Tebentafusp as a Promising Drug for the Treatment of Uveal Melanoma.

Uveal melanoma (UM) is the most common primary intraocular malignancy in adults and commonly occurs in the Caucasian population. The malignancy involves the uvea of the eye, which includes the iris, ciliary body, and choroid. The etiology of UM is still not well understood, but age is a risk factor. Symptoms include blurred vision, redness of the eye, floaters, dark spots, a change in the size of the pupil, and loss of vision. The location, shape, and size of the tumor are important for therapeutic purposes. Treating metastasis is always a challenge in UM cases. In cases of lung metastasis, the survival rate decreases. Treatment includes surgery, laser therapy, immunotherapy, hormone therapy, and chemotherapy. Recently, in 2022, the United States Food and Drug Administration (FDA) approved the drug tebentafusp. Tebentafusp was developed to target the most common HLA complex in humans. The present review discusses the indications for the use of a new drug tebentafusp, its mechanism of action, dose, pharmacokinetics, results of clinical trials conducted, and adverse effects like cytokine release syndrome. Hence, tebentafusp is the first T cell receptor (TCR) therapeutic drug that could be considered for the treatment of UM.

An insight into the neuroprotective effects and molecular targets of pomegranate (Punica granatum) against Alzheimer's disease.

Alzheimer's disease (AD) is a progressive neurodegenerative disease that still has no permanent cure. The drugs prescribed in the present days are only for symptomatic relief for the patients. Many studies correlating the reduction in the incidence of AD with the diet consumed have been published. These studies showed that a diet rich in polyphenols is associated with a decrease in the incidence of AD. The present review is focused on the ability of pomegranate and its bioactive components to ameliorate the progression of AD and their ability to exert a neuroprotective effect. Various studies showing the ability of pomegranate in inhibiting enzymes, reducing reactive oxygen species, inhibition of microglial activation, inhibition of tau protein hyperphosphorylation, maintenance of synaptic plasticity, anti-inflammatory activity and its ability to inhibit Beta secretase-1 (BACE-1) has been reviewed in this article. In spite of the lack of studies on humans, there are compelling evidence indicating that pomegranate can reduce various risk factors involved in the causation of AD and thus can be used as a persistent nutraceutical to slow ageing and for providing neuroprotection for the treatment of AD.Highlights An overview of traditional and pharmacological uses of pomegranate (POM).Potential of POM in the treatment of neurodegenerative diseases especially in AD.Insight into the molecular mechanisms of neuroprotective effects of POM in AD.Clinical evaluation studies involving POM and its bioactive components.

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.

Impact of Glutathione S-Transferase Polymorphisms on Busulfan Pharmacokinetics and Outcomes of Hematopoietic Stem Cell Transplantation.

BACKGROUND: Busulfan (Bu) is an alkylating drug used in many preparative regimens before hematopoietic stem cell transplantation (HSCT). It is conjugated in the liver mainly by glutathione S-transferase isoenzyme A1-1 ( GSTA1 ). Genetic polymorphisms in these isoenzymes may affect the pharmacokinetics of Bu and the clinical outcomes of HSCT. This study aimed to assess the impact of glutathione S-transferase ( GST ) genetic polymorphisms on the clearance of Bu and the clinical outcomes of patients undergoing HSCT. METHODS: This single-center retrospective study included patients who received IV Bu before HSCT at Sultan Qaboos University Hospital (SQUH), Oman from January 2003 to October 2016. Genotyping for polymorphisms was performed for GSTM1 , GSTT1 , GSTA1 , and GSTP1 . Each GST polymorphism was analyzed for its impact on Bu clearance and HSCT outcomes. RESULTS: A total of 135 patients were included. The mean Bu clearance was 3.7 ± 0.98 mL/min/kg. Patients with GSTA1 A-513G heterozygosity (AG) were found to have a higher incidence of graft loss ( P = 0.006). Homozygous double null of GSTM1 and GSTT1 was associated with a higher incidence of acute graft versus host disease ( P = 0.04). Double non-null GSTM1 and GSTT1 and non-null GSTM1 increased the risk of mortality ( P = 0.034 and 0.021, respectively). CONCLUSIONS: GST genotyping before HSCT may predict HSCT outcomes. The results of this preliminary retrospective study need to be confirmed in a larger prospective study.

