Cytochrome System Research Articles

Molecular Insights into the Interaction of Tryptophan Metabolites with the Human Aryl Hydrocarbon Receptor in Silico: Tryptophan as Antagonist and no Direct Involvement of Kynurenine.

A direct link between the tryptophan (Trp) metabolite kynurenine (Kyn) and the aryl hydrocarbon receptor (AhR) is not supported by metabolic considerations and by studies demonstrating the failure of Kyn concentrations of up to 100 μM to activate the receptor in cell culture systems using the proxy system of cytochrome P-450-dependent metabolism. The Kyn metabolite kynurenic acid (KA) activates the AhR and may mediate the Kyn link. Recent studies demonstrated down regulation and antagonism of activation of the AhR by Trp. We have addressed the link between Kyn and the AhR by looking at their direct molecular interaction in silico. Molecular docking of Kyn, KA, Trp and a range of Trp metabolites to the crystal structure of the human AhR was performed under appropriate docking conditions. Trp and 30 of its metabolites docked to the AhR to various degrees, whereas Kyn and 3-hydroxykynurenine did not. The strongest docking was observed with the Trp metabolite and photooxidation product 6-Formylindolo[3,2-b]carbazole (FICZ), cinnabarinic acid, 5-hydroxytryptophan, N-acetyl serotonin and indol-3-yllactic acid. Strong docking was also observed with other 5-hydroxyindoles. We propose that the Kyn-AhR link is mediated by KA. The strong docking of Trp and its recently reported down regulation of the receptor suggest that Trp is an AhR antagonist and may thus play important roles in body homeostasis beyond known properties or simply being the precursor of biologically active metabolites. Differences in AhR activation reported in the literature are discussed.

Understanding the Role of Candida Abicans in the Development of Cancer Cells, its Progression Mechanism, Possible Preventive Measures and Treatment

As a common human commensal fungus, Candida albicans may play an active part in cancer progression rather than just being present by chance in people who have cancer. A lot of research has shown that having Candida albicans in your body can make you more likely to get oral, esophageal, intestinal, and maybe even skin cancers. But more research needs to be done to find out exactly how this opportunistic pathogen adds to the development of cancer. The purpose of this review is to summarize the current data and possible ways that Candida albicans may be linked to cancer. The fungus may help tumors grow by using its cytochrome system to make DNA-damaging benzopyrene molecules. In addition, it can change the immune system by causing inflammation while blocking antitumor reactions. Candida albicans is a dimorphic fungus, which means it can change between yeast forms with only one cell and hyphal forms that invade host cells and help them spread. The pathogen may be protected by its biofilms, which may change the native microbiota makeup in ways that make people more likely to get cancer. Infected tissues could also have oncogenic signaling turned on by fungus virulence factors. Assuming that the link between Candida and cancer is a direct one, Candida albicans could be a useful way to tell which people are most likely to get cancer. Taking aim at the fungus is also a fresh way to make present cancer treatments better. But well-planned prospective clinical studies are still needed to make sure that the results of research on associations and animal models are correct. Getting clear on the molecular processes will help us understand how tumors grow and find new ways to treat them that focus on how the host and pathogen interact.

Pathogenetic basis of optic nerve atrophy in methanol poisoning

Optic nerve atrophy is a pathomorphological consequence of diseases of the peripheral neuron of the visual pathway, manifested as atrophy of nerve fibers of varying severity. The toxic effect of methanol is mainly associated with formic acid and formaldehyde, which suppress the cytochrome system, inhibit oxidative phosphorylation, and thereby cause a deficiency of adenosine triphosphoric acid, to which brain and retinal tissues are especially susceptible. When formiate accumulates, tissue respiration is disrupted, leading to pronounced tissue hypoxia. As a result of such methanol metabolism, metabolic acidosis occurs. Tissue hypoxia develops in the first few hours as a result of the action of formic acid on the respiratory enzyme chain at the cytochrome oxidase level. Hypoxia and, as a consequence, a decrease in energy supply lead to a disruption of biological oxidation and the development of apoptosis in the optic nerve fibers. Understanding the process of optic nerve atrophy development at the pathogenetic level in methyl alcohol intoxication will help make a correct early diagnosis and prescribe timely treatment.

