scholarly journals Influence of CYP3A Activity on the Efficacy and Safety of Fluvoxamine in Patients Depressive Disorders and Comorbid Alcohol Use Disorder

2018 ◽  
Vol 73 (6) ◽  
pp. 411-419 ◽  
Author(s):  
Mikhail S. Zastrozhin ◽  
Valery V. Smirnov ◽  
Alexander S. Sorokin ◽  
Elena A. Grishina ◽  
Kristina A. Ryzhikova ◽  
...  
Keyword(s):  
Alcohol Dependence ◽  
Selective Serotonin Reuptake Inhibitors ◽  
Depressive Disorders ◽  
Average Power ◽  
Inverse Correlation ◽  
Efficacy And Safety ◽  
Psychometric Scales ◽  
Safety Indicator ◽  
Endogenous Substrate ◽  
The Difference

Background: Alcohol dependence is often combined with affective disorders, in particular, depressive disorder (DD), which worsens adversely affects the prognosis of the course of both diseases and their outcomes. For the treatment of DD, drugs from the group of selective serotonin reuptake inhibitors, whose representative is fluvoxamine, are used. Fluvoxamine therapy is often associated with a risk of development is shown to be ineffective, and a part of patients develop dose-dependent adverse drug reactions (ADR) and pharmacoresistance.Objective: To study the effects of CYPD6 isoenzyme activity on the efficacy and safety of fluvoxamine therapy in patients with depressive disorders, comorbid with alcoholism.Methods: The study was conducted on 117 Russian patients with DD, alcohol-dependent comorbid. For the purpose of correction of depressive disorders within the framework of cyclothymia, fluvoxamine (Fevarin) was administered to patients at a dosage of 50−150 mg/day. Genotyping was carried out by the method of polymerase chain reaction in Real-time mode with allele-specific hybridization. Efficacy and safety were assessed using validated psychometric scales and an assessment of the severity of ADR. To evaluate the activity of CYP2D6, the method of high performance liquid chromatography with mass spectrometry was used to measure the urinary content of the endogenous substrate of this isoenzyme and its metabolite, the ratio of 6-hydroxy-1,2,3,4-tetrahydro-beta-carboline.Results: By the 9th day of the study, the severity of depressive symptoms on the HAMD scale was statistically significantly different in patients with different genotypes: (GG) 7.0 [6.0; 8.0], (GA) 4.0 [3.0; 5.0] (p0.001); safety indicator, estimated on a UKU scale: 3.0 [2.0; 4.0], (GA) 4.0 [4.0; 4.2] (p0.001). The presence of differences persisted on the 16th day: (GG) 5.0 [3.0; 6.0], (GA) 1.5 [1.0; 3.0] (p0.001); safety indicator, estimated on a UKU scale: (GG) 9.0 [9.0; 10.0], (GA) 6.0 [6.0; 7.0] (p0.001). The calculation of the correlation coefficients between the difference in the number of scores on psychometric scales and the metabolic ratio showed a statistically significant inverse correlation of the average power degree between the efficiency index estimated by the HAMD scale (r=-0.467, p0.05). There was no connection with the difference on the UKU scale (r=0.173, p0.05).Conclusion: In a study of a group of 117 patients with DD, comorbid with alcohol dependence, the effect of CYP2D6 activity, estimated by the ratio of the endogenous substrate concentrations of pinolin and its metabolite 6-hydroxy-1,2,3,4-tetrahydro-beta-carboline, on the efficacy of fluvoxamine therapy. This effect was also shown using the results of genotyping. The results of genotyping also showed the existence of a difference in the safety index in patients with different genotypes from the polymorphic marker CYP2D6 1846GA.

scholarly journals The Effect of Cyp2d6 Gene Polymorphism on the Efficacy and Safety of Mirtazapine in Patients with Depressive Disorders Comorbid with Alcohol

2019 ◽  
Vol 74 (3) ◽  
pp. 185-191
Author(s):  
Mikhail S. Zastrozhin ◽  
Valery V. Smirnov ◽  
Alexander S. Sorokin ◽  
Elena A. Grishina ◽  
Kristina A. Ryzhikova ◽  
...  
Keyword(s):  
Gene Polymorphism ◽  
Depressive Disorder ◽  
Alcohol Dependence ◽  
Adverse Drug Reactions ◽  
Depressive Disorders ◽  
Efficacy And Safety ◽  
Drug Reactions ◽  
Cyp2d6 Gene ◽  
Safety Indicator ◽  
Tetracyclic Antidepressants

