A computer-aided drug design approach to discover tumour suppressor p53 protein activators for colorectal cancer therapy.

Colorectal cancer (CRC) is the third most detected cancer and the second foremost cause of cancer deaths in the world. Intervention targeting p53 provides potential therapeutic strategies, but thus far no p53-based therapy has been successfully translated into clinical cancer treatment. Here we developed a Quantitative Structure-Activity Relationships (QSAR) classification models using empirical molecular descriptors and fingerprints to predict the activity against the p53 protein, using the potency value with the active or inactive label, were developed. These models were built using in total 10,505 molecules that were extracted from the ChEMBL, ZINC and Reaxys® databases, and recent literature. Three machine learning (ML) techniques e.g., Random Forest, Support Vector Machine, Convolutional Neural Network were explored to build models for p53 inhibitor prediction. The performances of the models were successfully evaluated by internal and external validation. Moreover, based on the best in silico p53 model, a virtual screening campaign was carried out using 1443 FDA-approved drugs that were extracted from the ZINC database. A list of virtual screening hits was assented on base of some limits established in this approach, such as: (1) probability of being active against p53; (2) applicability domain; (3) prediction of the affinity between the p53, and ligands, through molecular docking. The most promising according to the limits established above was dihydroergocristine. This compound revealed cytotoxic activity against a p53-expressing CRC cell line with an IC50 of 56.8 µM. This study demonstrated that the computer-aided drug design approach can be used to identify previously unknown molecules for targeting p53 protein with anti-cancer activity and thus pave the way for the study of a therapeutic solution for CRC.

[Assessment of quality of life and treatment adherence in patients with dizziness treated with vasobral]. / Otsenka kachestva zhizni i priverzhennosti lecheniiu preparatom vazobral patsientov s golovokruzheniem.

AIM: To study indicators of quality of life and adherence to treatment with vazobral in patients with dizziness of vascular genesis. MATERIAL AND METHODS: Vazobral was administered to 330 patients with vertigo due to cerebrovascular disease for 3 months during a non-inferiority, open-label study. Quality of life (measured using VAS and the second part of the EQ-5D questionnaire), severity and frequency of dizziness attacks (using VAS), the overall effectiveness of treatment on the basis of objective (according to the doctor) and subjective (using CGI) assessments, treatment adherence were evaluated. RESULTS AND CONCLUSION: The positive effect of vazobral was reported by 320 patients (97.0%), 223 of them (67.6%) indicated a decrease in the frequency of episodes of dizziness by at least 50%, and 95 patients (28.8%) had complete relief of dizziness. Two hundred and sixty-two (79.4%) patients took the drug in full accordance with recommendations. Patients living alone missed drug intake more often. Improvement of quality of life was noted in 326 (98.8%) patients, scores for all domains of the questionnaire EQ-5D at baseline and in the end of the study were 50.8±18.1 and 78.8±14.7%, respectively (p<0.001). The tolerability of treatment was characterized by good tolerability.

Lipase-catalyzed synthesis of ethyl (R)-2-benzyloxy-2-isopropylhydrogenmalonate: a useful combination of chemical synthesis with enzymatic methods.

Ethyl (R)-2-benzyloxy-2-isopropylhydrogenmalonate is a key intermediate for the synthesis of the side chain in ergopeptines. In this work, we adopted a method to prepare enantiomerically pure title monoester via immobilized Candida antarctica lipase B (Novozym 435)-catalyzed hydrolysis of the corresponding diester.

Miscellaneous treatments for antipsychotic-induced tardive dyskinesia.

