Sidiming attenuates morphine withdrawal syndrome and nitric oxide (synthase) levels in morphine-dependent rats and rhesus monkeys

The present study analyzed the effects of Sidiming, a Chinese herbal compound, on withdrawal syndrome, body weight loss, and serum levels of nitric oxide and its synthase in morphine- dependent rats and rhesus monkeys. These effects were compared with clonidine, an active control drug used for clinical treatment. Results showed that 4 and 8 g/kg Sidiming, respectively, significantly suppressed morphine withdrawal syndrome and reduced body mass loss in morphine-dependent rats. In addition, 2.4 and 4.8 g/kg Sidiming, respectively, significantly attenuated withdrawal syndrome in rhesus monkeys. High-dose Sidiming （8 g/kg in rats and 4.8 g/kg in rhesus monkeys） led to significantly inhibited serum levels of nitric oxide and its synthase in morphine-dependent rats and rhesus monkeys, which were greater than clonidine. These findings suggested that Sidiming treatment attenuated withdrawal syndrome in morphine-dependent rats and rhesus monkeys by inhibiting serum nitric oxide and its synthase.

Effect of testosterone on morphine withdrawal syndrome in rats

Aim： To determine whether testosterone is involved in morphine withdrawal syndrome （WS）. Methods： In order to induce dependency, rats were treated with subcutaneous injection of morphine （days 1-2, 5 mg/kg; days 3-5, 7.5 mg/kg; days 6-8, 10 mg/kg）, and after the last dose of morphine （day 8） WS was induced by intraperitoneal injection of naloxone （1 mg/kg）. Wet dog shake （WDS）, abdomen writhing （AW）, and jumps （J） were recorded as indicators of WS. Results： The severity of WDS, AW, and J in male rats was greater than that in females. Accordingly, in 4-week castrated and flutamide-treated （10 mg/kg/day for 8 days, i.p.） male rats, WDS, AW, and J were significantly decreased compared to male control rats. Testosterone replacement therapy （10 mg/kg/day for 8 days, i.m.） in 4-week castrated rats restored the severity of WDS, AW, and J behaviors to the level of non-castrated male rats, whereas testosterone potentiated the WDS behavior in non-castrated male rats. Conclusion： It can be concluded that testosterone might be effectively involved in morphine WS.

Protective effect of Ocimum sanctum Linn. leaf extract on ethanol withdrawal syndrome in Wistar rats

Objective: To evaluate the effects of Oscimum sanctum L(O. sanctum), an important medicinal herb, on alcohol withdrawal syndrome in Wistar rats. Methods: Liquid diet with 7.2%, v/v ethanol was administered to the rats for 21 d. Control group animals received sucrose as an isocaloric liquid diet. After alcohol withdrawal, rats were examined at 6 th and 24 th hour for major withdrawal signs that included anxiety and hyper locomotor activity. Ethanol withdrawal anxiety was tested using elevated plus maze, light and dark model; the hyper locomotor activity using actophotometer. O. sanctum leaf extract(100, 200 and 300 mg/kg, oral) and diazepam(2 mg/kg, i.p) were administered to the treatment group animals 30 min before alcohol withdrawal estimation. Drug treatment was also given 30 min before the second observation at 24 th hour. On the last day of the protocol, rats were sacrificed by cervical dislocation liver, kidney and brain were isolated and preserved in formalin for further histopathological examination. Results: Findings from the present study revealed that O. Sanctum leaf extract treatment at doses 100, 200 and 300 mg/kg, oral had a significant protective effect on signs and symptoms of ethanol withdrawal in alcohol-dependent rats. However, no remarkable pathological and microscopic alterations were observed in histopathological examination. Conclusions: O. sanctum seems to be an active drug for the treatment of alcohol abstinence syndrome.

