Disulfiram enhances the antitumor activity of cisplatin by inhibiting the Fanconi anemia repair pathway / 浙江大学学报（英文版）（B辑：生物医学和生物技术）

A series of chemotherapeutic drugs that induce DNA damage, such as cisplatin (DDP), are standard clinical treatments for ovarian cancer, testicular cancer, and other diseases that lack effective targeted drug therapy. Drug resistance is one of the main factors limiting their application. Sensitizers can overcome the drug resistance of tumor cells, thereby enhancing the antitumor activity of chemotherapeutic drugs. In this study, we aimed to identify marketable drugs that could be potential chemotherapy sensitizers and explore the underlying mechanisms. We found that the alcohol withdrawal drug disulfiram (DSF) could significantly enhance the antitumor activity of DDP. JC-1 staining, propidium iodide (PI) staining, and western blotting confirmed that the combination of DSF and DDP could enhance the apoptosis of tumor cells. Subsequent RNA sequencing combined with Gene Set Enrichment Analysis (GSEA) pathway enrichment analysis and cell biology studies such as immunofluorescence suggested an underlying mechanism: DSF makes cells more vulnerable to DNA damage by inhibiting the Fanconi anemia (FA) repair pathway, exerting a sensitizing effect to DNA damaging agents including platinum chemotherapy drugs. Thus, our study illustrated the potential mechanism of action of DSF in enhancing the antitumor effect of DDP. This might provide an effective and safe solution for combating DDP resistance in clinical treatment.

Chemical composition of Zhumeria majdae essential oil and its effects on the expression of morphine withdrawal syndrome and tolerance to the anticonvulsant effect of morphine on pentylenetetrazole-induced seizures in mice / Composição química do óleo essencial de Zhumeria majdae e seus efeitos na expressão da síndrome de abstinência de morfina e tolerância ao efeito anticonvulsivante da morfina em crises induzidas por pentilenotetrazol em camundongos

Abstract Regarding the proven anticonvulsant effect of Zhumeria majdae essential oil (ZMEO) in previous studies we were prompted to investigate the ZMEO effects on the tolerance to the anticonvulsant effects of morphine and the morphine withdrawal syndrome. Tolerance to the morphine anticonvulsant effect was induced in mice by subcutaneous injection of 2.5 mg/kg of morphine for 4 days. Subsequent doses of ZMEO (20 mg/kg) were used to study the expression and development of morphine tolerance. Clonidine was used as the standard drug to inhibit the morphine withdrawal syndrome symptoms. To study the ZMEO effect on withdrawal syndrome, mice received appropriate morphine values for 4 days and on the fifth day, 60 min before administration of naloxone. The effective dose of ZMEO was determined and the number of jumps, stands and changes in the dry stool weight, as symptoms of withdrawal syndrome were evaluated. The dose of 20 mg/kg of ZMEO decreased the tolerance in development and expression groups significantly. Counting the number of jumping, standing and defecation were assessed 30 min after morphine and 1 h after the vehicle and clonidine. The dose of 40 mg/kg ZMEO decreased all the signs of withdrawal syndrome significantly. ZMEO was analyzed by GC/MS and linalool (53.1%) and camphor (23.8%) were characterized as the main components. The results suggest that ZMEO possesses constituent(s) that have activity against tolerance to the anticonvulsant effects of morphine and the morphine withdrawal symptoms.

Resumo Em relação ao efeito anticonvulsivante comprovado do óleo essencial de Zhumeria majdae (ZMEO) em estudos anteriores, fomos instigados a investigar os efeitos do ZMEO em relação à tolerância aos efeitos anticonvulsivantes da morfina e da síndrome de abstinência de morfina. A tolerância ao efeito anticonvulsivante da morfina foi induzida em camundongos por injeção subcutânea de 2,5 mg/kg de morfina por 4 dias. Doses subsequentes de ZMEO (20 mg/kg) foram utilizadas para estudar a expressão e o desenvolvimento da tolerância à morfina. A clonidina foi usada como droga padrão para inibir os sintomas da síndrome de abstinência da morfina. Para estudar o efeito do ZMEO na síndrome de abstinência, os camundongos receberam valores apropriados de morfina por 4 dias e, no 5º dia, 60 minutos antes da administração de naloxona. A dose efetiva de ZMEO foi determinada, e o número de saltos e de permanência e as alterações no peso das fezes secas, conforme os sintomas da síndrome de abstinência, foram avaliados. A dose de 20 mg/kg de ZMEO diminuiu significativamente a tolerância nos grupos de desenvolvimento e expressão. A contagem do número de saltos, permanência e defecação foi avaliada 30 minutos após a morfina e 60 minutos após o veículo e a clonidina. A dose de 40 mg/kg de ZMEO diminuiu significativamente todos os sinais da síndrome de abstinência. O ZMEO foi analisado por GC/MS, e linalol (53,1%) e cânfora (23,8%) foram caracterizados como os principais componentes. Os resultados sugerem que o ZMEO apresenta constituintes que possuem atividade contra a tolerância aos efeitos anticonvulsivantes da morfina e aos sintomas de abstinência da morfina.