BACKGROUND: Antipsychotic (neuroleptic) medication is used extensively to treat people with chronic mental illnesses. Its use, however, is associated with adverse effects, including movement disorders such as tardive dyskinesia (TD) - a problem often seen as repetitive involuntary movements around the mouth and face. This review, one in a series examining the treatment of TD, covers miscellaneous treatments not covered elsewhere. OBJECTIVES: To determine whether drugs, hormone-, dietary-, or herb-supplements not covered in other Cochrane reviews on TD treatments, surgical interventions, electroconvulsive therapy, and mind-body therapies were effective and safe for people with antipsychotic-induced TD. SEARCH METHODS: We searched the Cochrane Schizophrenia Group's Study-Based Register of Trials including trial registers (16 July 2015 and 26 April 2017), inspected references of all identified studies for further trials and contacted authors of trials for additional information. SELECTION CRITERIA: We included reports if they were randomised controlled trials (RCTs) dealing with people with antipsychotic-induced TD and schizophrenia or other chronic mental illnesses who remained on their antipsychotic medication and had been randomly allocated to the interventions listed above versus placebo, no intervention, or any other intervention. DATA COLLECTION AND ANALYSIS: We independently extracted data from these trials and we estimated risk ratios (RR) or mean differences (MD), with 95% confidence intervals (CIs). We assumed that people who left early had no improvement. We assessed risk of bias and created 'Summary of findings' tables using GRADE. MAIN RESULTS: We included 31 RCTs of 24 interventions with 1278 participants; 22 of these trials were newly included in this 2017 update. Five trials are awaiting classification and seven trials are ongoing. All participants were adults with chronic psychiatric disorders, mostly schizophrenia, and antipsychotic-induced TD. Studies were primarily of short (three to six6 weeks) duration with small samples size (10 to 157 participants), and most (61%) were published more than 20 years ago. The overall risk of bias in these studies was unclear, mainly due to poor reporting of allocation concealment, generation of the sequence, and blinding.Nineteen of the 31 included studies reported on the primary outcome 'No clinically important improvement in TD symptoms'. Two studies found moderate-quality evidence of a benefit of the intervention compared with placebo: valbenazine (RR 0.63, 95% CI 0.46 to 0.86, 1 RCT, n = 92) and extract of Ginkgo biloba (RR 0.88, 95% CI 0.81 to 0.96, 1 RCT, n = 157), respectively. However, due to small sample sizes we cannot be certain of these effects.We consider the results for the remaining interventions to be inconclusive: Low- to very low-quality evidence of a benefit was found for buspirone (RR 0.53, 95% CI 0.33 to 0.84, 1 RCT, n = 42), dihydrogenated ergot alkaloids (RR 0.45, 95% CI 0.21 to 0.97, 1 RCT, n = 28), hypnosis or relaxation, (RR 0.45, 95% CI 0.21 to 0.94, 1 study, n = 15), pemoline (RR 0.48, 95% CI 0.29 to 0.77, 1 RCT, n = 46), promethazine (RR 0.24, 95% CI 0.11 to 0.55, 1 RCT, n = 34), insulin (RR 0.52, 95% CI 0.29 to 0.96, 1 RCT, n = 20), branched chain amino acids (RR 0.79, 95% CI 0.63 to 1.00, 1 RCT, n = 52), and isocarboxazid (RR 0.24, 95% CI 0.08 to 0.71, 1 RCT, n = 20). There was low- to very low-certainty evidence of no difference between intervention and placebo or no treatment for the following interventions: melatonin (RR 0.89, 95% CI 0.71 to 1.12, 2 RCTs, n = 32), lithium (RR 1.59, 95% CI 0.79 to 3.23, 1 RCT, n = 11), ritanserin (RR 1.00, 95% CI 0.70 to 1.43, 1 RCT, n = 10), selegiline (RR 1.37, 95% CI 0.96 to 1.94, 1 RCT, n = 33), oestrogen (RR 1.18, 95% CI 0.76 to 1.83, 1 RCT, n = 12), and gamma-linolenic acid (RR 1.00, 95% CI 0.69 to 1.45, 1 RCT, n = 16).None of the included studies reported on the other primary outcome, 'no clinically significant extrapyramidal adverse effects'. AUTHORS' CONCLUSIONS: This review has found that the use of valbenazine or extract of Ginkgo biloba may be effective in relieving the symptoms of tardive dyskinesia. However, since only one RCT has investigated each one of these compounds, we are awaiting results from ongoing trials to confirm these results. Results for the remaining interventions covered in this review must be considered inconclusive and these compounds probably should only be used within the context of a well-designed evaluative study.

Validated liquid chromatography-tandem mass spectrometry method for simultaneous determination of clopamide, reserpine and dihydroergotoxine: Application to pharmacokinetics in human plasma.

