Band 38, Heft 2

Pharmacogenetics (PGx)-guided prescribing is an evidence-based precision medicine strategy. Although the past two decades have reported significant advancements in both the quality and quantity of PGx research studies, they are seldom done in developing countries like Bangladesh. This review identified and summarized PGx studies conducted in the Bangladeshi population by searching PubMed and Google Scholar. Additionally, a quality evaluation of the identified studies was also carried out. Eleven PGx studies were identified that looked at the effects of genetic variants on blood thinners ( CYP2C9 , VKORC1 , and ITGB3 ), cancer drugs ( TPMT , MTHFR , DPYD , ERCC1 , GSTP1 , XPC , XRCC1 , TP53 , XPD , and ABCC4 ), statins ( COQ2 , CYP2D6 , and CYP3A5 ), and prednisolone ( ABCB1 , CYP3A5 , and NR3C1 ) in the Bangladeshi population. Most studies were of low to moderate quality. Although the identified studies demonstrated the potential for PGx testing, the limited PGx literature in the Bangladeshi population poses a significant challenge in the widespread implementation of PGx testing in Bangladesh.

Objectives Extrapyramidal symptoms (EPS) are one of the most prominent side effects of haloperidol. Variability of EPS severity may be associated with the genetic factors, affecting both haloperidol pharmacokinetics (e.g., CYP2D6) and pharmacodynamics (e.g., DRD2, ANKK1). We conducted a 3-week prospective study to investigate the associations of ANKK1/DRD2 TaqIA (rs1800497), DRD2 −141C Ins/Del (rs1799732) polymorphisms and CYP2D6 metabolic phenotype on the efficacy of haloperidol treatment and severity of EPS in patients with schizophrenia spectrum disorders. Methods In total, 57 inpatients with schizophrenia spectrum disorders (24 (42.1%)) females; age −46.7 (11.8) years (M(SD)) of European ancestry were enrolled. BARS and SAS scales were used to assess EPS. PANSS and CGI scales – to assess the efficacy of haloperidol treatment. Genotyping was performed by real-time PCR. CYP2D6 metabolic phenotype was predicted by the CYP2D6 *3, *4, *5, *6, *9, *10, *41 and xN genotypes. Results Minor C allele of TaqIA was associated with higher scores of BARS (p=0.029) and SAS (p=0.024) on day 21 and minor Del allele of −141C Ins/Del – with more prominent clinical improvement by CGI scale (p=0.007) but not by PANSS. These differences were observed only in extensive CYP2D6 metabolizers, although no associations with the metabolic type itself were found. General linear model showed that the combination of TaqIA genotype and metabolic type was significantly associated with BARS score on day 21 (p=0.013). Conclusions Our results highlight the importance of using both pharmacokinetic and pharmacodynamic genetic markers for predicting haloperidol treatment response to personalize schizophrenia spectrum disorders treatment.

Objectives Timolol maleate is used for the treatment of glaucoma and metabolized by cytochrome CYP2D6 in the liver. The aim of this study was the evaluation of the influence of CYP2D6*4 and CYP2D6*10 gene polymorphisms on the safety of medications containing 0.5% of timolol maleate as glaucoma treatment in patients with primary open-angle glaucoma (POAG). Methods 105 patients with POAG were prescribed glaucoma medications, containing 0.5% timolol maleate. The safety of glaucoma treatment was determined by electrocardiography (ECG) (to assess heart rate (HR) and PQ interval) and blood pressure (BP) measurements. The real-time polymerase chain reaction method was used for the detection of single nucleotide polymorphisms (SNP). Results The risk of adverse drug reactions was higher in patients with the CYP2D6*4  GA genotype compared with GG: mean HR change at 1 month (2.88 ± 4.68 and 6.44 ± 5.57, p<0.001) and 6 months (5.14 ± 8.93 and 7.88 ± 5.65, p<0.001), mean PQ interval change at 1 (0.01 ± 0.031 and 0.02 ± 0.022, p=0.003) and 6 months (0.01 ± 0.032 and 0.02 ± 0.024, p=0.003). The risk of adverse drug reactions was higher in patients with the CYP2D6*10 CT genotype compared with CC: mean HR change at 1 month (2.94 ± 4.65 and 6.34 ± 5.66, p<0.001) and 6 months (5.20 ± 8.90 and 7.78 ± 5.75, p<0.001), mean PQ interval change at 1 (0.01 ± 0.032 and 0.02 ± 0.021, p=0.014) and 6 months (0.01 ± 0.033 and 0.02 ± 0.022, p=0.014). Conclusions CYP2D6*4 and CYP2D6*10 gene polymorphisms may affect a higher risk of timolol-induced bradycardia and increased PQ interval of treatment medications containing 0.5% of timolol maleate in patients with POAG.

