Joint Analysis of Phenotypic and Genomic Diversity Sheds Light on the Evolution of Xenobiotic Metabolism in Humans.

Variation in genes involved in the absorption, distribution, metabolism, and excretion of drugs (ADME) can influence individual response to a therapeutic treatment. The study of ADME genetic diversity in human populations has led to evolutionary hypotheses of adaptation to distinct chemical environments. Population differentiation in measured drug metabolism phenotypes is, however, scarcely documented, often indirectly estimated via genotype-predicted phenotypes. We administered seven probe compounds devised to target six cytochrome P450 enzymes and the P-glycoprotein (P-gp) activity to assess phenotypic variation in four populations along a latitudinal transect spanning over Africa, the Middle East, and Europe (349 healthy Ethiopian, Omani, Greek, and Czech volunteers). We demonstrate significant population differentiation for all phenotypes except the one measuring CYP2D6 activity. Genome-wide association studies (GWAS) evidenced that the variability of phenotypes measuring CYP2B6, CYP2C9, CYP2C19, and CYP2D6 activity was associated with genetic variants linked to the corresponding encoding genes, and additional genes for the latter three. Instead, GWAS did not indicate any association between genetic diversity and the phenotypes measuring CYP1A2, CYP3A4, and P-gp activity. Genome scans of selection highlighted multiple candidate regions, a few of which included ADME genes, but none overlapped with the GWAS candidates. Our results suggest that different mechanisms have been shaping the evolution of these phenotypes, including phenotypic plasticity, and possibly some form of balancing selection. We discuss how these contrasting results highlight the diverse evolutionary trajectories of ADME genes and proteins, consistent with the wide spectrum of both endogenous and exogenous molecules that are their substrates.

Rational drug design strategies for the development of promising multi-target directed indole hybrids as Anti-Alzheimer agents.

Alzheimer's disease (AD) is a neurological disorder that leads to dementia i.e., progressive memory loss accompanied with worsening of thinking ability of an individual. The cause of AD is not fully understood but it progresses with age where brain cells gradually die over time. According to the World Health Organization (WHO), currently 50 million people worldwide are affected by dementia and 60-70% of the cases belong to AD. Cumulative research over the past few decades have shown that molecules that act at a single target possess limited efficacy since these investigational drugs are not able to act against complex pathologies and thus do not provide permanent cure. Designing of multi-target directed ligands (MTDLs) appears to be more beneficial and a rational approach to treat chronic complex diseases including neurodegenerative diseases. Recently, MTDLs are being extensively researched by the medicinal chemists for the development of drugs for the treatment of various multifactorial diseases. Indole is one of the privileged scaffolds which is considered as an essential mediator between the gut-brain axis because of its neuroprotective, anti-inflammatory, ß-amyloid anti-aggregation and antioxidant activities. Herein, we have reviewed the potential of some indole-hybrids acting at multiple targets in the pathogenesis of AD. We have reviewed research articles from the year 2014-2021 from various scientific databases and highlighted the synthetic strategies, mechanisms of neuroprotection, toxicity, structure activity relationships and molecular docking studies of various indole-hybrid derivatives. This literature review of published data on indole derivatives indicated that developing indole hybrids have improved the pharmacokinetic profile with lower toxicity, provided synergistic effect, helped to develop more potent compounds and prevented drug-drug interactions. It is evident that this class of compounds have potential to inhibit multiple enzymes targets involved in the pathogenesis of AD and therefore indole hybrids as MTDLs may play an important role in the development of anti-AD molecules.

Drug Prescribing Practices in Dental Care Patients at a Dental and Maxillofacial Surgery Clinic in Oman.