A simple, sensitive and rapid high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method was developed and validated for the simultaneous quantitation of clopamide, reserpine and dihydroergotoxine (ergoloid mesylates) in human plasma. Under basic conditions, liquid-liquid extraction using ethyl acetate was efficiently used for extraction of the analytes from plasma samples in presence of indapamide as internal standard (IS). The analytes were separated with isocratic elution on Phenomenex(®) Synergi Fusion-RP 80A column (50×4.6mm, 4µm). With positive ion electrospray ionization (ESI), the analytes were quantified and monitored on a triple quadrupole mass spectrometer using Multiple Reaction Monitoring (MRM) scanning mode. Satisfactory results regarding linearity, recovery, stability, accuracy and precision of the analytes were obtained. The method was linear in the concentration range of 0.04-30.00ng/mL for reserpine, 1-96.00ng/mL for clopamide, and 0.05-40.00ng/mL for dihydroergotoxine alkaloids, respectively. For all analytes, the high sensitivity of HPLC-MS/MS method revealed sufficient lower limit of quantification (LLOQ) ranged from 0.04-1ng/mL using 1mL of plasma. The recoveries from spiked control samples were ≥86.16% for all analytes and IS. The intra- and inter-day precision variations were lower than 13.03% while the accuracy values ranged from 91.76% to 111.50%. The developed method was successfully applied to pharmacokinetic study of fixed dose combination of clopamide, reserpine and dihydroergotoxine in healthy male volunteers.

[Efficacy of the combination drug vasobral in chronic vascular encephalopathy].

OBJECTIVE: Despite the high prevalence of chronic vascular encephalopathy, its diagnosis and treatment remain understudied. This observational multicenter trial assessed the efficacy and safety of vasobral in patients with cerebral ischemia. MATERIAL AND METHODS: The open observational study was carried out in 37 centers in 11 Russian cities and included 300 patients with confirmed diagnosis of chronic vascular encephalopathy, stages 1 and 2, without dementia. The patients received 1 tablet (4 mg α-dihydroergocryptine and 40 mg caffeine) 2 times a day during 3 months. RESULTS AND CONCLUSION: There was an improvement of cognitive and affective status as well as quality of life and a decrease of subjective signs of chronic vascular encephalopathy. Vasobral did not cause significant fluctuations of arterial pressure and was safe for patients with chronic vascular encephalopathy and arterial hypertension.

[Vasobral in the treatment of brain lesions: views of physicians and patients].

A study was based on the survey of 419 neurologists and 1189 their patients with different forms of cerebrovascular diseases using a specially developed questionnaire. In most cases, vasobral was used as a monotherapy or in a complex treatment. Twenty-two percent of physicians reported that vasobral was the most effective compared to other drugs. The good tolerability of treatment (18%) and the broad spectrum of indications and clinical effects (17%) were reported as well. The large percentage (75%) of patients indicated the positive effect of vasobral on memory, reasoning, vertigo etc The maximal effect was identified in the treatment of mild cognitive impairment caused by chronic brain ischemia and vertebrobasilar insufficiency. Vasobral is recommended for a use in a complex therapy in patients with more severe brain lesions and cognitive deficit.

Influence of dihydroergotoxine, bromocriptine, and ergotamine on penile erection in Wistar rats.

The pilot study presented was conducted to determine as to whether ergot alkaloids (alpha-adrenergic blockers) have a potential effect on penile erectile function. The influence of dihydroergotoxine, bromocriptine, and ergotamine was studied on the erection ability in intact, two-grade outbred male Wistar albino rats that were out of their estrous phase. The experimental animals were injected intrapenially with the substances under examination: dihydroergotoxine mesylate (0.1 mg/0.1 mL, 0.3 mg/0.1 mL, and 1 mg/0.1 mL), bromocriptine mesylate (0.3 mg/0.1 mL, 1 mg/0.1 mL, and 3 mg/0.1 mL), and ergotamine tartrate (0.1 mg/0.1 mL, 0.3 mg/0.1 mL, and 1mg/0.1 mL). Every dose was tested on a pattern of 30 rats. These mentioned substances were injected in the amount of 1 mm to the left of the proximal part of the superficial dorsal vein of the penis, in the region of the penis root. After injection, the animals were then observed within the next 90 minutes. In the trial, the following was observed: the number of rats with an erection achieved, the period of time from intrapenial application to the appearance of the first erection, and the duration of the erection. Ultimately, the research results confirm the efficiency of dihydroergotoxine and bromocriptine as erectogenic agents, as well as ergotamine as a detumescent compared with saline solutions.