Primary Complete Transurethral Resection of Bladder Tumor Using Photodynamic Diagnosis for High-Risk Nonmuscle Invasive Bladder Cancer: Is a Restaging Photodynamic Transurethral Resection Really Necessary?

Objectives: To evaluate the risk of residual tumor and tumor upstaging during a second resection after primary complete transurethral resection of bladder tumor (TURBT) using photodynamic diagnosis (PDD) for high-risk nonmuscle invasive bladder cancer (NMIBC). Patients and Methods: From January 2014 to March 2020, a single-institutional study was conducted including consecutive patients with high-risk NMIBC (T1 and/or cis and/or high grade) who underwent a restaging transurethral resection (reTUR) within 12 weeks after a primary complete resection. Each TURBT was performed using blue light after intravesical instillation of hexaminolevulinate. The primary endpoint was detection of residual tumor at reTUR, proved with positive pathology report. Results: A total of 109 consecutive patients with high-risk NMIBC underwent reTUR after a primary complete blue light resection. Pathologic evaluation of the surgical specimens of the primary TURBT revealed stage T1 and high-grade tumors in 69 (68.3%) and 108 (99%) patients, respectively, and concomitant carcinoma in situ was found in 45 patients (41.3%). The median time to reTUR was 8 (6-10) weeks. Residual tumor was detected histopathologically in 64 of 109 patients (58.7%) at the second TURBT with PDD. In five of these patients (4.5%), initial T1 tumors were upstaged to T2 tumors. Conclusions: We examined a contemporary series of patients undergoing reTUR with PDD as management of high-risk NMIBC proven at the first blue light resection. We reported a 54.2% risk of disease persistence and a 4.5% risk of understaging in T1 tumors. These findings support that reTUR is still necessary after initial complete TURBT with PDD. Further studies are needed to assess the long-term oncologic outcomes of reTUR with PDD.

The prognostic value of serum procalcitonin in acute obstructive pyelonephritis.

PURPOSE: To evaluate the prognostic value of procalcitonin (PCT) in the occurrence of infectious complications in the management of acute obstructive pyelonephritis (AOP) compared with other biological parameters (leucocyte count, C-reactive protein [CRP]). METHODS: We conducted a retrospective study including patients who were treated for AOP and performed serum PCT tests in our center between January 1, 2017 and December 31, 2017. Upper urinary tract obstruction was confirmed by either ultrasound or CT urography. Clinical examinations and laboratory tests including leukocyte count, CRP, urine and blood cultures, and serum PCT measurements were performed in the emergency unit. Treatment included early renal decompression using indwelling ureteral stents or nephrostomy and empiric antibiotic therapy. The primary endpoint was occurrence of severe sepsis (SS), a composite criterion including urosepsis and/or septic shock and/or admission to the intensive care unit (ICU) and/or death. RESULTS: A total of 110 patients (median age: 61 years) were included, of whom 56.3% were female. SS occurred in 39 cases (35.4%). Multivariate regression analysis showed that serum PCT (OR 1.08; 95% CI 1.03-1.17; p = 0.01), CRP (OR 1.007; 95% CI 1.001-1.015; p = 0.03), and diabetes mellitus (OR 5.1; 95% CI 1.27-27.24; p = 0.04) were independent predictors for SS. Serum PCT was the biological marker associated with the highest accuracy to predict SS (ROC 0.912 (95% CI 0.861-0.962) and was superior to CRP (p < 0.001): the sensitivity and specificity of PCT to predict SS were 95% and 77%, respectively, with a serum PCT cutoff value of 1.12 µg/L. CONCLUSIONS: PCT levels > 1.12 µg/L could help physicians to identify high-risk patients who could benefit from early and aggressive management in collaboration with intensive care specialists.

Micro-percutaneous nephrolithotomy (Microperc) for renal stones, outcomes and learning curve.