OBJECTIVES: We sought to assess medications prescribed to patients attending the Dental and Maxillofacial Surgery (DMS) clinic at Sultan Qaboos University Hospital (SQUH), Oman. METHODS: This was a retrospective cross-sectional study covering a six-month period from January to June 2018 including a sample of patients attending the DMS clinic. Drug utilization data like drug name, type, administration route, dosage frequency, and anatomical and therapeutic class were assessed. RESULTS: The study included 400 patients, of which 190 (47.5%) were males and 210 (52.5%) were females. A total of 88 different drugs were prescribed. Only 140 (35.0%) patients were prescribed drugs for their dental conditions or other comorbidities per visit, and the rest 260 (65.0%) were not prescribed any drugs. The dentists prescribed drugs only in 116 (29.0%) patients. The most common diagnosis was dental caries (n = 177, 44.3%) followed by chronic gingivitis (n = 15, 3.8%). The most common comorbidities in patients were anemia (n = 45, 11.3%) and diabetes (n = 21, 5.3%). The most common drugs prescribed were chlorhexidine mouthwash (n = 43, 37.1%) and paracetamol (n = 36, 31.0%) followed by ibuprofen (n = 10, 8.6%) and amoxicillin/clavulanate (n = 5, 4.3%). CONCLUSIONS: Drugs prescribing pattern was within the international norms. Sixty-five percent of the patients were not prescribed any drug by the dentist. Oral antiseptics, analgesics, and antibiotics were the most common drugs prescribed by dentists.

Chronic Water-Pipe Smoke Exposure Induces Injurious Effects to Reproductive System in Male Mice.

There is a global increase in the popularity of water-pipe tobacco smoking including in Europe and North America. Nevertheless, little is known about the male reproductive effects of water-pipe smoke (WPS), especially after long-term exposure. Here, we assessed effects of WPS exposure (30 min/day) in male mice for 6 months. Control mice were exposed to air-only for the same period of time. Twenty-four hours after the last exposure, testicular histopathology, and markers of inflammation and oxidative stress, and the tyrosine-protein kinase vascular endothelial growth factor receptor 1 (VEGFR1) were assessed in testicular homogenates. Moreover, plasma testosterone, estradiol, and luteinizing hormone (LH) concentrations were also measured. Chronic WPS exposure induced a significant decrease of testosterone and estradiol, and a slight but significant increase of LH. Glutathione reductase, catalase, and ascorbic acid were significantly decreased following WPS exposure. Plasma concentration of leptin was significantly decreased by WPS exposure, whereas that of tumor necrosis factor α and interleukin 6 was significantly increased. Histopathological analysis of the testes revealed the presence of a marked reduction in the diameter of the seminiferous tubules with reduced spermatogenesis. Transmission electron microscopy examination showed irregular thickening and wrinkling of the basement membranes with abnormal shapes and structures of the spermatozoa. VEGFR1 was overexpressed in the testis of the mice exposed to WPS and was not detected in the control. The urine concentration of cotinine, the predominant metabolite of nicotine, was significantly increased in the WPS-exposed group compared with the control group. We conclude that chronic exposure to WPS induces damaging effects to the reproductive system in male mice. If this can be confirmed in humans, it would be an additional concern to an already serious public health problem, especially with the increased use of WPS use all over the world, especially in young adults.

Prescribing Pattern of Antifungal Medications at a Tertiary Care Hospital in Oman.

INTRODUCTION: Inappropriate use of antifungal agents is implicated in the global burden of antifungal resistance, adverse outcomes like persistent infections, unnecessary exposure and increased cost. Data collection from time to time is to be done in order to have a check on the resistance/sensitivity pattern of the commonly prescribed antifungal drugs. AIM: To describe the pattern of antifungal drug prescription and administration to patients attending a university hospital in Oman. MATERIALS AND METHODS: This was a descriptive, retrospective cross-sectional study conducted at Sultan Qaboos University Hospital (SQUH), a university hospital in Oman that covered the electronic patient's data for a period of one year (January 2013 to December 2013). The study included inpatients and outpatients of all ages and both genders attending SQUH and receiving antifungal medications at the study period. Frequencies and percentages were reported for categorical variables, while the mean and standard deviation were used to summarize the data for continuous variables. RESULTS: A total of 1353 antifungal drug prescriptions were prescribed for 244 patients. More than half of all antifungal drug prescriptions were prescribed by haematology, infectious disease and family medicine departments. The majority of patients to whom these drugs were prescribed were diagnosed to have infectious diseases followed by prophylactic use in leukaemias and immunocompromised conditions. Fluconazole was the most commonly prescribed antifungal drug (n=715, 52.8%) followed by nystatin and voriconazole (n=233; 17.2% and n=152; 11.2%, respectively). CONCLUSION: This study will help in understanding antifungal prescription practices and help in directing future studies and also in developing local policies for appropriate use of antifungal drugs.

Renoprotective effects of gamma-aminobutyric acid on cisplatin-induced acute renal injury in rats.

