This case presents a rarely seen combination of two Cocaine-induced syndromes occurring simultaneously. Levamisole-adultered cocaine leads to Levamisole-induced Vasculitis (LIV), while cocaine’s vasoconstrictive effe...This case presents a rarely seen combination of two Cocaine-induced syndromes occurring simultaneously. Levamisole-adultered cocaine leads to Levamisole-induced Vasculitis (LIV), while cocaine’s vasoconstrictive effect causes destruction of the osteo-cartilaginous structures of nose called Cocaine-induced midline destructive lesions (CIMDL). This case raises awareness of a new pattern of recognition in order to avoid misdiagnosis. We present a case of a 51-year-old male cocaine user who developed severe left-sided ear pain and yellowish secretions with circular necrotic lesions in the nose, right earlobe, and dorsum of feet bilaterally. An extensive workup to assess purpuric lesions’ etiology, including vasculitis, collagen vasculitides, anti-phospholipid syndrome, hypercoagulable state and infectious process, was performed and found negative. He developed bilateral tympanic membrane perforation and purpuric necrotic skin lesions, at the same time, due to CIMDL and LIV, respectively. These two syndromes rarely present simultaneously in a patient. This case report exhibits a new Cocaine-induced clinical presentation that will help hospitalists recognize the disease and avoid misdiagnosis leading to unnecessary tests, prolonged hospitalization, and higher healthcare costs. Diagnosis is challenging, as it consists of establishing a temporal relationship between cocaine ingestion and symptoms’ onset. This disease usually has a benign progression because symptoms frequently resolve without intervention.展开更多
In adult animals,it is well established that stress has a proactive effect on psychostimulant responses.However,whether only a short period of stress during adolescence can also affect cocaine responses later in life ...In adult animals,it is well established that stress has a proactive effect on psychostimulant responses.However,whether only a short period of stress during adolescence can also affect cocaine responses later in life and what mechanisms are involved are unknown.Here,we showed that 5 days of social isolation during rat adolescence had a long-term impact on anxiety-like behaviors,cocaine-induced conditioned place preference,and the expression of sensitization during adulthood.At the molecular level,social isolation decreased the activity of the Wnt/β-catenin pathway in the prefrontal cortex(PFC).Furthermore,after the expression of cocaine sensitization,isolated rats showed an increase in this pathway in the nucleus accumbens.Together,these findings suggest that,adolescent social isolation by altering the Wnt/β-catenin pathway in the developing PFC might increase the cocaine responses during adulthood,introducing this pathway as a novel neuroadaptation in the cortical-accumbens connection that may mediate a stress-induced increase in vulnerability to drugs.展开更多
C57BL/6J and BALB/cJ mice display significant differences in sociability and response to drugs, but the phenotypic variability of their susceptibility to cocaine is still not well known. In this study, the differences...C57BL/6J and BALB/cJ mice display significant differences in sociability and response to drugs, but the phenotypic variability of their susceptibility to cocaine is still not well known. In this study, the differences between these two mice strains in the persistence of cocaine-induced conditioned place preference （CPP）, as well as the locomotion and social behaviors after the 24-hour withdrawal from a four-day cocaine （20 mg/kg/day） administration were investigated. The results showed that the cocaine-induced CPP persisted over two weeks in C57BL/6J mice, while it diminished within one week among BALB/cJ mice. After 24-hours of cocaine withdrawal, high levels of locomotion as well as low levels of social interaction and aggressive behavior were found in C57BL/6J mice, but no significant changes were found in BALB/cJ mice, indicating that cocaine-induced CPP persistence, locomotion and social behavior are not consistent between these two strains, and that overall C57BL/6J mice are more susceptible to cocaine than BALB/cJ mice at the tested doses.展开更多
BACKGROUND Chronic cocaine use is associated with stroke, coronary artery disease and myocardial infarction, resulting in severe impairments or sudden mortality. In the absence of clear cardiovascular symptoms, indivi...BACKGROUND Chronic cocaine use is associated with stroke, coronary artery disease and myocardial infarction, resulting in severe impairments or sudden mortality. In the absence of clear cardiovascular symptoms, individuals with cocaine use disorder (iCUD) seeking addiction treatment receive mostly psychotherapy and psychiatric pharmacotherapy, with no attention to vascular disease (i.e., atherosclerosis). Little is known about the pre-clinical signs of cardiovascular risk in iCUD and early signs of vascular disease are undetected in this underserved population. AIM To assess inflammation, plaque burden and plaque composition in iCUD aiming to detect markers of atherosclerosis and vascular disease. METHODS The bilateral carotid arteries were imaged with positron emission tomography/magnetic resonance imaging (PET/MRI) in iCUD asymptomatic for cardiovascular disease, healthy controls, and individuals with cardiovascular risk. PET with 18F-fluorodeoxyglucose (18F-FDG) evaluated vascular inflammation and 3-D dark-blood MRI assessed plaque burden including wall area and thickness. Drug use and severity of addiction were assessed with standardized instruments. RESULTS The majority of iCUD and controls had carotid FDG-PET signal greater than 1.6 but lower than 3, indicating the presence of mild to moderate inflammation. However, the MRI measure of wall structure was thicker in iCUD as compared to the controls and cardiovascular risk group, indicating greater carotid plaque burden. iCUD had larger wall area as compared to the healthy controls but not as compared to the cardiovascular risk group, indicating structural wall similarities between the non-control study groups. In iCUD, wall area correlated with greater cocaine withdrawal and craving. CONCLUSION These preliminary results show markers of carotid artery disease burden in cardiovascular disease-asymptomatic iCUD. Broader trials are warranted to develop protocols for early detection of cardiovascular risk and preventive intervention in iCUD.展开更多
Prior work has shown that systemic cocaine pretreatment augments cocaine conditioned place preference (CPP) in rats. In contrast, ghrelin receptor antagonism attenuates cocaine and amphetamine-induced CPP. In order to...Prior work has shown that systemic cocaine pretreatment augments cocaine conditioned place preference (CPP) in rats. In contrast, ghrelin receptor antagonism attenuates cocaine and amphetamine-induced CPP. In order to further investigate ghrelin’s role in dopamine-mediated reward, the present report examined whether pretreament with ghrelin, administered directly into the ventral tegmental area (VTA) of the midbrain, would potentiate the rewarding properties of cocaine as measured by CPP. Adult male Sprague-Dawley rats were given access to either side of the CPP chamber in order to determine initial side preferences. The rats were then restricted to either their non-preferred or preferred side over the course of conditioning which lasted for a total of 16 consecutive days. This was followed by a final test day to then reassess preference. On days where rats were confined to their non-preferred side, ghrelin (30-300 pmol) and cocaine (0.625-10 mg/kg IP) were administered immediately prior to the conditioning trial. On alternate days rats were treated with vehicle and placed into what was initially determined to be their preferred side. CPP was calculated as the difference in percentage of total time spent in the treatment-paired compartment during the post-conditioning session and the pre-conditioning session. Our results indicated that both cocaine and ghrelin elicited CPP and that ghrelin pretreatment potentiated the effect of cocaine on place preference. Overall, these findings provide additional support for the argument that ghrelin signaling within the VTA enhances the rewarding effects of psychostimulant compounds.展开更多