OBJECTIVE: To report the effectiveness, reliability and learning curve of Microperc, a minimal invasive percutaneous technique using a 4.85-Ch (16-gauge) sheath, in the treatment of nephrolithiasis. MATERIAL AND METHODS: 31 consecutive Micropercs for nephrolithiasis<2.5cm were performed by 2 operators in 2 different institutions from the 1st of May 2015 to 31st of December 2017. RESULTS: The mean size of stones was 19mm±11mm, and mean density was 1048±249UH. Stones were located in lower calyx in 21/31(68%), medium calyx in 3/31(10%), pelvis in 4/31(12%) and were multi-caliceal in 3/31(10%). Five patients (16%) had urinary diversion (4 ileal conduits, 1 enterocystoplasty with Mitrofanoff+bladder neck closure) all of those having neurological disease (2 multiple sclerosis, 3 spinal cord injury). Mean operating time was 83±35min and decreased after short period for both operators. 9/31(29%) patients had complication: 8 (26%) had fever (Clavien II) and 1 (3%) had renal colic pain (Clavien III) (required JJ stent). Stone-free was obtained in 13/31(42%) and 11/31(36%) had residual microfragments<3mm which did not require further treatment, corresponding to a technical success of 78% (24/31). Success rate was similar in patients with urinary diversion and patients with normal anatomy. CONCLUSIONS: This study showed that Microperc was an effective technic for kidney stone treatment with low complication rate, acceptable operating time and short learning curve. Microperc was useful for stones in the lower calyx and/or urinary diversion where retrograde ureteroscopy could reach its limits. LEVEL OF EVIDENCE: 3.

Recent Advances in the Development of Chemotherapeutic Agents for Malaria.

INTRODUCTION: Malaria, a devastating infectious parasitic disease, has been recognized by the World Health Organization (WHO) as a major public health problem worldwide. It is one of the leading causes of morbidity and mortality in developing countries. There are a number of antimalarial drugs available in the market to combat this deadly disease. The situation is further worsened due to the emergence of resistant strains of Plasmodium falciparum, which warrants the search for novel antimalarial drugs capable of acting at multiple targets to expand the current antimalarial drug arsenal for better therapeutic outcome. OBJECTIVES: This review aimed to provide the reader with the recent advances and progress made in the development of chemotherapeutic agents for malaria. METHODS: Literature review data on the chemistry and antimalarial activity of natural and synthetic heterocyclic compounds published in the last ten years were compiled by referring to various peerreviewed journal websites and medical search engines. RESULTS AND DISCUSSION: This review covers the recent advances and progress made in the treatment strategies, patent granted, synthetic approaches, mechanism of action with more emphasis on a Structure- activity Relationship (SAR) of potential chemotherapeutic agents as antimalarial agents which could pave the way for the development of more effective and potent antimalarial agents. This review might interest fellow researchers working on the development of novel antimalarial drug candidates with better therapeutic index. CONCLUSION: Based on the literature covered in the current review article and seeing the recent trends, authors are of the opinion that the multi-target conjugated hybrid approach is the best strategy to discover and develop effective antimalarial agents.

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.

Safety of the Geneva Cocktail, a Cytochrome P450 and P-Glycoprotein Phenotyping Cocktail, in Healthy Volunteers from Three Different Geographic Origins.