Phenobarbital Use as Adjunct to Benzodiazepines in the Treatment of Severe Alcohol Withdrawal Syndrome

Severe AWS （alcohol withdrawal syndrome） and AWD （alcohol withdrawal associated delirium） are common indications for intensive care unit admissions. Approximately 25% of patients with severe alcohol withdrawal require prolonged critical care hospital courses, often complicated by respiratory failure, need for mechanical ventilation due to administration of sedative continuous infusions and development of nosocomial infections. Although benzodiazepines are the mainstay of therapy for alcohol withdrawal, some patients exhibit benzodiazepine-refractory alcohol withdrawal. The use of phenobarbital as adjunct to benzodiazepines has been shown in studies to be effective in enhancing therapeutic responsiveness to benzodiazepines and reducing the need for mechanical ventilation. The objective of this study is to evaluate whether severe alcohol withdrawal treatment based on combining symptom-triggered benzodiazepine therapy with adjunctive phenobarbital will result in decreased mechanical ventilation rates, decreased use of continuous sedative infusions, decreased time to withdrawal symptom resolution and decreased length of stay in the intensive care unit. Chart reviews were utilized to determine total amount of benzodiazepine and phenobarbital use, need for mechanical ventilation, requirement of continuous lorazepam, dexmedetomidine or propofol infusions, average intensive care unit length of stay and incidence of adverse effects.

Research progress on benzodiazepines to treat alcohol withdrawal syndrome

Alcohol withdrawal syndrome(AWS)refers to a series of symptoms and signs that chronic al-coholics experience when they suddenly stop drinking or reduce their drinking,usually 12 to 24 h later.These in-clude tremors,fatigue,sweating,hyperreflexia,and gas-trointestinal symptoms.This article will analyze the drug treatment of this disease and make a brief review.

Phenobarbital in the treatment of alcohol withdrawal syndrome

Alcohol withdrawal syndrome(AWS)is a serious disorder affecting alcohol-dependent patients who abruptly stop or reduce their drinking.Mild or moderate AWS usually appears within 6 to 24 h after the last drink,and symptoms may include increased blood pressure and rapid pulse,tremors,high fever,irritability,anxiety,headache,nausea,and vomiting.These symptoms may progress to a more severe AWS characterized by delirium tremens,seizures,coma,cardiac arrest,and death.This article will analyze the phenobarbital(PB)treatment of AWS and make a brief review'.

Acupuncture with Methadone for heroin withdrawal syndrome: a meta-analysis of randomized controlled trials

Objective： To assess the efficacy of acupuncture plus Methadone in treating heroin withdrawal syndrome. Methods： According to the requirements of evidence-based medicine, the inclusion criteria, exclusion criteria and retrieval strategy were set for original documents. Randomized controlled trials（RCTs） involving acupuncture plus Methadone in treating heroin withdrawal syndrome were retrieved from China National Knowledge Infrastructure Database（CNKI）,Wanfang Academic Journal Full-text Database（Wanfang）, Chinese Biomedical Literature Database（CBM）, Chongqing VIP Database（CQVIP）, PubM ed, Cochrane Library and EMBASE. According to the Cochrane Handbook for Systematic Reviews of Interventions, each included trial was assessed strictly including risk of bias and quality evaluation. Meta-analysis and descriptive-analysis were conducted using the RevM an 5.3 software. Results： A total of 8 trials involving 931 patients were included. Meta-analysis showed that there was no statistical significance [RR=1.05; 95%CI（0.99, 1.11）; P=0.11] in comparing total effective rate between the acupuncture plus Methadone and Methadone alone; the cure rate of acupuncture plus Methadone was higher than that of Methadone alone[RR=1.45; 95%CI（1.19, 1.78）; P=0.0003]; the relapse rate of the acupuncture plus Methadone was lower [RR=0.691;95%CI（0.60, 0.80）; P〈0.00001]. On the basis of these results, the method recommended by the Grading of Recommendations Assessment, Development and Evaluation（GRADE） was taken to evaluate the quality of the evidence. It showed that the level of the evidence was low and it was weakly recommended. Conclusion： According to the included trials, acupuncture plus Methadone in treating heroin withdrawal syndrome is more effective and better than Methadone alone, but it still needs more high-quality, large sample, and polycentric researches to confirm it.