Abstinência à cocaína e suas consequências no sistema colinérgico muscarínico / Abstinencia a la cocaína y sus consecuencias en el sistema colinérgico muscarínico / Abstinence from cocaine and its consequences on the muscarinic cholinergic system

Uma das principais dificuldades enfrentadas na dependência à cocaína está relacionada aos sintomas de abstinência, como ansiedade, desejo e irritabilidade. Estes efeitos podem durar meses ou anos após a interrupção do consumo prolongado, fazendo com que o indivíduo volte a procurá-la. Os efeitos recompensadores da cocaína levam a alterações neurobiológicas do sistema mesocorticolímbico dopaminérgico, que se origina na área tegmental ventral e se projeta para o núcleo accumbens, e córtex pré-frontal, áreas intimamente ligadas ao desenvolvimento da dependência. Esses neurônios dopaminérgicos recebem estímulos dos neurônios colinérgicos que contribuem para os aspectos cognitivos da dependência. Devido à complexidade neurobilógica envolvida durante a abstinência, pouco se sabe sobre as alterações no sistema colinérgico muscarínico durante este período no encéfalo, objetivo deste estudo. Para tal, camundongos machos adultos Swiss-Webster foram submetidos à cocaína em padrão agudo em binge (3×30 mg/kg/dia) e cronicamente por escalonamento de dose em binge por 14 dias (3×15 mg/kg/dia nos dias 1-4; 3×20 mg/kg/dia nos dias 5-8; 3×25 mg/kg/dia nos dias 9-12; e 3×30 mg/kg/dia nos dias 13 e 14). A atividade locomotora de cada animal foi avaliada em campo aberto (CA), onde permaneceram no aparato por 60 minutos entre cada administração. Após o período de exposição os animais permaneceram 14 dias em abstinência, a fim de avaliar a ansiedade no labirinto em cruz elevado (LCE). Em seguida os animais foram eutaniasiados, sendo o córtex pré-frontal (CPF), o estriado e o hipocampo dissecados e armazenados a -80ºC para a análise dos receptores dopaminérgicos D1 e D2, receptores colinérgicos muscarínicos M1, M2, M3, M4 e M5 (mAChRs) e moléculas colinérgicas (acetilcolinesterase, AChE; colina acetiltransferase, ChAT e transportador vesicular de acetilcolina, VAChT) por Western Blotting (n=6). Os resultados comportamentais mostraram maior atividade locomotora nos animais tratados com cocaína no tratamento agudo ou crônico, quando comparado ao basal. Mais ainda, a sensibilização comportamental foi detectada a partir do segundo dia de administração de cocaína. No teste de LCE, realizado 14 dias após a interrupção da administração de cocaína, não foi observada diferença estatística entre os animais previamente expostos à cocaína e grupo controle. No CPF observou-se diminuição de D2R, M1 mAChRs e aumento M2 e M4 mAChRs no tratamento agudo; no tratamento crônico houve diminuição de M1 e M5 mAChRs e ChAT. No estriado observou-se aumento de D1R, M1 e M2 mAChRs, ChAT no tratamento agudo; e aumento D1R, VAChT, ChAT e diminuição D2R, M1 e M2 mAChRs no tratamento crônico. Já no hipocampo observou-se aumento de D1R, D2R, M2 mAChRs, VAChT e diminuição M1 mAChRs no tratamento agudo; e aumento de D1R, VAChT e diminuição D2R, M1 mAChRs no tratamento crônico. Nossos resultados mostram envolvimento de processo de neuroplasticidade, tanto no sistema dopaminérgico quanto no colinérgico muscarínico, em ambos os protocolos utilizados, mesmo após 14 dias de abstinência

