Predicting and managing adverse reactions of psychotropic drugs.

BACKGROUND: Neuroleptic induced extrapyramidal disorders are often presented in a form of orofacial hyperkinesias and dystonia. Rational use of neuroleptic drugs requires individualised approach to a patient, however simple criteria for determining individual, "personalised" dosage regimen have not been fully developed for routine practice in resource-limited hospital settings. OBJECTIVE: To study the tonus of tongue muscles as a measure of orofacial dystonia and the total hepatic oxidative capacity as a potential predictor of excessive vulnerability to neuroleptic-induced dystonia in psychiatric patients. METHODS: We measured the maximal force of the tongue manoeuvre (F, g/cm2), the total (integral) hepatic oxidative capacity by the antipyrine-test and used chlorpromazine equivalent to calculate the total daily neuroleptic load in 283 psychiatric patients and 30 healthy volunteers. RESULTS: The tonus of tongue muscles depends on the total daily neuroleptic dose and the length of antipsychotic treatment. The higher the total daily neuroleptic dose and the longer the treatment history, the greater the tongue muscles' tonus is. The tongue muscles' tonus was greater in patients with low rate of oxidative antipyrine metabolism. Antidepressants contributed to the increased tonus of the tongue muscles in "slow metabolisers" of antipyrine. CONCLUSIONS: The simple and cheap measurements of total hepatic oxidative capacity and of muscle tonus of the tongue could be used to predict and manage neuroleptic-induced adverse reactions.

Fluoroquinolones for treating tuberculosis (presumed drug-sensitive).

BACKGROUND: Currently the World Health Organization only recommend fluoroquinolones for people with presumed drug-sensitive tuberculosis (TB) who cannot take standard first-line drugs. However, use of fluoroquinolones could shorten the length of treatment and improve other outcomes in these people. This review summarises the effects of fluoroquinolones in first-line regimens in people with presumed drug-sensitive TB. OBJECTIVES: To assess fluoroquinolones as substitute or additional components in antituberculous drug regimens for drug-sensitive TB. SEARCH METHODS: We searched the Cochrane Infectious Diseases Group Specialized Register; CENTRAL (The Cochrane Library 2013, Issue 1); MEDLINE; EMBASE; LILACS; Science Citation Index; Databases of Russian Publications; and metaRegister of Controlled Trials up to 6 March 2013. SELECTION CRITERIA: Randomized controlled trials (RCTs) of antituberculous regimens based on rifampicin and pyrazinamide and containing fluoroquinolones in people with presumed drug-sensitive pulmonary TB. DATA COLLECTION AND ANALYSIS: Two authors independently applied inclusion criteria, assessed the risk of bias in the trials, and extracted data. We used the risk ratio (RR) for dichotomous data and the fixed-effect model when it was appropriate to combine data and no heterogeneity was present. We assessed the quality of evidence using the GRADE approach. MAIN RESULTS: We identified five RCTs (1330 participants) that met the inclusion criteria. None of the included trials examined regimens of less than six months duration. Fluoroquinolones added to standard regimensA single trial (174 participants) added levofloxacin to the standard first-line regimen. Relapse and treatment failure were not reported. For death, sputum conversion, and adverse events we are uncertain if there is an effect (one trial, 174 participants, very low quality evidence for all three outcomes). Fluoroquinolones substituted for ethambutol in standard regimens Three trials (723 participants) substituted ethambutol with moxifloxacin, gatifloxacin, and ofloxacin into the standard first-line regimen. For relapse, we are uncertain if there is an effect (one trial, 170 participants, very low quality evidence). No trials reported on treatment failure. For death, sputum culture conversion at eight weeks, or serious adverse events we do not know if there was an effect (three trials, 723 participants, very low quality evidence for all three outcomes). Fluoroquinolones substituted for isoniazid in standard regimens A single trial (433 participants) substituted moxifloxacin for isoniazid. Treatment failure and relapse were not reported. For death, sputum culture conversion, or serious adverse events the substitution may have little or no difference (one trial, 433 participants, low quality evidence for all three outcomes). Fluoroquinolines in four month regimensSix trials are currently in progress testing shorter regimens with fluoroquinolones. AUTHORS' CONCLUSIONS: Ofloxacin, levofloxacin, moxifloxacin, and gatifloxacin have been tested in RCTs of standard first-line regimens based on rifampicin and pyrazinamide for treating drug-sensitive TB. There is insufficient evidence to be clear whether addition or substitution of fluoroquinolones for ethambutol or isoniazid in the first-line regimen reduces death or relapse, or increases culture conversion at eight weeks. Much larger trials with fluoroquinolones in short course regimens of four months are currently in progress.