Effect of calcium levels on structure and function of mitochondria in yeast under high glucose fermentation.

In this study, the effects of calcium levels on structure and function of mitochondria under high glucose environment were studied. In the high glucose environment, yeast growth capacity was inhibited, and intracellular reactive oxygen species (ROS) content was increased from 6 h to 12 h, while ROS content was reduced in group with 1 × 10-1 and 1 g/L CaCl2 level from 24 h to 36 h. Exogenous calcium addition had a significant effect on the elevation of intracellular Ca2+ and cytochrome C content in yeast from 6 h to 12 h; mitochondrial membrane potential decreased with the increase of CaCl2 level under high glucose levels. Mitochondrial swelling of yeast was influenced by high glucose levels and showed a regulatory dynamic change by Ca2+ levels. Isocitrate dehydrogenase activity increased in 1 × 10-3 g/L CaCl2 level from 6 h to 12 h, α-ketoglutarate dehydrogenase activity increased with an increase in CaCl2 level from 6 h to 24 h. Calcium affected the structure and function of mitochondria by regulating the intracellular signal, enzymes in tricarboxylic acid cycle, and cytochrome system of yeast under high glucose stress.

Metabolic adverse effects of antipsychotics: the state of the problem and management options

Antipsychotic drugs are widely used for many psychiatric disorders, such as schizophrenia, bipolar affective disorder, delusions and hallucinations due to neurological disorders, depression with severe psychotic symptoms. Metabolic disorders including weight gain, dyslipidemia and hyperglycemia are one of the most common side effects of antipsychotic therapy. Psychiatric patients have higher risk of cardiovascular disease, so that the development of metabolic side effects is an important clinical problem that should be solved. Antipsychotic-induced weight gain may cause distress that leads to antipsychotics withdraw and repeated hospitalizations. Lifestyle changes, correction of the antipsychotic treatment, additional medications and their combination are the possible solutions of antipsychotic metabolic side effects. Lifestyle modification is a first-line therapy that should complement other options, when it feasible. At the same time, it can be extremely difficult for patients receiving antipsychotic to adhere dietary and physical activity recommendations. Replacing an antipsychotic with a milder drug is not always possible and may not be enough effective. Metformin seems to be the most well-studied, safe and effective agent that is prescribed to deal with antipsychotic-induced weight gain and associated metabolic disorders. Glucagon-like peptide type 1 receptor agonists and thiazolidinediones are mentioned as alternative medications, but clinical data on their efficacy and safety in this patient group are extremely limited. Dyslipidemia can develop as an independent antipsychotic side effect even without an increase in body weight. The most effective treatment, as in the general population, is statin therapy. However, the joint appointment of statins and antipsychotic significantly increases the risk of adverse reactions, such as myalgia, myopathy, increased creatine kinase levels, due to the competition of drugs for the cytochrome system. It is still unknown what scales should be used for cardiovascular risk stratification in patients taking antipsychotic and whether it is possible to use metformin to prevent antipsychotic-induced weight gain, and if so, how to select patients for whom such therapy can be indicated. Finally, more clinical trials are needed to evaluate the efficacy and safety of other classes of hypoglycemic and lipid-lowering drugs in patients on antipsychotics.