INTRODUCTION AND OBJECTIVE: Cytochrome P450 enzymes are the major drug-metabolizing enzymes in humans and the importance of drug transport proteins, in particular P-glycoprotein, in the variability of drug response has also been highlighted. Activity of cytochrome P450 enzymes and P-glycoprotein can vary widely between individuals and genotyping and/or phenotyping can help assess their activity. Several phenotyping cocktails have been developed. The Geneva cocktail is composed of a specific probe for six different cytochrome P450 enzymes and one for P-glycoprotein and was used in the context of a research aiming at exploring genotypes and phenotypes in distinct human populations (NCT02789527). The aim of the present study is to solely report the safety results of the Geneva cocktail in the healthy volunteers of these populations. MATERIALS AND METHODS: The Geneva cocktail is composed of caffeine, bupropion, flurbiprofen, omeprazole, dextromethorphan, midazolam, and fexofenadine. The volunteers fasted and avoided drinking caffeine-containing beverages or food and grapefruit juice overnight before receiving the cocktail orally. They provided blood spots for the probes' concentrations at 2, 3, and 6 h after ingestion and were asked about adverse events. RESULTS: A total of 265 healthy adult volunteers were included from Ethiopia, Oman, and the Czech Republic. The mean plasma concentrations at the 2-h sampling time of each probe drug in the total sample were: 1663 ng/mL for caffeine, 8 ng/mL for bupropion, 789 ng/mL for flurbiprofen, 6 ng/mL for dextromethorphan, 2 ng/mL for midazolam, 35 ng/mL for fexofenadine, and 103 ng/mL for omeprazole. Four adverse events were observed representing an occurrence of 1.5%. All these events were categorized as mild to moderate, non-serious, and resolved spontaneously. A causal link with the cocktail cannot be excluded because of the temporal relationship but is at most evaluated as possible according to the World Health Organization-Uppsala Monitoring Centre causal assessment system. CONCLUSIONS: In this research, healthy volunteers from three different human populations were phenotyped with the Geneva cocktail. Four adverse events were observed, confirming the safety of this cocktail that is given at lower than clinically relevant doses and therefore results in concentrations lower than those reported to cause adverse events.

Diagnostic ureteroscopy prior to nephroureterectomy for urothelial carcinoma is associated with a high risk of bladder recurrence despite technical precautions to avoid tumor spillage.

PURPOSE: There have recent reports in the literature of increased rates of bladder recurrence (BR) after radical nephroureterectomy (RNU) when diagnostic flexible ureteroscopy (DFU) was performed before RNU. The technical heterogeneity of DFU was a major bias in these studies. Our purpose was to evaluate the impact of a standardized DFU technique before RNU on the risk of BR. METHODS: A retrospective monocenter study including patients who underwent RNU for upper tract urothelial carcinoma (UTUC) between 2005 and 2017. 171 patients were identified. 78 patients were excluded owing to a history of bladder cancer before RNU or neo-adjuvant/adjuvant chemotherapy. 93 included patients were stratified according to pre-RNU ureteroscopy (DFU + 70 patients) or no pre-RNU ureteroscopy (DFU-23 patients). The standardized DFU technique consisted of systematic ureteral sheath (ch9-10), flexible ureteroscopy, biopsy, and drainage with a mono-J/bladder catheter to avoid contact of contaminated urine of the upper tract with the bladder. RESULTS: Epidemiological, initial staging, and postoperative tumoral characteristics were similar in both groups. Mean follow-up was 35 months [2-166], 47(50%) BR occurred with 41(87%) in the DFU + group, and pre-RNU-DFU was an independent predictive factor of BR (OR = 4[1.4-11.9], P = 0.01) (Cox regression model). The characteristics of BR were similar in both groups, although BR occurred earlier in DFU + (427 days vs. 226 days (P = 0.07)). CONCLUSION: Bladder recurrence after diagnostic ureteroscopy + nephroureterectomy was high despite technical precautions to avoid contact of bladder mucosa with contaminated urine from the upper urinary tract. Post-DFU endovesical instillation should be investigated.

Potentially Inappropriate Prescribing among Elderly Patients at a Primary Care Clinic in Oman.

Drug prescribing to the elderly increases the risk of potential adverse drug reactions as well as potentially inappropriate medications. The goal of this study was to describe drug prescribing patterns in elderly patients and to measure the prevalence of potentially inappropriate medications using updated Beers' criteria and the STOPP criteria. This was a retrospective cross-sectional study for all patients aged ≥65 years who attended regularly a primary care clinic at Sultan Qaboos University Hospital in Oman. Data of 377 patients were analyzed using the software Statistical Package for Social Sciences version 23.0 (SPSS™, Chicago, IL, USA). Using Beers criteria, the prevalence of potentially inappropriate medications was 12.7% as 48 patients had at least one potentially inappropriate medication. Beers criteria revealed a statistical association between the occurrence of potentially inappropriate medications with polypharmacy (p < 0.001), with female gender (p = 0.002) and with asthma as a comorbidity (p = 0.020). STOPP criteria showed that the prevalence of potentially inappropriate medications was 17.2% as 65 patients had at least one potentially inappropriate medication. STOPP criteria revealed a statistical association between the occurrence of potentially inappropriate medications and osteoarthritis as a comorbidity (p = 0.032). The study revealed moderate prevalence of potentially inappropriate medications prescribing in elderly patients which was mainly associated with polypharmacy and female gender. Safe prescribing practices in the elderly requires increasing the awareness of healthcare providers and efficiently reporting drug-related problems.