Objectives Determine the frequency of actionable mutations in non-small cell lung cancer (NSCLC) and their correlation with overall survival (OS) and the site of metastases. Methods We performed a descriptive cross-sectional study at the Hospital de Especialidades Eugenio Espejo, Ecuador, between 2017 and 2020. Demographic, pathological, and molecular alterations in epidermal growth factor (EGFR), Anaplastic lymphoma kinase (ALK), ROS proto-oncogene 1 (ROS1), Programmed death-ligand 1 (PD-L1) expression, and clinical data detailed in patients’ medical records with metastatic NSCLC were collected and analyzed. Seventy-nine stage IV patients had NSCLC; adenocarcinoma histology represents 56 (70.9%). The predominant mutation was in EGFR (22.8%); the most common variant was the deletion of exon 19 (72.2%). The most common metastatic site was in the contralateral lung (22.3%); however, this variable showed no significant correlation to the molecular markers (p=0.057). The overall survival (OS) and the status of molecular markers are not statistically significant (p=0.27). OS was better for non-mutated EGFR than for mutated EGFR (p=0.012). However, the frequency values are unrelated to contralateral lung metastasis or survival. Conclusions Our frequency mutations are concordant with those found in other studies in Latin America. EGFR was the most common biomarker mutation, and there was a better OS in EGFR non-mutated patient.

Objectives Single nucleotid polymorphisms (SNPs) of Fc-gamma receptors (FcgRs), by inducing a variation of their affinity to the Fc-region of immunoglobulins, might influence the efficacy of Fc-containing biologics prescribed in rheumatoid arthritis (RA). Our aim was to investigate associations of FCGR2A , FCGR3A and FCGR3B SNPs with TNF-inhibitors (TNFi)’ response in Tunisian RA patients. Methods A cross-sectional, observational and analytic multicentric cohort study was conducted in a group of 47 Tunisian RA patients treated with (etanercept [ETA], adalimumab [ADL] and infliximab [IFX]). Treatment outcome was evaluated after 6 months. R131H-FCGR2A , F158V-FCGR3A and NA1/NA2-FCGR3B SNPs were genotyped. Results The analytic study including all types of TNFi showed that FCGR3A-F/F low-affinity receptor was associated with a greater decrease of DAS28, while FCGR3B-NA1/NA1 high-affinity receptor was associated with a lower decrease of DAS28 in ADL group. Furthermore, both of high affinity receptors FCGR3B-NA1/NA1 and FCGR3A-V/V were more prevalent in non-responders to ADL, according to EULAR criteria. Conclusions Identifying reliable biomarkers of response to biologics in RA is necessary to improve responsiveness, preserve joints’ functions and structure, and reduce treatment’s cost. Our study showed that FCGR3A and FCGR3B polymorphisms might have an impact on TNFis’ response in RA Tunisian patients since bad response was more frequent in homozygous carriers of high affinity alleles FCGR3A-V and FCGR3B-NA1.