Una de las dificultades enfrentadas en la dependencia de cocaína son los síntomas de abstinencia, como ansiedad, deseo y irritabilidad. Estos efectos pueden durar meses o años después de la interrupción del consumo prolongado, haciendo que el individuo vuelva a consumirlo. Los efectos recompensadores de la cocaína causa alteraciones neurobiológicas del sistema mesocorticolímbico dopaminérgico, que se origina en el área tegmental ventral y se proyecta hacia el núcleo accumbens y córtex pré-frontal, áreas íntimamente ligadas al desenvolvimiento de la dependencia. Esas neuronas dopaminérgicas reciben estímulos de neuronas colinérgicas la cual contribuyen para los aspectos cognitivos de la dependencia. Debido a la complejidad neurobiológica involucrada durante la abstinencia, poco se sabe sobre las alteraciones del sistema colinérgico muscarínico durante este periodo en el encéfalo, objetivo de este estudio. Por tanto, ratones adultos macho Swiss-Webster fueron sometidos a cocaína en dosis padrón agudo en binge (3×30 mg/kg/día) y crónicamente por escalonamiento de dosis en binge por 14 días (3×15 mg/kg/día en los días 1-4; 3×20 mg/kg/día en los días 5-8; 3×25 mg/kg/día en los días 9-12; y 3×30 mg/kg/día en los días 13 e 14). La actividad locomotora de cada animal fue evaluada en el test de campo abierto (CA), donde permanecieron por 60 minutos entre cada administración. Después del periodo de exposición los animales permanecieron 14 días de abstinencia, a fin de evaluar la ansiedad en el labirinto de cruz elevado (LCE). En seguida los animales fueron eutanasiados, donde el córtex pré-frontal (CPF), estriado y hipocampo fueron disecados y almacenados a -80ºC para analizar los receptores dopaminérgicos D1 e D2, receptores colinérgicos muscarínicos M1, M2, M3, M4 y M5 (mAChRs) y moléculas colinérgicas (acetilcolinesterasa, AChE; colina acetiltransferasa, ChAT y transportador vesicular de acetilcolina, VAChT) por Western Blotting (n=6). Los resultados comportamentales mostraron mayor actividad locomotora en los animales tratados con cocaína en tratamiento agudo y crónico, comparado al control. Por otra parte, la sensibilización comportamental fue detectado a partir de segundo día de administración de cocaína. En la prueba de LCE, realizado después de 14 días de interrupción de la administración de cocaína, no fue observado diferencia estadística entre los animales previamente expuestos a la cocaína y el grupo control. En CPF se observó disminución de D2R, M1 mAChRs y aumento de M2 y M4 mAChRs en tratamiento agudo; en el tratamiento crónico mostro disminución de M1 y M5 mAChRs y ChAT. En el estriado se observó aumento de D1R, M1 y M2 mAChRs, ChAT en el tratamiento agudo; aumento D1R, VAChT, ChAT y disminución de D2R, M1 y M2 mAChRs en el tratamiento crónico. Por último, en el hipocampo se observó aumento de D1R, D2R, M2 mAChRs, VAChT y disminución M1 mAChRs en el tratamiento agudo; aumento de D1R, VAChT y disminución D2R, M1 mAChRs en el tratamiento crónico. Nuestros resultados muestran envolvimiento de procesos de neuroplasticidad, tanto en el sistema dopaminérgico como el sistema colinérgico muscarínico, en ambos protocolos utilizados, después de 14 días de abstinencia

[Effect of hydroalcoholic extract of Cinnamomum on morphine-induced withdrawal symptoms in rats]