To investigate the effect of gamma-aminobutyric acid (GABA) on acute renal injury (ARI), we used here a rat model of acute tubular necrosis induced by the anticancer drug cisplatin (CP). GABA was given orally (100 or 500 mg/kg/day for ten consecutive days), and on the 6th day, some of the treated rats were also injected intraperitoneally with either saline or CP (6 mg/kg). Four days after CP treatment, urine was collected from all rats, which were then anaesthetized for blood pressure and renal blood flow monitoring. This was followed by intravenous injection of norepinephrine for the assessment of renal vasoconstrictor responses. Thereafter, blood and kidneys were collected for measurement of several functional, biochemical and structural parameters. GABA treatment (at 500 but not 100 mg/kg) significantly mitigated all the measured physiological and biochemical indices. Sections from saline- and GABA-treated rats showed apparently normal proximal tubules. However, kidneys of CP-treated rats had a moderate degree of necrosis. This was markedly lessened when CP was given simultaneously with GABA (500 mg/kg). The concentration of platinum in the cortical tissues was not significantly altered by GABA treatment. The results suggested that GABA can ameliorate CP nephrotoxicity in rats. Pending further pharmacological and toxicological studies, GABA may be considered a potentially useful nephroprotective agent in CP-induced ARI.

Reproductive toxicity to male mice of nose only exposure to water- pipe smoke.

BACKGROUND/AIMS: Water-pipe smoking (WPS) is popular in the Middle East and is starting to gain popularity in several Western countries as well. It is widely and erroneously perceived to be less harmful than other forms of tobacco use. The reproductive adverse effects of cigarette smoking have been studied before with conflicting results, but data on the possible adverse reproductive effects of WPS are lacking. Here, we assessed the effects of nose-only exposure to mainstream WPS generated by commercially available honey-flavored "moasel" tobacco in mice. METHODS: The duration of the session was 30 min/day for one month. Control mice were exposed to air. Twenty-four h after the last exposure, mice were killed and the testes and plasma removed for analysis. In testicular homogenates total protein, alkaline phosphatase activity, several indices of oxidative damage and Vascular Endothelial Growth Factor Receptor 2 (VEGFR2) were quantified. The plasma concentrations of leptin, testosterone, estrogen and luteinizing hormone (LH) were also measured. Histological analysis of testes and lungs was also conducted. RESULTS: WPS caused statistically significant decreases in the plasma concentrations of leptin, testosterone, and LH, and in the concentrations of total protein and the antioxidant indices measured. A statistically non-significant decrease in VEGFR2 protein in the WPS--exposed mice compared to the control mice was also found. The body and testicular weights of mice exposed to WPS, as well as their testicular alkaline phosphatase activity and light microscopic histology, and plasma estrogen concentration were all not significantly affected by WPS. CONCLUSION: Further studies on the functional implications of these findings in mice exposed to WPS for longer durations are warranted.

Does swimming exercise affect experimental chronic kidney disease in rats treated with gum acacia?

Different modes of exercise are reported to be beneficial in subjects with chronic kidney disease (CKD). Similar benefits have also been ascribed to the dietary supplement gum acacia (GA). Using several physiological, biochemical, immunological, and histopathological measurements, we assessed the effect of swimming exercise (SE) on adenine-induced CKD, and tested whether SE would influence the salutary action of GA in rats with CKD. Eight groups of rats were used, the first four of which were fed normal chow for 5 weeks, feed mixed with adenine (0.25% w/w) to induce CKD, GA in the drinking water (15% w/v), or were given adenine plus GA, as above. Another four groups were similarly treated, but were subjected to SE during the experimental period, while the first four groups remained sedentary. The pre-SE program lasted for four days (before the start of the experimental treatments), during which the rats were made to swim for 5 to 10 min, and then gradually extended to 20 min per day. Thereafter, the rats in the 5th, 6th, 7th, and 8th groups started to receive their respective treatments, and were subjected to SE three days a week for 45 min each. Adenine induced the typical signs of CKD as confirmed by histopathology, and the other measurements, and GA significantly ameliorated all these signs. SE did not affect the salutary action of GA on renal histology, but it partially improved some of the above biochemical and physiological analytes, suggesting that addition of this mode of exercise to GA supplementation may improve further the benefits of GA supplementation.

Glycemic control among patients with type 2 diabetes at a primary health care center in Oman.

