In vitro-in vivo extrapolation predicts drug-drug interactions arising from inhibition of codeine glucuronidation by dextropropoxyphene, fluconazole, ketoconazole, and methadone in humans.

Because codeine (COD) is eliminated primarily via glucuronidation, factors that alter COD glucuronide formation potentially affect the proportion of the dose converted to the pharmacologically active metabolite morphine. Thus, in vitro-in vivo extrapolation approaches were used to identify potential drug-drug interactions arising from inhibition of COD glucuronidation in humans. Initial studies characterized the kinetics of COD-6-glucuronide (C6G) formation by human liver microsomes (HLM) and demonstrated an 88% reduction in the Michaelis constant (K(m)) (0.29 versus 2.32 mM) for incubations performed in the presence of 2% bovine serum albumin (BSA). Of 13 recombinant UDP-glucuronosyltransferase (UGT) enzymes screened for COD glucuronidation activity, only UGT2B4 and UGT2B7 exhibited activity. The respective S(50) values (0.32 and 0.27 mM) generated in the presence of BSA were comparable with the mean K(m) observed in HLM. Known inhibitors of UGT2B7 activity in vitro or in vivo and drugs marketed as compound formulations with COD were investigated for inhibition of C6G formation by HLM. Inhibition screening identified potential interactions with dextropropoxyphene, fluconazole, ketoconazole, and methadone. Inhibitor constant values generated for dextropropoxyphene (3.5 microM), fluconazole (202 microM), ketoconazole (0.66 microM), and methadone (0.32 microM) predicted 1.60- to 3.66-fold increases in the area under the drug plasma concentration-time curve ratio for COD in vivo. Whereas fluconazole and ketoconazole inhibited UGT2B4- and UGT2B7-catalyzed COD glucuronidation to a similar extent, inhibition by dextropropoxyphene and methadone resulted largely from an effect on UGT2B4. Interactions with dextropropoxyphene, fluconazole, ketoconazole, and methadone potentially affect the intensity and duration of COD analgesia.

Screening of codeine, dextromethorphan & dextropropoxyphene for their genotoxicity in Swiss albino mice.

BACKGROUND & OBJECTIVE: It is mandatory for all new drugs to be tested for their potential genotoxicity in addition to general toxicity testing. Some old drugs have not been tested adequately for their genotoxic effects as these were in use before the regulations were enforced. The present study therefore aims to explore the genotoxic potential of some commonly used opioids like codeine, dextromethorphan and dextropropoxyphene in swiss albino mice. METHODS: Therapeutic equivalent doses of codeine, dextromethorphan and dextropropoxyphene were given orally. Single dose for acute study and multiple doses (repeated every 24 h for 7 times) in additional groups of mice (n=5 in each) for subacute study. Cyclophosphamide served as positive control while normal saline as negative control. About 0.5 ml of blood was collected by retroorbital sinus for comet assay and later the mice were sacrificed to aspirate the femoral bone marrow for micronucleus test. Percentage of micronucleated polychromatic erythrocytes (MnPCE) and comet tail length were calculated in micronucleus assay and comet assay respectively, which served as markers of genotoxicity. RESULTS: Significant (P<0.001) increase in comet tail length and % MnPCE was observed in both acute and subacute studies of cyclophosphamide group, whereas codeine, dextromethorphan and dextropropoxyphene treated groups did not show any significant changes. INTERPRETATION & CONCLUSION: The results indicated that codeine, dextromethorphan and dextropropoxyphene were devoid of genotoxicity in mice.

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.

Tratamiento farmacológico de la dependencia de opiáceos / Advances in the opiate dependence treatment. Clinical perspectives

