different strains of mice were investigated for their suitability to serve as models for the study of long-term effects of propoxyphene napsylate (PN) on narcotic-dependent mice. The NIH/Swiss outbred strain proved to be most suitable because of its high liability to manifest physical dependence on morphine. Following removal of subcutaneously-implanted morphine pellets from the mice, the incidence of spontaneous withdrawal jumping was used as a quantifiable criterion of physical dependence. An orally administered suspension of PN suppressed the withdrawal jumping in a dose-dependent manner. However, chronic (daily) administration of PN at doses high enough to prevent withdrawal jumping was characterized by a high degree of toxicity.