AIMS: To determine the status of blood sugar control by using fasting blood sugar (FBS) of ≤6.1 mmol/l and glycosyted hemoglobin A1c (HbAc1) of <7% as indictors of glycemic control and to assess the influence of demographic, blood pressure (BP) and lipid characteristics on glycemic control. METHODS: This retrospective study included all Omani patients with type 2 diabetes (N=177) attended a primary health care center in Al-Dakhiliya region, Oman. RESULTS: The overall mean age of the cohort was 53±12 years (range: 24-91) with females representing 60% (n=106) of the study sample. The study found that only 9.6% (n=17) and 35% (n=62) of the patients attained optimal FBS and HbAc1 levels, respectively. Higher HbA1c was significantly associated with higher diastolic BP (84 versus 80 mm Hg; p=0.006), higher total cholesterol (5.2 versus 4.7 mmol/l; p=0.002) and higher low-density lipoprotein cholesterol (3.8 versus 3.0 mmol/l; p=0.034). CONCLUSIONS: The results demonstrated poor glycemic control in Oman type 2 diabetic patients comparable to local and global studies especially in those hypertensive and dyslipidemic patients. Implementation of early and aggressive management of diabetes mellitus at the primary care setting is warranted.

Frequency of CYP2C9 genotypes among Omani patients receiving warfarin and its correlation with warfarin dose.

OBJECTIVES: This study was conducted to determine the frequency of CYP2C9 alleles in Omani patients receiving warfarin and to correlate genotyping data with warfarin dosage. The Omani population has Asian and African ethnicities. METHODS: CYP2C9 genotypes were determined by the polymerase chain reaction restriction fragment length polymorphism method. Non-parametric Kruskal-Wallis test was used to compare groups of continuous data for significance differences. RESULTS: Genotyping data showed that 12.7 and 5.8% of the samples were heterozygous for the CYP2C9*2 and CYP2C9*3 alleles, respectively. The CYP2C9*2 allele frequency was 0.074 in our population. It was 0.029 for CYP2C9*3. CONCLUSION: This is the first report on the presence of CYP2C9*2 allele homozygocity in any Asian or African population.

Beta2-adrenoceptor polymorphisms and asthma from childhood to middle age in the British 1958 birth cohort: a genetic association study.

BACKGROUND: Functionally relevant polymorphisms of the beta2-adrenoceptor gene (ADRB2) are common in white populations, but their contribution to the burden of airways disease in the population is uncertain. We aimed to relate the long-term prevalence of asthma or wheeze to functional coding region polymorphisms in the ADRB2 gene. METHODS: The British 1958 birth cohort consisted of all people born in Britain during a week in 1958. Asthma, wheezy bronchitis, and wheezing were ascertained by interview at ages 7, 11, 16, 23, 33, and 42 years, and lung function tests at 35 and 45 years. DNA samples from 8018 participants in the 45-year follow-up were genotyped for three coding variants in the ADRB2 gene. We extend the follow-up of this nationwide cohort by a further 10 years and relate asthma prevalence, prognosis, and lung function to functional coding region polymorphisms in the ADRB2 gene in the cohort members who contributed DNA samples. We also compared and combined our findings with those reaching significance in two previous meta-analyses. FINDINGS: Half the cohort (4105 of 8018) had some history of wheezing illness by age 42 years. Neither lifetime prevalence nor age at onset were related to ADRB2 coding variants. However, the common polymorphisms Arg16Gly (rs1042713, Arg 16 allele frequency 36.3%) and Gln27Glu (rs1042714, Glu 27 allele frequency 44.6%) were significantly associated with persistence of asthmatic symptoms from childhood to middle age. Among homozygotes for the Arg16-Gln27 haplotype at these loci, 19.3% (41 of 212) childhood wheezers had five or more wheezing episodes in the past year at age 42, compared with 11.9% (71 of 599) with no copy of this haplotype. However, only 3% of all frequent adult wheezing was statistically attributable to this haplotype. The less common Thr164Ile polymorphism (rs1800888, Ile allele frequency 1.5%) was not a major predictor of either frequency or prognosis of asthma. Our data do not support the findings of previous meta-analyses when considered in isolation or when combined with their contributory studies. INTERPRETATION: ADRB2 polymorphisms might predict a small component of the long-term prognosis in childhood asthma, but are not important determinants of asthma incidence or prevalence in the British population.