Kegg Pathway: Benzodiazepine family

Can Fam Physician. 2009 Nov; 55(11): 1108-1109.e5
Kahan M, Wilson L, Midmer D, Ordean A, Lim H

OBJECTIVE: To evaluate patient outcomes in an addiction shared care program that is managed by family physicians working in a primary care setting. DESIGN: Prospective cohort study. SETTING: The addiction shared care program at St Joseph's Health Centre in Toronto, Ont, which is staffed by a nurse clinician, an addiction therapist, a clinical fellow, and 6 family physicians in an academic family medicine unit. PARTICPANTS: Participants included patients who attended at least one session in the program. The patients were self-referred or referred by family doctors, government agencies, or the emergency department. INTERVENTIONS: The service provided brief counseling interventions, outpatient medical detoxification, pharmacotherapy, and follow-up, and there was communication with the referring family physicians. MAIN OUTCOME MEASURES: Changes in self-reported substance use were measured through interviews at intake and at 3 to 4 months after the initial office visit. RESULTS: The study was conducted between January 2005 and April 2006. Out of 204 patients who gave consent to participate at baseline, we interviewed 71 patients about 4 months later. Among 33 problem drinkers, the mean number of standard drinks consumed per week declined from 32.9 at baseline to 9.6 at follow-up (P < .0005). Of the 29 problem opioid users, 6 were started on methadone treatment and 13 had decreased their opioid consumption from a mean morphine equivalent of 168.38 mg to 70.85 mg daily (P = .001). There was also a significant decline in the problematic use of Benzodiazepines (P = .004) and other drugs (P = .005), but there was no significant decline in the problematic use of cannabis or cocaine. Twenty-two patients (31%) participated in Alcoholics Anonymous or formal addiction treatment. CONCLUSION: Shared care is a promising new strategy for delivering addiction intervention. Further evaluation is warranted, with more complete follow-up and objective outcome measures.

Can Fam Physician. 2009 Nov; 55(11): 1085-8
Thompson JM, Chiasson R, Loisel P, Besemann LC, Pranger T

A few years after leaving the navy, a 50-year-old Veteran* presents to a new family physician with chronic knee and back pain. He is seeking a new physician for opioid and Benzodiazepine refills, referrals for ongoing acupuncture and massage therapy, and completion of Veteran Affairs Canada (VAC) disability claim forms for his back. He was medically released at the rank of Petty Officer owing to knee impairment secondary to a fracture sustained aboard ship. He twice strained his back on deployments, but did not develop chronic low back pain until after leaving the Canadian Forces (CF). On release from the CF he completed comprehensive medical, psychosocial, and vocational rehabilitation in the VAC Rehabilitation Program for disability related to his knee impairment. Lately, chronic low back pain prevents him from continuing civilian employment and enjoying life.The physician takes the Veteran's history, performs appropriate physical examination and diagnostic investigations, and obtains previous medical records. The physician diagnoses chronic mechanic allow back pain and knee osteoarthritis, and is concerned about the Veteran's mental health. When the family physician tries to explore the mental health differential diagnosis, the Veteran initially becomes upset,but he responds to motivational interviewing. The physician books follow-up appointments to develop a therapeutic relationship with the Veteran and completes the VAC forms. With consent, the physician also sends a referral letter to the VAC district office, outlining the Veteran's health issues. The client is found to be eligible to re-enter the VAC Rehabilitation Program to manage disability related to his back pain. The Veteran is ultimately able to withdraw from chronic opiate and Benzodiazepine medications and optimize his participation in life.

Am J Forensic Med Pathol. 2009 Nov 6;
Maravelias C, Stefanidou M, Dona A, Athanaselis S, Spiliopoulou C

The number of drug-facilitated sexual assault incidents has lately been increased all over the world leading law enforcement agencies and hospital doctors to constant alert. The drugs involved may be Benzodiazepines, hypnotics, other sedatives, anesthetics, drugs of abuse or ethanol. The detection of these agents in biologic fluids is difficult, since most of them are shortly acting, and provoke victim's amnesia which in turn leads the victim to report the allegation late. An unusual case-study of a 35-year-old, married woman who was admitted to the hospital with dizziness and loss of memory for a period of 10 days is here reported. The toxicological analysis of the victim's blood and urine for unknown sedative drugs, achieved by GC-MS, revealed the presence of zolpidem (Stilnox), a nonBenzodiazepine hypnotic. Concentration of zolpidem in blood, 11 hours after the last supposedly intake, was 47 mug/L. After family counseling at the hospital, the victim's husband confessed that he was replacing the contents of Losec capsules of his wife, with Stilnox tablets. This unjust act was committed by the husband in order for him to have sex with his wife, since she was not willing to participate in a sexual intercourse due to her religious restraints for a fasting period of 40 days. The aim of this article is 2-fold. First, to emphasize the fact that a sexual assault can take place not only between 2 strangers, but also within a happily married couple. Second, to remind doctors that any case of sexual assault must be examined toxicologically, for a better and thorough investigation.