Therapeutic Efficacy Observation on Acupuncture for Post-withdrawal Syndrome of Heroin Dependence

Obj ective： To observe and analyze the intervention effects of needling different points for post- withdrawal syndrome of heroin dependence, and thus provide clinical basis for screening specific points. Methods： A total of 60 males with heroin dependence were randomly allocated into 3 groups, the Neiguan （PC 6） group, the Shenmen （HT 7） group and the control group. The results were observed and evaluated before, during, and 3 weeks after treatment using the rating scale for post-withdrawal syndrome and Hamilton anxiety scale （HAMA）. Results： In regards to the control of post-withdrawal symptoms, the groups of Neiguan （PC 6） and Shenmen （HT 7） showed statistical difference when compared with the control group （P〈0.05, P〈0.01）; however, there was no statistical difference between the Neiguan （PC 6） group and Shenmen （HT 7） group （P〉0.05）. Conclusion： Acupuncture can alleviate the post-withdrawal syndrome and anxiety of heroin dependence. Although both Neiguan （PC 6） and Shenmen （HT 7） have equally remarkable effects, Shenmen （HT 7） have a better tendency for marked effect for heart-mind related symptoms.

Clinical Observation on Improvement of Heroin Withdrawal Syndrome by Acupuncture plus Methadone

Purpose： To observe therapeutic effect of acupuncture plus Methadone on improvement of heroin withdrawal syndrome. Methods： Sixty cases of heroin dependence patients were divided into the treatment group and the control group. The treatment group was given acupuncture plus Methadone, and the control group was treated with Methadone. Results： The score of the withdrawal symptoms was lower in the treatment group than in the control group （P〈 0.05）. The improvement of withdrawal symptoms was significantly better in the treatment group than in the control group （P〈 0.05）. Conclusion： Acupuncture plus Methadone can significantly improve heroin withdrawal syndrome.

Dopaminergic system does not play a major role in the precipitated cannabinoid withdrawal syndrome

AIM:To determine the dopaminergic system involvement in precipitated cannabinoid withdrawal syndrome.METHODS:The dopamine D_(1)receptor antagonist SCH23390 or the dopamine D_(2)receptor antagonist sulphide was administered to rats chronically treated with either△^(9)-tetrahydrocannabinol(THC)or vehicle.Subjects were then injected with either SR141716A or vehicle and behavior was observed for 1 h.RESULTS:Administration of the cannabinoid receptor antagonist SR141716A to animals chronically treated with THC as described by Tsou et al(1995)produced a profound withdrawal syndrome.Treatment with dopamine antagonists did not attenuate cannabinoid precipitated withdrawal syndrome in THC tolerant animals while the agonists increased the syndrome.CONCLUSION:It is unlikely that the dopaminergic system plays a major role in mediating the behavioral aspects of the cannabinoid withdrawal syndrome.

THERAPEUTIC EFFECT OF ABSTINENCE CAPSULE ON WITHDRAWAL SYMPTOMS OF HEROIN ADDICTS

435 heroin addicts were treated for 10 days to evaluate the therapeutic effectiveness ofabstinence capsule on heroin withdrawal symptoms and its main adverse actions.Lofexidine was applied in a control group of 48 addicts.The single blind method and somedetermination methods used internationally were employed to evaluate the therapeuticeffectiveness and adverse actions of the drugs.The results showed that the abstinence capsulehas better therapeutic effectiveness,with less adverse actions,wider safety range,longer timeof action and less cost than lofexidine.

