Systematic review of cholinergic drugs for neuroleptic-induced tardive dyskinesia: a meta-analysis of randomized controlled trials

The authors evaluated the efficacy of cholinergic drugs in the treatment of neuroleptic-induced tardive dyskinesia (TD) by a systematic review of the literature on the following agents: choline, lecithin, physostigmine, tacrine, 7-methoxyacridine, ipidacrine, galantamine, donepezil, rivastigmine, eptastigmine, metrifonate, arecoline, RS 86, xanomeline, cevimeline, deanol, and meclofenoxate. All relevant randomized controlled trials, without any language or year limitations, were obtained from the Cochrane Schizophrenia Group's Register of Trials. Trials were classified according to their methodological quality. For binary and continuous data, relative risks (RR) and weighted or standardized mean differences (SMD) were calculated, respectively. Eleven trials with a total of 261 randomized patients were included in the meta-analysis. Cholinergic drugs showed a minor trend for improvement of tardive dyskinesia symptoms, but results were not statistically significant (RR 0.84, 95% confidence interval (CI) 0.68 to 1.04, p=0.11). Despite an extensive search of the literature, eligible data for the meta-analysis were few and no results reached statistical significance. In conclusion, we found no evidence to support administration of the old cholinergic agents lecithin, deanol, and meclofenoxate to patients with tardive dyskinesia. In addition, two trials were found on novel cholinergic Alzheimer drugs in tardive dyskinesia, one of which was ongoing. Further investigation of the clinical effects of novel cholinergic agents in tardive dyskinesia is warranted. (C) 2004 Elsevier Inc. All rights reserved.

Developmental vitamin D deficiency alters adult behaviour: An informative animal model of schizophrenia

Background: There is growing evidence that vitamin D is active in the brain but until recently there was a lack of evidence about its role during brain development. Guided by certain features of the epidemiology of schizophrenia, we have explored the role of vitamin D in the developing brain and behaviour using whole animal models. Methods: Sprague-Dawley rats were fed a vitamin D deficient diet (DVD) or control diet 6 weeks prior to mating and housed under UVB-free lighting conditions. On the day of birth all rats were fed a control diet for the remainder of the study. We observed behaviour at two timepoints; on the day of birth to study maternal behaviour, and at 10 weeks of age to study offspring behaviour in adulthood, under baseline and drug induced conditions (MK-801, haloperidol, amphetamine). Results: Prenatal vitamin D deficiency results in subtle alterations in maternal behaviour as well as long lasting effects on the adult offspring, despite a return to normal vitamin D levels during postnatal life. These affects were specific to transient prenatal vitamin D depletion as adult vitamin D depletion, combined prenatal and chronic postnatal vitamin D depletion, or ablation of the vitamin D receptor in mice led to markedly different outcomes. Conclusions: The developmental vitamin D (DVD) model now draws strength from epidemiological evidence of schizophrenia and animal experiments. Although the DVD model does not replicate every aspect of schizophrenia, it has several attractive features: (1) the exposure is based on clues from epidemiology; (2) it reproduces the increase in lateral ventricles; (3) it reproduces well-regarded behavioural phenotypes associated with schizophrenia (e.g. MK- 801 induced hyperlocomotion); and (4) it implicates a disturbance in dopamine signaling. In summary, low prenatal levels of vitamin D can influence critical components of orderly brain development and that this has a long lasting effect on behaviour.

Conclusions

The researchers focussed on the impact of the heroin shortage that occurred in early 2001 on three Australian jurisdictions, namely NSW, Vic and SA. They interviewed 82 heroin dependent heroin users and 172 key informants from health and law enforcement agencies. They also examined a range of indicator data such as drug seizures, drug-related arrests, deaths related to drug use, emergency department admissions for overdose or drug induced psychosis , calls to telephone help lines about drug use, needles distributed for drug use, and notifications about blood borne diseases. In addition a range of documentation, in particular from the law enforcement sector, was examined.