Bioconjug Chem. 2009 Nov 18; 20(11): 2082-2089
Samuelson LE, Dukes MJ, Hunt CR, Casey JD, Bornhop DJ

While it has become common practice for dendrimers to deliver imaging and therapeutic agents, there are few reported examples of cellular internalization of dendrimers. Moreover, targeting of dendrimers to the mitochondria in cells has not yet been reported. Previously, we have delivered small molecule imaging agents into glioma and breast cancer cells by targeting the translocator protein (TSPO; formerly known as the peripheral Benzodiazepine receptor or PBR) with a family of high-affinity conjugable ligands. The 18 kDa multimeric TSPO is expressed in steroid-producing cells, primarily on the outer mitochondrial membrane. This protein is a prime candidate for molecular targeting because tumors and other disease-related cells contain high densities of TSPO. Here, we present the synthesis, characterization, and cellular internalization into C6 rat glioma cells of a TSPO targeted dendrimer imaging agent.

J Psychiatr Pract. 2009 Sep; 15(5): 415-22
Lewis L, Kahn DA

A Case is presented of a 23-year-old woman with progressive onset of paranoid psychosis and catatonia, who was ultimately found to have both vitamin B12 deficiency and a family history of bipolar disorder. The patient was initially diagnosed with schizophrenia and treated with the antipsychotic medication ziprasidone. Her condition rapidly worsened to a state consistent with either neuroleptic malignant syndrome or malignant catatonia. Work-up then revealed vitamin B12 deficiency and a family history of bipolar disorder. Her symptoms improved rapidly but partially with Benzodiazepines and electrocon-vulsive therapy, and completely with addition of valproic acid, vitamin B12 replacement, and re-introduction of antipsychotic medication in the form of olanzapine. The authors discuss the differential diagnosis of catatonia as reflecting a high likelihood of underlying mood disorder; the evaluation and management of malignant catatonia and malignant neuroleptic syndrome; and the role of vitamin B12 deficiency in precipitating psychotic symptoms. The case also illustrates the problems of diagnosing and managing a multifactorial disorder with psychiatric, general medical, and perhaps iatrogenic components.

J Intern Med. 2009 Nov; 266(5): 419-31
Ekbom K, Ulfberg J

Restless legs syndrome (RLS) is a common neurological sensory-motor disorder that is characterized by intense restlessness and unpleasant creeping sensations deep inside the lower legs. Symptoms appear when the legs are at rest and are worst in the evening and at night. They force patients to keep moving their legs, and often to get out of bed and wander about. Periodic limb movements (PLMS) are also common during sleep amongst those suffering from RLS, and sleep efficiency is severely reduced. There are idiopathic as well as symptomatic forms of RLS, the latter being associated with e.g. pregnancy, iron deficiency and chronic renal failure. A family history of RLS is very common and pedigrees in these cases suggest an autosomal-dominant transmission with high penetrance. Genetic investigations have been performed in order to identify genes associated with RLS. Several loci have been found (on chromosomes 12q, 14q, 9p, 2q, 20p and 16p). Pathophysiology of RLS remains incompletely understood. However, advanced brain imaging studies and positive results of dopaminergic treatment suggest that RLS may be generated by dopamine dysfunction locally within the central nervous system. At present, there is a wide range of treatment options including levodopa, dopamine agonists, opioids, Benzodiazepines, antiepileptic drugs and iron supplements.

