MANAGEMENT OF RISKS OF ADVERSE DRUG REACTIONS ACCORDING TO ADR REPORT FORM DATA FROM LVIV REGION HEALTHCARE FACILITIES IN 2022.

The study aimed to analyse the adverse drug reactions report form data received by the State Expert Center of the Ministry of Health of Ukraine from healthcare professionals in the Lviv region in 2022. Regarding specific types of medicines, the ones with proven cause-and-effect relationships that caused the highest frequency of adverse drug reactions incidents were chemotherapeutic agents (35.5%), medicines affecting the cardiovascular system (20.3%), and non-steroidal anti-inflammatory drugs (8%). Within the penicillin class, amoxicillin potentiated by clavulanate (67%) and amoxicillin (29%) were the dominant drugs showing the highest incidence rate of adverse reactions. Among cephalosporins, ceftriaxone (46%) and cefixime (15%) were found to take the lead in terms of adverse reaction frequency. The highest proportion among all adverse drug reactions caused by penicillins and cephalosporins was attributed to allergic reactions. To confirm or rule out immediate or delayed type allergies in patients, as well as in patients with a history of immediate-type allergic reactions to ß-lactams and planned administration of another ß-lactam, it is necessary to conduct skin testing (skin prick test, or, in the case of parenteral administration, intradermal test) with the planned ß-lactam antibiotic. The second highest proportion of induced adverse drug reactions was attributed to drugs affecting the cardiovascular system (20.3%). The leading medications in the angiotensin-converting enzyme inhibitors category were enalapril (47%) and the combination of lisinopril with hydrochlorothiazide (24%). In the angiotensin II receptor blockers category of medications, valsartan (30%) and telmisartan-hydrochlorothiazide combination (20%) ranked highest. In the category of CCB drugs, amlodipine (66%) and nifedipine (20%) held the leading positions. among angiotensin-converting enzyme inhibitors, enalapril caused the most prevalent and predicted adverse reaction, that of cough, affecting 10.5% of patients, whereas, with the combination therapy of lisinopril and hydrochlorothiazide, the cough was observed in only 5.2% of patients. Angiotensin II receptor blockers have a better safety profile, particularly concerning cough. Analysis of adverse drug reactions reports for angiotensin II receptor blockers showed no cases of cough with valsartan and telmisartan-hydrochlorothiazide combination. Among calcium channel blocker medications, amlodipine emerged to rank highest, causing one of the predicted adverse drug reactions, that of lower extremity oedema in 64% of patients. The second position was taken by the combination of amlodipine with valsartan, which showed a statistically significant reduction of 14.3% (p≤0.05) in the incidence of oedema. Using amlodipine at a dose of 5 mg in combination with sartan medicines as angiotensin receptor blockers is an effective therapeutic alternative not only for enhancing blood pressure control in hypertensive patients but also for improving the safety profile of amlodipine. Among all the non-steroidal anti-inflammatory drugs prescribed to patients in the Lviv region in 2022, the highest number of adverse reactions was associated with the administration of diclofenac, ibuprofen, paracetamol, and nimesulide, causing adverse drug reactions in 22%, 19%, 17%, and 10% of cases, respectively. The most common systemic manifestations of adverse reactions with these non-steroidal anti-inflammatory drugs were allergic reactions (63.4%) and gastrointestinal disorders (26.8%). From an evidence-based medicine perspective, the most justified approach for primary and secondary prevention of gastrointestinal complications is the use of proton pump inhibitors.

Epidemiology, Prevention, and Assessment of Tardive Dyskinesia and Advances in Treatment.

​​ Tardive dyskinesia (TD) is a disorder characterized by involuntary movements, typically of the orofacial muscles and also of the extremities and other muscle groups. The condition is associated with exposure to dopamine receptor blocking agents, including antipsychotics. Because the indications and off-label uses for these agents have expanded over the last 2 decades, a larger number of patients are receiving antipsychotic medications than in the past. While evidence suggests that patients being treated with second-generation antipsychotics have less risk for developing TD than those treated with first-generation antipsychotics, the decreased risk is not as great as was originally expected. In addition, patients with chronic psychiatric conditions often require long-term use of antipsychotics, putting them at risk for TD. This article addresses the prevalence, risk factors, and prevention of TD; assessment strategies including diagnostic criteria and rating scales; and evidence for TD treatments, including 2 newly approved medications: deutetrabenazine and valbenazine. ​​​.

Isolation and assessment of the in vitro anti-tumor activity of smenothiazole A and B, chlorinated thiazole-containing peptide/polyketides from the Caribbean sponge, Smenospongia aurea.