Quality information for quality use of medicines; 2nd International Conference, Kazan, 15-16 October 2010.

Kazan hosted Russia's first international conference on medicines that was entirely independent of the pharmaceutical industry, attracting 414 participants from 9 countries and 20 regions of the Russian Federation. The meeting was greeted and endorsed by world leaders in pharmaceutical information, policy and regulation. Delegates discussed the professional and social problems arising from unethical drug promotion, including compromised evidence from clinical trials and consequent impairments in health service delivery. The Conference adopted a resolution prioritizing policy development and health system needs, notably including the development of clinical pharmacology. A website documents conference materials and provides an interface for future collaboration: http://evidenceupdate-tatarstan.ru/confer.

Tuberculosis (HIV-negative people).

INTRODUCTION: About one third of the world's population has latent tuberculosis. In 2004, more than 14 million people had active tuberculosis. About 1.7 million people died from the infection in 2006. More than 80% of new cases diagnosed in 2004 were in people in Africa, South-East Asia, and Western Pacific regions. METHODS AND OUTCOMES: We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of interventions to prevent tuberculosis in people without HIV infection at high risk of developing tuberculosis? What are the effects of interventions to prevent tuberculosis in people without HIV infection at high risk of developing multidrug-resistant tuberculosis? What are the effects of different drug regimens in people with newly diagnosed pulmonary tuberculosis without HIV infection? What are the effects of different drug regimens in people with multidrug-resistant tuberculosis without HIV infection? What are the effects of low-level laser therapy in people with tuberculosis without HIV infection? Which interventions improve adherence to treatment in people with tuberculosis without HIV infection? We searched: Medline, Embase, The Cochrane Library, and other important databases up to June 2010 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). RESULTS: We found 32 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. CONCLUSIONS: In this systematic review, we present information relating to the effectiveness and safety of the following interventions: adding pyrazinamide in chemotherapy regimens lasting up to 6 months, adding rifampicin to isoniazid regimens, benefits of different regimens, chemotherapy for <6 months, daily chemotherapy, direct observation treatment, intermittent chemotherapy for 6 months or longer, isoniazid, low-level laser therapy for pulmonary tuberculosis, regimens containing quinolones, rifampicin plus isoniazid, substituting rifampicin with ethambutol in the continuous phase, and support mechanisms for directly observed treatment.

Cerebrolysin for acute ischaemic stroke.

BACKGROUND: Cerebrolysin is a mixture of low-molecular-weight peptides and amino acids derived from pigs' brain tissue which has proposed neuroprotective and neurotrophic properties. It is widely used in the treatment of acute ischaemic stroke in Russia and China. OBJECTIVES: To assess the benefits and risks of cerebrolysin for treating acute ischaemic stroke. SEARCH STRATEGY: We searched the Cochrane Stroke Group Trials Register (February 2009), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library Issue 1, 2009), MEDLINE (1966 to February 2009), EMBASE (1974 to February 2009), LILACS (1982 to February 2009), Science Citation Index (1940 to February 2009), SIGLE Archive (1980 to March 2005), and a number of relevant Russian Databases (1988 to February 2009). We also searched reference lists, ongoing trials registers and conference proceedings. SELECTION CRITERIA: Randomised controlled trials comparing cerebrolysin with placebo or no treatment in patients with acute ischaemic stroke. DATA COLLECTION AND ANALYSIS: Three review authors independently applied the inclusion criteria, assessed trial quality and extracted the data. MAIN RESULTS: We included one trial involving 146 participants. There was no difference in death (6/78 in the cerebrolysin group versus 6/68 in the placebo group; risk ratio (RR) 0.87, 95% confidence interval (CI) 0.29 to 2.58) or in the total number of adverse events (16.4% versus 10.3%; RR 1.62, 95% CI 0.69 to 3.82) between the treatment and control groups. AUTHORS' CONCLUSIONS: There is not enough evidence to evaluate the effect of cerebrolysin on survival and dependency in people with acute ischaemic stroke. High-quality and large-scale randomised controlled trials may help to gain a better understanding of the potential value of cerebrolysin in acute ischaemic stroke.

