Kegg Pathway: Benzodiazepine family

Acc Chem Res. 2008 Jul 11;
Lewis JC, Bergman RG, Ellman JA

Nitrogen heterocycles are present in many compounds of enormous practical importance, ranging from pharmaceutical agents and biological probes to electroactive materials. Direct functionalization of nitrogen heterocycles through C-H bond activation constitutes a powerful means of regioselectively introducing a variety of substituents with diverse functional groups onto the heterocycle scaffold. Working together, our two groups have developed a family of Rh-catalyzed heterocycle alkylation and arylation reactions that are notable for their high level of functional-group compatibility. This Account describes our work in this area, emphasizing the relevant mechanistic insights that enabled synthetic advances and distinguished the resulting transformations from other methods. We initially discovered an intramolecular Rh-catalyzed C-2 alkylation of azoles by alkenyl groups. That reaction provided access to a number of di-, tri-, and tetracyclic azole derivatives. We then developed conditions that exploited microwave heating to expedite these reactions. While investigating the mechanism of this transformation, we discovered that a novel substrate-derived Rh- N-heterocyclic carbene (NHC) complex was involved as an intermediate. We then synthesized analogous Rh-NHC complexes directly by treating precursors to the intermediate [RhCl(PCy 3) 2] with N-methylbenzimidazole, 3-methyl-3,4-dihydroquinazoline, and 1-methyl-1,4-Benzodiazepine-2-one. Extensive kinetic analysis and DFT calculations supported a mechanism for carbene formation in which the catalytically active RhCl(PCy 3) 2 fragment coordinates to the heterocycle before intramolecular activation of the C-H bond occurs. The resulting Rh-H intermediate ultimately tautomerizes to the observed carbene complex. With this mechanistic information and the discovery that acid cocatalysts accelerate the alkylation, we developed conditions that efficiently and intermolecularly alkylate a variety of heterocycles, including azoles, azolines, dihydroquinazolines, pyridines, and quinolines, with a wide range of functionalized olefins. We demonstrated the utility of this methodology in the synthesis of natural products, drug candidates, and other biologically active molecules. In addition, we developed conditions to directly arylate these heterocycles with aryl halides. Our initial conditions that used PCy 3 as a ligand were successful only for aryl iodides. However, efforts designed to avoid catalyst decomposition led to the development of ligands based on 9-phosphabicyclo[4.2.1]nonane (phoban) that also facilitated the coupling of aryl bromides. We then replicated the unique coordination environment, stability, and catalytic activity of this complex using the much simpler tetrahydrophosphepine ligands and developed conditions that coupled aryl bromides bearing diverse functional groups without the use of a glovebox or purified reagents. With further mechanistic inquiry, we anticipate that researchers will better understand the details of the aforementioned Rh-catalyzed C-H bond functionalization reactions, resulting in the design of more efficient and robust catalysts, expanded substrate scope, and new transformations.