The study of the secondary metabolites contained in the organic extract of Caribbean sponge Smenospongia aurea led to the isolation of smenothiazole A (3) and B (4), hybrid peptide/polyketide compounds. Assays performed using four solid tumor cell lines showed that smenothiazoles exert a potent cytotoxic activity at nanomolar levels, with selectivity over ovarian cancer cells and a pro-apoptotic mechanism.

Optogenetic assessment of horizontal interactions in primary visual cortex.

Columnar organization of orientation selectivity and clustered horizontal connections linking orientation columns are two of the distinctive organizational features of primary visual cortex in many mammalian species. However, the functional role of these connections has been harder to characterize. Here we examine the extent and nature of horizontal interactions in V1 of the tree shrew using optical imaging of intrinsic signals, optogenetic stimulation, and multi-unit recording. Surprisingly, we find the effects of optogenetic stimulation depend primarily on distance and not on the specific orientation domains or axes in the cortex, which are stimulated. In addition, across a wide range of variation in both visual and optogenetic stimulation we find linear addition of the two inputs. These results emphasize that the cortex provides a rich substrate for functional interactions that are not limited to the orientation-specific interactions predicted by the monosynaptic distribution of horizontal connections.

The balance of striatal feedback transmission is disrupted in a model of parkinsonism.

Inhibitory connections among striatal projection neurons (SPNs) called "feedback inhibition," have been proposed to endow the striatal microcircuit with computational capabilities, such as motor sequence selection, filtering, and the emergence of alternating network states. These properties are disrupted in models of Parkinsonism. However, the impact of feedback inhibition in the striatal network has remained under debate. Here, we test this inhibition at the microcircuit level. We used optical and electrophysiological recordings in mice and rats to demonstrate the action of striatal feedback transmission in normal and pathological conditions. Dynamic calcium imaging with single-cell resolution revealed the synchronous activation of a pool of identified SPNs by antidromic stimulation. Using bacterial artificial chromosome-transgenic mice, we demonstrate that the activated neuron pool equally possessed cells from the direct and indirect basal ganglia pathways. This pool inhibits itself because of its own GABA release when stimuli are frequent enough, demonstrating functional and significant inhibition. Blockade of GABAA receptors doubled the number of responsive neurons to the same stimulus, revealing a second postsynaptic neuron pool whose firing was being arrested by the first pool. Stronger connections arise from indirect SPNs. Dopamine deprivation impaired striatal feedback transmission disrupting the ability of a neuronal pool to arrest the firing of another neuronal pool. We demonstrate that feedback inhibition among SPNs is strong enough to control the firing of cell ensembles in the striatal microcircuit. However, to be effective, feedback inhibition should arise from synchronized pools of SPNs whose targets are other SPNs pools.

Improving drug adherence using fixed combinations caused beneficial treatment outcomes and decreased health-care costs in patients with hypertension.

We enrolled 196 patients with hypertension who were already being treated with free-drug combinations of angiotensin-II receptor blocker (ARB) and amlodipine. The free-drug combinations of ARB and amlodipine were replaced with the same dose of the fixed-dose combinations. The average home blood pressure (BP) in all patients receiving fixed-dose combinations was significantly lower than those receiving free-drug combinations (131 ± 10/75 ± 8 vs. 136 ± 11/77 ± 9 mm Hg, P < .01) accompanied with increasing drug adherence. After lowering BP by fixed-dose combinations, the costs for medications decreased by 31% over the 3 months.

Current management and recommendations for access to antiviral therapy of herpes labialis.

Herpes labialis is a common skin infective condition, worldwide, which is primarily caused by HSV-1. Recurrent episodes of herpes labialis, also known as cold sores, can be frequent, painful, long-lasting and disfiguring for infected patients. At present, there are two types of antivirals for the treatment of herpes labialis, topical and oral, which are available over the counter or as prescription-only. The aim of antiviral therapy is to block viral replication to enable shortening the duration of symptoms and to accelerate healing of the lesions associated with herpes labialis. This review examines the evidence for the effectiveness of current topical and oral antivirals in the management of recurrent episodes of herpes labialis. In most countries, oral antivirals for herpes labialis are available as prescription-only. However, in early 2010, the oral antiviral famciclovir was reclassified from prescription-only medicine to pharmacist-controlled status in New Zealand. The benefits and risks associated with moving an antiviral therapy for herpes labialis from prescription-only to pharmacist-controlled status are reviewed here, and the implications for patients, general physicians and pharmacists are considered.

[The significance of generic valsartan in the treatment of patients]. / A generikus valsartan jelentosege a betegek ellátásában.