A comparative review of the activity of enzymes of the cytochrome P450 system in humans and laboratory animals. Prognostic value of preclinical models in vivo

Cytochrome P450 enzymes play a key role in drug biotransformation. The expression and activity of each CYP450 is influenced by a unique combination of biochemical factors, species and genetic differences, age, sex, nutrition and etc.Cytochromes P450 are a family of heme-containing proteins involved in the metabolism of xenobiotics, drugs, and endogenous compounds. Drugs could act as inducers or inhibitors of cytochrome P450 enzymes. Understanding the mechanisms of inhibition or induction of enzymes is extremely important in preclinical studies and prescribing complex therapy. One of the main challenges in the development of therapeutic agents is to determine which animal species reflects the human ability to metabolize certain drugs. The study of CYPs and their interaction with drugs is an urgent problem in preclinical studies. Thus, an adequate and maximally similar experimental preclinical models are necessary to study the pharmacokinetic and pharmacodynamic properties of promising chemicals and their effect on certain cytochrome P450 enzymes.This review compares the main subfamilies and their enzymes of the cytochrome system of humans and laboratory animals involved in drug metabolism. The problems of choosing biological models in vivo in preclinical studies in the study of medicinal substances are considered. The predictive value of in vivo models of preclinical studies was analyzed from the point of view of the cytochrome P450 system in humans and laboratory animals.

The original anticonvulsant meta-Cl-benzhydrylurea (m-CL-BHM) induces of the liver monooxygenase system and stimulates the neuroimmune response in behavioral disorders of alcoholic origin

IntroductionThe anticonvulsant m-Cl-BHM is promising for the pathogenetically directed thrapy does not cause negative effects.ObjectivesInvestigation of the effect of m-Сl-BHM on “immunochemical homeostasis” in rats with experimental alcoholism.Methodsm-Cl-BHM was injected at a dose of 100 mg/kg (1/20 LD50) for 5 and 30 days into the stomach of male Wistar rats who preferred alcohol according to the screening conditions and kept for 10 months. in free access to a 15% ethanol solution, which made up the group of “heavy drinkers” (HD). Phenobarbital was administered at a dose of 25 mg/kg (1/20 LD50).ResultsThe features of the monooxygenase system of cytochrome P450 of the liver and ECT in the lymphoid organs of rats were studied at different periods of administration of m-CL-BHM -5 and 30 days. to HD rats. m-CL-BHM has an inducing effect on the monooxygenase system of the liver, causes phase changes in the lymphoid organs and ECT. Long-term administration of m-CL-BHM caused a depletion of the cellular composition of lymphoid organs, a decrease in ECT of spleen cells and peritoneal exudate, these changes were less pronounced compared with phenobarbital. The activation of the immune system inversely regulates the production of enzymes of the cytochrome system, since the concentration of low molecular weight targets is sharply reduced with the help of antibodies. m-Cl-BHM metabolites conjugated to endogenous macromolecules form a full-fledged stimulus for the immune system.ConclusionsNeuroimmune response to the introduction of m-CL-BHM is significant in behavioral disorders associated with alcoholism and the correction of this condition.DisclosureNo significant relationships.

L’utilisation des antidépresseurs dans l’épisode dépressif caractérisé unipolaire du sujet âgé