Drug-associated reward memories are conducive to intense craving and often trigger relapse.Simvastatin has been shown to regulate lipids that are involved in memory formation but its influence on other cognitive proce...Drug-associated reward memories are conducive to intense craving and often trigger relapse.Simvastatin has been shown to regulate lipids that are involved in memory formation but its influence on other cognitive processes is elusive.Here,we used a mass spectrometry-based lipidomic method to evaluate the impact of simvastatin on the mouse brain in a cocaine-induced reinstatement paradigm.We found that simvastatin blocked the reinstatement of cocaine-induced conditioned place preference(CPP)without affecting CPP acquisition.Specifically,only simvastatin administered during extinction prevented cocaine-primed reinstatement.Global lipidome analysis showed that the nucleus accumbens was the region with the greatest degree of change caused by simvastatin.The metabolism of fatty-acids,phospholipids,and triacylglycerol was profoundly affected.Simvastatin reversed most of the effects on phospholipids induced by cocaine.The correlation matrix showed that cocaine and simvastatin significantly reshaped the lipid metabolic pathways in specific brain regions.Furthermore,simvastatin almost reversed all changes in the fatty acyl profile and unsaturation caused by cocaine.In summary,pre-extinction treatment with simvastatin facilitates cocaine extinction and prevents cocaine relapse with brain lipidome remodeling.展开更多
Dopamine D1 receptors（D1Rs） play a key role in cocaine addiction, and multiple protein kinases such as GRKs, PKA, and PKC are involved in their phosphorylation. Recently, we reported that protein kinase D1 phosphory...Dopamine D1 receptors（D1Rs） play a key role in cocaine addiction, and multiple protein kinases such as GRKs, PKA, and PKC are involved in their phosphorylation. Recently, we reported that protein kinase D1 phosphorylates the D1 R at S421 and promotes its membrane localization. Moreover, this phosphorylation of S421 is required for cocaineinduced behaviors in rats. In the present study, we generated transgenic mice over-expressing S421A-D1 R in the forebrain. These transgenic mice showed reduced phospho-D1R（S421） and its membrane localization, and reduced downstream ERK1/2 activation in the striatum. Importantly, acute and chronic cocaine-induced locomotor hyperactivity and conditioned place preference were significantly attenuated in these mice. These findings provide in vivo evidence for the critical role of S421 phosphorylation of the D1 R in its membrane localization and in cocaine-induced behaviors. Thus, S421 on the D1 R represents a potential pharmacotherapeutic target for cocaine addiction and other drug-abuse disorders.展开更多
Plasticity in the glutamatergic synapses on striatal medium spiny neurons(MSNs)is not only essential for behavioral adaptation but also extremely vulnerable to drugs of abuse.Modulation on these synapses by even a sin...Plasticity in the glutamatergic synapses on striatal medium spiny neurons(MSNs)is not only essential for behavioral adaptation but also extremely vulnerable to drugs of abuse.Modulation on these synapses by even a single exposure to an addictive drug may interfere with the plasticity required by behavioral learning and thus produce impairment.In the present work,we found that the negative reinforcement learning,escaping mild foot-shocks by correct nose-poking,was impaired by a single in vivo exposure to 20 mg/kg cocaine 24 h before the learning in mice.Either a single exposure to cocaine or reinforcement learning potentiates the glutamatergic synapses on MSNs expressing the striatal dopamine 1(D1)receptor(D1-MSNs).However,24 h after the cocaine exposure,the potentiation required for reinforcement learning was disrupted.Specific manipulation of the activity of striatal D1-MSNs in D1-cre mice demonstrated that activation of these MSNs impaired reinforcement learning in normal D1-cre mice,but inhibition of these neurons reversed the reinforcement learning impairment induced by cocaine.The results suggest that cocaine potentiates the activity of direct pathway neurons in the dorsomedial striatum and this potentiation might disrupt the potentiation produced during and required for reinforcement learning.展开更多
<b>Aim:</b> The effect of patented nutritional supplementation on drug-seeking behavior in cocaine addicted rats during acute drug withdrawal was investigated using a biased Conditioned Place Preference (C...<b>Aim:</b> The effect of patented nutritional supplementation on drug-seeking behavior in cocaine addicted rats during acute drug withdrawal was investigated using a biased Conditioned Place Preference (CPP) paradigm. <b>Method:</b> Twenty-four (24) male Sprague-Dawley rats with pre-conditioned preference for the black chamber of the CPP box were randomly divided into Cocaine (COC) or Saline (SAL) treated groups. Rats (n = 12) treated with cocaine hydrochloride 20 mg/kg/ml, <i>i.p.</i> (COC group) were confined individually to the white chamber on days 1, 3, 5 and 7. On alternate days, they were given 1 ml saline vehicle, <i>i.p.</i> and confined to the black chamber. Control rats (SAL group, n = 12) received only vehicle on all 8 days and were confined on alternate days to the white or black chamber. Positive place preference was confirmed for COC rats, which subsequently received 6 increasing daily doses of cocaine. CPP performances of both COC and SAL rats were recorded following an acute 3-day withdrawal period. All animals were then randomly assigned to rats fed either chow reconstituted with the nutritional supplement (COC-S and SAL-S) or standard rat chow (COC-N and SAL-N) for 8 weeks, followed by final CPP performances. <b>Results:</b> Following supplementation, COC-S rats made significantly less entries and time spent in the white chamber (p < 0.05) compared with COC-N rats. COC-S rats exhibited significant place aversion to the white chamber similar to drug-naive animals;whereas COC-N continued to show positive place preference. <b>Conclusion:</b> Drug-seeking behavior that persisted during cocaine withdrawal was significantly diminished in the nutritionally supplemented.展开更多
Cocaine and crack cocaine are usually seized with a great diversity of adulterants, such as benzocaine, lidocaine, caffeine, and procaine. The forensic identification of cocaine in these drug mixtures is normally perf...Cocaine and crack cocaine are usually seized with a great diversity of adulterants, such as benzocaine, lidocaine, caffeine, and procaine. The forensic identification of cocaine in these drug mixtures is normally performed using colorimetric testing kits, but these tests may suffer from interferences providing false-positive or false-negatives. In this work, we describe the use of thin layer chromatography coupled to easy sonic-spray ambient ionization mass spectrometry (TLC/EASI-MS) for rapid and secure analysis of cocaine and crack cocaine. Fifteen cocaine samples were analyzed, and all of them revealed positive TLC/EASI-MS results for cocaine, but other drugs and adulterants were also detected such as lidocaine, caffeine, benzocaine, lactose, benzoylecgonine, and ecgonidine. False positives and false negatives, as judged by the TLC Rf values, were identified via on-spot characterization by EASI-MS. The TLC/EASI-MS combination seems therefore to provide an appropriate technique for secure forensic investigations of illicit drugs.展开更多