Los avances científicos han permitido conocer mejor los mecanismos fisiopatológicos (celulares, moleculares y genéticos) de las drogodependencias, lo que se ha traducido en una concepción actual de la misma como una verdadera enfermedad cerebral y mental, crónica, recidivante y tratable mediante fármacos específicos. Sin embargo, el tratamiento farmacológico de las mismas no ha experimentado grandes cambios en los últimos años, al menos en lo que se refiere a nuevos fármacos. Es el caso de la dependencia de opiáceos, una dependencia que parece estabilizada, tras unas consecuencias históricas dramáticas, pero que puede resurgir con otros nuevos patrones de consumo. En efecto, el tratamiento de la intoxicación aguda, de la desintoxicación y de la deshabituación siguen, desde hace años, protocolos similares en todos los dispositivos asistenciales para heroinómanos. Salvo pequeñas novedades farmacológicas, finalmente abandonadas en España (levo-alfa-acetil-metadol), y ciertos estudios de investigación en el campo de la reducción de daños con suministro contralado de heroína, que no han probado claramente su efectividad, los tratamientos farmacológicos siguen siendo los tradicionales (sustitutivos con agonistas y no sustitutivos con antagonistas), si bien se intenta modificar y simplificar el protocolo terapéutico mediante, por ejemplo, pautas rápidas y ultrarrápidas de desintoxicación, dosis individualizadas de metadona y de buprenorfina en deshabituación, etc. Este trabajo pretende revisar los avances farmacológicos más significativos en la dependencia de opiáceos y, por ende, los avances en los mecanismos de acción de los mismos (AU)

The scientific advance have allowed to know the cellular, molecular and genetic mechanism of the drugs dependence, what it has been translated in a present conception of the same one like a true brain and mental disease, chronic, relapse and by treatable means of specific drugs. Nevertheless, the pharmacological treatment of the same ones has not experienced great changes in the last years, at least in which one talks about new drugs. It is the case of the opiate dependence, a dependency that seems stabilized, after dramatic historical consequences, but that can resurge with other new patterns of consumption. In effect, the treatment of the acute poisoning, of the chemical desintoxication and the maintenance dependence they follow, for years, similar protocols in all the welfare devices for heroin addicts. Except for small pharmacological new features, finally left in Spain (levo-alpha-acetyl-methadol), and certain studies of investigation in the field of the reduction of damages with controlled provision of heroin, that they have not proven clearly its effectiveness, the pharmacological treatments continue being the traditional ones (substitute with agonists, and non substitute with antagonists9, although it is tried to modify and to simplify the therapeutic protocol by means of, for example, fast and high speed guidelines of chemical desintoxication, doses individualized of methadone and buprenorfine in maintenance dependence, etc. this work tries to review more significant the pharmacological advances in the opiate dependence and therefore, the advances in the mechanisms of action of such (AU)

Differential in vitro inhibition of M3G and M6G formation from morphine by (R)- and (S)-methadone and structurally related opioids.

AIMS: To determine the in vitro kinetics of morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) formation and the inhibition potential by methadone enantiomers and structurally related opioids. METHODS: M3G and M6G formation kinetics from morphine were determined using microsomes from five human livers. Inhibition of glucuronide formation was investigated with eight inhibitors (100 microm) and the mechanism of inhibition determined for (R)- and (S)-methadone (70-500 microm) using three microsomal samples. RESULTS: Glucuronide formation displayed single enzyme kinetics. The M3G Vmax (mean+/-SD) was 4.8-fold greater than M6G Vmax (555+/-110 vs. 115+/-19 nmol mg-1 protein h-1; P=0.006, mean of difference 439; 95% confidence interval 313, 565 nmol mg-1 protein h-1). Km values for M3G and M6G formation were not significantly different (1.12+/-0.37 vs. 1.11+/-0.31 mm; P=0.89, 0.02; -0.29, 0.32 mm). M3G and M6G formation was inhibited (P<0.01) with a significant increase in the M3G/M6G ratio (P<0.01) for all compounds tested. Detailed analysis with (R)- and (S)-methadone revealed noncompetitive inhibition with (R)-methadone Ki of 320+/-42 microm and 192+/-12 microm for M3G and M6G, respectively, and (S)-methadone Ki of 226+/-30 microm and 152+/-20 microm for M3G and M6G, respectively. Ki values for M3G inhibition were significantly greater than for M6G for (R)-methadone (P=0.017, 128; 55, 202 microm) and (S)-methadone (P=0.026, 75; 22, 128 microm). CONCLUSIONS: Both methadone enantiomers noncompetitively inhibited the formation of morphine's primary metabolites, with greater inhibition of M6G formation compared with M3G. These findings indicate a mechanism for reduced morphine clearance in methadone-maintained patients and reduced relative formation of the opioid active M6G compared with M3G.

Characterizing the subjective, psychomotor, and physiological effects of oral propoxyphene in non-drug-abusing volunteers.