ObjectiveTo study the ageing-related pharmacological modifications about major depressive episodes in the elderly and their impact on the efficiency and tolerability of antidepressants. MethodsResearch through Pubmed and the Cochrane Database of Systematic Reviews, using the following keywords “antidepressant” ; “treatment”; “late life depression”; “elderly”; up until July 2021. ResultsAntidepressants were found to be more efficient than a placebo in the elderly's response to and remission from major depressive episodes. Some depressive episode subtypes seem to be less responsive to antidepressants, such as depressive episodes of vascular origin, for which treating cardiovascular risk factors by statins, angiotensin receptor blockers or calcium channel blockers seems relevant. Two other depressive episode subtypes were highlighted : post-stroke depressive episodes and those induced by major neurocognitive disorders. Antidepressants showed an efficient response in the first case but not in the second. Even though antidepressants are known to stimulate cognitive performances in animals, as yet there is not sufficient evidence to prove they indeed improve cognitive functions, or reduce the risk of developing a neurocognitive disorder, or decelerate the cognitive decline in major neurocognitive disorders in humans. Ageing creates pharmacodynamical changes that increase older people's vulnerability to the side effects of antidepressants. Moreover, age-related pharmacokinetic modifications can also change every step in a drug's transformation process in the body, which leads to a high probability of having adverse effects. Since most antidepressants are eliminated using the P450 cytochrome system, their dosage must be adapted to changes of the P450 system. Somatic comorbidities can, in themselves, influence the pharmacokinetics of antidepressants. Many antidepressants interact with the P450 cytochrome and the P-GP protein, which puts them at a high risk of drug interactions. There is no proven efficiency difference between antidepressant classes. Some antidepressant adverse effects can be of particular importance in the elderly, like the risk of bleeding, cardiovascular episodes, hyponatremia, falling and fractures, anticholinergic effects, extrapyramidal syndrome, epilepsy, liver disease and death. Selective serotonin reuptake inhibitors have an indication as the first line of treatment, avoiding paroxetine and fluoxetine. Serotonin and norepinephrine re-uptake inhibitors are relevant if the patient presents psychomotor retardation or pain, while keeping in mind to check blood pressure. Tricyclics and monoamine oxidase inhibitors should be avoided because of their anticholinergic effects. Bupropion can be prescribed if the patient has extreme fatigue. Mirtazapine is useful when the patient presents sleep or appetite disturbance. Several molecules can be used in the case of drug-resistant depression, such as associating aripiprazole with small-dosage antidepressants, or electroconvulsive therapy, or repetitive Transcranial Magnetic Stimulation (rTMS). Ketamine and psychostimulants seem to have antidepressant effects, but complementary studies are needed to conclude. ConclusionsUnipolar major depressive episodes in the elderly are frequent and their medicinal treatment has specific features. Knowing the specificities of antidepressant use in the elderly allows to optimize its efficiency and to limit the risk of inappropriate prescription leading to harmful adverse effects.

The Efficacy of Sedation Depends on the Diet of Population

Physicians are often faced with the fact that the duration of anesthesia varies in different patients, which significantly complicates the process of surgical intervention and may confront the surgeon with an unforeseen situation. Recently, publications have appeared in the literature on the effects of various, including exotic products on anesthesia. There are also many conflicting statements about the effect of camel milk (CM) on the duration of anesthesia. Some data show that CM prolongs anesthesia, while other scientists argue the exact opposite: CM shortens the effect of the anesthetic. We decided to shed light on these studies by analyzing the effect of CM consumption on the effectiveness of local anesthesia in different patients. This article highlights the significant changes that occur in anesthesia due to the patients’ diet. To achieve the set goal, we sort the twenty patients underwent local anesthesia into groups depending on the habit of using CM. The first, control, group consisted of practically healthy patients who did not use CM throughout their lives, and the second group had the habit of regularly taking CM. In both groups, local anesthesia was first performed without pre-drink CM. For the second time, participants in the control and experimental groups were asked to drink CM before the anesthesia procedure. Both in the control and experimental groups, patients drank CM one hour before local anesthesia. A significant correlation was found between the use of CM and the duration of anesthesia in both groups. Consumption of CM had a different effect on the duration of local anesthesia in the experimental and control groups. When milk was consumed before the use of analgesics in these two different groups, it changed exactly the opposite: for those who usually drink milk, it was shortened, and for those who did not drink it daily, lengthened. Thus, we found that the differences in the statements of scientists about the CM impact on anesthesia are based on the fact of different effects of CM in its single and long-term use. We attribute this to the suppression under long-term use of CM the cytochrome system neutralizing both foreign compounds and nutrients entering the organ. However, further long-term studies with larger sample sizes are needed to elucidate the molecular mechanisms behind this phenomenon.