Aim： To investigate the effect of cocaine on apoptosis and caspase-3 activity in germ cells in male rats at different ages. Methods： Cocaine hydrochloride was given （15 mg/kg body weight s.c.） to male Sprague-Dawl...Aim： To investigate the effect of cocaine on apoptosis and caspase-3 activity in germ cells in male rats at different ages. Methods： Cocaine hydrochloride was given （15 mg/kg body weight s.c.） to male Sprague-Dawley rats of 3 weeks （n = 8）, 6 weeks （n = 8） and 12 weeks （n = 8） of age, daily for 28 days. The serum levels of follicle stimulating hormone （FSH）, luteinizing hormone （LH）, prolactin （PRL）, testosterone （T） and estrogen （E2） were assayed, and the DNA fragmentation of germ cells was determined by gel eletronphoresis. The cell cycle, apoptosis and caspase-3 activity of germ cells were tested by flow cytometry. Results： After the 28-day cocaine treatment, testes weight of the 3-week-old rats, the testes and body weights of the 6-week-old rats were decreased significantly compared to those of their corresponding controls （P 〈 0.05）. The serum level of T was decreased significantly in the 3-week-old and 6-week-old rats, and the serum level of PRL was also decreased significantly in 12-week-old rats compared to the controls （P 〈 0.05）, In all the three cocaine-treated groups, the isolated DNA displayed a clear ladder pattern, especially in the 6-week old rats. The number of apoptosic germ cells increased significantly in 3- and 6- week-old rats treated with cocaine （P 〈 0.05）. The caspase-3 activity in all three groups increased significantly compared to the controls （P 〈 0.05）, especially in the 6-week-old rats. Conclusion： Cocaine exposure for 28 days leads to significant damage to male gonad and apoptosis elevation in testes of rats of different ages, especially in those of 6 weeks of age. The increase in caspase-3 activity might be a key pathway related to the early stage of apoptosis as the mechanism of cocaine-induced germ cell loss.展开更多
Coronary artery ectasia(CAE)often represents a coronary angiography finding casually detected or following the occurrence of an acute coronary syndrome.The pathogenetic role of cocaine abuse in the genesis of CAE is s...Coronary artery ectasia(CAE)often represents a coronary angiography finding casually detected or following the occurrence of an acute coronary syndrome.The pathogenetic role of cocaine abuse in the genesis of CAE is still little known and very few data are available in literature.We describe a case of a 31-year-old male cocaine user admitted to our department for typical acute chest pain.Coronary angiography showed diffuse coronary ectasia with slow flows and without hemodynamically significant stenosis.An increasing of matrix metalloproteinases values and a reduction of their tissue inhibitors was showed both during hospitalization and at one month after discharge.This case report emphasizes the close relationship between cocaine abuse,CAE and acute coronary syndromes in patients without hemodynamically significant coronary stenosis.As reported by Satran et al,cocaine abuse should be considered an important risk factor for CAE and these patients appear to be at increased risk of angina and acute myocardial infarct.Further studies that can strengthen this hypothesis would be useful to deepen and better analyze this interesting association.展开更多
OBJECTIVE Phosphoinositide 3-kinase(PI3K) activation was reported to participate in the development of effect of some drugs,such as morphine and cocaine dependence.We previous found nischarin is associated with the ac...OBJECTIVE Phosphoinositide 3-kinase(PI3K) activation was reported to participate in the development of effect of some drugs,such as morphine and cocaine dependence.We previous found nischarin is associated with the activation of PI3K.It is our great interest to investigate the involvement of nischarin in PI3K dependent modulation of morphine versus cocaine dependence.METHODS In order to study the role of nischarin in drug dependence and tolerance,nischarin knockout mice were used for our research.Effect of psychological dependence was studied by conditioned place preference(CPP),and the effect of physical dependence was tested by naloxone-precipitated withdrawal signs.Some brain tissues were harvested 24 h after the behavioral experiment for the further measurement.RESULTS PI3K specific inhibitor LY294002 significantly blocked the acquisition of morphine-induced CPP in wild-type mice,but had no effect on its expression.In comparison,LY294002 failed to block the acquisition of cocaine-induced CPP but inhibited the expression.Furthermore,we found naloxoneprecipitated withdrawal signs in the morphine dependent mice was inhibited by LY294002.Nischarin knockout in mice could abolish the effect of LY294002 on blocking the effects of morphine,but had no effect on cocaine.CONCLUSION PI3K activation is involved in the different phases of morphine and cocaine dependence,and nischarin plays an important role in the process.展开更多
Accelerated epicardial coronary artery atherosclerosis has been well-documented in cocaine users.There are only two reported cases of cocaine-associated diffuse intimal expansion by proliferated smooth muscle cells ca...Accelerated epicardial coronary artery atherosclerosis has been well-documented in cocaine users.There are only two reported cases of cocaine-associated diffuse intimal expansion by proliferated smooth muscle cells causing significant coronary luminal compromise.This type of lesion histologically resembled chronic trans-plant arteriopathy.Here,we report a third such case.展开更多
BACKGROUND Atraumatic splenic rupture(ASR)accounts for just over 3%of all cases of splenic rupture and is associated with a high mortality rate.The most common culprit is acute infection with Epstein-Barr virus(EBV)bu...BACKGROUND Atraumatic splenic rupture(ASR)accounts for just over 3%of all cases of splenic rupture and is associated with a high mortality rate.The most common culprit is acute infection with Epstein-Barr virus(EBV)but other documented aetiologies include neoplasia,other viral/bacterial infections,acute and chronic pancreatitis,amyloidosis and anticoagulant medications.There are four previous reports of cocaine-associated ASR but never before has it been documented in combination with concurrent acute EBV infection.CASE SUMMARY A 21-year-old man presented to hospital with acute left shoulder pain which radiated to the right shoulder and upper abdomen.He denied any history of recent trauma and had no relevant past medical history.He took no regular prescription medications but had used cocaine within the previous 24 h.Investigations revealed splenomegaly,a Grade 3 subcapsular splenic haematoma,moderate haemoperitoneum and an incidental 9 mm splenic artery pseudoaneurysm.There was also serological evidence of acute EBV infection.Prophylactic endovascular embolisation of the pseudoaneurysm was performed and the splenic rupture was managed non-operatively.The patient remained admitted in hospital for seven days and did not require any transfusion of blood products.Serial imaging showed complete resolution of the haemoperitoneum after 5 wk.The importance of abstinence from illicit drug use was emphasised to the patient but it is unknown whether or not he remains compliant.CONCLUSION This case demonstrates that ASR is a rare condition that can result from acute EBV infection and cocaine ingestion and requires a high index of suspicion to diagnose clinically.展开更多
Management of patients carrying packets of drugs in the digestive tract is a frequent medical problem.Wereport on a patient who was referred by the police after ingestion of packets of cocaine.After spontaneous elimin...Management of patients carrying packets of drugs in the digestive tract is a frequent medical problem.Wereport on a patient who was referred by the police after ingestion of packets of cocaine.After spontaneous elimination of 81 drug packets,the patient had three unremarkable stools.A plain abdominal X-ray disclosed no residual packet but computed tomography(CT) scan showed one in the stomach.As this was not eliminated during the 10 d following ingestion,it was removed through gastrotomy.This case stresses the usefulness of the CT scan to ensure that no residual packet is present before hospital discharge.展开更多