Tuberculosis (HIV-negative people).

INTRODUCTION: About a third of the world's population has latent tuberculosis. In 2004, over 14 million people had active tuberculosis. Approximately 1.7 million people died from the infection. Over 80% of new cases diagnosed in 2004 were in people in Africa, South-East Asia, and Western Pacific regions. METHODS AND OUTCOMES: We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of interventions to prevent tuberculosis in people without HIV infection at high risk of developing tuberculosis? What are the effects of interventions to prevent tuberculosis in people without HIV infection at high risk of developing multidrug-resistant tuberculosis? What are the effects of different drug regimens in people with newly diagnosed pulmonary tuberculosis without HIV infection? What are the effects of different drug regimens in people with multidrug-resistant tuberculosis without HIV infection? What are the effects of low-level laser therapy in people with tuberculosis without HIV infection? Which interventions improve adherence to treatment in people with tuberculosis without HIV infection? We searched: Medline, Embase, The Cochrane Library, and other important databases up to July 2008 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). RESULTS: We found 31 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. CONCLUSIONS: In this systematic review we present information relating to the effectiveness and safety of the following interventions: adding pyrazinamide in chemotherapy regimens lasting up to 6 months; adding rifampicin to isoniazid regimens; benefits of different regimens; chemotherapy for less than 6 months; daily chemotherapy; direct observation treatment; intermittent chemotherapy for 6 months or longer; isoniazid; low-level laser therapy for pulmonary tuberculosis; regimens containing quinolones; rifampicin plus isoniazid; substituting rifampicin with ethambutol in the continuous phase; and support mechanisms for directly observed treatment.

Identification and management of patients with hypertension in the polyclinic system of the Russian Federation.

BACKGROUND: Cardiovascular diseases, including hypertension and type 2 diabetes mellitus, are the major determinants of poor health in the Russian Federation. METHODS: This study assessed the feasibility of establishing a program to identify and manage hypertension and associated cardiovascular risk factors in an outpatient clinic within the Russian polyclinic system. In urban polyclinic in Kazan, Tatarstan, which is responsible for 77,000 covered lives, we enrolled 192 patients with hypertension of whom 68 had type 2 diabetes mellitus screened from various clinics within the polyclinic. After collection of baseline data, patients were treated for hypertension and those risk factors amenable to pharmaceutic intervention and counseled on those that required behavior modification. RESULTS: Baseline blood pressure was 173.9+/-20.7/104.2+/-15.3 mm Hg in those with hypertension only (n=124) and 172.9+/-26.0/97.9+/-16.4 mm Hg in those with both hypertension and type 2 diabetes mellitus. More than 80% of the entire group had a body mass index >25 kg/m2 and left ventricular hypertrophy. Nearly 70% had total cholesterol >5.2 mmol/L. Of the diabetics, more than 50% had glycosylated hemoglobin (HbA1c)>or=8%. Less than 10% of this self-selected population smoked. Blood pressure decreased modestly, but significantly, in both groups of patients. There were no significant changes in obesity, cholesterol, smoking, or HbA1c in the diabetics. CONCLUSIONS: Identification, recruitment, management, and follow-up of patients with chronic disorders is feasible within the Russian polyclinic system. However, to have a more profound effect on risk factor profiles, a wider effort is needed than one restricted to the clinic itself.

Potentiation of uterine effects of prostaglandin F2{alpha} by adenosine 5'-triphosphate.