Transactivation-deficient p73 alpha (p73 Delta exon2) inhibits apoptosis and competes with p53

p73 has recently been identified as a structural and functional homolog of the tumor suppressor protein p53. Overexpression of p53 activates transcription of p53 effector genes, causes growth inhibition and induced apoptosis. We describe here the effects of a tumor-derived truncated transcript of p73 alpha (p73 Delta exon2) on p53 function and on cell death. This transcript, which lacks the acidic N-terminus corresponding to the transactivation domain of p53, was initially detected in a neuroblastoma cell line. Overexpression of p73 Delta exon2 partially protects lymphoblastoid cells against apoptosis induced by anti-Fas antibody or cisplatin. By cotransfecting p73 Delta exon2 with wild-type p53 in the p53 null line Saos 2, we found that this truncated transcript reduces the ability of wild-type p53 to promote apoptosis. This anti-apoptotic effect was also observed when p73 Delta exon2 was co-transfected with full-length p73 (p73 alpha). This was further substantiated by suppression of p53 transactivation of the effector gene p21-Waf1 in p73 Delta exon2 transfected cells and by inhibition of expression of a reporter gene under the control of the p53 promoter. Thus, this truncated form of p73 can act as a dominant-negative agent towards transactivation by p53 and p73 alpha, highlighting the potential implications of these findings for p53 signaling pathway. Furthermore, we demonstrate the existence of a p73 Delta exon2 transcript in a very significant proportion (46%) of breast cancer cell lines. However, a large spectrum of normal and malignant tissues need to be surveyed to determine whether this transdominant p73 variant occurs in a tumor-specific manner.

Steatosis: Co-factor in other liver diseases

The prevalence of fatty liver is rising in association with the global increase in obesity and type 2 diabetes. In the past, simple steatosis was regarded as benign, but the presence of another liver disease may provide a synergistic combination of steatosis, cellular adaptation, and oxidative damage that aggravates liver injury. In this review, a major focus is on the role of steatosis as a co-factor in chronic hepatitis C (HCV), where the mechanisms promoting fibrosis and the effect of weight reduction in minimizing liver injury have been most widely studied. Steatosis, obesity, and associated metabolic factors may also modulate the response to alcohol- and drug-induced liver disease and may be risk factors for the development of hepatocellular cancer. The pathogenesis of injury in obesity-related fatty liver disease involves a number of pathways, which are currently under investigation. Enhanced oxidative stress, increased susceptibility to apoptosis, and a dysregulated response to cellular injury have been implicated, and other components of the metabolic syndrome such as hyperinsulinernia and hyperglycemia are likely to have a role. Fibrosis also may be increased as a by-product of altered hepatocyte regeneration and activation of bipotential hepatic progenitor cells. In conclusion, active management of obesity and a reduction in steatosis may improve liver injury and decrease the progression of fibrosis.

Modulating the rate and rhythmicity of perceptual rivalry alternations with the mixed 5-HT2A and 5-HT1A agonist psilocybin

Binocular rivalry occurs when different images are presented simultaneously to corresponding points within the left and right eyes. Under these conditions, the observer's perception will alternate between the two perceptual alternatives. Motivated by the reported link between the rate of perceptual alternations, symptoms of psychosis and an incidental observation that the rhythmicity of perceptual alternations during binocular rivalry was greatly increased 10 h after the consumption of LSD, this study aimed to investigate the pharmacology underlying binocular rivalry and to explore the connection between the timing of perceptual switching and psychosis. Psilocybin (4-phosphoryloxy-N,N-dimethyltryptamine, PY) was chosen for the study because, like LSD, it is known to act as an agonist at serotonin (5-HT)(1A) and 5-HT2A receptors and to produce an altered state sometimes marked by psychosis-like symptoms. A total of 12 healthy human volunteers were tested under placebo, low-dose ( 115 mg/kg) and high-dose ( 250 mg/kg) PY conditions. In line with predictions, under both low- and high-dose conditions, the results show that at 90 min postadministration ( the peak of drug action), rate and rhythmicity of perceptual alternations were significantly reduced from placebo levels. Following the 90 min testing period, the perceptual switch rate successively increased, with some individuals showing increases well beyond pretest levels at the final testing, 360 min postadministration. However, as some subjects had still not returned to pretest levels by this time, the mean phase duration at 360 min was not found to differ significantly from placebo. Reflecting the drug-induced changes in rivalry phase durations, subjects showed clear changes in psychological state as indexed by the 5D-ASC ( altered states of consciousness) rating scales. This study suggests the involvement of serotonergic pathways in binocular rivalry and supports the previously proposed role of a brainstem oscillator in perceptual rivalry alternations and symptoms of psychosis.

Is cannabis use a contributory cause of psychosis?