Osteoporos Int. 2008 Jul 3;
Pinheiro MM, Ciconelli RM, Martini LA, Ferraz MB

The Brazilian Osteoporosis Study (BRAZOS) is the first epidemiological study carried out in a representative sample of Brazilian men and women aged 40 years or older. The prevalence of fragility fractures is about 15.1% in the women and 12.8% in the men. Moreover, advanced age, sedentarism, family history of hip fracture, current smoking, recurrent falls, diabetes mellitus and poor quality of life are the main clinical risk factors associated with fragility fractures. INTRODUCTION: The Brazilian Osteoporosis Study (BRAZOS) is the first epidemiological study carried out in a representative sample of Brazilian men and women aged 40 years or older with the purpose of identifying the prevalence and the main clinical risk factors (CRF) associated with osteoporotic fracture in our population. METHODS: A total of 2,420 individuals (women, 70%) from 150 different cities in the five geographic regions in Brazil, and all different socio-economical classes were selected to participate in the present survey. Anthropometrical data as well as life habits, fracture history, food intake, physical activity, falls and quality of life were determined by individual quantitative interviews. The representative sampling was based on Brazilian National data provided by the 2000 and 2003 census. Low trauma fracture was defined as that resulting of a fall from standing height or less in individuals 50 years or older at specific skeletal sites: forearm, femur, ribs, vertebra and humerus. Sampling error was 2.2% with 95% confidence intervals. Logistic regression analysis models were designed having the fragility fracture as the dependent variable and all other parameters as the independent variable. Significance level was set as p < 0.05. RESULTS: The average of age, height and weight for men and women were 58.4 +/- 12.8 and 60.1 +/- 13.7 years, 1.67 +/- 0.08 and 1.56 +/- 0.07 m and 73.3 +/- 14.7 and 64.7 +/- 13.7 kg, respectively. About 15.1% of the women and 12.8% of the men reported fragility fractures. In the women, the main CRF associated with fractures were advanced age (OR = 1.6; 95% CI 1.06-2.4), family history of hip fracture (OR = 1.7; 95% CI 1.1-2.8), early menopause (OR = 1.7; 95% CI 1.02-2.9), sedentary lifestyle (OR = 1.6; 95% CI 1.02-2.7), poor quality of life (OR = 1.9; 95% CI 1.2-2.9), higher intake of phosphorus (OR = 1.9; 95% CI 1.2-2.9), diabetes mellitus (OR = 2.8; 95% CI 1.01-8.2), use of Benzodiazepine drugs (OR = 2.0; 95% CI 1.1-3.6) and recurrent falls (OR = 2.4; 95% CI 1.2-5.0). In the men, the main CRF were poor quality of life (OR = 3.2; 95% CI 1.7-6.1), current smoking (OR = 3.5; 95% CI 1.28-9.77), diabetes mellitus (OR = 4.2; 95% CI 1.27-13.7) and sedentary lifestyle (OR = 6.3; 95% CI 1.1-36.1). CONCLUSION: Our findings suggest that CRF may contribute as an important tool to identify men and women with higher risk of osteoporotic fractures and that interventions aiming at specific risk factors (quit smoking, regular physical activity, prevention of falls) may help to manage patients to reduce their risk of fracture.

Scand J Prim Health Care. 2008 Jun; 26(2): 80-5
Brekke M, Rognstad S, Straand J, Furu K, Gjelstad S, Bjørner T, Dalen I

OBJECTIVE: To assess Norwegian general practitioners' (GPs') level of potentially harmful drug prescribing for elderly patients. DESIGN: Prescription data for 12 months were retrospectively retrieved from the Norwegian Prescription Database (NorPD). Data were assessed in relation to 13 prescription quality indicators. SETTING: General practice. SUBJECTS: A total of 454 GPs attending continuous medical education (CME) groups in Southern Norway, 85,836 patients >or=70 years who received any prescription from the GPs during the study period. MAIN OUTCOME MEASURES: Number of prescriptions assessed in relation to pharmacological inappropriateness based on a list of 13 explicit prescription quality indicators. RESULTS: Some 18.4% of the patients (66% females with mean age 79.8 years, 34% males with mean age 78.7 years) received one or more inappropriate prescriptions from their GP. An NSAID in a potentially harmful combination with another drug (7%) and a long-acting Benzodiazepine (4.6%) were the most frequent inappropriate prescriptions made. Doctor characteristics associated with more inappropriate prescribing practice were old age and working single-handed with many elderly patients. CONCLUSION: The study reveals areas where GPs' prescribing practice for elderly patients can be improved and which can be targeted in educational interventions.

Scand J Prim Health Care. 2008 Jun; 26(2): 74-9
Gorgels W, Oude Voshaar R, Mol A, Van De Lisdonk E, Mulder J, Van Den Hoogen H, Van Balkom A, Breteler M, Zitman F

OBJECTIVE: The efficacy of programmes to reduce long-term Benzodiazepine use could be compromised by subsequent increases in contacts with the family practice. In this study the hypothesis was tested as to whether participation in a Benzodiazepine discontinuation programme affects the frequency of contacts with the family practice. DESIGN: A controlled stepped-care intervention programme to decrease long-term Benzodiazepine use. SETTING: family practices in the Netherlands. Subjects. The experimental group consisted of 996 long-term Benzodiazepine users and a control group of 883 long-term Benzodiazepine users. MAIN OUTCOME MEASURES: Practice contacts before and up to 12 months after the start of the programme. RESULTS: There was a general tendency visible for contacts to decrease during the follow-up time. The course of the number of contacts during the follow-up was not different for the experimental and control groups (p=0.45). The level of non-Benzodiazepine prescriptions was generally not altered. The number of non-Benzodiazepine prescriptions decreased in Benzodiazepine quitters during the follow-up of the programme. CONCLUSION: No clinically important differences in practice contacts were observed when the course of the number of contacts and non-Benzodiazepine prescriptions were compared between the experimental and control groups. family practitioners do not have to anticipate an increased workload associated with participation in such a Benzodiazepine discontinuation programme.