BACKGROUND: The subjective, psychomotor, and physiological effects of a widely prescribed prescription opioid, propoxyphene, have not been studied in a population of non-drug-abusing people. The drug also has potential for abuse and it was of interest in the present study to determine if the drug had any abuse liability-related subjective effects in this population. METHODS: Eighteen volunteers participated in a crossover, randomized, double-blind study in which they received, all p.o., placebo; 50 mg propoxyphene napsylate; 100 mg propoxyphene napsylate; 200 mg propoxyphene napsylate; 40 mg morphine sulfate; and 2 mg lorazepam. Measures were assessed before and for 300 min after drug administration. RESULTS: Both morphine and lorazepam produced subjective effects. There were no statistically significant subjective effects obtained with any dose of propoxyphene in the group as a whole, but approximately 30-50% of the subjects did appear to experience subjective effects from the drug. Drug liking was not consistently observed in this subset. Propoxyphene, unlike lorazepam, did not impair psychomotor or cognitive performance. Both propoxyphene and morphine produced miosis. CONCLUSIONS: There was a lack of statistically significant subjective effects of propoxyphene in the group as a whole, including a propoxyphene dose that was twice as high as the typical clinically-prescribed dose of 100 mg. However, there were some subjects who did report effects, consistent with the notion that patients differ in their sensitivity to opioid effects.

Drug- and mutagenesis-induced changes in the selectivity filter of a cardiac two-pore background K+ channel.

OBJECTIVE: As compared with voltage-gated K(+) channels (Kv-type), our knowledge of the structure-function and pharmacology of two-pore background K(+) channels is still very limited. Here we have used a drug- and mutagenesis-based approach to study the effect of the antidepressant fluoxetine (FL) and analgesic D-norpropoxyphene (NORP) on the cardiac two-pore background K(+) channel. METHODS: Whole-cell currents of the cTBAK-1 channel expressed in Xenopus laevis oocytes were investigated using conventional two-microelectrode voltage-clamp recording method combined with functional mutagenesis of the channel protein. RESULTS: Both drugs inhibit cTBAK-1 current: FL proved to be a voltage-dependent pore-blocker, while NORP induced a change in the selectivity of cTBAK-1 giving rise to a shift in the reversal potential (E(rev)) toward more positive voltages due to an increased Na(+) permeability. Mutations were introduced into the selectivity filter of the first (Y105F) and the second (F211Y) pore to mimic the P-region of HERG (GFGN) and Kv1.1 (GYGD) channels. Point mutations in the channel resulted in two distinct phenotypes of cTBAK-1: the mutant Y105F channel lost its selectivity and was unaffected by NORP, in contrast to the F211Y mutant. CONCLUSION: FL and NORP block the current of cTBAK-1 channels differently, the latter modified the selectivity of the channel pore. Our mutagenesis study revealed that NORP interacts with the selectivity filter of cTBAK-1. The significant role of the GYGD motif in this type of K(+) channels is emphasized.

Cocaine-like discriminative stimulus effects and [3H]dopamine uptake inhibition produced by selected partial opioid agonists.

Partial opioid agonists can produce their actions at opioid as well as some non-opioid sites. Although the receptor systems underlying these non-opioid effects are not completely clear, recent studies indicate the possible involvement of activity at the dopamine uptake site. One purpose of the present investigation was to examine the ability of selected partial opioid agonists (dezocine, meperidine and [+]-propoxyphene) with non-opioid actions to produce cocaine-like stimulus effects. Because non-opioid effects can be apparent under conditions in which opioid-mediated effects are blocked or at doses that markedly decrease responding, these opioids were also examined in combination with the opioid antagonist naltrexone. A second purpose was to determine the ability of these opioids to inhibit [3H]dopamine uptake in rat caudate putamen. Cocaine and the direct-acting dopamine agonist (-)-quinpirole, but not (+)-propoxyphene, butorphanol, morphine, U50,488 and pentobarbital, substituted completely for the cocaine stimulus. Dezocine substituted for the cocaine stimulus in the majority of the rats tested only when administered in combination with naltrexone. Meperidine also substituted for the cocaine stimulus in the majority of the rats tested, although this pattern of substitution was not consistently altered by naltrexone. Dezocine and meperidine inhibited [3H]dopamine uptake in a manner consistent with that produced by cocaine. The results suggest that dezocine and meperidine can produce cocaine-like stimulus effects and that these effects are likely mediated by activity at the dopamine uptake site.

The cognitive and psychomotor effects of morphine in healthy subjects: a randomized controlled trial of repeated (four) oral doses of dextropropoxyphene, morphine, lorazepam and placebo.