Objective: To assess whether cannabis use in adolescence and young adulthood is a contributory cause of schizophreniform psychosis in that it may precipitate psychosis in vulnerable individuals. Method: We reviewed longitudinal studies of adolescents and young adults that examined the relations between self-reported cannabis use and the risk of diagnosis with a psychosis or of reporting psychotic symptoms. We also reviewed studies that controlled for potential confounders, such as other forms of drug use and personal characteristics that predict an increased risk of psychosis. We assessed evidence for the biological plausibility of a contributory causal relation. Results: Evidence from 6 longitudinal studies in 5 countries shows that regular cannabis use predicts an increased risk of a schizophrenia diagnosis or of reporting symptoms of psychosis. These relations persisted after controlling for confounding variables, such as personal characteristics and other drug use. The relation did not seem to be a result of cannabis use to self-medicate symptoms of psychosis. A contributory causal relation is biologically plausible because psychotic disorders involve disturbances in the dopamine neurotransmitter systems with which the cannabinoid system interacts, as demonstrated by animal studies and one human provocation study. Conclusion: It is most plausible that cannabis use precipitates schizophrenia in individuals who are vulnerable because of a personal or family history of schizophrenia.

Disruption of NaS1 sulfate transport function in mice leads to enhanced acetaminophen-induced hepatotoxicity

Sulfate is required for detoxification of xenobiotics such as acetaminophen (APAP), a leading cause of liver failure in humans. The NaS1 sulfate transporter maintains blood sulfate levels sufficiently high for sulforiation reactions to work effectively for drug detoxification. In the present study, we identified two loss-of-function polymorphisms in the human NaS1 gene and showed the Nas1-null mouse to be hypersensitive to APAP hepatotoxicity. APAP treatment led to increased liver damage and decreased hepatic glutathione levels in the hyposulfatemic Nas1-null mice compared with that in normosulfatemic wild-type mice. Analysis of urinary APAP metabolites revealed a significantly lower ratio of APAP-sulfate to APAP-glucuronide in the Nas1-null mice. These results suggest hyposulfatemia increases sensitivity to APAP-induced hepatotoxicity by decreasing the sulfonation capacity to metabolize APAP. In conclusion, the results of this study highlight the importance of plasma sulfate level as a key modulator of acetaminophen metabolism and suggest that individuals with reduced NaS1 sulfate transporter function would be more sensitive to hepatotoxic agents.

Drug targets and mechanisms of resistance in the anaerobic protozoa

The anaerobic protozoa Giardia duodenalis, Trichomonas vaginalis, and Entamoeba histolytica infect up to a billion people each year. G. duodenalis and E. histolytica are primarily pathogens of the intestinal tract, although E. histolytica can form abscesses and invade other organs, where it can be fatal if left untreated. T. vaginalis infection is a sexually transmitted infection causing vaginitis and acute inflammatory disease of the genital mucosa. T. vaginalis has also been reported in the urinary tract fallopian tubes, and pelvis and can cause pneumonia, bronchitis, and oral lesions. Respiratory infections can be acquired perinatally. T. vaginalis infections have been associated with preterm delivery, low birth weight, and increased mortality as well as predisposing to human immunodeficiency virus infection, AIDS, and cervical cancer. All three organisms lack mitochondria and are susceptible to the nitroimidazole metronidazole because of similar low-redox-potential anaerobic metabolic pathways. Resistance to metronidazole and other drugs has been observed clinically and in the laboratory. Laboratory studies have identified the enzyme that activates metronidazole, pyruvate:ferredoxin oxidoreductase, to its nitroso form and distinct mechanisms of decreasing drug susceptibility that are induced in each organism. Although the nitroimidazoles have been the drug family of choice for treating the anaerobic protozoa, G. duodenalis is less susceptible to other antiparasitic drugs, such as furazolidone, albendazole, and quinacrine. Resistance has been demonstrated for each agent and the mechanism of resistance has been investigated. Metronidazole resistance in T. vaginalis is well documented, and the principal mechanisms have been defined Bypass metabolism, such as alternative oxidoreductases, have been discovered in both organisms. Aerobic versus anaerobic resistance in T. vaginalis is discussed. Mechanisms of metronidazole resistance in E. histolytica have recently been investigated ruing laboratory-induced resistant isolates. Instead of downregulation of the pyruvate:ferredoxin oxidoreductase and ferredoxin pathway as seen in G. duodenalis and T. vaginalis, E. histolytica induces oxidative stress mechanisms, including superoxide dismutase and peroxiredoxin. The review examines the value of investigating both clinical and laboratory-induced syngeneic drug-resistant isolates and dissection of the complementary data obtained. Comparison of resistance mechanisms in anaerobic bacteria and the parasitic protozoa is discussed as well as the value of studies of the epidemiology of resistance.