The renin-angiotensin-aldosterone system (RAAS) is involved in the regulation of electrolyte and water balance primarily; however, it also influences vascular function and increases blood pressure--especially under pathological conditions. Hypertension, post-myocardial infarction state, and heart failure are, for example, associated with excessive systemic and/or local activation of the RAAS. Angiotensin II (AT-II) generated by the latter, contributes--along with additional factors and through its deleterious effects (vasoconstriction, endothelial dysfunction, atherosclerosis, prothrombotic state, fibrosis, etc.)--to damage to the target organs involved in the sequence of cardiovascular events. Inhibiting the RAAS at different levels is of therapeutic importance--its purpose is to delay disease progression, to prevent end organ damage, and to achieve a better outcome. As AT-II acts on several (AT1 and AT2) receptors, using angiotensin receptor blocking (ARB) agents with a high selectivity for the AT1 receptor is the rational choice. In view of its favourable therapeutic properties and efficacy demonstrated by morbidity and mortality studies, a generic formulation of appropriate quality, containing valsartan as active substance could prove to be the ideal treatment for patients with hypertension and other cardiovascular disorders.

Synaptic vesicle retrieval time is a cell-wide rather than individual-synapse property.

Although individual nerve terminals from the same neuron often differ in neurotransmitter release characteristics, the extent to which endocytic retrieval of synaptic vesicle components differs is unknown. We used high-fidelity optical recordings to undertake a large-scale analysis of endocytosis kinetics of individual boutons in hippocampal rat neurons. Our data indicate that endocytosis kinetics do not differ substantially across boutons from the same cell but instead appear to be controlled at a cell-wide level.

Baseline sensitivity and resistance-risk assessment of Phytophthora capsici to iprovalicarb.

Iprovalicarb has been used to control Phytophthora capsici, a devastating pathogen of many economically important crops. To evaluate the risk of fungicide resistance, 158 isolates of P. capsici were examined for sensitivity to iprovalicarb by measuring mycelial growth. Values of effective concentrations for 50% mycelial growth inhibition varied from 0.2042 to 0.5540 µg/ml and averaged 0.3923 (±0.0552) µg/ml, with a unimodal distribution. This is the first report of P. capsici isolates highly resistant to iprovalicarb (resistance factor >100). Resistance of the isolates was stable through 10 transfers on iprovalicarb-free medium, and most resistant isolates had the same level of fitness (mycelial growth, zoospore production, and virulence) as their corresponding parents, indicating that iprovalicarb resistance was independent from other general growth characters. There was cross-resistance among all tested carboxylic acid amide (CAA) fungicides, including iprovalicarb, flumorph, dimethomorph, and mandipropamid, but not with non-CAA fungicides, including azoxystrobin, chlorothalonil, cymoxanil, etridiazole, metalaxyl, and zoxamide. Based on the present results, resistance risk of P. capsici to CAAs could be moderate and resistance management should be considered.

Differential analysis of secondary metabolites by LC-MS following strain improvement of Streptomyces lydicus AS 4.2501.

Metabolite variations in a high-yielding mutant and its parent strain were studied by comparative LC-MS analysis after strain improvement. Streptomyces lydicus AS 4.2501-P28, a propionate-resistant mutant isolated by the high-frequency screening method using the principle of eliminating precursor inhibition effects, showed an increase of 267% in streptolydigin titre over the starting strain. Culture extracts of this mutant and its parent strain were analysed in parallel by an LC-MS technique, including full scan and extracted-ion scan, ESI-MS (electrospray-ionization MS) detection, DAD (diode-array detection) and MS2 (tandem MS) measurement. The main metabolic variations were obviously found in intermediates, metabolites and biosynthetic pathways: two unknown metabolites with the molecular [M-H]- ions at m/z 423.3 and 687.2, corresponding to two branch pathways, were blocked in the mutant, and the accumulation of a significant intermediate at m/z 363.1 [M-H]- decreased dramatically in the mutant cultures, resulting in the overproduction of streptolydigin (an antibiotic that inhibits prokaryotic RNA polymerase) in the mutant. Ion fragmentations of the tandem-MS spectra provided experimental evidence for the structural characterization of the three compounds obtained. In comparison with the traditional methods, comparative LC-MS analysis was rapid, sensitive and suitable for characterizing intermediates, metabolites and pathways for elucidation of the metabolic alterations after the isolation of improved strains.

Telmisartan but not valsartan increases caloric expenditure and protects against weight gain and hepatic steatosis.