Ten healthy subjects (four male) of mean age 31 years (range 25-40) took part in a randomized double-blind four-way crossover study to examine the cognitive and psychomotor effects of repeated oral doses of dextropropoxyphene and morphine. Four treatments were compared: dextropropoxyphene napsylate 100 mg, morphine sulphate 10 mg, lorazepam 0.5 mg and placebo. Four doses of each drug were given at 4-h intervals to each subject on four separate study days at least 1 week apart. Cognitive function was assessed using choice reaction time, number vigilance, memory scanning, immediate and delayed word recall, word recognition, picture recognition, critical flicker fusion threshold (CFFT) and subjective measures of alertness, calmness and contentment. Lorazepam impaired the speed of responding on all tasks in which speed was recorded (except digit vigilance) and increased subjective ratings of calmness. Morphine had one major effect, which was to increase the accuracy of responding on the choice reaction time task, at every assessment. Morphine produced some sporadic effects in other tests and an increase in subjective calmness. Dextropropoxyphene impaired performance on choice reaction time and picture recognition. These data show that oral morphine may enhance performance in some measures of cognitive function, whereas dextropropoxyphene (in usual therapeutic doses) seems more likely to cause impairment. Neither opioid has substantial effects on cognition and psychomotor function compared with lorazepam.

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

The dual modulation of GIRK1/GIRK2 channels by opioid receptor ligands.

It is well known that activation of the cloned kappa-opioid receptor by nanomolar concentrations of U50488H (trans-(+/-)-3, 4-dichloro-N-methyl-N-(2-[1-pyrrolidinyl]cyclohexyl-benzeneacetamide) , a selective kappa-opioid receptor agonist, leads to the opening of GIRK1 channels. In this study, we demonstrate that the cloned kappa-opioid receptor functionally couples to GIRK1/GIRK2 channels (G-protein-coupled inwardly rectifying K(+) channels), mimicking the probable heteromultimeric state of neuronal GIRK channels. We also show that micromolar concentrations of U50488H reduce GIRK1/GIRK2 current through direct GIRK1/GIRK2 channel block in a voltage-independent manner (IC(50)=70.28+/-3.68 microM). Similarly, it was found that propoxyphene, methadone, and naloxone also can block GIRK1/GIRK2 current. In contrast, elevated concentrations of morphine (up to 1 mM) did not cause channel block. The related inwardly rectifying K(+) channel, IRK1, was not affected by elevated concentrations of these drugs. We conclude that nanomolar concentrations of opioid receptor ligands activate GIRK1/GIRK2 channels through a receptor-mediated pathway, while micromolar concentrations of some opioid receptor ligands inhibit GIRK1/GIRK2 channels by direct channel block.

Norpropoxyphene-induced cardiotoxicity is associated with changes in ion-selectivity and gating of HERG currents.

OBJECTIVE: Norpropoxyphene (NP) is a major metabolite of propoxyphene (P), a relatively weak mu-opioid receptor agonist. Toxic blood concentrations ranging from 3 to 180 mumol/l have been reported and the accumulation of NP in cardiac tissue leads to naloxone-insensitive cardiotoxicity. Since several lines of evidence suggest that not only block of INa but also IK block may contribute to the non-opioid cardiotoxic effects of P and NP, we investigated the effects of P and NP on HERG channels. HERG presumably encodes IKr, the rapidly-activating delayed rectifier K+ current, which is known to have an important role in initiating repolarization of action potentials in cardiac myocytes. METHODS: Using the 2-microelectrode voltage clamp technique we investigated the interaction of P and NP with HERG channels, expressed in Xenopus oocytes. RESULTS: Our experiments show that low drug concentrations (5 mumol/l) facilitate HERG currents, while higher drug concentrations block HERG currents (IC50-values of approx. 40 mumol/l) and dramatically shift the reversal potential to a more positive value because of a 30-fold increased Na(+)-permeability. P and NP also alter gating of HERG channels by slowing down channel activation and accelerating channel deactivation kinetics. The mutant S631C nullifies the effect of P and NP on the channel's K(+)-selectivity. CONCLUSION: P and NP show a complex and unique drug-channel interaction, which includes altering ion-selectivity and gating. Site-directed mutagenesis suggests that an interaction with S631 contributes to the drug-induced disruption of K(+)-selectivity. No specific role of the minK subunit in the HERG block mechanism could be determined.