The exact mechanisms of morphine dependence and withdrawal syndrome remain unclear. Many studies have been performed to find agents with minimal dependency side effects for prevention of withdrawal symptoms. Cinnamomum is a herbal medicine that has been used for respiratory disorders, digestive problems, arthritis, dysmenorrhea, and sore throat. Cinnamomum has been used as an alternative traditional treatment for sedative agents in China and India. This study aimed at investigating the effect of hydroalcoholic extract of cinnamomum on morphine withdrawal symptoms in the male rats. Adult mal Wistar rats weighting 225 -275 g were randomly selected and divided into 5 groups [8 rats per group]. In order to induce dependency, additive doses of morphine were injected subcutaneously for 13 days. On the day 13, 30 minutes after the last dose of morphine, control group received saline ip [1 ml/kg: control] and 3 treatment groups received hydroalcoholic extracts of Cinnamomum [50, 100, 200 mg/kg respectively] intraperitoneally. Thirty minutes later,all groups received naloxone injection [4 mg/kg, ip] and withdrawal symptoms including: jumping, rearing, genital grooming, abdominal writhing, and wet dog shake were recorded for 60 minutes. Our results showed that hydroalcoholic extract of Cinnamomum at doses of 50, 100and 200 mg/kg decreased genital grooming. In addition,all doses of the extract of Cinnamomum decreased the total withdrawal scores signficantly. Hydroalcoholic extract of Cinnamomum was effective in reducing the symptoms of morphine withdrawal

effects of gabapentin on methadone based addiction treatment: a randomized controlled trial

Gabapentin is a potentially useful drug in alleviating the hyperexcitatory painful states in the control of opiate dependence in acute detoxification and the stabilization phase. This study aim was to evaluate the effectiveness of gabapentin adds-on methadone therapy on lowering the methadone. This randomized double blind controlled clinical trial conducted at an outpatient rehabilitation clinic. Sixty patients using opium, opium extract and heroin were randomly assigned to two groups [34 in treatment group and 26 in control group]; one group was prescribed combination of methadone [40-120 mg] and gabapentin [300 mg] as group A, and the other group was given methadone [40-120] and placebo as group B. The subjects were followed up for three weeks after intervention. There were 60 outpatients including 51 males with the mean age of 40.9 +/- 9.2. Daily dose and cumulative dose of methadone during the treatment was found to be significantly higher in group B [73.8 +/- 19.5 mg daily vs. 58.9 +/- 11 mg daily and cumulatively 1550.7 +/- 409.7 mg vs. 238.3 +/- 238.2 mg, p= 0.001]. When the patients were stratified based on the kind of abused drug, the methadone dose was seen to be significantly reduced in the opium addicted patients in the group A. Group A showed more withdrawal symptoms whereas the most common complain of group B was sedation particularly during the first three days. The results showed that gabapentin is an effective adds-on therapy when is added to methadone. This drug leads to relief of withdrawal symptoms and lower methadone consumption

Comparison of efficacy of thioridazine with clonidine acting through different mechanisms in acute opioid abstinence syndrome

To compare the efficacy, safety and tolerability of thioridazine with clonidine in patients with Acute opioid Abstinence Syndrome. This single blind comparative clinical trial was carried out at Department of Pharmacology, Basic Medical Sciences Institute [BMSI], Jinnah Postgraduate Medical Center [JPMC], Karachi. Fifty two addicts were selected randomly and were grouped into, group-A to received thioridazine 100 mg/day and group -B to received clonidine 150mcg/day. All participants completed the treatment program and stayed in hospital for ten days. The efficacy safety and tolerability of thioridazine was scant, while clonidine showed statistically significant turn down in the objective signs of acute opioid abstinence syndrome. Clonidine had more powerful effects than thioridazine. While treating the withdrawal signs of opioid abstinence syndrome may possibly pointed out that over activation of norepinephrine is a major factor contributes to the commencement of opioid abstinence syndrome

Suppressive effects of Rosa damascena essential oil on naloxone-precipitated morphine withdrawal signs in male mice

This research was done to test the effect of Rosa damascena essential oil on withdrawal signs of naloxone-precipitated morphine in male mice. Morphine dependence was induced by injection [IP] three times daily at doses of 50, 50 and 75 mg/kg, respectively, for 3 days. On day 4, after the last administration of morphine, Rosa damascena essential oil was administered at different concentrations [5, 2 and 40%, IP] 30 min before administration of naloxone [5 mg/kg, IP]. The following actions were taken as signs of withdrawal and records taken for jumping as a number and scores of 0 to 3 were given for incidences of grooming, teeth chattering, rearing, writing, diarrhea, wet dog shakes and climbing during a 30 min period. Results showed that different concentrations of Rosa damascena essential oil significantly reduced signs of morphine withdrawal compared to the control group in terms of number of jumps [p < 0.05 and p < 0.01], grooming, teeth chattering, rearing, climbing, wet dog shakes and writhing, but not for diarrhea [p < 0.05]. In conclusion it seems that GABAergic activity induced by flavonoids from Rosa damascena essential oil can alleviate signs of morphine withdrawal, but further studies need to be done to better understand this mechanism