Objectives CYP2C9 gene polymorphic variants can decrease the effects of losartan, reducing active metabolite (E-3174) formation. Study aims to determine the influence of *2 (+430C>T; rs799853) and *3 (+1075A>C; rs1057910) CYP2C9 gene polymorphic variants on the hypotensive and uricosuric effect of losartan on patients with arterial hypertension. Methods Eighty one patients with stage 1–2 arterial hypertension newly diagnosed with ABMP were enrolled in the study. Physicians started losartan treatment and then we measured urine concentration of E-3174/losartan to estimate CYP2C9 activity. After 3-month losartan treatment we compared effectiveness of the therapy with ABPM and plasma uric acid level between carriers of CYP2C9 *1/*1 and CYP2C9 gene polymorphic variants ( *2 and *3 ). Results Carriage of CYP2C9*2 and CYP2C9*3 alleles reduced the hypotensive effect of losartan (p<0.001, OR=8.13 (95% CI, 2.75–23.97)). Analysis of the ABPM data revealed that blood pressure was significantly higher in patients with polymorphic genotypes. There was no significant difference in uric acid level in plasma and losartan and its metabolite concentration in urine between genotypes. Conclusions Carriage of low function polymorphic variants of the CYP2C9 gene ( *2 and *3 ) reduced the hypotensive effect of losartan according to ABPM and don’t affect uric acid level in plasma and E-3174/losartan in urine.

Objectives The recent trends of rising unresponsive cases of dermatophytosis to conventional therapies pose a challenge in clinical practice. Unani medicine offers effective treatment for dermatophytosis. This study aimed to evaluate the efficacy and safety of the Unani herbo-mineral preparations Qurs-e-Asfar (QA) and Rogan-e-Narjeel (RN) in dermatophytosis. Methods This was a randomized, active-controlled and open-label clinical study. The participants diagnosed with dermatophytosis (n=78) randomized into treatment group (n=40) receiving oral QA (778 mg twice a day) and topical RN and control group (n=38) receiving oral Itraconazole (100 mg/day) and topical Terbinafine hydrochloride (1%) for 6 weeks. Results We found post-treatment improvement in itching by 86.3% vs. 78% (treatment vs. control group), erythema by 96.4% vs. 94.3%, scaling by 93% vs. 92.2% and peripheral raised margins by 82.3% vs. 81%. Furthermore, this study showed that the differences in the mean Total Signs and Symptoms Score (TSSS) and positive KOH mount were clinically and statistically significant (p<0.05) in both the groups. On comparing inter group, the differences in mean TSSS (p=0.07) and positive KOH mount (p=0.717) were found statistically insignificant. Conclusions This study concludes that the formulations QA and RN were effective and safe in the treatment of dermatophytosis.

Objectives Antioxidant property like radical scavenging is a primary target to elucidate the efficacy mechanism of a drug against diseases linked to oxidative stress such as cancer, metabolic disorders, rheumatoid arthritis, etc. In alternative therapies, homeopathy is one of the preferred choices by patients and clinicians due to its potential to cure chronic and complex illnesses. However, the efficacy of homeopathic preparations at high diluted potencies attracts rational criticism due to insufficient scientific knowledge supporting the mechanism of action. Therefore, an attempt was made to estimate the total phenolic content (TPC) and radical scavenging activity of clinically prescribed homeopathic drugs. Methods With gallic acid as a reference control, mother tinctures (MTs) and different potencies of Eucalyptus globulus (EG), Syzygium jambolanum (SJ), Ruta graveolens (RG), and Thuja occidentalis (TO) were used to perform Folin–Ciocalteu test, 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulphonic acid) (ABTS), and 2,2-diphenyl-1-picrylhydrazyl (DPPH) assays. Results The results showed TPC of MTs equivalent to µg/mL of gallic acid viz; EG (4,872.5 ± 133.2), SJ (8,840.5 ± 14.8), RG (985.6 ± 39.1), and TO (341.5 ± 19.5) with significant ABTS and DPPH radical scavenging potential. Whereas 30C and 200C potencies of each homeopathic drug showed undetectable phenolic content and insignificant radical scavenging potential compared to vehicle control, i.e., alcohol 90% (2.0 ± 1.5). Conclusions The reported efficacy of 30C and 200C potencies of homeopathic medicines against oxidative stress-related illnesses might be due to mechanisms other than radical scavenging. Furthermore, the assays studied can be helpful in drug standardization and quality control of MTs that are used as starting material in homeopathic preparations.