Background: Alcohol dependence is often combined with affective disorders, in particular, depressive disorder, which adversely affects the prognosis of the course of both diseases. For the treatment of a depressive disorder, drugs from the group of tetracyclic antidepressants, of which mirtazapine is a representative, are used. Therapy with mirtazapine is associated with the risk of undesirable drug reactions and pharmacoresistance. Aim: To study the effect of CYPD6 isoenzyme activity on the efficacy and safety of mirtazapine therapy in patients with depressive disorders comorbid with alcoholism. Methods: The study was conducted on 109 Russian patients with a depressive disorder, comorbid with alcohol dependence. For the correction of depressive disorders within the framework of cyclothymia, mirtazapine was prescribed to patients at a dosage of 1545 mg/day. CYP2D6*4 genotyping (1846G A, rs3892097) was carried out using Real-time polymerase chain reaction with allele-specific hybridization. Efficacy and safety were assessed using validated psychometric scales and an assessment of the severity of adverse drug reactions. Results: By the 9th day of the study, the severity of depressive symptoms on the HAMD scale was significantly different in patients with different genotypes: (GG) 7.0 [6.0; 8.0], (GA) 4.0 [3.8; 5.0] (p0.001), safety indicator, estimated on a UKU scale: (GG) 3.0 [3.0; 3.0], (GA) 4.0 [4.0; 5.0] (p0.001). The presence of differences persisted on the 16th day: (GG) 5.0 [3.0; 6.0], (GA) 1.5 [0.8; 3.2] (p0.001), safety indicator, estimated on a UKU scale: (GG) 6.0 [6.0; 7.0], (GA) 8.5 [8.0; 10.0] (p0.001). Conclusion: In this study, the effect of CYP2D6 gene polymorphism on the efficacy and safety of therapy with mirtazapine was demonstrated. Carrying a minor allele A is associated with an increased risk of adverse drug reactions, but improving performance profile performance.

Effects of CYP2D6 activity on the efficacy and safety of mirtazapine in patients with depressive disorders and comorbid alcohol use disorder

2019 ◽  
Vol 97 (8) ◽  
pp. 781-785 ◽  
Author(s):  
M.S. Zastrozhin ◽  
V.Y. Skryabin ◽  
V.V. Smirnov ◽  
E.A. Grishina ◽  
K.A. Ryzhikova ◽  
...  
Keyword(s):  
Alcohol Use ◽  
High Performance ◽  
Alcohol Use Disorder ◽  
Depressive Disorders ◽  
Rating Scale ◽  
Correlation Coefficients ◽  
Inverse Correlation ◽  
Efficacy And Safety ◽  
Cyp2d6 Activity ◽  
Scale Scores

The objective of the study was to investigate the effects of CYP2D6 activity on the efficacy and safety of mirtazapine in patients with depressive disorders and comorbid alcohol use disorder who received mirtazapine. The study included 109 Russian patients who received mirtazapine at a dose of 30.0 [15.0; 45.0] mg per day. Genotyping of CYP2D6*4 (1846G > A, rs3892097) was performed using real-time polymerase chain reaction with allele-specific hybridization. The activity of CYP2D6 was evaluated by determining the concentration of endogenous substrate of the enzyme and its urinary metabolite — pinoline to 6-hydroxy-1,2,3,4-tetrahydro-beta-carboline ratio, using high-performance liquid chromatography – mass spectrometry. The statistically significant differences between the scores on the Hamilton Depression Rating Scale (HAMD) in patients with different genotypes were revealed by day 16: (GG) 5.0 [3.0; 6.0], (GA) 1.5 [1.0; 3.2] (p < 0.001), and for the The UKU Side Effects Rating Scale (UKU): (GG) 6.0 [6.0; 7.0], (GA) 8.5 [8.0; 10.0] (p < 0.001). The calculation of correlation coefficients between the differences in scale scores and metabolic rate showed the presence of statistically significant weak inverse correlation with the efficacy indicator evaluated by HAMD (r = −0.278, p < 0.05), but not by UKU (r = 0.274, p > 0.05). This study demonstrated that an increased CYP2D6 activity reduces the efficacy of treatment with mirtazapine.