Slowing conduction and prolonged repolarization have been implicated in cocaine-induced cardiac arrhythmia.However,the importance of these properties at any given cocaine concentration[C]remains unknown. Using standar...Slowing conduction and prolonged repolarization have been implicated in cocaine-induced cardiac arrhythmia.However,the importance of these properties at any given cocaine concentration[C]remains unknown. Using standard microelectrode techniques, we studied the effect of different [C] (ranging from 9.spmol/L to 300 μmol/L) on action potential duration(APD)and dv/dtmax of phase 0 in 16 canine papillary muscle preparations Paced at 1 000 msec cycle. In contrast to dy/dtmax which showed progressive decrease from(201±19)v/s during control to (33±7)v/s at [C] of 300μmol/L, APD90showed an initial increase from(193±15) msec to a peak of(232±17)msec at 113μmol/ L and a gradual decrease back to control at 188 μmol/L and further decrease to below baseline to a nadir of (168±14) msec at 263 μmol/L. The resting membrane potentials did not change significantly during the progressive increase of [C]. The bimodal response of APD may be explained by blockade of the delayed rectifier potassium current as well as blockade of window sodium current by cocaine. The findings imply that up to [C] of 188μmol/L may cause arrhythmia by slowing of conduction and prolongation of repolarization. At [C] above 188μmol/L the prolongation of repolarization is unlikely to be the mechanism.展开更多
The effects of chronic cocaine administration on the locomotor rhythmic patterns of adult female Sprague-Dawley (SD) rats were recorded using an open-field testing assay. The animals were divided into four groups, con...The effects of chronic cocaine administration on the locomotor rhythmic patterns of adult female Sprague-Dawley (SD) rats were recorded using an open-field testing assay. The animals were divided into four groups, control (saline), 3.0 mg/kg, 7.5 mg/kg, and 15.0 mg/kg i.p. cocaine group respectively. On experimental day (ED 1), all animals were treated with saline. On ED 2 to ED 7, either saline or cocaine (3.0, 7.5, or 15.0 mg/kg i.p.) was given followed by three days of no treatment (ED 8 to ED 10). On ED 11, rats were treated as they were on ED 2 to ED 7, i.e. either saline, 3.0, 7.5, or 15.0 mg/kg i.p. cocaine. The locomotor activities of rats were recorded for 23 hours daily, allowing one hour for the animal handling and injections, using open field cages with 16 infrared beams of motion detectors. Any breakages of these beams due to the movement of the animals were recorded and compiled by a computer and analyzed. It was observed that all three doses of repeated cocaine administration (3.0 mg/kg, 7.5 mg/kg, and 15.0 mg/kg i.p. cocaine) significantly alter the locomotor rhythmic activity patterns of the adult female SD rats, which suggest that repeated cocaine exposure modulates body homeostasis.展开更多
The effects of Nω-nitro-L-arginine methyl ester(L-NAME)i.v.and nitric oxide(NO) inhalation on integrated systemic responses to cocaine were studied in lightly anesthetized, paralyzed, and mechanically ventilated rats...The effects of Nω-nitro-L-arginine methyl ester(L-NAME)i.v.and nitric oxide(NO) inhalation on integrated systemic responses to cocaine were studied in lightly anesthetized, paralyzed, and mechanically ventilated rats.Cocaine [4 mg/(kg. min) i.v.] produccd seizures then isoelectric electrocephalographic(isoEEG)activity as well as an initial increase in systolic blood pressure and heart rate,then progressive cardiovascular system depression culminating in asystole. Pretreatment with L-NAME[2 mg/(kg. min)i.v. ] for 30 min significantly reduced the incidence of seizure as compared to saline treated animals (saline 7/8; L-NAME 3/8).Doses of cocaine that produced arrhythmias, isoEEG and asystole were significantly lower in the L-NAME treated animals as compared to the saline group. L-NAME did not affect peak systolic blood pressure and heart rate responses to cocaine. NO inhalation(80 ppm)did not affect CNS and cardiovascular responses to cocaine in control animals but enhanced the effects of L-NAME on cocaine toxicity. The results show that pretreatment with L-NAME reduces the central nervous system stimulatory effect of cocaine (reduced seizure incidence) and enhances its depressant effect on both the central nervous system (lower does for isoEEG) and the cardiovascular stimulatory action of cocaine. NO inhalation does not protect against any of the systemic effects of cocaine in animals with normal or suppressed NO production.展开更多
Objective: To determine the efficacy and tolerability of a long-acting intramuscular formulation of Vanoxerine (Vanoxerine Consta 394.2 mg) for treatment of cocaine-dependent patients. Design, Setting, and Participant...Objective: To determine the efficacy and tolerability of a long-acting intramuscular formulation of Vanoxerine (Vanoxerine Consta 394.2 mg) for treatment of cocaine-dependent patients. Design, Setting, and Participants: A 12-week, A multicenter, randomized, placebo-controlled trial conducted between June 2009-July 2011, at 17 Hospital-based drug clinics, in the 15 countries. Participants were 18 years or older, had Diagnostic and Statistical Manual of Mental Disorders-5 cocaine use disorder. Of the 2800 patients who were assessed between March 10, 2009 to August 10, 2010, 2600 (93%) were eligible and willing to take part in the trial and were enrolled: 1300 were randomly assigned to receive injections of Long-acting depot formulations of Vanoxerine (Vanoxerine Consta 394.2 mg) given intramuscularly once in 12 weeks and 1300 to receive Placebo injections, given intramuscularly once in 12 weeks. Only 100 of 2800 patients (3.6%) did not meet the inclusion criteria. Main Outcomes and Measures: The primary endpoints (protocol) were: Confirmed Cocaine abstinence (percentage i.e. the number of patients who achieved complete abstinence during 12 weeks). Confirmed abstinence or “cocaine-free” was defined as a negative urine drug test for cocaines and no self-reported cocaine use. Secondary end points included a number of days in treatment, treatment retention and craving. The study also investigated, on 275 participants, degree and time course of Central Dopamine transporter receptor occupancy following single doses of long-acting intramuscular formulation of Vanoxerine (Vanoxerine Consta 394.2 mg) as well as the plasma concentration of Vanoxerine and 17-hydroxyl Vanoxerine. Safety was assessed by adverse event reporting. Results: Of 2600 participants, mean (SD) age was 28.5 (±5.5) years and 598 (23%) were women. 1300 individuals were randomized to receive injections of Long-acting depot formulations of Vanoxerine (Vanoxerine Consta 394.2 mg) and 1300 to receive injections of Placebo. 1417 participants (54.5.0%) completed the trial. Primary Endpoints: Confirmed Cocaine Abstinence: Complete abstinence was sustained by 72% (n = 936) of Vanoxerine patients (patients treated with Vanoxerine Consta 394.2 mg, long-acting depot formulations) compared with 37% (n = 481) of patients treated with Placebo, during weeks 5 - 12. The difference was significant as evaluated using a Chi-square test (χ2 = 672.34, P < 0.0001). Secondary Endpoint: Craving: A statistically and clinically significant reduction in cocaine craving was observed with Vanoxerine (Vanoxerine Consta 394.2 mg, long-acting depot formulations) vs. Placeboby week 4 (P = 0.0048), which persisted every week through 12 (P < 0.0001). Patients given Vanoxerine (Vanoxerine Consta 394.2 mg, long-acting depot formulations) had a 87% decrease in craving from baseline to 12th week. Patients given a Placebo had a 2% increase in craving from baseline to 12th week. Secondary Endpoint: Treatment Retention: Long-acting intramuscular formulation of Vanoxerine (Vanoxerine Consta 394.2 mg) helped significantly more patients complete 12 weeks treatment (n = 936, 72%) compared with Placebo (n = 481, 37%) (χ2 = 635.53, P < 0.0001). Patients on the long-acting intramuscular formulation of Vanoxerine (Vanoxerine Consta 394.2 mg) had longer treatment retention than patients on Placebo. Concentrations of Vanoxerine and 17-Hydroxyl Vanoxerinein Plasma: Analyses were made of 275 study samples. There