OBJECTIVE: To investigate the interaction of exogenous adenosine 5'-triphosphate (ATP), a P2 receptor agonist, with prostaglandin F(2alpha) (PGF(2alpha)) on pregnant women in labor as well as on isolated human pregnant uterus preparations. METHODS: For an in vitro study, myometrial samples were obtained from 27 women undergoing elective cesarean delivery at term. Concentration-response relationships for ATP (10(-8) -3 x 10(-4) mol/L), PGF(2alpha) (10(-9) -10(-5) mol/L), and their combination were obtained by using routine pharmacological organ bath technique. An in vivo study was performed with 34 pregnant women with dysfunctional abnormalities of the active stage of labor who were randomly allocated into 2 study groups. The women in the control group (18 patients) received intravenous prostaglandin F(2alpha) at an initial rate of 7.5 mug/min, whereas the women in the ATP group (16 patients) received prostaglandin F(2alpha) concomitantly with ATP (0.45 nmol/min, intravenously). RESULTS: Adenosine 5'-triphosphate at concentrations of 10(-6) -3 x 10(-4) mol/L and PGF(2alpha) at concentrations of 10(-8) -10(-5) mol/L caused concentration-dependent contractions of isolated smooth muscle preparations of the human pregnant uterus. At concentrations of 10(-6) mol/L and below, ATP had no effects on mechanical activity of the isolated uterus, but at concentrations of 10(-7) mol/L and 10(-6) mol/L, it significantly potentiated the contractile responses of the uterus induced by PGF(2alpha) (P < .05, 2-way analysis of variance). Patients receiving intravenous infusion of ATP as a supplement to PGF(2alpha) treatment, compared with those without ATP, had a significantly shorter interval from the start of the treatment to full cervical dilatation (3.31 +/- 1.49 hours and 4.67 +/- 1.11 hours in ATP and control groups, respectively; P = .014, Wilcoxon Mann-Whitney test). The total dose of prostaglandin received was significantly lower in the ATP group than that of controls (1,489.8 +/- 699.9 mug and 3,394.2 +/- 1,951.9 mug, respectively; P = .003, Wilcoxon Mann-Whitney test). No side effects of ATP treatment were observed during or after infusion. CONCLUSION: Adenosine 5'-triphosphate potentiates effects of PGF(2alpha) on pregnant human uterus in vitro and in vivo and thus could be a useful supplemental drug to increase uterine contractility at labor.

The influence of hypothermia on P2 receptor-mediated responses of frog skeletal muscle.

The contractile responses of isolated Rana ridibunda frog sartorius muscle contractions evoked by electrical field stimulation (EFS) were studied at three temperature conditions of 17, 22 and 27 degrees C. Temperature-dependent increase of muscle contractility was found. ATP (10-100 microM) concentration dependently inhibited the electrical field stimulation-evoked contractions of sartorius muscle at all three temperatures; this effect was significantly more prominent at a temperature of 17 degrees C than at other two temperatures. Adenosine (100 microM) also caused inhibition of electrical field stimulation-evoked contractions which was statistically identical at all three temperature conditions tested. A P2 receptor antagonist, pyridoxalphosphate-6-azophenyl-2',4'-disulphonic acid (PPADS, 10 microM) reduced the inhibitory effect of ATP at all three temperatures but did not affect inhibitory action of adenosine. In contrast, 8-(p-sulfophenyl)theophylline (8-SPT, 100 microM), a nonselective P1 receptor antagonist, abolished inhibitory effects of adenosine at all three temperature conditions but did not antagonize inhibition caused by ATP. In electrophysiological experiments, ATP (100 microM) and adenosine (100 microM) temperature dependently reduced end-plate currents recorded in sartorius neuromuscular junction by voltage-clamp technique. The inhibitory effects of both agonists were enhanced with the decrease of temperature. 8-SPT (100 microM) abolished the inhibitory effect of adenosine but not ATP on end-plate currents. Suramin (100 microM), a nonselective P2 receptor antagonist, inhibited the action of ATP but not adenosine, while PPADS (10 microM) had no influence on the effects of either ATP or adenosine. It is concluded from this study that the effectiveness of P2 receptor-mediated inhibition of frog skeletal muscle contraction in contrast to that of adenosine is dependent on the temperature conditions.

Varicose disease affects the P2 receptor-mediated responses of human greater saphenous vein.