J Opioid Manag. 2008 Mar-Apr; 4(2): 63-71
Havens JR, Walker R, Leukefeld CG

OBJECTIVE: The purpose of this study is to describe the sample characteristics and methods for a study of rural medical and nonmedical prescription opioid users with a history of OxyContin use. DESIGN AND SETTING: Snowball sampling was used to recruit 221 rural Appalachian residents. Participants included those under medical supervision for pain (n = 101) as well as those self-reporting nonmedical use of prescription opioids (n = 120). Participants were given an intervieuwer-administered questionnaire. OUTCOME MEASURES: Data relating to demographics, illicit and nonmedical prescription drug use, medical, legal, family, and psychiatric status, as well as pain history were collected. The primary outcomes of interest were differences in past 30 day prescription drug use between pain patients and nonmedical opioid users. RESULTS: A significantly greater proportion of those treated for pain reported using oxycodone and hydrocodone prescribed by a physician in the prior 30 days (p < 0.001); however, more than third of pain participants also reported nonmedical use of OxyContin, methadone, hydrocodone, Benzodiazepines, and marijuana in the prior 30 days. CONCLUSIONS: A large proportion of rural opioid users who reported being treated for pain also reported nonmedical use ofprescription drugs. Similarly, among the nonmedical users, half of those reported experiencing pain that interfered with their daily life. These results suggest that many rural prescription drug users are being either incorrectly or perhaps inadequately treated for chronic nonmalignant pain. Therefore, developing educational materials and training for rural physicians about pain treatment (including drug seeking behavior) is proposed.

MMW Fortschr Med. 2008 Apr 10; 150 Suppl 1: 27-30
Markus L

Chem Res Toxicol. 2008 May 31;
Hu WP, Tsai FY, Yu HS, Sung PJ, Chang LS, Wang JJ

DC-81, an antitumor antibiotic produced by Streptomyces species, belongs to the pyrrolo[2,1- c][1,4]Benzodiazepine (PBD) family, which are potent inhibitors of nucleic acid synthesis. We previously reported an efficient synthesis of PBD hybrids linked with indole carboxylates. Recently, we have also shown that a PBD hybrid (IN6CPBD) agent can activate the apoptotic pathway mediated by mitochondria. In this study, we will examine the transcription factors nuclear factor-kappaB (NF-kappaB) and activator protein-1 (AP-1) that functionally regulate cell proliferation, transformation, and apoptosis. To investigate the IN6CPBD-induced alterations in NF-kappaB and AP-1 activity that involve cell cycle regulation, we exposed human melanoma A375 cells to different concentrations of IN6CPBD. Our data revealed that treatment of A375 cells with IN6CPBD resulted in a marked loss of cells from the G2/M phase of the cell cycle and an increase in Ca (2+) and cAMP and promoted phosphorylation of Jun N-terminal kinase (JNK) expression. By using the luciferase reporter assay, the NF-kappaB activities were decreased; however, AP-1 activity was further enhanced after A375 cells were treated with graded concentrations of IN6CPBD. Blockade of NF-kappaB or JNK activity further enhanced caspase-3 substrate PARP cleavage and subsequent apoptotic cell death.

BMC Complement Altern Med. 2008; 8: 15
Nirmal J, Babu CS, Harisudhan T, Ramanathan M