The potential effects of angiotensin II receptor blockers (ARBs) on adipose tissue biology and body weight are of considerable interest, because these agents are frequently used to treat hypertension in patients who are prone to visceral obesity, the metabolic syndrome, and diabetes. In rats fed a high-fat, high-carbohydrate diet, we compared the effects of 2 ARBs, telmisartan and valsartan, on body weight, food intake, energy expenditure, fat accumulation, fat cell size, and hepatic triglyceride levels. Telmisartan, but not valsartan, promoted increases in caloric expenditure and protected against dietary-induced weight gain. In the telmisartan-treated rats, absolute food intake, but not food intake adjusted for body weight, was lower than in valsartan-treated rats or controls. Telmisartan reduced the accumulation of visceral fat and decreased adipocyte size to a much greater extent than valsartan and was also associated with a significant reduction in hepatic triglyceride levels. Moreover, telmisartan, but not valsartan, increased the expression of both nuclear-encoded and mitochondrial-encoded genes in skeletal muscle known to play important roles in mitochondrial energy metabolism. Thus, in addition to a class effect of ARBs in modulating adipocyte size, these findings raise the possibility that certain molecules, like telmisartan, may have a particularly strong impact on fat cell volume and fat accumulation, as well as distinctive effects on energy metabolism, that may help protect against dietary-induced visceral obesity and weight gain.

Assessment of angiotensin II receptor blockade in humans using a standardized angiotensin II receptor-binding assay.

An in vitro angiotensin II (AngII) receptor-binding assay was developed to monitor the degree of receptor blockade in standardized conditions. This in vitro method was validated by comparing its results with those obtained in vivo with the injection of exogenous AngII and the measurement of the AngII-induced changes in systolic blood pressure. For this purpose, 12 normotensive subjects were enrolled in a double-blind, four-way cross-over study comparing the AngII receptor blockade induced by a single oral dose of losartan (50 mg), valsartan (80 mg), irbesartan (150 mg), and placebo. A significant linear relationship between the two methods was found (r = 0.723, n = 191, P<.001). However, there exists a wide scatter of the in vivo data in the absence of active AngII receptor blockade. Thus, the relationship between the two methods is markedly improved (r = 0.87, n = 47, P<.001) when only measurements done 4 h after administration of the drugs are considered (maximal antagonist activity observed in vivo) suggesting that the two methods are equally effective in assessing the degree of AT-1 receptor blockade, but with a greatly reduced variability in the in vitro assay. In addition, the pharmacokinetic/pharmacodynamic analysis performed with the three antagonists suggest that the AT-1 receptor-binding assay works as a bioassay that integrates the antagonistic property of all active drug components of the plasma. This standardized in vitro-binding assay represents a simple, reproducible, and precise tool to characterize the pharmacodynamic profile of AngII receptor antagonists in humans.

Assessment of effects of amino acids and branched chain keto acids on leucine oxidation in human lymphocytes.

Effects of amino acids and branched chain keto acids on leucine transamination and oxidation were assessed in peripheral human lymphocytes. Isoleucine (80-200 mumol/l) and valine (250-500 mumol/l) diminished transamination and oxidation of leucine up to 25%, glutamine (50-1000 mumol/l) up to 55%. alpha-Ketoisocaproic acid (KIC; 200 mumol/l) augmented the activity state of branched chain keto acid dehydrogenase by 40%. It is concluded that in peripheral human lymphocytes (1) isoleucine, valine and glutamine are physiological inhibitors of leucine catabolism, and (2) leucine can promote its own degradation via KIC.

Assessment of in vivo protein synthesis in lamb tissues with [3H]valine flooding doses.

Week-old lambs received an intravenous injection of 4.3, 8.5, 12.8 or 17.1 mmol [3H]valine/5 kg body weight, i.e., 3.6-14.4-times the whole-body free valine content. To ensure that protein synthesis measurements in lambs are reliable within a 30-min period, these large amounts of valine must account for at least around 11-times the total free pool of valine. This amounted to 12.8 mmol valine/5 kg body weight. There were no significant variations in plasma insulin and plasma glucagon levels 5, 13 and 30 min after the injection of so much valine. The fractional rates of protein synthesis were determined in tissues of animals receiving either 12.8 or 17.1 mmol valine/5 kg body weight. The rates of protein synthesis in the jejunum (87.5%/day), liver (106.6%/day) and tensor fasciae latae muscle (18.8%/day) of lambs injected with the 12.8 mmol [3H]valine flooding dose, were in the range of data obtained in immature rats. Increasing the flooding amount of valine up to 17.1 mmol/5 kg body weight did not significantly alter protein synthesis rates in the jejunum, liver or skeletal muscle. This suggested that both the flooding-dose method in itself and valine had no effect on in vivo protein synthesis.