Effects of CYP2C19*17 polymorphisms on the efficacy and safety of bromodigyrochlorophenylbenzodiazepine in patients with anxiety disorder and comorbid alcohol use disorder

2018 ◽  
Vol 33 (4) ◽  
pp. 187-194 ◽  
Author(s):  
Michael S. Zastrozhin ◽  
Anastasiya P. Antonenko ◽  
Elena V. Nesterenko ◽  
Leyla I. Seyfullaeva ◽  
Violetta R. Mustafina ◽  
...  
Keyword(s):  
Anxiety Disorders ◽  
Alcohol Dependence ◽  
Depression Scale ◽  
Polymorphic Marker ◽  
Efficacy And Safety ◽  
Psychometric Scales ◽  
Specific Hybridization ◽  
Severity Scores ◽  
Allele Specific

Abstract Background Bromodihydrochlorophenylbenzodiazepine (Phenazepam®) is used in the therapy of anxiety disorders in patients with alcohol dependence. However, Phenazepam therapy often turns out to be ineffective, and some patients develop dose-related adverse drug reactions (ADR): severe sedation, dizziness, headache, dyspepsia, falling, etc. That ensures the effectiveness of this category of patients. Despite the popularity of Phenazepam® as an anxiolytic drug, there is currently no accurate data on its biotransformation, as well as the effect of polymorphism of a gene on the efficacy and safety of bromodihydrochlorophenylbenzodiazepine in patients. The aim of our study was to study the effect of the polymorphism of the CYP2C19 gene on the efficacy and safety index of Phenazepam® for patients with anxiety disorders, using algorithms for optimizing the therapy of Phenazepam® to reduce the risk of pharmacological resistance and increase the effectiveness of therapy. Methods The study was conducted on 86 Russian patients suffering from alcohol dependence. Patients with trauma anxiety disorders received bromdihydrochlorphenylbenzodiazepine in tablets at a dose of 4.0 [2.0; 6.0] mg per day for 5 days. Genotyping was carried out by the method of polymer chain reaction in real time with allele-specific hybridization. Efficiency and safety assessment was carried out using psychometric scales and scales of Hospital Anxiety and Depression Scale (HADS) severity scores. Results Based on the results of the study, statistically significant differences in the number of scores on the scale of HADS severity of CYP2C19 CT on the third day of therapy were the following: (CC) 10.00 [9.00; 11.00], (CT) 14.00 [13.00; 16.00], (TT) 18.00 [17.00; 19.00], p=0.00, and also on the fifth day: (CC) 6.00 [5.00; 7.00], (CT) 17.50 [16.25; 19.75], (TT) 22.50 [20.00; 24.00], p=0.00. ADRs in patients with different genotypes for this polymorphic marker did not differ. Conclusions Thus, it has been shown that the polymorphism of the CYP2C19 gene may influence the effectiveness indices of Phenazepam therapy in patients with anxiety disorders comorbid with alcohol dependence. This should be taken into account in the appointment of this drug in this way in order to increase effectiveness of therapy and improve the quality of life.

Using the CYP3A Activity Evaluation to Predict the Efficacy and Safety of Diazepam in Patients With Alcohol Withdrawal Syndrome

2021 ◽  
pp. 089719002199700
Author(s):  
Valentin Yu. Skryabin ◽  
Mikhail S. Zastrozhin ◽  
Elena A. Grishina ◽  
Kristina A. Ryzhikova ◽  
Valery V. Shipitsyn ◽  
...  
Keyword(s):  
Alcohol Withdrawal ◽  
Withdrawal Syndrome ◽  
Alcohol Withdrawal Syndrome ◽  
Cyp3a Activity ◽  
Efficacy And Safety ◽  
Psychometric Scales ◽  
Endogenous Substrate ◽  
Male Patients ◽  
The Given ◽  
Cortisol Ratio