BACKGROUND: Various human diseases have oxidative stress as one of their component. Many herbs have been reported to exhibit properties that combat oxidative stress through their active constituents such as flavonoids, tannins, phenolic compounds etc. Cytisus scoparius (CS) Link, (family: Leguminosae), also called Sarothamnus scoparius, has been shown in invitro experiments to be endowed with anti-diabetic, hypnotic and sedative and antioxidant activity. Therefore this study was carried out to evaluate CS for its anxiolytic, antidepressant and anti-oxidant activity in stressed rats. METHODS: 60% methanolic extract of CS was quantified for phenolic content by Folin-Ciocalteau's method. Chronic unpredictable mild stress (CMS) was employed to induce stress in rats. CS (125 and 250 mg/kg, p.o) and diazepam (DZM) (2 mg/kg, p.o) was administered during the 21 day stress exposure period. Anxiolytic and antidepressant activities of CS were assessed in open field exploratory and behavioural despair paradigms, respectively. Plasma glucose and total lipids; endogenous antioxidant enzymes such as superoxide dismutase (SOD), catalase (CAT); non-enzymic-ascorbic acid and thiobarbituric acid reactive substances (TBARS) levels were measured in brain, kidneys and adrenals using standard protocols to assess the effect of CS. RESULTS: Total phenolic content of CS was found to be 8.54 +/- 0.16% w/w. CMS produced anxiogenic and depressive behaviour in experimental rats with metabolic disturbance. Significant decrease in SOD, CAT levels and increase in lipid peroxidation level was observed in stressed rats. CS administration for 21 days during stress exposure significantly increased the ambulatory behaviour and decreased the freezing time in open field behaviour. In behavioural despair test no significant alteration in the immobility period was observed. CS also improved SOD, CAT, and ascorbic acid level and controlled the lipid peroxidation in different tissues. CONCLUSION: CS possesses anti-stress and moderate anxiolytic activity which may be due, in part, to its antioxidant effect that might warrant further studies.

Psychiatr Pol. 2007 Sep-Oct; 41(5): 679-91
Krzyzkowiak W

Depression after myocardial infarction has influence on patients quality of life, compliance and probably cardiological prognosis. The recognition of factors connected with post infarct depressive symptoms has a significant role for rehabilitation in coronary heart disease. AIM: The aim of the study was: 1) the assessment of depressive symptoms intensity after myocardial infarction (MI), 2) to estimate correlations between post infarct depressive symptoms intensity and present examination of cardiovascular system, past history of depression and coronary heart disease, some psychosocial factors and life events during the one year period before coronary infarct. METHOD: A structured interview--Mini International Neuropsychiatric Interview, Beck Depression Inventory, Social Readjustment Rating Scale and Recent Life Changes Scale were used in the analysis of 102 in-patients after myocardial infarction. RESULTS: Significant correlations between higher depression symptoms intensity after MI and: stressful life events before MI, unemployment, lower education level, history of treated coronary artery disease, depression in the last 6 months before MI, high BMI and Benzodiazepine use in the last year were stated. The most often depressive symptoms were not very specific for depressive syndrome. CONCLUSIONS: Clinical (major) depression was diagnosed in 10.8% of the patients after heart infarct. However depressive symptoms (more than 10 Beck points) were present in 40%. The diagnosis of post-myocardial depression may be essentially difficult because of the non-specific character of complains. Significant correlations between intensity of depressive symptoms after myocardial infarct and psychosocial stressors was confirmed. It seems that the most important stressors are those connected with home and family.

Crisis. 2008; 29(1): 32-7
Zakiullah N, Saleem S, Sadiq S, Sani N, Shahpurwala M, Shamim A, Yousuf A, Khan MM, Nayani P

INTRODUCTION: Previous deliberate self-harm (DSH) is the strongest predictor of suicide. Although several studies exist in other countries, characteristics of DSH have not been well-studied in Pakistan. AIMS: To identify characteristics of deliberate self-harm in a hospital population, building on previous work carried out on this subject at this center. METHODS: 284 cases admitted to the Aga Khan University Hospital, Karachi, between January 1997 and August 2003 were studied by analyzing medical records. Information was collected regarding demographics, family history, personal history, suicidal ideation, current stressors, the act of DSH and its management. RESULTS: The most common age group was 21-25 years of age. The majority were females (60.3%). 95.1% of patients used self-poisoning as a method of deliberate self-harm. 47.3% used Benzodiazepines for self-poisoning. Precipitating factors included conflict with family, marital problems, chronic illnesses, and unemployment. Comorbid psychiatric disorders were present in 76.4% patients. DISCUSSION: Despite the difference in socio-cultural background of our patients, many of our results were found to be consistent with Western data. Our findings suggest that problem-solving therapy, stress management and improved mental health care may be effective interventions in preventing DSH. Prescription of medications should be regulated. Further studies are suggested at the community level.