Ugeskr Laeger. 2009 Oct 5; 171(41): 2999-3003
Jørgensen VR

INTRODUCTION: The consumption of Benzodiazepines (BZ) and cyclopyrrolones (CP) has attracted great interest in recent years due to the serious side-effects associated with these drugs. Two medical practices introduced a more restrictive approach to the prescription of BZ and CP. The intervention reduced the total consumption of anxiolytica by 75% and hypnotica by 90% during the two and a half year period. There is a general lack of knowledge about whether an intervention of this nature reduces drug consumption in general, or merely substitutes the consumption of drugs. Here, antidepressants (AD) are especially relevant substitutes. MATERIAL AND METHODS: In two medical practices, the consumption of AD was followed before, during and after the intervention. Consumption was followed via the Danish Medicines Agency's website Ordiprax, which listed the amount of prescription medicines sold from pharmacies. RESULTS: The total quantity of prescribed AD remained unchanged in the two practices (p = 0.05). There were minor shifts in prescription classes. This result should be seen in the context of the consumption of AD in the county as a whole, which rose by 8.6% per annum during the intervention period. CONCLUSION: In the primary sector, it is possible to reduce the amount of BZ and CP without causing a concomitant increase in the prescription of AD. The two medical practices of the present survey did not introduce a deliberately restrictive approach, but simply an increasing awareness when prescribing to patients, especially regarding the duration of prescriptions.

Clin Ther. 2009 Aug; 31(8): 1859-70
Lai HY, Hwang SJ, Chen YC, Chen TJ, Lin MH, Chen LK

BACKGROUND: The use of potentially inappropriate medications can have profound medical consequences for elderly patients and place a substantial burden on the health care system. OBJECTIVES: This study was conducted to determine the prevalence of potentially inappropriate medication prescribing at ambulatory care visits by patients aged > or =65 years covered by the Taiwanese National Health Insurance program, to examine the characteristics of and risk factors for such prescribing, and to investigate its influence on health care resource utilization. METHODS: Ambulatory care visits by patients aged > or =65 years in 2001-2004 were identified from the National Health Insurance claims database. The 2003 Beers criteria for drugs to be avoided in the elderly were used to identify potentially inappropriate medications prescribed at these visits. Only drugs with the potential to lead to higher-severity adverse events were included. Multivariate logistic regression was used to determine predictors of the prescribing of potentially inappropriate medications at ambulatory care visits. Independent variables in the regression model included patient characteristics (eg, sex, age), physician characteristics (sex, age, and specialty), and visit characteristics (site and prescribed drug number). The dependent variable was visits that included a prescription for a potentially inappropriate medication. RESULTS: Overall, 176,661,994 ambulatory care visits by patients aged > or =65 years were identified in 2001-2004. Of these, 19.1% involved a prescription for a potentially inappropriate medication. Although the frequency of potentially inappropriate medication prescribing declined over the study period, 62.5% of elderly patients were exposed to such medications in 2004. The only patient characteristic associated with an increased likelihood of the prescribing of potentially inappropriate medications was female sex (male sex: odds ratio [OR] = 0.982 [95% CI, 0.980-0.983], P < 0.001). Physician characteristics associated with a greater likelihood of the prescribing of potentially inappropriate medications was male sex (OR = 1.206 [95% CI, 1.202-1.210], P < 0.001); older age (43-50 years: OR = 1.021 [95% CI, 1.018-1.025], P < 0.001; >/=51 years: OR = 1.238 [95% CI, 1.235-1.242], P < 0.001); and family medicine/general practice (OR = 1.267 [95% CI, 1.265-1.269], P < 0.001). For visit characteristics, significant associations were found with visits to a primary care clinic (OR = 1.887 [95% CI, 1.881-1.892], P < 0.001) and the number of drugs prescribed (4-6 drugs: OR = 2.701 [95% CI, 2.696-2.706], P < 0.001; > or =7 drugs: OR = 4.528 [95% CI, 4.517-4.538], P < 0.001). The most commonly prescribed types of potentially inappropriate medications were antihistamines (4.8% of all prescriptions in 48.3% of elderly patients), muscle relaxants/antispasmodics (4.0% and 40.3%, respectively), and long-acting Benzodiazepines (2.4% and 21.4%). In 2004, the mean number of ambulatory care visits per patient was significantly higher among those who received potentially inappropriate medications compared with those who did not (30.78 vs 16.57, respectively; P < 0.001). Patients who received potentially inappropriate medications also had significantly more emergency department visits (0.27 vs 0.15; P < 0.001) and hospital admissions (0.46 vs 0.27; P < 0.001). CONCLUSION: There was a high prevalence of the prescribing of potentially inappropriate medications at ambulatory care visits by elderly patients in Taiwan in 2001-2004.