Polymorphisms in CYP2C8 Gene in Pakistani Population and Their Frequencies in Various Ethnic Groups

Cytochrome P4502C8 represents 7% of the hepatic cytochrome system and metabolizes around 5% of drugs in phase I processes. It also plays a significant role in the metabolism of endogenous compounds. More than 20 single nucleotide polymorphisms (SNPs) have been reported, mainly in exon 3, 5, and 8. Some of the SNP’s lead to decreased enzyme activity and may have impact on drug metabolism. This research study aims to determine the frequencies of the most common SNPs of the CYP2C8 gene (CYP2C8*2, *3, *4) in the Pakistani population. A cross-sectional study consisting of 391 healthy humans was conducted after taking informed consent. DNA was extracted using commercial kits, and allelic and genotype frequencies were determined after PCR amplification, restriction fragment length polymorphism, and gel electrophoresis. The rate of minor allele was found to be 11.64% for CYP2C8*2, 14.71% for CYP2C8*3, and 1.53% for CYP2C8*4. Comparison with the 1000 Genome project reveals that the allelic frequencies of CYP2C8*4 in Pakistani population were similar to other South Asian populations while the frequencies of CYP2C8*2 and CYP2C8*3 as significantly different from other South Asian populations. A significant interethnic variation was also observed among Pakistani ethnicities. The CYP2C8*2 allele was highest in the Sindhi population, CYP2C8*3 in the Pashtoon population and CYP2C8*4 in the Balochi population. These data suggest that the frequency of poor metabolizers of CYP2C8 is high enough in the Pakistani population to warrant further genotype-phenotype correlations studies on individual drugs metabolized by CYP2C8 enzyme.

Pitavastatin: focus on safety and drug interactions

Pitavastatin is a drug from the group of HMG-CoA reductase inhibitors, which has good lipid-lowering efficacy and has no significant effect on the risk of diabetes mellitus. This drug is non significantly metabolized by the P450 cytochrome system, which minimizes the risk of possible drug-drug interactions. Peptide organic anionic transporter inhibitors also may affect the efficacy and safety of the drug. This review summarizes the data on the problems of drug interactions of pitavastatin.

Biological profile of medical response in alcoholic patients of different ethnic groups in Siberia

IntroductionThe individual sensitivity of a person to the effects of alcohol is defined as the possibility of adaptive reactions, which are controlled by various factors associated in their manifestation with characteristics in various ethnic populations.ObjectivesTo determine biological profile of medical response in alcoholic patients of different ethnic groups.Methods168 alcoholic men, aged 17 to 62 years were examined. For the therapeutic correction of withdrawal and post-withdrawal symptoms of patients from two different ethnic groups (Tatars and Russians in Siberia), the original anticonvulsant galodif (M-chloro-benzhydrylurea) was used. Pharmacokinetic parameters were calculated a model-independent method of statistical moments: half-life (T1/2,h), total clearance (Clt,ml/min), average time of the residual drug in the body (MRI,h), average elimination time (MET,h), the area under the pharmacokinetic curve (AUC, μg/ml).ResultsGalodif causes a reduction in almost half T1/2, a significant decrease in the average time of the residual drug in the body MRI, and the average elimination time MET. Overall clearance increased. Under the influence of the course with Galodif, antipyrine elimination intensified, which indicates the induction of the cytochrome P-450 system of microsomal liver monooxygenases in Russian alcoholic patients. Galodif causes a reduction of almost five-fold T1/2, a significant decrease MRI and MET. Activation of oxidative metabolism of xenobiotics in Tatar alcoholic patients is more significant.ConclusionsThe increased sensitivity of P-450 cytochrome system to anticonvulsants action with inductive detoxification properties reflects differences in adaptive mechanisms in human from various ethnic groups, what is significant in the therapy.DisclosureNo significant relationships.