Brain-derived neurotrophic factor and Bcl-2 expression in rat brain areas following chronic morphine treatment

The ventral tegmental area and the locus coeruleus are associated with psychological and physical dependence of opioid addiction. To date, very little is known about brain-derived neurotrophic factor （BDNF） and Bcl-2 gene and protein changes following morphine addiction. The present study utilized immunohistochemistry and in situ hybridization techniques, which revealed that there were increased BDNF levels, but decreased Bcl-2 levels in the prefrontal cortex, locus coeruleus, hippocampus, and the ventral tegmental area during morphine-dependence formation and abstinence. However, the levels of BDNF remained unchanged, and Bcl-2 expression was increased in the nucleus accumbens. These results showed that BDNF and Bcl-2 are involved in the development of morphine dependence, and precipitation of abstinence syndrome.

Shen's Experience in Application of the Drugs for Tonifying the Kidney to.Reduce and Withdraw Adrenocortical Hormone

Adrenocortical hormone (ACH) has antiinflammatory and antiallergic actions, changes stress state and controls the attack of some severe and obstinate diseases. The treatment of chronic diseases with ACH often leads to its dependence; especially oral administration of ACH for a long time is liable to inhibit the function of hypothalamus-pituitary-adrenocortical-thymic axis (HPAT), and results in the hypo-reservation of adrenal cortex. Hence, sudden ACH withdrawal or decrease often causes the disease recurrence, even adrenocortical crisis. Academician Shen Ziyin has a wealth of clinical experience in both the withdrawal and reduction of ACH and the keeping of therapeutical effectiveness to form his unique remedy in the application of drugs. Shen's rich experience is described as follows.

The Infectious Tricuspid Endocarditis in ICU： Clinical Features, Management and Outcome

Objectives： Infectious tricuspid endocarditis is known to simply require antibiotherapy and to have good prognosis in most cases. Few studies focused on severe episodes managed in ICU. We aimed to describe clinical and microbiological features, and fmal outcome of infectious tricuspid endocarditis managed in ICU. Methods： From 1 January 2009 to 31 August 2017, all patients hospitalized in intensive care unit with infectious tricuspid endocarditis were enrolled. Key findings： We collected 15 episodes of infectious tricuspid endocarditis. Median age was of 39 years. Risk factors were： intravenous drug users （n = 10）, pace maker （n = 1）, vascular device （n = 2）, none （n = 2）. Median SAPS II, APACHE II and SOFA on admission were 21, 10 and 2 respectively. Organ failures on admission were： acute respiratory failure （n = 10）, sepsis （n = 7）, coma （n = 1） and acute kidney injury （n = 8）. The most frequent causative pathogen was Staphylococcus Aureus. Antibiotherapy failure happened in 10 patients from whom 8 underwent cardiac surgery （53.3%）. Most frequent complications were acute kidney injury （n = 14） and withdrawal syndrom. Infectious tricuspid endocarditis relapse on bioprosthesis occurred within 2 intravenous drug users after hospital discharge. Overall in-hospital mortality was 40%. Conclusions： Infectious tricuspid endocarditis in ICU is fitted with poor prognosis and high need to cardiac surgery. Special care should be provided to intravenous drug users to prevent relapse.

Clinical Observation of Electroacupuncture in Treating Withdrawal Anxiety in Heroin-dependent Patients

Objective： To observe the effects of electroacupuncture on withdrawal anxiety in heroin-dependent patients. Methods： Sixty heroin-withdrawal subjects with negative urine morphine were digitally randomized into two groups： acupuncture group in which 30 cases were treated by electroacupuncture and control group in which 30 cases were given no treatment. The patients were assessed by Hamilton anxiety scale before treatment and one week, two weeks and three weeks after treatment. Results： After treatment, the anxiety symptoms of heroin-dependent patients were improved more significantly in the acupuncture group than in the control group （P〈0.01）. Conclusion： Electroacupuncture has good effects on anxiety symptoms and emotions of heroin-dependent patients.