was no statistically significant difference for plasma Vanoxerine concentrations between days 2 and 84 (p = 0.416). The plasma concentration of Vanoxerine were 70.4 and 94.3 ng/ml and concentrations of 17-hydroxyl Vanoxerine were 10.5 and 13.2 ng/ml, respectively. Plasma levels of Vanoxerine remained above 70 ng/ml for approximately 12 weeks after administration of Vanoxerine, long-acting depot formulations (Vanoxerine Consta 394.2 mg). PET Assessments: Very high central dopamine transporter receptor occupancy by Vanoxerine was detected 1 day after treatments, at which time point the occupancy was 100.0% after Vanoxerine injection (Vanoxerine Consta 394.2 mg). At days 7, 28, 56 and 84 post-Vanoxerine Consta 394.2 mg administration, occupancies were 95% to 79%. Vanoxerine Consta 394.2 mg injection (long-acting intramuscular formulation of Vanoxerine) led to very high occupancy of Central Dopamine transporter receptors in all brain areas examined;nucleus accumbens, caudate nucleus and putamen. Depending on the brain area Central Dopamine transporter receptor occupancy varied between 95.0% and 79% at days 7, 28, 56 and 84 after dosing. High Vanoxerine occupancy (77%) persisted at 12 weeks after the dosings. Adverse Reactions: Adverse events were similar in cocaine-dependent patients treated with the long-acting intramuscular formulation of Vanoxerine (Vanoxerine Consta 394.2 mg) vs. patients treated with Placebo. Conclusions and Relevance: Long-acting depot formulations of Vanoxerine (Vanoxerine Consta 394.2 mg) were more effective than Placebo injection in maintaining short-term abstinence from cocaine and should be considered as a treatment option for cocaine-dependent individuals.展开更多
文摘This case presents a rarely seen combination of two Cocaine-induced syndromes occurring simultaneously. Levamisole-adultered cocaine leads to Levamisole-induced Vasculitis (LIV), while cocaine’s vasoconstrictive effect causes destruction of the osteo-cartilaginous structures of nose called Cocaine-induced midline destructive lesions (CIMDL). This case raises awareness of a new pattern of recognition in order to avoid misdiagnosis. We present a case of a 51-year-old male cocaine user who developed severe left-sided ear pain and yellowish secretions with circular necrotic lesions in the nose, right earlobe, and dorsum of feet bilaterally. An extensive workup to assess purpuric lesions’ etiology, including vasculitis, collagen vasculitides, anti-phospholipid syndrome, hypercoagulable state and infectious process, was performed and found negative. He developed bilateral tympanic membrane perforation and purpuric necrotic skin lesions, at the same time, due to CIMDL and LIV, respectively. These two syndromes rarely present simultaneously in a patient. This case report exhibits a new Cocaine-induced clinical presentation that will help hospitalists recognize the disease and avoid misdiagnosis leading to unnecessary tests, prolonged hospitalization, and higher healthcare costs. Diagnosis is challenging, as it consists of establishing a temporal relationship between cocaine ingestion and symptoms’ onset. This disease usually has a benign progression because symptoms frequently resolve without intervention.
基金supported by Consejo Nacional de Investigaciones Cientificas y Tecnicas(CONICET,PIP 112-201001-00243)Secretaria de Ciencia, Tecnologia e Innovacion Productiva de la Prov.Santa Fe (SeCTeI, 2010-058-12)Universidad Nacional de Rosario(UNR,BIO 295).
文摘In adult animals,it is well established that stress has a proactive effect on psychostimulant responses.However,whether only a short period of stress during adolescence can also affect cocaine responses later in life and what mechanisms are involved are unknown.Here,we showed that 5 days of social isolation during rat adolescence had a long-term impact on anxiety-like behaviors,cocaine-induced conditioned place preference,and the expression of sensitization during adulthood.At the molecular level,social isolation decreased the activity of the Wnt/β-catenin pathway in the prefrontal cortex(PFC).Furthermore,after the expression of cocaine sensitization,isolated rats showed an increase in this pathway in the nucleus accumbens.Together,these findings suggest that,adolescent social isolation by altering the Wnt/β-catenin pathway in the developing PFC might increase the cocaine responses during adulthood,introducing this pathway as a novel neuroadaptation in the cortical-accumbens connection that may mediate a stress-induced increase in vulnerability to drugs.
基金Foundation items： This research was supported by the National Nat- ural Science Foundation of China （31260513）, the National Natural Science Foundation of Ningxia （NZ14077） and the Science Foundation of Beifang University of Nationalities （2012Y052）
文摘C57BL/6J and BALB/cJ mice display significant differences in sociability and response to drugs, but the phenotypic variability of their susceptibility to cocaine is still not well known. In this study, the differences between these two mice strains in the persistence of cocaine-induced conditioned place preference （CPP）, as well as the locomotion and social behaviors after the 24-hour withdrawal from a four-day cocaine （20 mg/kg/day） administration were investigated. The results showed that the cocaine-induced CPP persisted over two weeks in C57BL/6J mice, while it diminished within one week among BALB/cJ mice. After 24-hours of cocaine withdrawal, high levels of locomotion as well as low levels of social interaction and aggressive behavior were found in C57BL/6J mice, but no significant changes were found in BALB/cJ mice, indicating that cocaine-induced CPP persistence, locomotion and social behavior are not consistent between these two strains, and that overall C57BL/6J mice are more susceptible to cocaine than BALB/cJ mice at the tested doses.
基金Supported by NIDA,No.K23DA045928-01(to Bachi K) and No.R01DA041528(to Goldstein RZ)NIH/NHLBI,No.R01HL071021+1 种基金Translational and Molecular Imaging Institute internal funding(to Fayad ZAF)American Heart Association Grant in Aid,No.17GRNT33420119(to Mani VM)
文摘BACKGROUND Chronic cocaine use is associated with stroke, coronary artery disease and myocardial infarction, resulting in severe impairments or sudden mortality. In the absence of clear cardiovascular symptoms, individuals with cocaine use disorder (iCUD) seeking addiction treatment receive mostly psychotherapy and psychiatric pharmacotherapy, with no attention to vascular disease (i.e., atherosclerosis). Little is known about the pre-clinical signs of cardiovascular risk in iCUD and early signs of vascular disease are undetected in this underserved population. AIM To assess inflammation, plaque burden and plaque composition in iCUD aiming to detect markers of atherosclerosis and vascular disease. METHODS The bilateral carotid arteries were imaged with positron emission tomography/magnetic resonance imaging (PET/MRI) in iCUD asymptomatic for cardiovascular disease, healthy controls, and individuals with cardiovascular risk. PET with 18F-fluorodeoxyglucose (18F-FDG) evaluated vascular inflammation and 3-D dark-blood MRI assessed plaque burden including wall area and thickness. Drug use and severity of addiction were assessed with standardized instruments. RESULTS The majority of iCUD and controls had carotid FDG-PET signal greater than 1.6 but lower than 3, indicating the presence of mild to moderate inflammation. However, the MRI measure of wall structure was thicker in iCUD as compared to the controls and cardiovascular risk group, indicating greater carotid plaque burden. iCUD had larger wall area as compared to the healthy controls but not as compared to the cardiovascular risk group, indicating structural wall similarities between the non-control study groups. In iCUD, wall area correlated with greater cocaine withdrawal and craving. CONCLUSION These preliminary results show markers of carotid artery disease burden in cardiovascular disease-asymptomatic iCUD. Broader trials are warranted to develop protocols for early detection of cardiovascular risk and preventive intervention in iCUD.