Toxicol In Vitro. 2009 Sep 16;
Funar-Timofei S, Ionescu D, Suzuki T

Benzodiazepines belong to a large family of drugs, being used as hypnotics, anxiolytics, tranquillizers, anticonvulsants, in pre-medication and intravenous sedation. Several quantitative structure-toxicity (lethal oral dose for mouse) relationship (QSTR) models for 54 Benzodiazepine derivatives have been developed. The molecular structure of these compounds was energetically optimized by molecular mechanics calculations. To the lowest energy conformations thus obtained, quantum chemical calculations (RM1 approach) were applied to finally optimize the structures. Several structural descriptors, volumes, molecular surface area, hydrophobicities and quantum chemical descriptors were calculated from the minimized structures. Multiple linear regression (MLR) combined with genetic algorithm for variable selection, artificial neural networks (ANNs), support vector machines (SVMs) and partial least squares (PLS) have been employed. Few satisfactory MLR models with predictive power were obtained. Nonlinear modelling methods of ANNs and SVMs gave somewhat better models than those obtained by MLR using same set of descriptors. Additional information on the factors which influence the Benzodiazepine toxicity was given by PLS. The obtained models can be used for a rough evaluation of Benzodiazepine toxicity.

Pediatr Blood Cancer. 2009 Dec 15; 53(7): 1200-4
Hedén L, von Essen L, Frykholm P, Ljungman G

BACKGROUND: Children with cancer often mention needle procedures as the most frightening, distressing, and sometimes painful aspect of the disease and treatment. The aim was to investigate whether children experience less fear, distress, and/or pain according to parents, nurses, and children >or=7 years of age when they receive oral midazolam versus placebo before a needle is inserted in a subcutaneously implanted intravenous port. PROCEDURE: Fifty children 1-18 years of age who were being treated in a pediatric oncology and hematology setting were included consecutively when undergoing routine needle insertion into an intravenous port. All children were subjected to one needle insertion in this randomized, triple-blind, placebo-controlled study in which orally administered midazolam (n = 24) 0.3 mg/kg body weight (maximum 10 mg) was compared with placebo (n = 26). Parents, nurses, and children >or=7 years reported the patients' fear, distress, and pain on 0-100 mm Visual Analogue Scales. RESULTS: Fear was lower in the midazolam group according to parents (P = 0.001), nurses (P = 0.001), and children (P = 0.015). Parents and nurses also reported lower distress (P = 0.020 and 0.007, respectively). Post hoc analyses indicated that the effects were more pronounced in younger children (<7 years of age). CONCLUSION: Low-dose oral midazolam was effective in reducing fear and distress in pediatric oncology patients, especially in younger children, undergoing subcutaneous port needle insertion.

Niger J Med. 2009 Apr-Jun; 18(2): 128-33
Iyalomhe GB

INTRODUCTION: Drug addiction, particularly among teenagers and young adults, has become a serious public health problem globally. Drugs with addictive potential include the non-therapeutic drugs that are licit/legal (caffeine, tobacco or nicotine, alcohol) and those that are illegal/illicit for common use such as Benzodiazepines, amphetamines, cocaine and crack, heroin and cannabis. Worldwide, the challenge of cannabis abuse and addiction is particularly devastating, nay in Nigeria. Despite this ugly scenario, the use of cannabis continues unabated and its control remains enigmatic. The aim of the present review is to provide a contemporary comprehensible overview of exciting recent developments in the understanding of brain circuits related to the nature and effects of cannabis abuse and addiction as well as to highlight the current therapeutic approach to effective management. METHOD: A thorough manual literature and internet (Medline and HINARI databases) search were conducted. RESULT: It was found that recent advances in the neurobiology of drug abuse and addiction have led to the identification of neuronal substrates (eg dopamine, 5-hydroxyltrypytamine etc) as being responsible for the rewarding effects of cannabis and are also crucial to the addictive process/behaviour. There is increasing evidence that prolonged exposure to drugs of abuse including cannabis, produces long-lasting effects in cognitive and drug-rewarding brain circuits. Hence, addiction is now generally considered a chronic brain disease. Chronic use of cannabis impairs cognitive functions, perception, reaction time, learning, memory, concentration, social skills and control of emotions. There may also be panic reactions, hallucinations, paranoid states with fixed delusions and even acute psychosis. These impairments have obvious negative implications for the operation of a motor vehicle or machinery and performance at school or workplace as well as the development of a healthy family, a strong national economy and a secure society. Complications of use, including psychosis and withdrawal effects, can be treated. Psychosocial measures and rehabilitation, together with effective prevention initiatives are essential in the management of individuals with drug-related problems. CONCLUSION: Cannabis abuse and addiction is destructive and may affect all of our lives and the fabric of the society. The development of long-term management strategies based on medication, psychosocial support and continued monitoring as well as preventive initiatives to reduce risk factors and strengthen protective factors against drug abuse is a challenging clinical goal.