Specialized dietary food products in oncological practice

This review presents current data on the role of nutritional support in patients with cancer. The main reasons for the decrease in body weight, protein-energy deficiency in the development of malignant neoplasms are described. The data substantiating the appointment of dietary food products in various phases of the disease to patients receiving systemic anticancer therapy (chemotherapy, targeted therapy, immunotherapy) for a long time, and to cancer patients who underwent volumetric abdominal surgery are presented. The mechanisms of intoxication arising as a result of the disease itself, as well as a result of prolonged polychemoor irradiation therapy, are described in detail. The concept and mechanisms of endogenous intoxication syndrome are given. Special attention is paid to the role of the cytochrome system of the liver in detoxification processes. It has been shown that the accumulation of toxic metabolites in cancer disrupts the activity of the organs of detoxification and excretion, metabolites accumulate in tissues, which leads to difficulty in regulating the functions of the body and its protection from intoxication factors. The results of clinical studies of the data are presented and their effectiveness of the use of specialized dietary products of domestic production for cancer patients is presented. Detoxification protein cocktail for cancer patients (based on animal protein), Lactose-free detoxification protein cocktail for cancer patients (based on plant protein) and Drink detoxification for cancer patients (fruit-based). These specialized products have promote tonic, antioxidant, anti-inflammatory, analgesic, anti-toxic, detoxifying properties. It has been shown that dietary products contribute to the restoration of the concentration in the blood of the most important enzymes of antitoxic liver defense – ALT and AST, gamma-HT, total and direct bilirubin, and urea.

THE ROLE OF DETERMINING SOME GENETIC POLYMORPHISMS IN PATIENTS WITH NEURO-CIRCULATOR ASTHE- NIA AND HYPERTENSIVE HEART DISEASE OF STAGE I

Arterial hypertension is a multifactorial disease, a significant role in the pathogenesis of which is played by a genetic factor. In recent years, many studies have been carried out to identify genes in various diseases, including arterial hypertension, and candidate gene databases have appeared, to which the results of these studies have been added. There are known polymorphisms of genes associated with the development of arterial hypertension, as well as with a change in the pharmacodynamics of antihypertensive drugs. The following genes and the peculiarities of metabolism and activity of pressor systems associated with their polymorphisms are most studied: genes of the cytochrome system (CYP2D6, CYP2C9, CYP11B2); genes of the renin-angiotensin-aldosterone system: ACE (angiotensin-converting enzyme gene), AGT (angiotensinogen gene), AGTR1 and AGTR2 (angiotensin 1 and angiotensin 2 receptor genes). The objective of the study was to study the frequency of detection of gene polymorphisms associated with the development of arterial hypertension in patients with hypertensive neurocirculatory asthenia and stage I hypertension. A total of 77 conscripts and contract employees between the ages of 18 and 40 were examined. Using the amplifier, the following genes were studied by polymerase chain reaction and detection: the p-450 cytochrome gene (CYP11B2) and the AGT renin-angiotensin-aldosterone system gene: 704 T> C. Polymorphisms of candidate genes for arterial hypertension were found in 100% of the examined. AGT polymorphisms: 704 T> C and CYP11B2 were more often detected in stage I hypertension than in hypertensive neurocirculatory asthenia. Conducting genetic research at a young age in patients with hypertensive neurocirculatory asthenia will reveal a risk group for the development of hypertension.

The pharmacogenetics of hypoglycemia and the glycemic variability at the patients ith type 2 diabetes mellitus

To investigate the link between the hypoglycemia (registrated accurately by the professional Continuous Glucose Monitoring CGM; severe hypoglycemia at home) and the hetero-/homozygote carriage of single nucleotide polymorphisms (SNP) of cytochrome systems geneCYP2C9(rs1799853CYP2C9*2 иrs1057910CYP2C9*3) at the patients with Type 2 Diabetes Mellitus (T2DM) used sulphonylurea (SU). In Study Case-Control 120 T2DM-SU-patients genotyped by SNPs of geneCYP2C9(using PCR-RT) had been done the professional CGM (System iPro2, Medtronic) recorded Time in Range of Hypoglycemia (TIR-HYPO), level of Minimal CGM-hypoglycemia (MinGl) and standard CGM-parameters of Glycemic Variability. Severe hypoglycemia at home was recorded from visit to visit. The odds ratio (OR) of metabolic disturbances had been assessed for carriage SNPs in comparison with wide alleles. The Study established that carriage of SNPsrs1799853andrs1057910geneCYP2C9at T2DM-SU-patients associated with rising of Glycemic Variability and frequency of CGM-hypoglycemia (MinGl decreasing, increasing of TIR-HYPO and number of Glycemia Excursion 4 mmol/L/h), as well as increasing severe hypoglycemia at home (p0.05). Thus, OR at the carriage ofrs1799853andrs1057910respectively equaled: for CGM-hypoglycemia 7.78 (3.0220.01) and 5.80 (0.23145.87); number of Glycemia Excursion 4 mmol/L/h 5.76 (2.2914.43) and 4.44 (1.4313.76); MinGl3.9 mmol/L 4.39 (1.7910.75) and 6.26 (1.8421.30); CV40% (vs30%) 3.63 (1.0412.62) and 15.22 (0.59393.94);p0.05. At the real clinical practice the assessment of carriage of SNPs of geneCYP2C9before inclusion of SU to glucose-lowering scheme of T2DM-therapy it necessary to carry out for the detecting patients with a higher risk of hypoglycemia and rising of Glycemic Variability.