文摘Prior work has shown that systemic cocaine pretreatment augments cocaine conditioned place preference (CPP) in rats. In contrast, ghrelin receptor antagonism attenuates cocaine and amphetamine-induced CPP. In order to further investigate ghrelin’s role in dopamine-mediated reward, the present report examined whether pretreament with ghrelin, administered directly into the ventral tegmental area (VTA) of the midbrain, would potentiate the rewarding properties of cocaine as measured by CPP. Adult male Sprague-Dawley rats were given access to either side of the CPP chamber in order to determine initial side preferences. The rats were then restricted to either their non-preferred or preferred side over the course of conditioning which lasted for a total of 16 consecutive days. This was followed by a final test day to then reassess preference. On days where rats were confined to their non-preferred side, ghrelin (30-300 pmol) and cocaine (0.625-10 mg/kg IP) were administered immediately prior to the conditioning trial. On alternate days rats were treated with vehicle and placed into what was initially determined to be their preferred side. CPP was calculated as the difference in percentage of total time spent in the treatment-paired compartment during the post-conditioning session and the pre-conditioning session. Our results indicated that both cocaine and ghrelin elicited CPP and that ghrelin pretreatment potentiated the effect of cocaine on place preference. Overall, these findings provide additional support for the argument that ghrelin signaling within the VTA enhances the rewarding effects of psychostimulant compounds.
基金the National Natural Science Foundation of China(81871043 and 82071494)the National Science and Technology Major Project of China(2018ZX09201017 and 2018ZX09201018)the 1.3.5 Project for Disciplines of Excellence,West China Hospital,Sichuan University(ZYGD18024).
文摘Drug-associated reward memories are conducive to intense craving and often trigger relapse.Simvastatin has been shown to regulate lipids that are involved in memory formation but its influence on other cognitive processes is elusive.Here,we used a mass spectrometry-based lipidomic method to evaluate the impact of simvastatin on the mouse brain in a cocaine-induced reinstatement paradigm.We found that simvastatin blocked the reinstatement of cocaine-induced conditioned place preference(CPP)without affecting CPP acquisition.Specifically,only simvastatin administered during extinction prevented cocaine-primed reinstatement.Global lipidome analysis showed that the nucleus accumbens was the region with the greatest degree of change caused by simvastatin.The metabolism of fatty-acids,phospholipids,and triacylglycerol was profoundly affected.Simvastatin reversed most of the effects on phospholipids induced by cocaine.The correlation matrix showed that cocaine and simvastatin significantly reshaped the lipid metabolic pathways in specific brain regions.Furthermore,simvastatin almost reversed all changes in the fatty acyl profile and unsaturation caused by cocaine.In summary,pre-extinction treatment with simvastatin facilitates cocaine extinction and prevents cocaine relapse with brain lipidome remodeling.
基金supported by grants from the National Natural Science Foundation of China (91332119,81161120497,30925015,30830044,31371143,30900582 and 81221002)the National Basic Research Development Program from the Ministry of Science and Technology of China (2014CB542204)
文摘Dopamine D1 receptors（D1Rs） play a key role in cocaine addiction, and multiple protein kinases such as GRKs, PKA, and PKC are involved in their phosphorylation. Recently, we reported that protein kinase D1 phosphorylates the D1 R at S421 and promotes its membrane localization. Moreover, this phosphorylation of S421 is required for cocaineinduced behaviors in rats. In the present study, we generated transgenic mice over-expressing S421A-D1 R in the forebrain. These transgenic mice showed reduced phospho-D1R（S421） and its membrane localization, and reduced downstream ERK1/2 activation in the striatum. Importantly, acute and chronic cocaine-induced locomotor hyperactivity and conditioned place preference were significantly attenuated in these mice. These findings provide in vivo evidence for the critical role of S421 phosphorylation of the D1 R in its membrane localization and in cocaine-induced behaviors. Thus, S421 on the D1 R represents a potential pharmacotherapeutic target for cocaine addiction and other drug-abuse disorders.
基金the National Natural Science Foundation of China(81971285,11727813)the Fundamental Research Funds for the Central Universities(GK202005001),Shaanxi Normal University.
文摘Plasticity in the glutamatergic synapses on striatal medium spiny neurons(MSNs)is not only essential for behavioral adaptation but also extremely vulnerable to drugs of abuse.Modulation on these synapses by even a single exposure to an addictive drug may interfere with the plasticity required by behavioral learning and thus produce impairment.In the present work,we found that the negative reinforcement learning,escaping mild foot-shocks by correct nose-poking,was impaired by a single in vivo exposure to 20 mg/kg cocaine 24 h before the learning in mice.Either a single exposure to cocaine or reinforcement learning potentiates the glutamatergic synapses on MSNs expressing the striatal dopamine 1(D1)receptor(D1-MSNs).However,24 h after the cocaine exposure,the potentiation required for reinforcement learning was disrupted.Specific manipulation of the activity of striatal D1-MSNs in D1-cre mice demonstrated that activation of these MSNs impaired reinforcement learning in normal D1-cre mice,but inhibition of these neurons reversed the reinforcement learning impairment induced by cocaine.The results suggest that cocaine potentiates the activity of direct pathway neurons in the dorsomedial striatum and this potentiation might disrupt the potentiation produced during and required for reinforcement learning.
文摘<b>Aim:</b> The effect of patented nutritional supplementation on drug-seeking behavior in cocaine addicted rats during acute drug withdrawal was investigated using a biased Conditioned Place Preference (CPP) paradigm. <b>Method:</b> Twenty-four (24) male Sprague-Dawley rats with pre-conditioned preference for the black chamber of the CPP box were randomly divided into Cocaine (COC) or Saline (SAL) treated groups. Rats (n = 12) treated with cocaine hydrochloride 20 mg/kg/ml, <i>i.p.</i> (COC group) were confined individually to the white chamber on days 1, 3, 5 and 7. On alternate days, they were given 1 ml saline vehicle, <i>i.p.</i> and confined to the black chamber. Control rats (SAL group, n = 12) received only vehicle on all 8 days and were confined on alternate days to the white or black chamber. Positive place preference was confirmed for COC rats, which subsequently received 6 increasing daily doses of cocaine. CPP performances of both COC and SAL rats were recorded following an acute 3-day withdrawal period. All animals were then randomly assigned to rats fed either chow reconstituted with the nutritional supplement (COC-S and SAL-S) or standard rat chow (COC-N and SAL-N) for 8 weeks, followed by final CPP performances. <b>Results:</b> Following supplementation, COC-S rats made significantly less entries and time spent in the white chamber (p < 0.05) compared with COC-N rats. COC-S rats exhibited significant place aversion to the white chamber similar to drug-naive animals;whereas COC-N continued to show positive place preference. <b>Conclusion:</b> Drug-seeking behavior that persisted during cocaine withdrawal was significantly diminished in the nutritionally supplemented.
基金financial support from the Brazilian Science foundations CNPq,FAPESP,FINEP and Inmetro.
文摘Cocaine and crack cocaine are usually seized with a great diversity of adulterants, such as benzocaine, lidocaine, caffeine, and procaine. The forensic identification of cocaine in these drug mixtures is normally performed using colorimetric testing kits, but these tests may suffer from interferences providing false-positive or false-negatives. In this work, we describe the use of thin layer chromatography coupled to easy sonic-spray ambient ionization mass spectrometry (TLC/EASI-MS) for rapid and secure analysis of cocaine and crack cocaine. Fifteen cocaine samples were analyzed, and all of them revealed positive TLC/EASI-MS results for cocaine, but other drugs and adulterants were also detected such as lidocaine, caffeine, benzocaine, lactose, benzoylecgonine, and ecgonidine. False positives and false negatives, as judged by the TLC Rf values, were identified via on-spot characterization by EASI-MS. The TLC/EASI-MS combination seems therefore to provide an appropriate technique for secure forensic investigations of illicit drugs.