Intervenções farmacológica e psicossocial para os distúrbios por uso da cannabis / Pharmacological and psychosocial interventions for cannabisuse disorders

OBJETIVO: A cannabis continua sendo a substância ilegal mais amplamente utilizada na maioria dos países desenvolvidos. Seu potencial aditivo foi estabelecido e a necessidade de intervenções em problemas relacionados à cannabis se tornou clara. Este artigo faz uma revisão sobre as pesquisas que avaliam os tratamentos potenciais para transtornos por uso de cannabis. MÉTODO: Uma busca nos bancos de dados de publicações identificou os estudos e revisões na literatura científica sobre as intervenções psicossociais e farmacológicas nos transtornos por uso de cannabis. RESULTADOS: Para adultos, as intervenções com base comportamental geram efeitos positivos significativos na abstinência e nas reduções no uso de cannabis. Em adolescentes, tratamentos similares e intervenções com base na família demonstraram eficácia. Entre os estudos, os índices de resposta parecem ser modestos mesmo com os mais potentes tratamentos psicossociais. As avaliações das abordagens farmacológicas para os transtornos por uso de cannabis têm ainda que fornecer dados sobre a eficácia clínica de qualquer medicação específica. Enfoques baseados em agonistas e antagonistas parecem ser os mais promissores. Os avanços na compreensão da neurobiologia do sistema canabinoide são fonte de otimismo no sentido de que a síntese de compostos que alteram o funcionamento do sítio receptor CB1 possa produzir medicações promissoras. CONCLUSÃO: As pesquisas clínicas identificaram tratamentos psicossociais eficazes, mas ainda não produziram farmacoterapias eficazes. Muitos estudos ainda têm que ser feitos para aumentar a potência e o acesso às intervenções para aqueles que buscam o tratamento para transtornos por uso de cannabis.

OBJECTIVE: Cannabis remains the most widely used illicit substance in most developed countries. Its addictive potential has been established and the need for interventions for cannabis-related problems has become apparent. This article provides a review of the research evaluating potential treatments for cannabis use disorders. METHOD: A search of publication databases identified research studies and reviews of the scientific literature on psychosocial and pharmacological interventions for cannabis use disorders. RESULTS: For adults, behaviorally-based interventions engender significant positive effects on abstinence and reductions in cannabis use. With adolescents, similar treatments and family-based interventions have demonstrated efficacy. Across studies, response rates appear modest even with the most potent psychosocial treatments. Evaluations of pharmacological approaches to cannabis use disorders have yet to provide clinical efficacy data for any specific medication. Agonist and antagonist approaches appear to offer the most promise. Advances in understanding of the neurobiology of the cannabinoid system provide optimism that the synthesis of compounds that alter CB1 receptor site functioning may produce promising medications. CONCLUSION: Clinical research has identified effective psychosocial treatments, but has yet to yield effective pharmacotherapies. Much work remains to enhance the potency of and access to interventions for those seeking treatment for cannabis use disorders.

Vitamina B en paciente alcohólico: relato de un caso / Vitamine B in alcoholic patient: case report

Métodos: A partir del año 2007 se efectúan estudios en nuestro Instituto para precisar una dosis adecuada de complejo B a aplicar en el Síndrome de Deprivación Alcohólico (Ibáñez y Bustamante) Resultados: Después de tres semanas de tratamiento con benzodiacepina y complejo B (tiamina) según el nuevo protocolo se logra una recuperación motora y mental de un paciente con un Síndrome Korsakoiwideo alcohólico y un cuadro de paraparesia. Conclusión: Los resultados sugieren que la encefalopatía de Wernicke tratada con dosis superiores a 300 mg/diarios de tiamina puede tener un resultado altamente beneficioso para el paciente con síndrome de deprivación alcohólico.