Effect of reward alteration following acupuncture for morphine withdrawal rats on neuronal discharges in the ventral medial prefrontal cortex

Objective：To observe the effect of reward alteration following acupuncture for morphine withdrawal rats on the behavior and neuronal discharges in the medial prefrontal cortex （mPFC）. Methods：The Sprague-Dawley （SD） rats were randomly allocated into a model group, a confinement group, an electroacupuncture （EA） group, and a control group. Rats with morphine addiction were made by intraperitoneal injection of naloxone （same dose injection of saline for rats in the control group）, followed by a 2-week morphine withdrawal. Acupuncture and confinement were completed during the morphine withdrawal period. Upon withdrawal, the rats received conditioned place preference （CPP） training and open field test. The multi-channel neural signal processor was used in the electrophysiological experiment to measure the neuronal discharges in different subareas of prefrontal cortex in CPP box and aversion box. Results：Rats in the model group and the confinement group spent longer period of time in CPP box than those in the EA group and the control group （allP〈0.01）; there was no statistically significant difference between the EA group and the control group. The total distances of movement by rats in the model group and the confinement group were longer than those in the EA group and the control group （allP〈0.01）. The mPFC neuronal discharge frequencies were compared between morphine preference box and aversion box. The mPFC neuronal discharge frequencies in the model group and the confinement group were higher than those in the EA group and the control group （allP〈0.05）; there was no statistically significant difference between the EA group and the control group. Conclusion：Acupuncture can effectively interfere with the reward alteration following morphine withdrawal, possibly because of its involvement with the mPFC neuronal discharges.

Sex differences in morphine dependence and plasma levels of morphine and morphine-3-glucuronide in rats

To examine whether there are sex differences in morphine dependence and its metabolism. Naloxone-precipitated withdrawal study was performed. Twenty rats were induced by naloxone 1 h after a single dose of morphine injection. The withdrawal syndromes were recorded and an HPLC-UV method was set up to quantify the plasma levels of morphine and morphine-3-glucuronide（M3G）. In the spontaneous withdrawal study, 97 rats were treated with progressive morphine for 28 d to develop physical dependence. The spontaneous withdrawal syndromes were recorded and plasma levels of morphine and M3G were determined after the last injection. No significant differences were observed in withdrawal syndrome of naloxone precipitating. More severe spontaneous withdrawal syndromes were produced by chronic morphine injection in male rats than in female rats（P0.05）. Higher maximum plasma concentration（Cmax） of morphine was measured in male rats than female rats, while female rats had higher Cmax of M3G than male rats in both acute and chronic morphine administration. Our results indicated that sex differences existed in withdrawal syndrome of morphine-dependent rats, and the pharmacokinetics of morphine showed sex difference by both acute and chronic administration. There might be a relationship between the severity of withdrawal syndrome and the plasma concentrations of morphine, M3G, and the ratio of morphine to M3G（M3G/MOR）.

Effect of acupuncture in intervening heroin-induced brain damage via regulating ubiquitin-proteasome pathway

Objective：To observe the effect of acupuncture in regulating ubiquitin-proteasome pathway （UPP）,and discuss the action of acupuncture in intervening heroin-induced brain damage.Methods：Thirty male Sprague-Dawley （SD） rats were divided into a control group,a model group and an acupuncture group by using the random number table.Rats in the model and acupuncture groups received intramuscular heroin injection for successive 8 d at a progressively increased dose.Afterwards,the injection was suspended for 5 d for withdrawal.The heroin relapse rat model was established by repeating the drug addiction and withdrawal process for 3 times.The control group followed the step of the model establishment,but was given intramuscular injection of normal saline at the stage of addiction and no intervention at the stage of withdrawal;the model group was given intramuscular heroin injection at a progressively increased dose at the addiction stage and no intervention at the withdrawal stage;the acupuncture group was dealt in the same way as the model group at the addiction stage,but received acupuncture at Baihui （GV 20） and Dazhui （GV 14） at the withdrawal stage,with the needles retained for 30 min each time,1 session a day,for successive 5 d.On the 39th day,brain tissues were extracted from the hippocampus and ventral tegmental area （VTA） of the three groups of rats.The apoptosis of brain nerve cells was detected by using terminal deoxynucleotidyl transferase-mediated nick and labeling （TUNEL）.The mRNA and protein expressions of ubiquitin （Ub）,ubiquitin protein ligase （E3） and 26S were examined by immunohistochemistry and quantitative real-time polymerase chain reaction （RT-qPCR）.Results：Compared with the model group,rat＇s hippocampus and VTA in the acupuncture group showed significantly fewer cells positively stained by TUNEL staining （P〈0.01）,and its mRNA and protein expressions of Ub,E3,26S were significantly lower （P〈0.01）.Conclusion：Reducing nerve cell apoptosis and regulating the mRNA and protein expressions of Ub,E3 and 26S in rat＇s hippocampus and VTA are possibly one of the action mechanisms of acupuncture in intervening heroin-induced brain damage.