文摘Aim： To investigate the effect of cocaine on apoptosis and caspase-3 activity in germ cells in male rats at different ages. Methods： Cocaine hydrochloride was given （15 mg/kg body weight s.c.） to male Sprague-Dawley rats of 3 weeks （n = 8）, 6 weeks （n = 8） and 12 weeks （n = 8） of age, daily for 28 days. The serum levels of follicle stimulating hormone （FSH）, luteinizing hormone （LH）, prolactin （PRL）, testosterone （T） and estrogen （E2） were assayed, and the DNA fragmentation of germ cells was determined by gel eletronphoresis. The cell cycle, apoptosis and caspase-3 activity of germ cells were tested by flow cytometry. Results： After the 28-day cocaine treatment, testes weight of the 3-week-old rats, the testes and body weights of the 6-week-old rats were decreased significantly compared to those of their corresponding controls （P 〈 0.05）. The serum level of T was decreased significantly in the 3-week-old and 6-week-old rats, and the serum level of PRL was also decreased significantly in 12-week-old rats compared to the controls （P 〈 0.05）, In all the three cocaine-treated groups, the isolated DNA displayed a clear ladder pattern, especially in the 6-week old rats. The number of apoptosic germ cells increased significantly in 3- and 6- week-old rats treated with cocaine （P 〈 0.05）. The caspase-3 activity in all three groups increased significantly compared to the controls （P 〈 0.05）, especially in the 6-week-old rats. Conclusion： Cocaine exposure for 28 days leads to significant damage to male gonad and apoptosis elevation in testes of rats of different ages, especially in those of 6 weeks of age. The increase in caspase-3 activity might be a key pathway related to the early stage of apoptosis as the mechanism of cocaine-induced germ cell loss.
文摘Coronary artery ectasia(CAE)often represents a coronary angiography finding casually detected or following the occurrence of an acute coronary syndrome.The pathogenetic role of cocaine abuse in the genesis of CAE is still little known and very few data are available in literature.We describe a case of a 31-year-old male cocaine user admitted to our department for typical acute chest pain.Coronary angiography showed diffuse coronary ectasia with slow flows and without hemodynamically significant stenosis.An increasing of matrix metalloproteinases values and a reduction of their tissue inhibitors was showed both during hospitalization and at one month after discharge.This case report emphasizes the close relationship between cocaine abuse,CAE and acute coronary syndromes in patients without hemodynamically significant coronary stenosis.As reported by Satran et al,cocaine abuse should be considered an important risk factor for CAE and these patients appear to be at increased risk of angina and acute myocardial infarct.Further studies that can strengthen this hypothesis would be useful to deepen and better analyze this interesting association.
基金National Natural Science Foundation of China (81673409).
文摘OBJECTIVE Phosphoinositide 3-kinase(PI3K) activation was reported to participate in the development of effect of some drugs,such as morphine and cocaine dependence.We previous found nischarin is associated with the activation of PI3K.It is our great interest to investigate the involvement of nischarin in PI3K dependent modulation of morphine versus cocaine dependence.METHODS In order to study the role of nischarin in drug dependence and tolerance,nischarin knockout mice were used for our research.Effect of psychological dependence was studied by conditioned place preference(CPP),and the effect of physical dependence was tested by naloxone-precipitated withdrawal signs.Some brain tissues were harvested 24 h after the behavioral experiment for the further measurement.RESULTS PI3K specific inhibitor LY294002 significantly blocked the acquisition of morphine-induced CPP in wild-type mice,but had no effect on its expression.In comparison,LY294002 failed to block the acquisition of cocaine-induced CPP but inhibited the expression.Furthermore,we found naloxoneprecipitated withdrawal signs in the morphine dependent mice was inhibited by LY294002.Nischarin knockout in mice could abolish the effect of LY294002 on blocking the effects of morphine,but had no effect on cocaine.CONCLUSION PI3K activation is involved in the different phases of morphine and cocaine dependence,and nischarin plays an important role in the process.
文摘Accelerated epicardial coronary artery atherosclerosis has been well-documented in cocaine users.There are only two reported cases of cocaine-associated diffuse intimal expansion by proliferated smooth muscle cells causing significant coronary luminal compromise.This type of lesion histologically resembled chronic trans-plant arteriopathy.Here,we report a third such case.
文摘BACKGROUND Atraumatic splenic rupture(ASR)accounts for just over 3%of all cases of splenic rupture and is associated with a high mortality rate.The most common culprit is acute infection with Epstein-Barr virus(EBV)but other documented aetiologies include neoplasia,other viral/bacterial infections,acute and chronic pancreatitis,amyloidosis and anticoagulant medications.There are four previous reports of cocaine-associated ASR but never before has it been documented in combination with concurrent acute EBV infection.CASE SUMMARY A 21-year-old man presented to hospital with acute left shoulder pain which radiated to the right shoulder and upper abdomen.He denied any history of recent trauma and had no relevant past medical history.He took no regular prescription medications but had used cocaine within the previous 24 h.Investigations revealed splenomegaly,a Grade 3 subcapsular splenic haematoma,moderate haemoperitoneum and an incidental 9 mm splenic artery pseudoaneurysm.There was also serological evidence of acute EBV infection.Prophylactic endovascular embolisation of the pseudoaneurysm was performed and the splenic rupture was managed non-operatively.The patient remained admitted in hospital for seven days and did not require any transfusion of blood products.Serial imaging showed complete resolution of the haemoperitoneum after 5 wk.The importance of abstinence from illicit drug use was emphasised to the patient but it is unknown whether or not he remains compliant.CONCLUSION This case demonstrates that ASR is a rare condition that can result from acute EBV infection and cocaine ingestion and requires a high index of suspicion to diagnose clinically.
文摘Management of patients carrying packets of drugs in the digestive tract is a frequent medical problem.Wereport on a patient who was referred by the police after ingestion of packets of cocaine.After spontaneous elimination of 81 drug packets,the patient had three unremarkable stools.A plain abdominal X-ray disclosed no residual packet but computed tomography(CT) scan showed one in the stomach.As this was not eliminated during the 10 d following ingestion,it was removed through gastrotomy.This case stresses the usefulness of the CT scan to ensure that no residual packet is present before hospital discharge.
文摘Slowing conduction and prolonged repolarization have been implicated in cocaine-induced cardiac arrhythmia.However,the importance of these properties at any given cocaine concentration[C]remains unknown. Using standard microelectrode techniques, we studied the effect of different [C] (ranging from 9.spmol/L to 300 μmol/L) on action potential duration(APD)and dv/dtmax of phase 0 in 16 canine papillary muscle preparations Paced at 1 000 msec cycle. In contrast to dy/dtmax which showed progressive decrease from(201±19)v/s during control to (33±7)v/s at [C] of 300μmol/L, APD90showed an initial increase from(193±15) msec to a peak of(232±17)msec at 113μmol/ L and a gradual decrease back to control at 188 μmol/L and further decrease to below baseline to a nadir of (168±14) msec at 263 μmol/L. The resting membrane potentials did not change significantly during the progressive increase of [C]. The bimodal response of APD may be explained by blockade of the delayed rectifier potassium current as well as blockade of window sodium current by cocaine. The findings imply that up to [C] of 188μmol/L may cause arrhythmia by slowing of conduction and prolongation of repolarization. At [C] above 188μmol/L the prolongation of repolarization is unlikely to be the mechanism.