Background:Diazepam is one of the most commonly prescribed tranquilizers for the therapy of alcohol withdrawal syndrome (AWS). Despite its popularity, there is currently no precise information on the effect of genetic polymorphisms on the efficacy and safety of diazepam therapy.Objective:The objective of our study was to study the effect of CYP3A isoenzymes activity on the efficacy and safety of diazepam in patients with AWS.Methods:The study was conducted on 30 Russian male patients suffering from the AWS who received diazepam in injections at a dosage of 30.0 mg / day for 5 days. The efficacy and safety assessment was performed using psychometric scales and scales for assessing the severity of adverse drug reactions.Results:Based on the results of the study, we revealed the differences in the efficacy of therapy in patients with different CYP3A4 C>T intron 6 ( rs35599367) genotypes: ( CC) −9.0 [−13.0; −5.0], ( CT+TT) −13.5 [−15.0; −10.0], p = 0.014. The scores on the UKU scale, which was used to evaluate the safety of therapy, were also different: ( CC) 7.5 [6.0; 11.0], ( CT+TT) 11.0 [8.0; 12.0], p = 0.003.Conclusion:Possible relationship between the CYP3A activity, evaluated by the content of the urinary endogenous substrate of the given isoenzyme and its metabolite, the 6-beta-hydroxy cortisol (6-β-HC) / cortisol ratio, and the efficacy of diazepam was demonstrated. This possible relationship was also supported by the genotyping results. This should be taken into consideration when prescribing this drug to such patients in order to reduce the risk of pharmacoresistance.

scholarly journals Possibilities and limitations of antidepressant use to correct depressive and negative symptoms in schizophrenia

2021 ◽  
Vol 1 (2) ◽  
pp. 21-45
Author(s):  
M. A. Novitsky ◽  
A. De Sousa ◽  
A. R. Asadullin ◽  
O. A. Gavrilyuk ◽  
A. V. Petrov ◽  
...  
Keyword(s):  
Depressive Episode ◽  
Selective Serotonin Reuptake Inhibitors ◽  
Negative Symptoms ◽  
Depressive Disorders ◽  
Real Life ◽  
Hepatic Metabolism ◽  
Clinical Situation ◽  
Efficacy And Safety ◽  
Antidepressant Use ◽  
Online Library

The purpose of this review is to analyze approaches to the treatment of depressive and negative disorders in schizophrenia in terms of their level of efficacy and safety. Materials and Methods: A search was conducted for full-text articles published over the last 10 years in PubMed, Springer, Wiley Online Library, Taylor & Francis Online, APA PsycInfo, CORE, Science Direct, and eLIBRARY.RU databases. Several articles published previously to this period were also included into the review due to their high scientific value. Results: Our review suggests that antidepressants (ADs) are effective medications and they can be prescribed to correct depressive disorders and negative symptoms in patients with schizophrenia when used in combination with antipsychotics (АPs). However, when administering ADs and АPs combinations, it is important to consider the safety profile of these combinations as well as their tolerance. Negative symptoms of schizophrenia, including those induced by a number of АP, are less amenable to correction by АDs monotherapy, which requires a long period of АPs (on average - 8 weeks), which can be limited in the real life of the patient outside the hospital. Current approaches to the therapy of depressive disorders in patients suffering from schizophrenia vary from country to country. However, most of АDs used in clinical psychiatric practice are widely used in the comorbid state under consideration. Conclusion: The efficacy and safety of АDs of the different classes considered in this review depends on their mechanisms of action, duration of admission, type of АPs taken, and specific clinical situation (acute depressive disorder, major depressive episode, or chronic depressive episode). Most promising in clinical practice are serotonin–norepinephrine reuptake inhibitors (SNRIs) and dual ADs. The use of tricyclic antidepressants (TCAs) is limited due to a higher risk of adverse drug reactions (ADRs). The use of most selective serotonin reuptake inhibitors (SSRIs) is limited due to the risk of aggravation of hallucinations (this risk being higher for patients with visual hallucinations, and lower for those with auditory hallucinations) and\or iatrogenic psychosis. These ADRs may probably occur in patients suffering from schizophrenia due to their ideal "poor metabolizer" pharmacogenetic profile, since most of the drugs considered in this review have hepatic metabolism.