Method: Since 2007, different studies have been made in our Institute, in order to find the right dose of Vitamin B Complex in cases of Alcohol Withdrawal Syndrome (Ibáñez y Bustamante). Results: After a 3 weeks treatment with Benzodiazepine and Vitamin B Complex (Thiamine), according to the new protocol, a patient with Alcoholic Korsakow Syndrome and Paraparesis, recovers his mental and motor functions. Conclusions: Wernicke’s encephalopathy can be treated with high doses of Thiamine (around 300 mg/a day), on patients with Alcohol Withdrawal Syndrome with highly good results.

Comparison of the efficacy and safety of chlorpromazine with verapamil for the treatment of acute opioid abstinence syndrome

To compare the efficacy and safety of chlorpromazine with Verapamil in patients with Acute opioid Abstinence Syndrome. Single blind comparative clinical trial was conducted at Department of Pharmacology, BMSI, JPMC, Karachi, over the period of one year. Forty opiate-dependent subjects were chosen at random who were in search of opioid abstinence treatment. All patients were grouped into two groups, group-I received chlorpromazine 150 mg/day and group-II received Verapamil 120mg/day in divided doses. Every patient completed the management plan while admitted in the hospital for 10 days. The chlorpromazine showed decreased efficacy and safety, whereas verapamil showed clinically pertinent decline in the subjective symptoms of acute opioid abstinence syndrome. The study showed Verapamit is superior to chlorpromazine in the treatment of opioid abstinence syndrome indicated by better reduction of withdrawal symptom scores, excessive opioid urinary excretion and lees side effects. The superiority of verapamil over chlorpromazine in controlling opioid abstinence syndrome may indicate that calcium is involved in the initiation and development of opioid abstinence syndrome

Dietary supplementations of amino acids: evidence for enhanced serotonergic functions following haloperidol withdrawal in rat medial prefrontal cortex

To investigate the effects of orally supplemented amino acids L-Tryptophan [Trp] and L-Valine [Val] in rats repeatedly injected with haloperidol following one week of drug withdrawal, with particular reference to extrapyramidal symptoms [EPS] and serotonin [5-hydroxytryptamine; 5-HT] metabolism in medial prefrontal cortex [mPFC]. Experimental study. Place and Duration of Study: Department of Biochemistry, University of Karachi from December 2007 to February 2008. The study was conducted on thirty six locally bred male Albino Wistar rats. Freshly prepared amino acids [Val and Trp] were added in the drinking water of rats on alternate days and haloperidol at doses of 5.0 mg/kg or saline were injected twice daily for three weeks following one week of withdrawal. Locomotor/ exploratory activities were scored in activity boxes and open field apparatuses. Catalepsy was monitored on an inclined surface. The animals tested for locomotor activity and catalepsy for two weeks follow-up post-injections plus one week of drug withdrawal were decapitated to collect mPFC regions of rat brain for neurochemical analysis by high performance liquid chromatography with electrochemical detection [HPLC-EC]. There was significant increase [p < 0.01] in locomotor activity in rats orally supplemented with Val and Trp following one week of drug withdrawal from repeated administration. Marked reduction in cataleptogenic effects of the drug was also observed. Significant [p < 0.01] increases in the brain Trp and mPFC 5-HT metabolism in Val and Trp supplemented animals were also noticed. These findings help to demonstrate the effect of dietary amino acids, in particular, Trp to potentiate mPFC serotonergic modulation of neuroleptic activity

Tratamiento del Síndrome de Retiro de Opiáceos: síndrome de retiro descrito como subjetivamente severo y objetivamente moderado / Drug therapy of opioid withdrawal

Si bien la dependencia a opiáceos es de baja frecuencia de aparición en nuestro medio, es importante conocer su manejo ya que requiere tratamiento farmacológico en la mayoría de los casos. En la actualidad, en nuestro país, se podría clasificar a las distintas poblaciones de pacientes capaces de presentar un síndrome de retiro a opiáceos en: pacientes sometidos a tratamiento crónico con opiáceos, pacientes internados en unidades de cuidados intensivos, neonato de madre adicta y pacientes adictos provenientes de la población en general o ligada al sistema de salud. Los programas de desintoxicación son caracterizados típicamente por un bajo índice de finalización del tratamiento y un alto índice de recaída. El síndrome de retiro a opiáceos es subjetivamente severo y objetivamente moderado y las metas de la terapia en el Síndrome de Retiro de Opiáceos son: evitar o reducir los síntomas objetivos y subjetivos de abstinencia; prevenir o tratar las complicaciones más serias; tratar las enfermedades psiquiátricas preexistentes o concurrentes; reducir la frecuencia o la severidad de las recaídas y rehabilitar a largo plazo.