Pediatr Neurol. 2009 Aug; 41(2): 135-8
Szczałuba K, Jurek M, Szczepanik E, Friedman A, Milewski M, Bal J, Mazurczak T

Paroxysmal nonkinesigenic dyskinesia is a condition characterized by attacks of sudden involuntary movements triggered by caffeine or alcohol intake, stress, or fatigue. The paroxysms are usually of the generalized type and may last up to an hour. Described here is a Polish family with this disorder seen in two children and their father. Variable expressivity as well as reduced penetrance of the causative mutation were noteworthy in this kindred. Treatment options included abortive diazepam and prophylactic levetiracetam, with the latter having a more pronounced effect in this family. Favorable response to levetiracetam is probably linked to action of the drug on calcium channels in neurons, muscle cells, or both.

J Pain. 2009 Sep; 10(9): 976-83
White LA, Robinson RL, Yu AP, Kaltenboeck A, Samuels S, Mallett D, Birnbaum HG

In 2004, the American Pain Society (APS) issued evidence-based fibromyalgia treatment recommendations. The objective of this claims database analysis is to describe prescription and medical use in patients with newly diagnosed and established fibromyalgia. Privately insured patients with 2+ myalgia/myositis claims (1999 to 2005) were categorized as newly diagnosed or established; this dichotomy involves comparisons between prediagnosis (S1) and postdiagnosis (S2) stages in the newly diagnosed and between newly diagnosed (S2) and established patients (S3). Use of APS guideline medications increased across stages: selective serotonin reuptake inhibitors (SSRIs) (S1, S2, S3: 20.6%, 22.9%, 25.3%), serotonin norepinephrine reuptake inhibitors (SNRIs) (4.5%, 6.4%, 8.9%), pregabalin/gabapentin (5.4%, 7.4%, 8.8%), Benzodiazepines (19.0%, 21.1%, 24.2%), non-Benzodiazepine sedatives (9.1%, 11.5%, 13.7%) (all P < .0001), and opioids (39.5%, 43.3%, 43.9%; S1 vs S2, P < .0001; S2 vs S3, P = .2835). Use of multiple therapeutic classes also increased across stages: 3+ classes (7.1%, 9.6%, 11.8%) (all P < .0001). Office visits to providers increased, on average, after diagnosis: primary care (70.9%, 78.3%, 76.3%; all P < .0001), chiropractors (28.8%, 51.1%, 53.3%; all P < .0001), rheumatologists (4.2%, 9.9%, 10.5%; S1 vs S2, P < .0001; S2 vs S3, P = .0595), mental health (6.4%, 7.3%, 8.3%; S1 vs S2, P < .0001, S2 vs S3, P = .0003). Average health care costs rose after diagnosis in the newly diagnosed group (S1: $6555 vs S2: $8654, P < .0001). PERSPECTIVE: This paper investigates prescription drug and medical care use with respect to stages of fibromyalgia diagnosis. Established fibromyalgia patients use more medical resources and have higher rates of concomitant medication use than newly diagnosed fibromyalgia patients. Findings can help educate providers regarding optimal drug treatment patterns in this population.

Encephale. 2009 Jun; 35(3): 226-33
Guillem E, Pelissolo A, Vorspan F, Bouchez-Arbabzadeh S, Lépine JP