JAMA. 2008 Mar 26; 299(12): 1457-67
Moryl N, Coyle N, Foley KM

The assessment and management of an acute pain crisis in the setting of advanced illness is challenging. Using the case of Mr X, a 33-year-old man with advanced metastatic mucinous adenocarcinoma of the appendix and "15 out of 10" pain, we explore the issues of acute pain and its management. We define a pain crisis as an event in which the patient reports pain that is severe, uncontrolled, and causing distress for the patient, family members, or both. Our management strategy focuses on making a pain diagnosis, differentiating reversible from intractable causes of pain, and making decisions about further workup; selecting the opioid and monitoring and treating opioid adverse effects; titrating and rotating opioid and coanalgesics; consulting experts to treat a pain crisis as quickly as possible to prevent unnecessary suffering; and co-opting the available institutional resources. The timely intervention of a palliative care team and its expertise can provide the staff, patients, and their families the benefit of an interdisciplinary approach and help the patients address goals of care; understand the benefits and risks of treatment decisions; and meet the psychological, social, and existential needs of the patient and the family commonly seen in this setting.

J Drug Educ. 2007; 37(4): 417-28
Peters RJ, Meshack AF, Kelder SH, Webb P, Smith D, Garner K

While the epidemiologic trends concerning alprazolam (Xanax) are unknown, the use of Benzodiazepines, in general, has increased in popularity among youth within recent years. To shed light on the drug problem, the current pilot study used a qualitative approach to investigate relevant beliefs, norms, and perceived addiction associated with alprazolam initiation among 46 youth who were attending an inpatient drug treatment program during the spring of 2004. Overwhelmingly, most participants stated that addiction to alprazolam occurs as early as initial consumption. Most youth in the study stated that their friends felt it was normal to use alprazolam. In addition, their control beliefs revealed that if someone wanted to stop it would be difficult because of the widespread use in their communities and family social reinforcement involved with its use. In this study, a majority of students stated that medical professionals such as doctors and pharmacists were the greatest facilitator of alprazolam acquisition. Implications for these results are discussed.

J Pharmacol Sci. 2008 Mar; 106(3): 361-8
Hirao A, Imai A, Sugie Y, Yamada Y, Hayashi S, Toide K

Nociceptin/orphanin FQ peptide (NOP)-receptor agonists have been shown to produce anxiolytic-like effects in rodents subjected to various behavioral assays. Recently, we developed a new nonpeptide agonist of the NOP receptor, 1-[1-(1-methylcyclooctyl)-4-piperidinyl]-2-[(3R)-3-piperidinyl]-1H-benzimidazole (MCOPPB), as an anxiolytic agent. MCOPPB has a high affinity for the human NOP receptor (pKi = 10.07 +/- 0.01) and selectivity for the NOP receptor over other members of the opioid receptor family: 12-, 270- and >1000-fold more selective for the NOP receptor than for the micro-, kappa-, and delta-receptor, respectively. In an ex vivo binding study, MCOPPB (10 mg/kg, p.o.) inhibited signaling through the NOP receptor in the mouse brain, suggesting that it penetrated into the brain after it was orally administered. In the mouse Vogel conflict test, MCOPPB (10 mg/kg, p.o.) and diazepam (3 mg/kg, p.o.) elicited anxiolytic-like effects, although MCOPPB produced a bell-shaped response curve. In addition, MCOPPB (10 mg/kg, p.o.) was still effective as an anxiolytic agent even after repeated administration for 5 days. MCOPPB at an oral dose of 10 mg/kg did not affect locomotor activity or memory, nor did it contribute to ethanol-induced hypnosis. On the other hand, the Benzodiazepine-type anxiolytic agent diazepam caused memory deficits and enhanced ethanol-induced hypnosis. These findings suggest that MCOPPB - a compound with few adverse effects on the central nervous system - is a potential therapeutic agent for the treatment of anxiety.