Although the opiate dependence is of low frequency in our midst, it is important to know its management because it requires medical treatment in most cases. At present, in our country, we may classify the different patient populations able to submit an opioid withdrawal syndrome in patients undergoing chronic treatment with opioids, patients in intensive care units; neonatal mother addicted patients and addicts from the general population or linked to the health system. Detoxification programs are typically characterized by a low rate of completion of treatment and a high rate of relapse. The opioid withdrawal syndrome is objectively and subjectively severe and moderate and the goals of the therapy for the Opiates Withdrawal Syndrome are: to prevent or reduce the objective and subjective symptoms of abstinence; to prevent or treat its most serious complications; to treat preexisting or concurrent psychiatric disorders; to reduce the frequency or severity of relapses and to rehabilitate in the long term.

Assessment of differential doses of buprenorphine for long term pharmacotherapy among opiate dependent subjects.

The aim of the present study was to evaluate, two different doses of sublingual buprenorphine (2 mg and 4 mg) among patients on maintenance treatment and to assess the relationship of steady state plasma level with craving. Twenty three male opioid dependent (ICD-10 DCR) subjects, were assigned to double blind randomized controlled trial of 2 and 4 mg/day doses of buprenorphine in an inpatient setting. They were evaluated thrice (2nd, 7th and 14th day) in 2 weeks for withdrawal symptoms (acute and protracted), sedation, euphoria, craving, side effects, global rating of well being and for measurement of plasma levels of buprenorphine. The data showed that there were no significant difference in scores of euphoria and sedation, protracted withdrawal symptoms and side effects, craving and overall well being and plasma level of buprenorphine among the subjects. However, both the groups had significant difference in score on almost all the measurements on final observation in comparison to initial observation. Both 2 mg/day and 4 mg/day dose of buprenorphine were effective in long term pharmacotherapy of opioid dependence without significant difference as compared by different measures used in the study.

Cetoacidosis diabética reversible con metotrexato: Resistencia al tratamiento insulínico. Caso clínico / Diabetic ketoacidosis responsive to methotrexate in a patient with a mixed connective tissue disease

We report a 42 year-old woman with a hypothyroidism and a mixed connective tissue disease treated with prednisone and methotrexate. The patient had normal blood glucose levels but when the methotrexate dose was tapered, she presented a diabetic ketoacidosis that required up to 520 units of insulin per day. Due to the intensification of the mixed connective tissue disease symptoms, the doses of methotrexate and prednisone were increased again with a simultaneous normalization of serum glucose levels and glucose tolerance. In the following six months, when the dose of methotrexate was tapered again, the hyperglycemia reappeared and was again controlled increasing the dose. Thirty months after the episode of keotacidosis, the patient was with a weekly dose of methotrexate, asymptomatic and with a normal glucose tolerance. Anti insulin antibodies were not detected and anti islet antibodies were indeterminate, due to interference with antinuclear antibodies. It is possible that the episode of ketoacidosis was unveiled by an autoimmune phenomenon.

Role of verapamil in acute opioid abstinence syndrome

To determine the effectiveness of calcium channel blocker, verapamil in the treatment of acute opioid withdrawal syndrome in patients with chronic dependence on opioid. A clinical study. The study was conducted at Psychological Medicine ward, Civil Hospital Karachi from January 1998 to April 1998. A total of twenty [20] patients were admitted for ten [10] days in hospital. No treatment was given during the first two days of admission after abrupt termination of opioid to observe the acute opioid withdrawal signs and symptoms. Then the verapamil was given orally to each patient in a 40mg dose thrice daily from day 3 to day 10 of admission. The intensity of signs and symptoms was recorded by using subjective and objective opiate withdrawal questionnaire. Urine analysis for opioids was done on day 1, 5 and 10 of admission. Verapamil significantly decreased the intensity of signs and symptoms of acute opioid withdrawal from day 4 to day 10 of admission. Urine analyses for opioids were positive on day 1 while zero on day 10. Verapamil was found to be safe and effective for the treatment of signs and symptoms of acute opioid withdrawal in in-door patients without any significant side effect