CONTEXT: In the 1990s, cannabis consumption in France increased considerably. So, in 10 years, the number of adolescents reporting regular cannabis use (10 or more times during the last 12 months) tripled. In 2004, an official program to address problems related to cannabis addiction was implemented. As part of this program, specific outpatient settings for cannabis use disorders were created. OBJECTIVE: We present the sociodemographic characteristics, the prevalence of cannabis, alcohol and others psychoactive substances and the prevalence of mental disorders in 90 cannabis users seen at an outpatient specific setting for cannabis use disorders in the Lariboisière hospital (a university hospital in Paris). MEASURES: Twelve months prevalence of substance abuse and dependence, psychiatric diagnoses based on the DSM-IV and the Mini-International Neuropsychiatric Interview (MINI) results are described. RESULTS: The study population had the following characteristics: 67% male, mean age 27.5 (S.D.=8.4) years and 59% single or divorced. Approximately, two-thirds of the users (67%) were students or currently working and 32% were unemployed. Twenty-two percent of the cannabis users received unemployment, welfare or disability benefits and 11% declared no source of revenue. Most of the users (63%) decided on their own to seek care at the setting. Seventy-three percent of the subjects had seen a psychologist or a psychiatrist in the past, with or without relation to cannabis use. By far, most of the users were cannabis dependent (82%) and 9% cannabis abusers in the last 12 months according to DSM-IV criteria prior to their visit. Seven percent of the cannabis users had alcohol dependence and 7% were abusers. The 12 months prevalence of cocaine or ecstasy dependence was 2% and the prevalence of Benzodiazepines, heroin or stimulants dependence 1%. The main substances used over lifetime were tobacco (99%); alcohol (96%); cocaine (41%); Benzodiazepines and hypnotics (41%); ecstasy (40%) and heroin (23%). Four percent of cannabis users had a history of intravenous drug use. The main consumption mode of cannabis in France is the blunt. About three-quarters of the consumption is in the form of resin (hashish) and one-quarter as marijuana (grass). The average consumption of cannabis in the last six months was equivalent to 5.8 blunts per day (S.D.=4.4) and 12 g per week (S.D.=10.5), and the average monthly cost was 159 euro (S.D.=133) (234 USD, S.D.=196). The prevalence of psychiatric disorders according to DSM-IV criteria in the sample is high. A current mood disorder was present in 48% and an anxiety disorder in 55% of the cannabis users in the last 12 months. The prevalence of affective disorders in the last 12 months was major depressive disorder (38%), dysthymia (19%), hypomania (3%) and mania (1%). The prevalence of anxiety disorders in the last 12 months was social phobia (29%); generalised anxiety disorder (17%); panic disorder with or without agoraphobia (16%); obsessive compulsive disorder (12%); agoraphobia without panic disorder (9%) and post-traumatic stress disorder (5%). The prevalence of schizophrenia was 4%. The prevalence of bulimia was 4% and no anorexia. Women are more likely to report an affective disorder (64% versus 41%; p=0.04) or a post-traumatic stress disorder (17% versus 0%; p<0.001) in the last 12 months. The prevalence of family history for psychiatric disorders was 52% and for addiction, 59%. CONCLUSIONS: The cannabis users seen in our specific setting are a fairly homogeneous group and for the most part addicted to cannabis only, but with very high rates of dependence. Indeed, other than tobacco dependence, 80% of the users were only dependent on, or abused on cannabis in the last 12 months. In comparison with the cohort of French cannabis users (n=4202) seen at specific outpatient settings for marijuana users in 2005, cannabis users seen in Lariboisière Hospital are older, the percentage of females is greater, they are more dependent on marijuana and have a high prevalence of affective and anxiety disorders.

BMJ. 2009; 338: b2225
McCowan C, Kidd B, Fahey T

OBJECTIVE: To assess predictors of mortality in a population of people prescribed methadone. DESIGN: Retrospective cohort study. SETTING: Geographically defined population in Tayside, Scotland. PARTICIPANTS: 2378 people prescribed and dispensed liquid methadone between January 1993 and February 2004. MAIN OUTCOME MEASURES: All cause mortality (primary outcome) and drug dependent cause specific mortality (secondary outcome) by means of Cox proportional hazards models during 12 years of follow-up. RESULTS: Overall, 181 (8%) people died. Overuse of methadone (adjusted hazard ratio 1.67, 95% confidence interval 1.05 to 2.67), history of psychiatric admission (2.47, 1.67 to 3.66), and increasing comorbidity measured as Charlson index >or=3 (1.20, 1.15 to 1.26) were all associated with an increase in all cause mortality. Longer duration of use (adjusted hazard ratio 0.95, 0.94 to 0.96), history of having urine tested (0.33, 0.22 to 0.49), and increasing time since last filled prescription were protective in relation to all cause mortality. Drug dependence was identified as the principal cause of death in 60 (33%) people. History of psychiatric admission was significantly associated with drug dependent death (adjusted hazard ratio 2.41, 1.25 to 4.64), as was history of prescription of Benzodiazepines (4.35, 1.32 to 14.30). CONCLUSIONS: Important elements of care in provision of methadone maintenance treatment are likely to influence, or be a marker for, a person's risk of death.