Efficacy and Safety of Oral Ivermectin and Topical Permethrin in the Treatment of Scabies

2020 ◽  
Vol 33 (1) ◽  
pp. 41-47
Author(s):  
Mohsena Akhter ◽  
Ishrat Bhuiyan ◽  
Zulfiqer Hossain Khan ◽  
Mahfuza Akhter ◽  
Gulam Kazem Ali Ahmad ◽  
...  
Keyword(s):  
Skin Diseases ◽  
Close Contact ◽  
Randomized Study ◽  
Sarcoptes Scabiei ◽  
Efficacy And Safety ◽  
Common Skin ◽  
Group A ◽  
The Mean ◽  
The Difference ◽  
Group B

Background: Scabies is one of the most common skin diseases in our country. It is caused by the mite Sarcoptes scabiei var hominis, which is an ecto-parasite infesting the epidermis. Scabies is highly contagious. Prevalence is high in congested or densely populated areas. Individuals with close contact with an affected person should be treated with scabicidal which is available in both oral and topical formulations. The only oral but highly effective scabicidal known to date is Ivermectin. Amongst topical preparations, Permethrin 5 % cream is the treatment of choice. Objective: To evaluate the efficacy & safety of oral Ivermectin compared to topical Permethrin in the treatment of scabies. Methodology: This prospective, non-randomized study was conducted at the out-patient department of Dermatology and Venereology of Shaheed Suhrawardy Medical College & Hospital over a period of 6 months, from August 2016 to January 2017. The study population consisted of one hundred patients having scabies, enrolled according to inclusion criteria. They were divided into two groups. group A was subjected to oral Ivermectin and the group B to Permethrin 5% cream. Patients were followed up on day 7 and 14 for assessment of efficacy and safety. Result: The mean scoring with SD in group A (Ivermectin) and group B (Permethrin) were 8.26 ± 2.22 and 7.59 ± 2.01 respectively at the time of observation. The difference between the mean score of the two group is not significant (p=0.117) the mean scoring with SD in group A and group B were 4.54 ± 2.05 and 1.64 ± 1.84 respectively at 7thdays. The difference between the mean score of the two group is significant (p<0.001). The mean scoring with SD in group A and group B were 2.68± 2.35 and .36± 1.10 respectively at 14th day difference between the mean score of the group is significant (p<0.001). Conclusion: Topical application of permethrin 5% cream is more effective and safer than oral Ivermectin in the treatment of scabies. TAJ 2020; 33(1): 41-47

31 A phase 3 open-label, controlled, randomized trial evaluating the efficacy and safety of a bioengineered allogeneic cellularized construct in patients with deep partial-thickness thermal burns

2021 ◽  
Vol 42 (Supplement_1) ◽  
pp. S25-S26
Author(s):  
Angela L F Gibson ◽  
James H Holmes ◽  
Jeffrey W Shupp ◽  
David Smith ◽  
Victor Joe ◽  
...  
Keyword(s):  
Donor Site ◽  
Efficacy And Safety ◽  
Phase 3 ◽  
Thermal Burns ◽  
Treatment Site ◽  
Severe Burns ◽  
Donor Site Pain ◽  
The Difference ◽  
Percent Area ◽  
Site Pain