Mayo Clin Proc. 2008 Mar; 83(3): 274-9
Hecksel KA, Bostwick JM, Jaeger TM, Cha SS

OBJECTIVE: To determine if hospitalized medical and surgical patients were placed inappropriately on symptom-triggered therapy (STT) for alcohol withdrawal syndrome (AWS) and if certain conditions were more likely to be associated with inappropriate STT use or adverse events. PATIENTS AND METHODS: We randomly selected 124 (25%) of the 495 Mayo Clinic inpatients who received STT according to the Revised Clinical Institute for Withdrawal Assessment for Alcohol (CIWA-Ar) protocol in 2003 and assessed them for STT appropriateness, defined as having both intact verbal communication and recent alcohol use. Adverse events, including delirium tremens, seizures, or death, were correlated with CIWA-Ar appropriateness. RESULTS: Of the 124 randomly selected patients, only 60 (48%) met both inclusion criteria. Of the remaining 64 patients, 9 (14%) were drinkers but could not communicate, and 35 (55%) could communicate but had not been drinking. Twenty (31%) met neither criterion. Univariate analysis identified a significant association between inappropriate initiation and chronic heart failure, postoperative status (POS), liver disease (LD), nonmetastatic cancer, and chemical dependency consultation. On multivariate analysis, only LD (P equals .02) and POS (P equals .01) retained significance, with LD more and POS less likely to predict appropriateness. Seven of 11 patients who experienced adverse events had received STT according to the CIWA-Ar protocol (P equals .05). Univariate analysis identified a significant association between adverse events and a history of alcohol dependence or AWS. Multivariate analysis showed significance only for a history of alcohol dependence (P equals .049). CONCLUSION: Fewer than half of the randomly selected patients met both of the inclusion criteria for the CIWA-Ar instrument, leading us to conclude that more stringent evaluation is needed. Particularly postoperatively, alternative explanations for putative AWS should be sought. Health care professionals should more aggressively seek information on recent alcohol use from medical records, family members, and patients themselves.

Aust N Z J Psychiatry. 2008 Mar; 42(3): 251-3
Chung A, Varghese J

OBJECTIVE: To report the case of an 11-year-old girl who presented with acute onset of psychotic symptoms with catatonic features treated with electroconvulsive therapy (ECT). METHOD: Described herein is the case of an 11-year-old, prepubertal girl who represented with catatonic symptoms unresponsive to conventional medical treatment. After thorough clinical investigation and obtaining a second opinion we gained consent from her parents to perform ECT as a life saving procedure. RESULTS: Six ECT treatments were administered with clinical improvement, the patient did develop hypomanic symptoms as a side-affect of ECT. CONCLUSION: The patient exhibited potentially life-threatening self-harming behaviour secondary to catatonic and psychotic symptoms. Her behaviour and symptoms responded to ECT. The patient developed hypomania that responded to mood stabilization. ECT was a safe and effective treatment for catatonia in this prepubescent girl.

Eur J Med Res. 2008 Jan 23; 13(1): 15-20
Zullino DF, Krenz S, Eap CB, Benguettat D, Khan R

Underreporting of drug use is commonly found more often than overreporting. Overreporting may, however, occur in particular settings, e.g. in subjects entering a detoxification program. METHODS: Self-reports (standardized semi structured interview) of recent drug use of 554 patients consecutively admitted to a drug detoxification inpatient unit were compared to urine screening results at admission. Overreporters were defined as indicating a consumption of a specific drug during the preceding 7 days (3 days for cocaine) which was not confirmed by the urine screening. Underreproters denied consumption but presented positive urine. RESULTS: Overreporting was especially prevalent for opiates, and relatively more frequent (59.9% heroin, 40% methadone) than underreporting (6.8% heroin, 20.4% methadone). Signs of intoxication at admission, current methadone substitution, and previous institutional detoxification experiences influenced opiate overreporting. CONCLUSIONS: Some of the retained parameters predicting overreporting of recent opiate consumption corroborated the hypothesis of patients trying to receive more consideration from the therapeutic team and to get more intensive pharmacological care.

Tidsskr Nor Laegeforen. 2008 Jan 17; 128(2): 166-70
Bachmann CS, Berg EA, Spigset O, Slørdal L