Przegl Epidemiol. 2009; 63(1): 125-9
Syweńki E, Lipińska-Gediga M

The adverse effects on fetal development of alcohol and other drugs such as tobacco, psychostimulants and opioids are well known. Women who are pregnant or who may become pregnant are therefore a high priority for interventions to reduce drug use. Substances discussed in this article include the licit substances (alcohol and tobacco), illicit substances (opioids and other drugs), and prescription medication known for its misuse (Benzodiazepines and barbiturates). Other topics covered include breastfeeding, vertical transmission of blood-borne viruses, psychosocial issues, the management of neonatal abstinence syndrome and early childhood development.

Chem Biol. 2009 May 29; 16(5): 473-8
Phelan VV, Du Y, McLean JA, Bachmann BO

We present here a rapid, highly sensitive nonradioactive assay for adenylation enzyme selectivity determination and characterization. This method measures the isotopic back exchange of unlabeled pyrophosphate into gamma-(18)O(4)-labeled ATP via matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MS), electrospray ionization liquid chromatography MS, or electrospray ionization liquid chromatography-tandem MS and is demonstrated for both nonribosomal (TycA, ValA) and ribosomal synthetases (TrpRS, LysRS) of known specificity. This low-volume (6 microl) method detects as little as 0.01% (600 fmol) exchange, comparable in sensitivity to previously reported radioactive assays and readily adaptable to kinetics measurements and high throughput analysis of a wide spectrum of synthetases. Finally, a previously uncharacterized A-T didomain from anthramycin biosynthesis in the thermophile S. refuinius was demonstrated to selectively activate 4-methyl-3-hydroxyanthranilic acid at 47 degrees C, providing biochemical evidence for a new aromatic beta-amino acid activating adenylation domain and the first functional analysis of the anthramycin biosynthetic gene cluster.

J Psychiatr Pract. 2009 May; 15(3): 227-34
Fareed A, Casarella J, Amar R, Vayalapalli S, Drexler K

BACKGROUND: Methadone maintenance treatment reduces rates of premature mortality in heroin addicts. However, few published studies have addressed the effectiveness of treatment, mortality rates, or causes of death in older (geriatric) patients maintained on methadone. Identifying risk factors for premature mortality and potential targets for early intervention may reduce rates of premature mortality in older patients maintained on methadone. METHODS: We conducted a retrospective chart review for patients enrolled in the methadone maintenance program at the Atlanta Veterans Affairs Medical Center. We reviewed the charts of 91 patients and collected the following information: demographics (age, gender, marital status, and race); composite score at admission on the Addiction Severity Index (ASI); most recent ASI score for alcohol use, drug use, and medical, psychiatric, family, legal, and employment problems; results of urine drug screens for opiates, cocaine, and Benzodiazepines (first 4 screens after admission and last 4 screens); dose and duration of methadone treatment; HIV and hepatitis B and C status; tobacco smoking; presence of diabetes mellitus, hypertension, heart disease, chronic obstructive pulmonary disease, or cancer; history of intravenous drug use; and missed primary care appointments (last five appointments). RESULTS: A statistically significant association was found between diabetes mellitus and between liver and gastrointestinal cancer and premature mortality in this sample of older patients maintained on methadone (OR=30.79, p=0.008 for diabetes mellitus; OR=19.91, p=0.017 for cancer). Patients who remained in treatment showed statistically significant improvement in ASI scores for problems related to drug use and for psychiatric, medical, and legal problems. They showed a nonsignificant trend toward reduction of problems associated with alcohol use. The group of patients who dropped out of methadone treatment did not show statistically significant improvement on any area of the ASI except family problems. The group who remained in treatment also showed a statistically significant reduction in drug use when results of the first four and last four urine drug screens for opiates, cocaine, and Benzodiazepines were compared (p<0.0001 for opiates and cocaine, p=0.02 for Benzodiazepines).On the other hand, the group who dropped out of methadone treatment did not show any statistically significant reduction in drug use based on urine screens (p=0.05 for opiates, p=0.38 for cocaine, and p=0.53 for Benzodiazepines). CONCLUSIONS: The results presented here suggest potential targets for intervention related to lifestyle risk factors and comorbid medical conditions, such as nicotine dependence and diabetes mellitus, that may have the potential to improve health outcomes for older patients with opioid dependence.