文摘The effects of chronic cocaine administration on the locomotor rhythmic patterns of adult female Sprague-Dawley (SD) rats were recorded using an open-field testing assay. The animals were divided into four groups, control (saline), 3.0 mg/kg, 7.5 mg/kg, and 15.0 mg/kg i.p. cocaine group respectively. On experimental day (ED 1), all animals were treated with saline. On ED 2 to ED 7, either saline or cocaine (3.0, 7.5, or 15.0 mg/kg i.p.) was given followed by three days of no treatment (ED 8 to ED 10). On ED 11, rats were treated as they were on ED 2 to ED 7, i.e. either saline, 3.0, 7.5, or 15.0 mg/kg i.p. cocaine. The locomotor activities of rats were recorded for 23 hours daily, allowing one hour for the animal handling and injections, using open field cages with 16 infrared beams of motion detectors. Any breakages of these beams due to the movement of the animals were recorded and compiled by a computer and analyzed. It was observed that all three doses of repeated cocaine administration (3.0 mg/kg, 7.5 mg/kg, and 15.0 mg/kg i.p. cocaine) significantly alter the locomotor rhythmic activity patterns of the adult female SD rats, which suggest that repeated cocaine exposure modulates body homeostasis.
文摘The effects of Nω-nitro-L-arginine methyl ester(L-NAME)i.v.and nitric oxide(NO) inhalation on integrated systemic responses to cocaine were studied in lightly anesthetized, paralyzed, and mechanically ventilated rats.Cocaine [4 mg/(kg. min) i.v.] produccd seizures then isoelectric electrocephalographic(isoEEG)activity as well as an initial increase in systolic blood pressure and heart rate,then progressive cardiovascular system depression culminating in asystole. Pretreatment with L-NAME[2 mg/(kg. min)i.v. ] for 30 min significantly reduced the incidence of seizure as compared to saline treated animals (saline 7/8; L-NAME 3/8).Doses of cocaine that produced arrhythmias, isoEEG and asystole were significantly lower in the L-NAME treated animals as compared to the saline group. L-NAME did not affect peak systolic blood pressure and heart rate responses to cocaine. NO inhalation(80 ppm)did not affect CNS and cardiovascular responses to cocaine in control animals but enhanced the effects of L-NAME on cocaine toxicity. The results show that pretreatment with L-NAME reduces the central nervous system stimulatory effect of cocaine (reduced seizure incidence) and enhances its depressant effect on both the central nervous system (lower does for isoEEG) and the cardiovascular stimulatory action of cocaine. NO inhalation does not protect against any of the systemic effects of cocaine in animals with normal or suppressed NO production.
文摘Objective: To determine the efficacy and tolerability of a long-acting intramuscular formulation of Vanoxerine (Vanoxerine Consta 394.2 mg) for treatment of cocaine-dependent patients. Design, Setting, and Participants: A 12-week, A multicenter, randomized, placebo-controlled trial conducted between June 2009-July 2011, at 17 Hospital-based drug clinics, in the 15 countries. Participants were 18 years or older, had Diagnostic and Statistical Manual of Mental Disorders-5 cocaine use disorder. Of the 2800 patients who were assessed between March 10, 2009 to August 10, 2010, 2600 (93%) were eligible and willing to take part in the trial and were enrolled: 1300 were randomly assigned to receive injections of Long-acting depot formulations of Vanoxerine (Vanoxerine Consta 394.2 mg) given intramuscularly once in 12 weeks and 1300 to receive Placebo injections, given intramuscularly once in 12 weeks. Only 100 of 2800 patients (3.6%) did not meet the inclusion criteria. Main Outcomes and Measures: The primary endpoints (protocol) were: Confirmed Cocaine abstinence (percentage i.e. the number of patients who achieved complete abstinence during 12 weeks). Confirmed abstinence or “cocaine-free” was defined as a negative urine drug test for cocaines and no self-reported cocaine use. Secondary end points included a number of days in treatment, treatment retention and craving. The study also investigated, on 275 participants, degree and time course of Central Dopamine transporter receptor occupancy following single doses of long-acting intramuscular formulation of Vanoxerine (Vanoxerine Consta 394.2 mg) as well as the plasma concentration of Vanoxerine and 17-hydroxyl Vanoxerine. Safety was assessed by adverse event reporting. Results: Of 2600 participants, mean (SD) age was 28.5 (±5.5) years and 598 (23%) were women. 1300 individuals were randomized to receive injections of Long-acting depot formulations of Vanoxerine (Vanoxerine Consta 394.2 mg) and 1300 to receive injections of Placebo. 1417 participants (54.5.0%) completed the trial. Primary Endpoints: Confirmed Cocaine Abstinence: Complete abstinence was sustained by 72% (n = 936) of Vanoxerine patients (patients treated with Vanoxerine Consta 394.2 mg, long-acting depot formulations) compared with 37% (n = 481) of patients treated with Placebo, during weeks 5 - 12. The difference was significant as evaluated using a Chi-square test (χ2 = 672.34, P < 0.0001). Secondary Endpoint: Craving: A statistically and clinically significant reduction in cocaine craving was observed with Vanoxerine (Vanoxerine Consta 394.2 mg, long-acting depot formulations) vs. Placeboby week 4 (P = 0.0048), which persisted every week through 12 (P < 0.0001). Patients given Vanoxerine (Vanoxerine Consta 394.2 mg, long-acting depot formulations) had a 87% decrease in craving from baseline to 12th week. Patients given a Placebo had a 2% increase in craving from baseline to 12th week. Secondary Endpoint: Treatment Retention: Long-acting intramuscular formulation of Vanoxerine (Vanoxerine Consta 394.2 mg) helped significantly more patients complete 12 weeks treatment (n = 936, 72%) compared with Placebo (n = 481, 37%) (χ2 = 635.53, P < 0.0001). Patients on the long-acting intramuscular formulation of Vanoxerine (Vanoxerine Consta 394.2 mg) had longer treatment retention than patients on Placebo. Concentrations of Vanoxerine and 17-Hydroxyl Vanoxerinein Plasma: Analyses were made of 275 study samples. There was no statistically significant difference for plasma Vanoxerine concentrations between days 2 and 84 (p = 0.416). The plasma concentration of Vanoxerine were 70.4 and 94.3 ng/ml and concentrations of 17-hydroxyl Vanoxerine were 10.5 and 13.2 ng/ml, respectively. Plasma levels of Vanoxerine remained above 70 ng/ml for approximately 12 weeks after administration of Vanoxerine, long-acting depot formulations (Vanoxerine Consta 394.2 mg). PET Assessments: Very high central dopamine transporter receptor occupancy by Vanoxerine was detected 1 day after treatments, at which time point the occupancy was 100.0% after Vanoxerine injection (Vanoxerine Consta 394.2 mg). At days 7, 28, 56 and 84 post-Vanoxerine Consta 394.2 mg administration, occupancies were 95% to 79%. Vanoxerine Consta 394.2 mg injection (long-acting intramuscular formulation of Vanoxerine) led to very high occupancy of Central Dopamine transporter receptors in all brain areas examined;nucleus accumbens, caudate nucleus and putamen. Depending on the brain area Central Dopamine transporter receptor occupancy varied between 95.0% and 79% at days 7, 28, 56 and 84 after dosing. High Vanoxerine occupancy (77%) persisted at 12 weeks after the dosings. Adverse Reactions: Adverse events were similar in cocaine-dependent patients treated with the long-acting intramuscular formulation of Vanoxerine (Vanoxerine Consta 394.2 mg) vs. patients treated with Placebo. Conclusions and Relevance: Long-acting depot formulations of Vanoxerine (Vanoxerine Consta 394.2 mg) were more effective than Placebo injection in maintaining short-term abstinence from cocaine and should be considered as a treatment option for cocaine-dependent individuals.