BACKGROUND: The large increase in sales of the Benzodiazepine-like hypnotics (z-hypnotics) zopiclone and zolpidem over the last decade prompted an investigation into Norwegian general practitioners' prescription habits, knowledge of and attitudes to these drugs. MATERIAL AND METHODS: A questionnaire was distributed to all 928 registered GPs in six Norwegian counties. The physicians were asked to assess statements, patient vignettes and drug preferences with regard to z-hypnotic and Benzodiazepine prescription practice. The responders were anonymized and grouped with respect to gender, county, years of professional experience, knowledge and attitudes.RESULTS: A total of 321 (36%) of the GPs responded. Among the respondents, physicians with adequate knowledge about clinical use of and restrictive prescription attitudes towards z-hypnotics and Benzodiazepines prescribed these drugs with a lower frequency. Prescription rates did not vary as a function of sex, geographical localization, work experience or knowledge about drug pharmacodynamics. A total of 56% of the respondents preferred zopiclone to zolpidem, whereas 8% preferred zolpidem. Many of the factors, which were used to justify the preferences, were irrelevant or erroneous. INTERPRETATION: The study revealed a lack of factual knowledge about these drugs, and may suggest that a rational prescription practice is restrictive.

Aust N Z J Psychiatry. 2008 Feb; 42(2): 166-9
Lucas-Ramadan T, Baxi S, Velamoor R

OBJECTIVE: A link between cancer and limbic encephalitis (LE) has been proposed. The aim of this case presentation is to further explore this association by literature review, inform clinicians of the investigations necessary to arrive at a diagnosis and to emphasize the clinical importance of liaison between psychiatry and other disciplines involved in management. METHOD: The case report of a 55 year old Niuean male school teacher with an acute onset of confusion and personality change is presented. The clinical data was obtained from various sources including the emergency room, medical ward, psychiatric ward as well as from discussions with other physicians involved in the management of this case. family members and friends were also contacted to obtain corroborative historical information. RESULTS: LE was diagnosed in this case based on clinical presentation with psychiatric symptoms, ruling out delirium due to infections, metabolic and other toxins as well as magnetic resonance imaging findings confirming temporal lobe changes. CONCLUSION: LE is a known paraneoplastic syndrome (PNS) that may precede the diagnosis of an underlying malignancy. Recent advances in laboratory technology now allow for antibodies to be identified in specific malignancies. This behooves the clinicians to maintain a high level of diagnostic suspicion so that timely interventions with oncology can follow.

Brain Res. 2008 Feb 8; 1193: 43-50
Stevenson CW, Marsden CA, Mason R

Maternal separation (MS) during the neonatal period enhances stress responsivity in adulthood. The medial prefrontal cortex (mPFC) and the basolateral amygdala (BLA) are involved in coordinating various stress responses. Evidence indicates that MS reduces Benzodiazepine and GABA(A) receptor expression in these regions, although their effects on neuronal function in the mPFC and the BLA remain unknown. The present study was conducted to assess the effects of MS on neuronal activity in the mPFC and BLA in response to the Benzodiazepine receptor partial inverse agonist N-methyl-beta-carboline-3-carboxamide (FG-7142). Rat pups were subjected to MS (360 min), brief handling (H; 15 min) or standard animal facility rearing (AFR) on postnatal days 2-14. In adult males, in vivo electrophysiology under isoflurane anesthesia was used to conduct acute recordings of extracellular unit activity in response to systemic FG-7142 administration. Animals subjected to H showed significantly increased basal mPFC activity compared to MS and AFR animals. There were no differences in basal BLA activity between the early rearing groups. In response to FG-7142, MS animals showed significantly attenuated mPFC activity compared to H animals and a nonsignificant trend towards attenuated mPFC activity compared to AFR animals. In contrast to mPFC, MS animals showed significantly potentiated FG-7142-induced activity in the BLA, compared to both H and AFR animals. These findings indicate that MS induces functionally relevant alterations in corticolimbic GABA(A) receptor signaling. Given that FG-7142 mimics several behavioral and physiological effects of stress, these results may also model stress-induced corticolimbic dysfunction caused by early life stress.

J Am Board Fam Med. 2008 Jan-Feb; 21(1): 70-4
Pastor CA, Mehta M

A 33-year-old Latin-American woman with a history of psychosis and mood disorder, but no cardiac history or risk factors, presented with heart failure after 6 weeks of clozapine and olanzapine therapy. Her presentation was ambiguous and further complicated by a highly suggestible nature, which delayed the proper diagnosis and treatment. After discontinuing the antipsychotic agents and completing an otherwise negative comprehensive work-up, her heart function significantly improved (left ventricular ejection fraction increased from 38% to 53%). A literature search showed that cardiomyopathy secondary to antipsychotics has been reported but remains poorly understood. This is the second documented case report of clozapine-induced cardiomyopathy in a Latin-American woman.