Cationic drug pharmacokinetics in diseased livers determined by fibrosis index, hepatic protein content, microsomal activity, and nature of drug

The disposition kinetics of six cationic drugs in perfused diseased and normal rat livers were determined by multiple indicator dilution and related to the drug physicochemical properties and liver histopathology. A carbon tetrachloride (CCl4)induced acute hepatocellular injury model had a higher fibrosis index (FI), determined by computer-assisted image analysis, than did an alcohol-induced chronic hepatocellular injury model. The alcohol-treated group had the highest hepatic alpha(1)- acid glycoprotein, microsomal protein (MP), and cytochrome P450 (P450) concentrations. Various pharmacokinetic parameters could be related to the octanol-water partition coefficient (log P-app) of the drug as a surrogate for plasma membrane partition coefficient and affinity for MP or P450, the dependence being lower in the CCl4-treated group and higher in the alcohol-treated group relative to controls. Stepwise regression analysis showed that hepatic extraction ratio, permeability-surface area product, tissue-binding constant, intrinsic clearance, partition ratio of influx (k(in)) and efflux rate constant (k(out)), and k(in)/k(out) were related to physicochemical properties of drug (log P-app or pK(a)) and liver histopathology (FI, MP, or P450). In addition, hepatocyte organelle ion trapping of cationic drugs was evident in all groups. It is concluded that fibrosis-inducing hepatic disease effects on cationic drug disposition in the liver may be predicted from drug properties and liver histopathology.

Drug resistance in the sexually transmitted protozoan Trichomonas vaginalis

Trichomoniasis is the most common, sexually transmitted infection. It is caused by the flagellated protozoan parasite Trichomonas vaginalis. Symptoms include vaginitis and infections have been associated with preterm delivery, low birth weight and increased infant mortality, as well as predisposing to HIV/AIDS and cervical cancer. Trichomoniasis has the highest prevalence and incidence of any sexually transmitted infection. The 5-nitroimidazole drugs, of which metronidazole is the most prescribed, are the only approved, effective drugs to treat trichomoniasis. Resistance against metronidazole is frequently reported and cross-resistance among the family of 5-nitroimidazole drugs is common, leaving no alternative for treatment, with some cases remaining unresolved. The mechanism of metronidazole resistance in T. vaginalis from treatment failures is not well understood, unlike resistance which is developed in the laboratory under increasing metronidazole pressure. In the latter situation, hydrogenosomal function which is involved in activation of the prodrug, metronidazole, is down-regulated. Reversion to sensitivity is incomplete after removal of drug pressure in the highly resistant parasites while clinically resistant strains, so far analysed, maintain their resistance levels in the absence of drug pressure. Although anaerobic resistance has been regarded as a laboratory induced phenomenon, it clearly has been demonstrated in clinical isolates. Pursuit of both approaches will allow dissection of the underlying mechanisms. Many alternative drugs and treatments have been tested in vivo in cases of refractory trichomoniasis, as well as in vitro with some successes including the broad spectrum anti-parasitic drug nitazoxanide. Drug resistance incidence in T. vaginalis appears to be on the increase and improved surveillance of treatment failures is urged.

Measurement of free drug and clinical end-point by high-performance liquid chromatography-mass spectrometry: Applications and implications for pharmacokinetic and pharmacodynamic studies

Free drug measurement and pharmacodymanic markers provide the opportunity for a better understanding of drug efficacy and toxicity. High-performance liquid chromatography (HPLC)-mass spectrometry (MS) is a powerful analytical technique that could facilitate the measurement of free drug and these markers. Currently, there are very few published methods for the determination of free drug concentrations by HPLC-MS. The development of atmospheric pressure ionisation sources, together with on-line microdialysis or on-line equilibrium dialysis and column switching techniques have reduced sample run times and increased assay efficiency. The availability of such methods will aid in drug development and the clinical use of certain drugs, including anti-convulsants, anti-arrhythmics, immunosuppressants, local anaesthetics, anti-fungals and protease inhibitors. The history of free drug measurement and an overview of the current HPLC-MS applications for these drugs are discussed. Immunosuppressant drugs are used as an example for the application of HPLC-MS in the measurement of drug pharmacodynamics. Potential biomarkers of immunosuppression that could be measured by HPLC-MS include purine nucleoside/nucleotides, drug-protein complexes and phosphorylated peptides. At the proteomic level, two-dimensional gel electrophoresis combined with matrix-assisted laser desorption/ionisation time-of-flight (TOF) MS is a powerful tool for identifying proteins involved in the response to inflammatory mediators. (C) 2003 Elsevier Science B.V. All rights reserved.