Opioid analgesics as noncompetitive N-methyl-D-aspartate (NMDA) antagonists.

Much evidence points to the involvement of N-methyl-D-aspartate (NMDA) receptors in the development and maintainance of neuropathic pain. In neuropathic pain, there is generally involved a presumed opioid-insensitive component, which apparently can be blocked by NMDA receptor antagonists. However, in order to obtain complete analgesia, a combination of an NMDA receptor antagonist and an opioid receptor agonist is needed. Recent in vitro data have demonstrated that methadone, ketobemidone, and dextropropoxyphene, in addition to being opioid receptor agonists, also are weak noncompetitive NMDA receptor antagonists. Clinical anecdotes suggest that the NMDA receptor antagonism of these opioids may play a significant role in the pharmacological action of these compounds; however, no clinical studies have been conducted to support this issue. In the present commentary, we discuss evidence for the NMDA receptor antagonism of these compounds and its relevance for clinical pain treatment; an overview of structure-activity relationships for the relevant opioids as noncompetitive NMDA receptor antagonists also is given. It is concluded that although the finding that some opioids are weak noncompetitive NMDA receptor antagonists in vitro has created much attention among clinicians, no clinical studies have been conducted to evaluate the applicability of these compounds in the treatment of neuropathic pain conditions.

Ação crônica do napsilato de propoxifeno na prenhez da rata / Chronic effects of propoxyphene napsylate on pregnant rats

O objetivo deste trabalho é avaliar os efeitos do napsilato de propoxifeno sobre a prenhez da rata albina. Para tanto utilizamos 50 ratas prenhes divididas ao acaso em cinco grupos iguais. Todas receberam diariamente, por gavagem, o volume de 1 ml, desde os dias 0 (zero) até o 20 de prenhez, com as seguintes características: grupo I - somente água destilada (controle): grupo II - soluçao aquosa de acácia 2 por cento (veículo); grupos III, IV e V - respectivamente, 5, 15 e 45 mg/kg de peso de napsilato de propoxifeno dissolvido em soluçao de acácia a 2 por cento. Os pesos maternos foram anotados nos dias 0 (zero), 7, 14 e 20 de prenhez; no 20 dia as matrizes foram sacrificadas. Nossos resultados mostraram que os animais tratados com 45 mg/kg do fármaco apresentaram reduçao dos pesos individuais dos fetos como também dos pesos das ninhadas e das placentas. Quanto às outras variáveis apreciadas: número de reabsorçoes, de implantaçoes e de placentas nao houve diferença significante entre os grupos tratados em relaçao ao grupo controle.

Cocaine use immediately prior to entry in an inpatient heroin detoxification unit as a predictor of discharges against medical advice.

Detection of benzyolecgonine, the major metabolite of cocaine, in the urinalysis conducted on the first day of an inpatient heroin detoxification treatment program was studied as a predictor of discharge against medical advice (AMA). With this aim, we conducted a chart-review procedure of 275 heroin dependents (DSM-III-R) who received methadone or dextropropoxyphene chlorhydrate to treat Opioid Withdrawal Syndrome. Data were analyzed following a case-control design. The 49 (17.8%) patients who did not complete the treatment due to discharged AMA were characterized by having achieved total heroin abstinence during fewer months from the time they began consumption of this substance to the time of hospitalization (p = .001). Moreover, those patients who requested discharge AMA were characterized by more frequent detection of benzoylecgonine in their urine on the day of admission (p = .004). The value of the odds ratio of this association was 3.81 (95% CI; 1.30 to 11.04). Lastly, noncompleters due to discharge AMA were more likely to be single than ever married (p = .037). The logistic regression model confirmed that there is a significant relationship between an AMA event and the presence of benzoylecgonine in urine upon beginning detoxification and to a shorter duration of the period of total heroin abstinence. In the discussion, the influence that recent interruption of cocaine consumption has on the decision to drop out of a detoxification program AMA is considered.

The clinical relevance of the interaction between carbamazepine and dextropropoxyphene in elderly patients in Gothenburg, Sweden.