Management of geriatric patients with benign prostatic hyperplasia

Multimorbid older men are increasingly more common in daily practice and present achallenge because they are often affected by lower urinary tract symptoms (LUTS) and age-associated benign prostatic hyperplasia (BPH). In order to identify possible risks in diagnostics, therapy and counselling at an early stage, screening for functional deficits or risk factors with standardized procedures is helpful. An initial screening with subsequent assessment of everyday skills using the Barthel Index, Timed up & Go Test, and acognitive test are recommended. If frailty syndrome is detected, it should be taken into account during the pre-, peri-, and postoperative management, as it may indicate increased morbidity and mortality. Noninvasive methods for reducing the prostate volume without anesthesia can be atherapy option in older multimorbid patients, and with individual planning and consideration of risk factors, up to 70% of individuals become symptom-free. However, there is currently no gold standard for this vulnerable patient group. Number of medications and concomitant diseases and higher need for help are per se risk factors for unsatisfactory results after transurethral resection of the prostate (TURP) or laser vaporization. With drug therapy, concomitant medications and their interactions, especially in the cytochrome system, an existing multimorbidity and adherence to therapy must be taken into account. Combination therapies may complement each other and may bridge the time until surgery. Minimally invasive methods that can be performed without general anesthesia are suitable for geriatric patients, especially those with recurrent retention. Studies with the Rezüm® system (NxThera Inc., Maple Grove, MN, USA) and UroLift® (NeoTract Inc., Pleasanton, CA, USA) show that about 70% of patients can be relieved from the permanent catheter.

In Response.

We thank Drs Charchaflieh and Zafar1 for their interest in our article2 regarding the effect of caffeine consumption on resident physician’s driving performance variables in a high-fidelity, immersive driving simulator. While Charchaflieh and Zafar1 are correct that we did not measure baseline caffeine consumption in the participants, we would submit that there is limited and conflicting evidence whether regular intake of caffeine alters caffeine pharmacokinetics.3–5 In contrast, there is pronounced variability in CYP1A2 activity influencing caffeine clearance related to sex, race, genetic polymorphisms, liver disease, and exposure to agents that further induce the cytochrome system.6–8 Caffeine is primarily metabolized in the liver by cytochrome P450 enzymes, principally by CYP1A2.6 We did not evaluate for genetic polymorphisms nor construct a caffeine dose-response effect. We did, however, incorporate a self-reported caffeine sensitivity measure from all participants. The dose of caffeine (160 mg) administered in this study is considered a pharmacologic dose, such that the difference between people who are perceived to be more or less resistant to the effects of caffeine is not likely to be relevant. In our study of residents at a single institution, it would have been challenging to control for all of the variables that may have impacted caffeine sensitivity, and for that reason, we used perceived caffeine sensitivity. Most importantly, we used a crossover design where each resident served as their own control, completing both arms of the study (caffeinated versus noncaffeinated energy beverage). To the extent that it is possible, this suggests that any observed effect resulted from the caffeine. Drs Charchaflieh and Zafar1 are correct that we did not use the word “simulated” in the title. We feel very strongly that this is not misleading as the aim of our study, stated in both the Introduction and the Conclusion, was to evaluate the impact of a caffeinated energy beverage on driving performance in a high-fidelity driving simulator. The Methods section clearly indicates that the study was performed in the simulator, and the Results section refers directly to improved driving performance variables in the driving simulator. Finally, we note that the words “simulated,” “simulation,” and “simulator” occur 37 times in the article, including 4 times in the Abstract alone! We do not agree with Charchaflieh and Zafar’s1 statement at the end of their letter that suggests that our title or reporting of results within sections of the article are at all misleading or “considered less than accurate.” Julie L. Huffmyer, MDDepartment of AnesthesiologyUniversity of Virginia HealthCharlottesville, Virginia[email protected]Edward C. Nemergut, MDDepartments of Anesthesiology and NeurosurgeryUniversity of Virginia HealthCharlottesville, Virginia