Effect of Electroacupuncture on Anxiety and Craving in Heroin Addicts During Detoxification

Objective:To observe the effect of electroacupuncture at Jiaji (EX-B 2) points for anxiety and craving in heroin addicts during detoxification. Methods:A total of 60 cases were randomized into an electro-acupuncture group and a control group, 30 in each group. Cases in the electroacupuncture group were treated with electroacupuncture at Jiaji (EX-B 2) points, whereas cases in the control group were treated with Methadone and Doxepin. Then scores were graded using Zung self-rating anxiety score (SAS) and self-made visual analogue scale (VAS). The assessment was conducted once a day to record the adverse reactions. Results:After treatment, the SAS and VAS scores in the electro-acupuncture group were significantly lower than that in the control group (P<0.01). Conclusion:Electroacupuncture at Jiaji (EX-B 2) points can effectively alleviate anxiety and craving intensity in heroin addicts during detoxification.

Effect of Acupuncture on Contents of Tyrosine Hydroxylase and Glial Fibrillary Acidic Protein in Ventral Tegmental Area of Heroin Self-administrating Rats

Objective： This present study is to investigate the biochemical adaptations in the rdated brain regions of the mesolimbic dopamine system, such as the ventral tegmental area （VFA）, nucleus accumbens （NAc）, amygdale （Amy）, prefrontal cortex （PFC） , substantia nigra （SN） and caudateputamen （CPu） in response to heroin self-administration in rats and observe the effect of electroacupuncture on them. Methods. Thirty rats were trained by nose-poking response to establish stable intravenous heroin self-administration within 14 days, and then divided randomly into model group （group B） including 6 rats, withdrawal group which were withdrawn from heroin for 1 week （group C, n = 6） and for 2 weeks （group D, n= 6）, during which time they only lived in their individual home cages, and dectrtyacupuncture group which were also withdrawn from heroin for 1 week （group E, n= 6） and for 2 weeks （group F, n = 6）, during which time they were given electro-acupuncture treatment for 20 min daily and then returned to their individual home cages; in the meantime, another 6 rats were trained by nose-poking response with saline for 14 days as control （group A）; Then the leeds of tyrosine hydroxylase （TH） and glial fibrillary acidic protein （GFAP） in VFA, NAc, Amy, PFC, SN, CPu were detected with immunohistochemistry method. Results. The leeds of TH and GFAP in VFA of the heroin self administrating rats were obviously increased, and the leeds of TH and GFAP in NAc were also decreased, and these changes were not found in SN, CPu, Amy and PFC; Electro-acupuncture could promote the up regulation of TH and GFAP in VTA and down-regulation of TH and GFAP in NAc to return to the normal leeel. Conclusions： The chronic heroin self administration produced some biochemical adaptations in the related brain regions of the mesolimbic dopamine system and electroacupuncture could promote the repair of the ＂injured＂ DA neurons in VTA of heroin addicted rats and their functional recovery.