Abstract Introduction Autograft (AG) is the standard of care for treatment of severe burns. While AG provides effective wound closure (WC), the procedure creates a donor site wound prone to pain and scarring. In a phase 1b trial, no deep partial-thickness (DPT) wound treated with a bioengineered allogeneic cellularized construct (BACC) required AG by Day 28 and WC at the BACC site was achieved in 93% of patients by Month (M) 3. This phase 3 study (NCT03005106) evaluated the efficacy and safety of this BACC in patients with DPT burns. Methods Enrolled patients were aged ≥18 years with 3–49% TBSA thermal burns on the torso or extremities. In each patient, two DPT areas (≤2,000 cm2 total) deemed comparable following excision were randomized to treatment with either cryopreserved BACC or AG. Coprimary endpoints were 1) the difference in percent area of BACC treatment site and AG treatment site autografted at M3 and 2) the proportion of patients achieving durable WC of the BACC treatment site without AG at M3. Ranked secondary endpoints were: 1) the difference between BACC and AG donor sites in average donor site pain intensity through Day 14; 2) the difference between BACC and AG donor site cosmesis at M3; and 3) the difference between BACC and AG treatment site cosmesis at M12. Safety assessments were performed in all patients through M12. Results Seventy-one patients were enrolled. By M3, there was a 96% reduction in mean percent area of BACC treatment sites that required AG, compared with AG treatment sites (4.3% vs 102.1%, respectively; P&lt;.0001). BACC treatment resulted in durable WC at M3 without AG in 92% (95% CI: 85.6, 98.8; 59/64) of patients for whom data was available. By M3, mean donor site Patient and Observer Scar Assessment Scale (POSAS) observer total score (±SD) was significantly lower (more like normal skin) for BACC donor sites compared with AG donor sites (6.3 ± 1.71 vs 16.3 ± 7.71; P&lt;.0001). At M12, mean POSAS observer total score (±SD) was 15.6 (± 8.34) for BACC treatment sites compared with 16.3 (± 9.41) for AG treatment sites (P=.4268). The most common BACC-related adverse event (AE) was pruritus, which occurred in 11 (15%) patients. All BACC-related AEs were mild or moderate in severity. Conclusions This phase 3 study achieved both coprimary endpoints, including significant autograft sparing and durable WC in DPT burns. Both donor site pain and donor site cosmesis were favorable outcomes of significantly reduced use of AG in BACC-treated patients. M12 POSAS for BACC did not differ significantly from AG. This BACC may offer a new treatment for severe burns to reduce or eliminate the need for AG. Applicability of Research to Practice This BACC has shown clinical benefit in patients with DPT thermal burns, potentially mitigating donor site morbidity. External Funding Stratatech, a Mallinckrodt Company; Funding and technical support for the Phase 3 clinical study were provided by the Biomedical Advanced Research and Development Authority (BARDA), under the Assistant Secretary for Preparedness and Response, within the U.S. Department of Health and Human Services, under Project BioShield Contract No. HHSO100201500027C.

scholarly journals Identification of novel DNA hypermethylation of the adenylate kinase 5 promoter in colorectal adenocarcinoma

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Bokyung Ahn ◽  
Yang Seok Chae ◽  
Soo Kyung Lee ◽  
Moa Kim ◽  
Hyeon Soo Kim ◽  
...  
Keyword(s):  
Mrna Expression ◽  
Cell Lines ◽  
Adenylate Kinase ◽  
Dna Methyltransferase ◽  
Colorectal Adenocarcinoma ◽  
Adenine Nucleotides ◽  
Inverse Correlation ◽  
Dna Hypermethylation ◽  
Normal Tissues ◽  
The Difference

AbstractAdenylate kinase 5 (AK5) belongs to the adenylate kinase family that catalyses reversible phosphate transfer between adenine nucleotides, and it is related to various energetic signalling mechanisms. However, the role of AK5 in colorectal cancer (CRC) has not been reported. In this study, AK5 was significantly hypermethylated in CRC compared to adjacent normal tissues (P < 0.0001) and normal tissues (P = 0.0015). Although the difference in mRNA expression was not statistically significant in all of them, the selected 49 cases of CRC tissues with AK5 hypermethylation with the cut off value of 40% showed a significant inverse correlation with mRNA expression (P = 0.0003). DNA methylation of AK5 promoter significantly decreased and AK5 expression recovered by 5-aza-2′-deoxycytidine, DNA methyltransferase inhibitor in CRC cell lines. In addition, AK5 promoter activity significantly decreased due to DNA methyltransferase, and it increased due to 5-aza. Moreover, AK5 regulated the phosphorylated AMPK and mTOR phosphorylation and inhibited the cell migration and cell invasion in CRC cell lines. Furthermore, low AK5 expression is associated with poor differentiation (P = 0.014). These results demonstrate that the AK5 promoter is frequently hypermethylated and induced methylation-mediated gene down-regulation. AK5 expression regulates AMPK/mTOR signalling and may be closely related to metastasis in colorectal adenocarcinoma.

scholarly journals Efficacy and safety of tianeptine in the treatment of depressive disorders in comparison with fluoxetine

1999 ◽  
Vol 56 (2-3) ◽  
pp. 109-118 ◽  
Author(s):  
H Lôo ◽  
J Saiz-Ruiz ◽  
J.A Costa e Silva ◽  
M Ansseau ◽  
R Herrington ◽  
...  
Keyword(s):  
Depressive Disorders ◽  
Efficacy And Safety
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