Antihistamines in the treatment of allergic rhinitis

Allergic rhinitis is a common allergic disease that have a substantially negative impact on the patients’ quality of life. Pharmacotherapy is essential to the treatment of allergic rhinitis, including the use of antihistamines, leukotriene receptor antagonists, topical steroids, decongestants, cromones, anticholinergics and their various combinations. Antihistamines are commonly prescribed drugs to treat mild, moderate, and severe disease. The article discusses the mechanisms of action of first- and second-generation antihistamines and compares the potential side effects and drug interactions.First-generation antihistamines differ in their significant sedative and hypnotic effect, mainly due to their pronounced lipophilic properties and ability to transverse the blood–brain barrier and bind to H1-histamine receptors in the central nervous system. Due to low selectivity of the first-generation antihistamines, they may interact with other receptors and develop adverse side effects, including dry mouth, nasopharynx, more rarely pupillary dilation, increased intraocular pressure, tachycardia, and urine retention. Bilastine is a highly selective second-generation antihistamine that has a rapid onset and a prolonged action. This drug does not interact with the P450 cytochrome system or undergo significant metabolism in the human body, and therefore the drug has low potential for drug-drug interactions. Bilastine is excreted almost completely unchanged and therefore does not require dose adjustment in patients with renal or hepatic impairment. Bilastine demonstrated similar efficacy in seasonal allergic rhinitis compared to cetirizine and desloratadine, as well as similar efficacy and safety in long-term treatment of patients with perennial rhinitis compared to cetirizine. Bilastine is well tolerated both at standard and at supratherapeutic doses, appears to have less sedative potential than other second-generation antihistamines, and has no cardiotoxicity.

Polymorphic variants of xenobiotic metabolism genes and body mass index in schizophrenia patients receiving antipsychotic therapy

The use of atypical antipsychotic drugs has made metabolic disorders one of the most common side effect of pharmacotherapy for schizophrenic patients. The aim of this study was to assess the contribution of polymorphic variants of genes of the P450 cytochrome system to changes in body mass index in patients with schizophrenia. As a result of the study, we did not identify significant associations of genotypes and alleles of the studied polymorphic variants of the CYP2D6, CYP1A2, CYP2C19 genes with weight gain in patients with schizophrenia of Russian nationality of the Siberian region receiving antipsychotic therapy and can revealed neither protective nor predisposing effects. Metabolic syndrome and, increase in body weight especially, are complex side effect, and further studies is needed to increase successful exploration and identification of the genetic component and assess contribution.

Micro-RNA as a new biomarker of activity of the cytochrome system P-450: significance for predicting the antiplatelet action of P2Y12 receptor inhibitors

MicroRNAs are short non - coding RNAs that correlate with the levels of platelet activation which can be utilized as a biomarker when guiding P2Y12 inhibitors therapy. In this literature review, the perspectives of microRNA as a novel biomarker are discussed when guiding P2Y12 inhibitors therapy among the patients with coronary artery disease.