Drug Saf. 2009; 32(6): 499-507
Kasliwal R, Wilton LV, Shakir SA

BACKGROUND:Varenicline tartrate (Champix), a new smoking cessation medicine, was launched in the UK in December 2006. Varenicline is a highly selective partial agonist of the alpha(4)beta(2) nicotinic acetylcholine receptor (alpha(4)beta(2) receptor). The partial agonistic binding leads to alleviation of symptoms of craving and withdrawal, and simultaneously prevents nicotine from binding to the alpha(4)beta(2) receptor thereby causing reduction in the rewarding and reinforcing effects of smoking. Regulatory concerns have arisen about psychiatric events associated with varenicline, including depression, suicidal ideation and changes in behaviour/emotion. AIM: To present the interim results of an ongoing study by the Drug Safety Research Unit (DSRU) monitoring the safety of varenicline. METHODS: The observational cohort study is being conducted to study the postmarketing safety of varenicline, using modified prescription-event monitoring (PEM) methodology. Patients are identified from dispensed prescriptions issued by general practitioners (GPs) from December 2006. Demographic, clinical event (during the course and 1 month after stopping varenicline, reasons for discontinuing and suspected adverse drug reactions [ADRs] to varenicline) and drug utilization data are collected from detailed study-specific questionnaires posted to GPs at least 4 months after the date of first prescription for each patient. Event incidence densities (IDs; number of first reports of an event/1000 patient-months of exposure) are calculated. RESULTS: The interim cohort comprises 2,682 patients: median age 47 years (interquartile range [IQR] 38-56), 60.7% females (n = 1627). Nausea/vomiting was the most frequent clinical reason for stopping varenicline (n = 91; 35.3% of clinical reasons) and the most frequently reported suspected ADR to varenicline (n = 60, 50.9% of patients for whom an ADR was reported). The most frequently reported psychiatric events (causality not implied) during treatment included (n; % of cohort): sleep disorder (43; 1.6%), anxiety (33; 1.2%), depression (29; 1.1%), abnormal dreams (26; 1.0%) and mood change (17; 0.6%). Two cases of attempted suicide were reported during treatment with varenicline (one patient took an overdose of a Benzodiazepine with alcohol, the other slashed their wrist). Both these patients had previous history of psychiatric illness and precipitating factors for the event. CONCLUSION: This study reflects 'real life' use of varenicline. Nausea/vomiting - the event most frequently reported as an ADR and as reason for stopping treatment - is listed in the UK Summary of Product Characteristics (SPC). The most frequently reported psychiatric events are listed in the UK SPC. All patients with suicidal events either had a past medical history of psychiatric illness prior to starting varenicline and/or a precipitating factor for the event. Clinicians should closely monitor patients with pre-existing psychiatric illness who are taking varenicline. Further evaluation of events of interest including psychiatric events is ongoing. Results presented are expected to change as the cohort size increases. Results of this study should be taken into account together with other clinical and pharmacoepidemiological studies.

Epilepsia. 2009 Nov; 50(11): 2369-76
Thibert RL, Conant KD, Braun EK, Bruno P, Said RR, Nespeca MP, Thiele EA

PURPOSE: Angelman syndrome (AS) commonly presents with epilepsy (>80%). The goal of this study was to examine the natural history and various treatments of epilepsy in AS in a large population. METHODS: A detailed electronic survey containing comprehensive questions regarding epilepsy in AS was conducted through the Angelman Syndrome Foundation. RESULTS: There were responses from 461 family members of individuals with AS, of whom 86% had epilepsy (60% with multiple seizure types), the most common being atonic, generalized tonic-clonic, absence, and complex partial. Partial-onset seizures only were reported in 11% of those with epilepsy. Epilepsy was most common among those with maternal deletions and unknown subtypes, with catastrophic epilepsies present in only these two subtypes. These epilepsies were refractory to medication, with only 15% responding to the first antiepileptic drug (AED). The most commonly prescribed AED were valproic acid and clonazepam, but lamotrigine and levetiracetam appeared to have similar efficacy and tolerability. DISCUSSION: This is the largest study to date assessing epilepsy in AS. Although epilepsy in AS is considered a generalized epilepsy, there was a high prevalence of partial seizures. There are few previous data regarding the use of newer AED in AS, and the results of this study suggest that these newer agents, specifically levetiracetam and lamotrigine, may have efficacy similar to that of valproic acid and clonazepam, and that they appear to have similar or better side-effect profiles. Nonpharmacologic therapies such as dietary therapy and vagus nerve stimulation (VNS) also suggest favorable efficacy and tolerability, although further studies are needed.