[Preventive treatment of migraine with vasobral: a multicenter trial].

The results of an open prospective trial on the treatment of migraine with vasobral which was conducted in 170 medical centers (27 cities) of the Russian Federation are summarized. The trial included 5475 patients treated with vasobral in dosage 2 ml (1 ml contains 1 mg of alpha-dihydroergocryptine and 10 mg of caffeine) twice a day during 2 months. Assessment criteria of treatment efficacy were frequency and duration of migraine seizures, pain syndrome severity, presence of concomitant syndromes, general state and working capacity of patients and side-effects. Vasobral was effective and safe medication for the prevention of migraine. Its preventive effect is due to the decrease of frequency and duration of migraine seizures, pain severity and to the overall improvement of patient's state. Vasobral can be recommended to many migraine patients, in particular to those in the young age and with short disease duration.

Mechanism for the inhibition of contractile activity of the gastric antrum and pylorus in rabbits during psychogenic stress.

Psychogenic stress in rabbits (fixation to a frame) was accompanied by the inhibition of contractile activity of the gastric antrum and pylorus. These changes persisted during blockade of muscarinic receptors, nicotinic receptors, alpha(2)-adrenoceptors, and beta(1)/beta(2) adrenoceptors. A stress-induced decrease in gastric motor activity was mediated by the nonadrenergic noncholinergic mechanism. It resulted from the influence of a hormonal stress factor on the stomach, which was probably realized through nonadrenergic inhibitory neurons of the enteric nervous system.

Expression of gamma-aminobutyric acid receptor (subtype A) in prostate cancer.

BACKGROUND: In prostate cancer, gamma-aminobutyric acid (GABA) has been previously reported to increase cellular proliferation via the ionotropic GABAa receptor (GABAar) and to promote cellular invasiveness via the metabotropic GABAb receptor. METHODS: In this study, we have investigated, by immunohistochemistry, GABAar levels in 12 normal human prostate, 13 benign prostatic hyperplasia (BPH) and 148 human prostate cancer specimens. We have also examined the effect of several GABA agonists and antagonists on the in vitro proliferation of four human prostate cancer cell lines: LNCaP, MDA-PCA-2b, DU145 and PC3. RESULTS: GABAar immunoreactivity was present in the stroma of ~75% of the normal and BPH specimens, and in 95% of the prostate cancer specimens. Also, low to moderate GABAar staining was observed in the acinar epithelium of 50 (33%) prostate cancer specimens. No correlation was observed between GABAar staining and patient age, Gleason Sum or TNM stage. A GABAa agonist isoguvacine, at doses between 5-50 microg/ml (31-310 microM), stimulated the proliferation of all four human prostate cancer cell lines, tested. Baclofen, a GABAb agonist (up to 50 microg/ml, 234 microM) had no effect on growth. Also, at concentrations up to 100 microg/ml, GABA antagonists, bicuculline (223 microM), picrotoxin (166 microM) and saclofen (400 microM), did not have significant growth-inhibitory effects. However, dihydroergotoxine, which binds the GABAar chloride ion-channel, inhibited cellular proliferation (IC(50) 18-38 microM). CONCLUSIONS: These data indicate frequent expression of GABAar in prostate cancer and support a role for GABAar in the proliferation of prostate cancer cells.

[Mechanisms of inhibition of the contractile activity in the ileo-caecal zone in rabbits under psychogenic stress].