OBJECTIVES: To evaluate the clinical importance of the interaction between carbamazepine (CBZ) and dextropropoxyphene in elderly patients. METHODS: All patients (n = 7263) in Gothenburg, Sweden, who were part of a drug-dispensing programme, were included in the study. Eight per cent of the patients took CBZ and 18% took dextropropoxyphene, continuously. Patients who used a combination of these drugs were compared with patients who took only CBZ or dextropropoxyphene or neither of the two drugs. These four groups of patients were matched to each other with reference to gender, age and concomitant medication, which finally resulted in 21 patients in each group. A questionnaire with 30 symptoms of well-being, including symptoms typical of adverse effects of CBZ, were answered by the patients with the help of a registered nurse. Venous blood samples were drawn from the patients for the analysis of CBZ, its metabolite CBZ 10,11-epoxide (CBZ-E) and dextropropoxyphene. RESULTS: The doses of CBZ and dextropropoxyphene were lower among patients who used the combination of the two drugs than among those who only used one of the drugs. The mean level of CBZ in serum (S-CBZ) was, however, significantly higher and the level of CBZ-E in serum (S-CBZ-E) significantly lower among the patients who used the combination of CBZ and dextropropoxyphene, thus indicating an inhibition of the metabolism of CBZ. The prevalence of symptoms indicating side effects of CBZ was significantly higher in the group of patients who used both drugs. CONCLUSION: This study has shown that the combination of CBZ and dextropropoxyphene is hazardous in elderly patients and should be used with caution.

Methadone block of K+ current in squid giant fiber lobe neurons.

Voltage-dependent ionic currents were recorded from squid giant fiber lobe neurons using the whole-cell patch-clamp technique. When applied to the bathing solution, methadone was found to block IK, I Na and I Ca. Both I Na and I Ca were reduced without apparent change in kinetics and exhibited IC(50)'s of 50-100 and 250-500 mu M, respectively, at +10 mV. In contrast, IK was reduced in a time-dependent manner that is well fit by a simple model of open channel block (K(D)= 32+/- or 2 mu M, +60 mV, 10 degrees Celsius). The mechanism of I(K) block was examined in detail and involves a direct action of methadone, a tertiary amine, on K channels rather than an opioid receptor-mediated pathway. The kinetics of I(K) block resemble those reported for internally applied long chain quaternary ammonium (QA) compounds; and recovery from I(K) block is QA-like in its slow time course and strong dependence on holding potential. A quaternary derivative of methadone (N-methyl-methadone) only reproduced the effects of methadone on I(K) when included in the pipette solution; this compound was without effect when applied externally. I(K) block thus appears to involve diffusion of methadone into the cytoplasm and occlusion of the open K channel at the internal QA blocking site by the protonated form of the drug. This proposed mode of action is supported by the pH and voltage dependence of block as well as by the observation that high external K+ speeds the rate of drug dissociation. In addition, the effect of methadone on I(K) evoked during prolonged (300 ms) depolarizations suggests that methadone block may interfere with endogenous K+ channel inactivation. The effects of temperature, methadone stereoisomers, and the methadone-like drugs propoxyphene and nor-propoxyphene on IK block were examined. Methadone was also found to block I(K) in GH3 cells and in chick myoblasts.

Determination of analgesic interaction between acetaminophen and d-propoxyphene obtained by means of the surface of synergistic interaction.

The analgesic effects of acetaminophen, p.o., (ACE) and d-propoxyphene, s.c., (PROP) administered either separately or in 24 different combinations were determined in a model of pain-induced functional impairment in the rat. This allowed us to detect the analgesic interaction profile of the combinations. Furthermore, we set out to determine the optimal degree of enhancement obtained with a specific combination of the above drugs by means of the surface of synergistic interaction (SSI) of the combinations. This parameter was calculated from the total analgesic effect produced by the combination after having subtracted the analgesic effect produced by each drug alone. The ED50s for ACE and PROP were 286.1 +/- 1.4 mg/kg and 66.3 +/- 1.2 mg/kg, respectively. Over the dose ranges used, the analgesic activities of both ACE and PROP tended to be smaller than those of their respective combinations. Furthermore, 11 combinations showed various degrees of enhancement (p<0.01), while the others (13) exhibited additive analgesic effects. The combination of ACE (562.3 mg/kg) and PROP (56.2 mg/kg) produced the maximum analgesic effect. However,5 combinations of ACE with PROP (177.8-56.2, 316.2-10.0, 316.2-17.8, 316.2-56.2 and 562.3-10.0 mg/kg) produced the highest enhancement. The SSI clearly showed which combination of these analgesic drugs produced the highest degree of enhancement in the rat. This study shows that a specific combination ratio of analgesic drugs can produce optimum enhancement of their analgesic effects.