The aim of the present study was to investigate in vitro the differences in P2 receptor mediated responses of human greater saphenous vein (GSV) taken from patients with varicose disease and obliterating atherosclerosis. Samples of the inguinal part of the GSV were taken from the patients who underwent phlebectomia operation due to varicose disease (n=9, VD group) or femoropoplitea bypass operation using auto-vein due to obliterating atherosclerosis of lower extremities (n=11, OA group). The mechanical responses of the isolated segments of GSV to P2 receptor agonists were tested using standard organ-bath technique. ATP (10(-6)-10(-4) M), ADP (10(-6)-10(-4) M) and alpha,betamethyleneATP (10(-8)-10(-5) M) caused concentration-dependent contractions of the veins of both groups, the latter agonist being approximately tenfold more active than first two. ATP at all concentrations tested, alpha,betamethyleneATP at concentrations of 10(-6) and 10(-5) M and ADP at a concentration of 10(-6) M produced significantly higher contractions of the GSV taken from OA group than from VD group. UTP (10(-6)-10(-4) M) caused concentration-dependent contractions of the veins taken from OA group, while in VD group this agonist was virtually without effect. Adenosine (10(-6)-10(-4) M) and 2-methylthio-ATP (10(-7)-10(-5) M) had no significant contractile activity in this tissue in both groups. It is concluded from this study that there are P2 receptor and adrenoceptor mediated contractions in human greater saphenous veins, which are impaired by varicose disease, in contrast to contractions produced by histamine and carbachol which are, if anything, enhanced.

The Russian health care system today: can American-Russian CME programs help?

The health of the Russian people has deteriorated dramatically since the fall of communism, due particularly to cardiovascular disease. The Eurasian Medical Education Program was developed in response to provide continuing medical education for Russian physicians. Programs are directed mainly toward primary care physicians and focus on outpatient management of diseases that cause high rates of mortality and morbidity. This experience provides an opportunity to assess the structure and functioning of the Russian health care system and emphasizes the importance of general internal medicine training in detection, management, and prevention of disease complications.

Temperature dependency of P2 receptor-mediated responses.

The P2 receptor-mediated responses of isolated guinea pig urinary bladder and vas deferens (P2X receptors) and taenia caeci (P2Y receptors) were registered at the three temperature conditions of 30, 37 and 42 degrees C. The contractile responses of both urinary bladder and vas deferens to a P2X receptor agonist alpha,beta-methylene ATP (alpha,beta-meATP; 0.01-30 microM) and to electrical field stimulation (1-64 Hz, 0.1 ms, supramaximal voltage) in the presence of atropine (0.1 microM) and phentolamine (1 microM) were markedly more prominent at a temperature of 30 degrees C than at 37 or 42 degrees C. Similarly, relaxation of carbachol-precontracted taenia caeci caused by electrical field stimulation (0.5-8 Hz, 0.1 ms, supramaximal voltage) temperature-dependently increased with decrease of temperature, while relaxation of this tissue by exogenous ATP (1-100 microM) was not affected by the temperature. A P2 receptor antagonist pyridoxalphosphate-6-azophenyl-2',4'-disulphonic acid (PPADS, 1-30 microM) at all three temperature conditions concentration-dependently antagonised contractile responses to alpha,beta-methylene ATP and electrical field stimulation in both urinary bladder and vas deferens. PPADS, even at the highest concentration tested (30 microM), had no effect on the relaxant responses of the taenia caeci either to electrical field stimulation or ATP and its action was not affected by the change of temperature. It is concluded from this study that the effectiveness of P2 receptor-mediated responses in guinea pig urinary bladder, vas deferens and taenia caeci increases by decrease of temperature.

Effects of chronic specific urogenital infections on contractility of the human isolated pregnant myometrium.

The contractile activity of the isolated myometrium of pregnant women with mycoplasma, chlamydia and mixed infections has been studied by pharmacological organ bath method. We found that mycoplasma infection decreased while chlamydia or mixed infection increased myometrium contraction evoked by oxytocin or prostaglandin F2alpha. The results of this study could be important for the prediction of possible complications during pregnancy and labour in women with chronic specific urogenital infections.