In experiments on unanaesthetized rabbits, myoelectric activity (contractile activity index) of distal ileum, caecum, and proximal colon in two sites was studied under stress induced by fastening a rabbit to the table in supine position. The stress caused sharp decrease (up to complete disappearance) of the contractile activity in all studied compartments of the ileocaecal intestine with partial or complete restoration after release of the animal. Nonselective blockade of pre- and postsynaptic alpha-adrenoceptor with dihydroergotoxin abolished the initial component of the specified inhibitory response. The latter was caused by "adrenergic inhibition" as a result of action of catecholamines circulating in blood on inhibitory smooth muscle alpha-adrenoceptor. Against the background of muscarinic cholinoceptor blockade, the stressor inhibition of ileocaecal contractile activity observed in control experiments was completely preserved. The periods of supression of ileoceacal contractile activity under stress resistant to blockade of alpha-, beta-adrenoceptor and muscarinic cholinoceptor, are caused by the mechanism of "nonadrenergic noncholinergic inhibition", which is realized at the expence of activation of the enteric inhibitory neurones.

[Early diagnosis and treatment of Alzheimer's disease. Implementation in the doctor's office]. / Frühdiagnostik und Therapie der Alzheimer-Krankheit. Zum Vorgehen in der Praxis.

The efficacy of antidemential agents proven in comprehensive studies and by clinical experience, now justifies an active and positive approach by the general physician to the diagnosis and treatment of patients with dementia. The proposals on how to implement diagnostic and therapeutic measures in the doctor's office comply both with medical quality criteria and the requirements for appropriateness of treatment and considerations of economy stipulated by German law. They therefore provide the basis for a modern diagnostic work-up and treatment strategy, which will also meet economical demands.

Erythromycin increases plasma concentrations of alpha-dihydroergocryptine in humans.

OBJECTIVE: Our objective was to investigate the potential for relevant pharmacotherapeutic interaction between cytochrome P4503A4 (CYP3A4)-inhibiting agents such as erythromycin and the dopamine agonist alpha-dihydroergocryptine (DHEC). METHODS: The study was carried out as a single-center, controlled, nonblinded, 2-way crossover clinical trial with randomly allocated period-balanced sequences, investigating two treatments of a single oral dose of 10 mg DHEC (on the morning of day 1), once administered alone (reference), once along with a 4-day treatment (days -2 to 1) of 500 mg erythromycin 3 times daily. Periods were separated by a washout of at least 14 days. Nine healthy white male volunteers, 22 to 42 years old, with a body weight range of 58 to 90 kg (body mass index, 20.2-25.1 kg x m(-2)) began the study. One subject discontinued prematurely, and 8 concluded the study in accordance with the study protocol. RESULTS: The plasma and urinary pharmacokinetics of DHEC and its metabolites were characterized by a large variability. Concomitant treatment with erythromycin led to respective increases of 9.5 (95% confidence interval [CI], 6.5 to 13.9) and 16.5 (95% CI, 8.7 to 31.5) times the maximum observed plasma drug concentration and the area under the time course of the plasma concentrations up to the last quantifiable concentration after dosing of unchanged DHEC (determined by radioimmunoassay). The 24-hour urinary excretion was on average 11 times larger (95% CI, 5.9 to 20.7). Qualitatively similar findings were recorded for the total of DHEC plus metabolites (as determined by enzyme immunoassay). CONCLUSIONS: The concomitant use of erythromycin or similarly CYP3A4-inhibiting agents along with direct dopaminergic agonists such as the ergoline DHEC may cause a clinically relevant increase in pharmacokinetic exposure, which may induce exaggerated dopaminergic effects.

Treatment of restless legs syndrome with the dopamine agonist alpha-dihydroergocryptine.

An open pilot study with the dopamine agonist alpha-dihydroergocryptine (DHEC) was conducted in 16 patients with idiopathic restless legs syndrome (RLS) over a period of 5 weeks. Following a drug-free interval of 1 week, the patients were treated with daily doses of 10 to 40 mg DHEC. As compared to baseline values, treatment led to a statistically significant reduction of subjective RLS symptoms. Overall complaints at night decreased significantly by 63.9 +/- 38.1% as measured by a visual analogue scale. Detailed evaluation of sensory discomfort, motor restlessness, involuntary movements, as well as sleep quality also showed significant improvement. Side effects were mostly mild and affected mainly the gastrointestinal tract. Five patients needed domperidone for treatment of concomitant nausea. One patient stopped the study due to nausea. In conclusion, the results of this open study suggest a role for DHEC in the treatment of RLS.