Métodos para abandono do tabagismo e tratamento da dependência da nicotina / Methods for smoking cessation and treatment of nicotine dependence

O tabagismo está relacionado a 30% das mortes por câncer. É fator de risco para desenvolver carcinomas do aparelho respiratório, esôfago, estômago, pâncreas, cérvix uterina, rim e bexiga. A nicotina induz tolerância e dependência pela ação nas vias dopaminérgicas centrais, levando às sensações de prazer e recompensa mediadas pelo sistema límbico. É estimulante do sistema nervoso central (SNC), aumenta o estado de alerta e reduz o apetite. A diminuição de 50% no consumo da nicotina pode desencadear sintomas de abstinência nos indivíduos dependentes: ansiedade, irritabilidade, distúrbios do sono, aumento do apetite, alterações cognitivas e fissura pelo cigarro. O aconselhamento médico é fundamental para o sucesso no abandono do fumo. A farmacoterapia da dependência de nicotina divide-se em: primeira linha (bupropiona e terapia de reposição da nicotina), e segunda linha (clonidina e nortriptilina). A bupropiona é um antidepressivo não-tricíclico que age inibindo a recaptação de dopamina, cujas contra-indicações são: epilepsia, distúrbios alimentares, hipertensão arterial não-controlada, abstinência recente do álcool e uso de inibidores da monoaminoxidase (MAO). A terapia de reposição de nicotina pode ser feita com adesivos e gomas de mascar. Os efeitos da acupuntura no abandono do fumo ainda não estão completamente esclarecidos. As estratégias de interrupção abrupta ou redução gradual do fumo têm a mesma probabilidade de sucesso.

Smoking is related to 30 percent of cancer deaths. It is a risk factor for respiratory tract, esophagus, stomach, pancreas, uterine cervix, kidney and bladder carcinomas. Nicotine induces tolerance and addiction by acting on the central dopaminergic pathways, thus leading to pleasure and reward sensations within the limbic system. It stimulates the central nervous system (CNS), enhances alertness and reduces the appetite. A 50 percent reduction of nicotine consumption may trigger withdrawal symptoms in addicted individuals: anxiety, anger, sleep disorders, hunger, cognitive dysfunction and cigarette craving. Medical advice is the cornerstone of smoking cessation. Pharmacotherapy of nicotine addiction comprises first-line (bupropion and nicotine replacement therapy) and second-line (clonidine and nortriptyline) drugs. Bupropion is a non-tricyclic antidepressant that inhibits dopamine uptake, whose contraindications are: epilepsy, eating disorders, uncontrolled hypertension, recent alcohol abstinence and current therapy with MAO inhibitors. Nicotine replacement therapy can be done with patches or gums. Counseling groups and behavioral interventions are efficacious. The effects of acupuncture on smoking cessation are not fully elucidated. Prompt smoking cessation or gradual reduction strategies have similar success rates.

Amitriptyline efficacy in control of acute opioid withdrawal syndrome

This study was conducted to evaluate the efficacy of Amitriptyline treatment in opioid withdrawal syndrome. A total of 44 opium dependent patients who met the DSMIV-TR criteria for opioid dependency were randomly assigned to treat with Amitriptyline or placebo during a 25-day double blind clinical trial. Opioid misuse was replaced by oral methadone during a 3 days stabilization period. Methadone was reduced to zero from the beginning of the study to 10th day and Amitriptylin or placebo also was administered. Amitriptylin prescribed as 25 mg tablets or placebo tablets that were completely similar to Amitriptylin tablet prescribed too. Amitriptylin group were prescribed 25 mg tablet per day and placebo tablet too. From second week, drug dosages for both groups were doubled. Rapid detoxification was performed by naloxon after 5 days washout period. The severity of opioid withdrawal and pain was measured by sows and MPQ at days 7/15/17 and 25. There was significant difference between Amitriptyline and placebo in reduction of opioid - withdrawal pain and mental symptoms. No significant difference was noted between the two groups on physical symptoms of withdrawal syndromes. Amitriptyline can be considered as an adjuvant drug for opioid withdrawal pain Management