Objectives Carbamazepine (CBZ) is a first-line antiseizure drug used for focal onset seizures. It exhibits inter-individual variability in plasma carbamazepine levels and there are both genetic and non-genetic factors having a role in the requirement of CBZ maintenance dose. The aim was to study the influence of EPHX1 c.337 T>C and UGT2B7*2 genetic polymorphisms on CBZ maintenance dose requirement in persons with epilepsy. Methods Persons with epilepsy (PWE) of both gender of age 15–65 years on carbamazepine monotherapy who had been taking same maintenance dose for one year were eligible. Five milliliter of venous blood was collected in 10% EDTA under aseptic precautions. After centrifugation, the cellular component was used for DNA extraction and genotyping. For three genotypes of EPHX1 c.337 T>C and UGT2B7*2 , the differences in mean carbamazepine dose were analyzed using Analysis of Variance (ANOVA). An unpaired t-test was used to draw a comparison between the genotypes and CBZ maintenance dose requirement for dominant and recessive models of EPHX1 c.337 T>C and  UGT2B7*2 . A value of p<0.05 was considered to be statistically significant. Results For UGT2B7*2 (rs 7439366), CT required a higher dose (CT 626 mg/day and TT 523 mg/day) but not found to be significant (p-value 0.167). PWE carrying CT genotype of  EPHX1 c.337 T>C had 62 mg higher dose when compared to homozygous mutant CC (590 mg/day for CT and 528 mg/day for CC) but p-value was not found to be significant (p-value 0.835). Conclusions The results of our study done in 115 PWE showed there was a lack of association between SNPs of EPHX1 c.337 T>C, UGT2B7*2 and CBZ maintenance dose requirement in Southern part of India and this finding has to be confirmed in a larger sample size.

Objectives Catha edulis (Vahl) Forssk. ex Endl. (Khat) is a stimulant plant that contains cathine and cathinone, which its abuses induce euphoria, alertness, and motor activity. Since the toxicokinetics of these substances remain unclear, this study was carried out to investigate the disposition kinetics of cathine and cathinone, the neurotransmitter profile, following a single dose of C. edulis extract in rats. Methods Twenty-four adult male Wistar albino rats (250–300 g) were randomly selected and divided into six groups of four rats each. All groups received a single oral dose of 2,000 mg/kg body weight, and blood and tissue samples from the brain, lung, heart, liver, and kidney were obtained at intervals of 0.5, 1, 2.5, 5, 12, and 24 h. The cathine and cathinone concentrations were identified and quantified using ion trap ultra-high performance liquid chromatography (HPLC-IT/MS). The neurotransmitter profile was detected using the quadrupole time of flight UPLC-QTOF/MS method. Results The lung, liver, and heart tissues attained the highest levels of cathine, while the highest level of cathinone was determined in the heart. Cathine and cathinone concentrations in the blood and heart peaked at 0.5 h. The concentrations peaked in the brain 2.5 h later, indicating that the heart had an immediate effect, whereas the brain had a longer-lasting one. They have longer half-lives (2.68 and 5.07 h, respectively) and may remain in the brain for longer durations (3.31 and 2.31 h, respectively). The neurotransmitters epinephrine, dopamine, norepinephrine, and serotonin were detected in a delayed, prolonged and organ-specific manner. Conclusions Cathine and cathinone were deposited in considerable concentrations in all tissues analyzed, with the highest C max in the lung and T max in the heart tissues but not in the brain. In addition, neurotransmitters such as adrenaline, dopamine, norepinephrine, and serotonin were differentially detected in all tested samples in a organ-specific fashion. More study is needed to identify cathine and cathinone’s effects on neurotransmitter profiles. Nevertheless, these findings provided a further basis for experimental, clinical, and forensic investigations.