[Experience in the administration of vasobral in sensorineural vascular hypoasusis]. / Obosnovanie primeneniia élasticheskoi tamponady posleoperatsionnykh polostei srednego ukha.

24 patients with neurosensory hypoacusis of vascular genesis related to chronic cerebral vascular deficiency in the vertebrobasillar bed combined with cervical osteochondrosis were given basobral. The drug produced positive changes in neurological symptoms, lowered hearing thresholds in the range of high frequencies, improved cerebral hemodynamics and hearing afferentation at the stem level of the acoustic analyzer.

The distribution of major lymphocyte subsets in cord blood is associated with its pH.

OBJECTIVES: To assess in venous cord blood the distribution of major lymphocyte subsets according to pH and medications used during labor. DESIGN AND METHODS: Venous cord blood was sampled immediately after labor from 70 newborns (35 males and 35 females) delivered vaginally. Lymphocytes were immunophenotyped by flow cytometry and pH was measured using the AVL 900 automated blood gas analysis system. Data on birth weight, gestational age at delivery, length of labor, presence of stained amniotic fluid, medications used during labor, maternal risk factors, age and parity were collected. RESULTS: The percentage of T lymphocytes decreased while the percentage of NK lymphocytes increased with decreasing pH over the whole range of pH values. The proportions of T and NK lymphocytes were associated with the administration of neuroplegics, spasmolytics or dihydroergotoxin in the first stage of labor. CONCLUSIONS: Cord blood pH and labor-associated variables should be taken into account to adequately interpret the profile of major lymphocyte subsets as a marker of the effect of different prenatal factors on the immune system of neonates.

Plasma and urine pharmacokinetics of the dopamine agonist alpha-dihydroergocryptine in patients with hepatic dysfunction.

OBJECTIVE: The aim of this study was to evaluate the pharmacokinetic behavior of unchanged alpha-dihydroergocryptine (DHEC, Almirid, Desitin Arzneimittel GmbH, Hamburg, Germany, under licence of Polichem S.A., Luxembourg) and total DHEC (unchanged DHEC and pooled metabolites) in plasma and urine in patients with impaired hepatic function, following administration of single oral doses. METHODS: The study was carried out according to an open, uncontrolled, parallel-group design, investigating two study groups: patients with hepatic dysfunction, i.e. with evidence of stable cirrhosis (n = 10) and age- and sex-matched healthy subjects (n = 8). Each subject received a single dose of 20 mg DHEC. Blood samples were taken at specified intervals up to 72 h after dosing and urine was collected fractionally for 24 h. Concentrations of unchanged DHEC were determined by RIA and concentrations of total DHEC (unchanged and pooled metabolites) by EIA. RESULTS: The plasma and urinary pharmacokinetics of DHEC and its metabolites were characterized by large variability. In patients with impaired hepatic function, the geometric mean Cmax and AUC(0-infinity) values for unchanged DHEC were 571.3 pg/ml (CV: 0.87) and 4038 pg x h/ml (CV: 1.04) and were approximately 2 times (2.04, 95% CI: 0.93 to 4.46 and 2.11, 95% CI: 0.58 to 7.73 for Cmax and AUC(0-infinity), respectively) larger than those measured in age-matched healthy controls. The 24-hour urinary excretion was approximately 3 times (3.41, 95% CI: 0.95 to 12.21) higher in patients with hepatic dysfunction. Similar results were obtained for total DHEC. CONCLUSIONS: The results reflect an increased systemic exposure in patients with impaired hepatic function which is not due to a reduced urinary excretion/elimination or reduced renal clearance. The most likely mechanism involved is a reduction in pre-systemic biotransformation. The observed range of effects on the pharmacokinetics of DHEC in patients with compromized hepatic function does not suggest the need to revise the dosage recommendations, since treatment with DHEC is generally started with low doses and is slowly up-titrated according to the individual response and the occurrence of adverse effects. Nevertheless, lower maintenance doses are likely to be achieved.