Comparative medico-economic study of reusable vs. single-use flexible ureteroscopes.

PURPOSE: Reusable flexible-ureteroscopes (fURS) require personnel and budget for processing and repairing, whereas single-use fURS were recently developed. After exclusive reusable fURS since 2011, we experienced high repair costs and single-use fURS were therefore introduced in mid-2017. We aimed to evaluate economic and practical advantages and disadvantages of reusable versus single-use fURS. MATERIALS AND METHODS: First, we evaluated the incidence of breakage and repairs of reusable fURS in 2017. We assessed the overall operational costs of reusable fURS including purchase, processing, and repairing in our institution from 2011 to 2017. Following our experience, we created a model to compare operation costs/procedure of single-use fURS with reusable fURS depending on repair costs. RESULTS: In 2017, repair costs of reusable fURS increased by 345% compared with the period 2011-2016, causing: a median unavailability per reusable fURS of 200 days/year (100-249), median number of functioning fURS 0/5-3/5 per operating day, while unavailability of reusable fURS had become the first reason for cancellation of procedure. Since it was introduced, single-use fURS accounted for 59% of the flexible ureteroscopy activity. Taking into account the costs of processing, maintenance and repair, in 2011-2016 versus 2017, the single-use fURS was cost-effective compared with the reusable fURS until the 22nd procedure versus the 73rd procedure, respectively. CONCLUSIONS: After years of exclusive reusable fURS, the rising incidence of breakage not only increased maintenance costs but also hampered daily activity owing to unavailability of the devices. The introduction of single-use with reusable fURS provided substantial help to maintain our activity.

Testicular Toxicity of Water Pipe Smoke Exposure in Mice and the Effect of Treatment with Nootkatone Thereon.

There is a worldwide increase in the popularity of water pipe (shisha) tobacco smoking including in Europe and North America. However, little is known about the effects of water pipe smoke (WPS) exposure on male reproductivity. We have recently demonstrated that WPS exposure in mice induces testicular toxicity including inflammation and oxidative stress. Nootkatone, a sesquiterpenoid found in grapefruit, has antioxidant and anti-inflammatory effects. However, the possible protective effect of nootkatone on WPS-induced testicular toxicity has not been reported before. Here, we tested the effects of treatment of mice with nootkatone on WPS-induced testicular toxicity. Mice were exposed to normal air or WPS (30 minutes/day, for 30 days). Nootkatone (90 mg/kg) was given orally to mice by gavage, 1 h before WPS or air exposure. Nootkatone treatment significantly ameliorated the WPS-induced increase in plasma levels of inhibin, uric acid, and lactate dehydrogenase activity. Nootkatone also significantly mitigated the decrease in testosterone, androgen-binding protein, and estradiol concentrations in the plasma induced by WPS. In testicular homogenates, WPS exposure caused a decrease in the total nitric oxide level and an increase in the proinflammatory cytokine interleukin-1ß level and oxidative stress markers including malondialdehyde, cytochrome C, and 8-Oxo-2'-deoxyguanosine. All the latter effects were significantly alleviated by nootkatone treatment. Moreover, in testicular homogenate, nootkatone inhibited the expression of nuclear factor-kappaB induced by WPS. Likewise, histological examination of mouse testes showed that nootkatone treatment ameliorated the deterioration of spermatogenesis induced by WPS exposure. We conclude that nootkatone ameliorated the WPS-induced testicular inflammation and oxidative stress and hormonal and spermatogenesis alterations.

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.

Frequencies of the Arg16Gly, Gln27Glu and Thr164Ile Adrenoceptor ß2 Polymorphisms among Omanis.

OBJECTIVES: This study aimed to assess the distribution of missense mutations in the adrenoceptor ß2 (ADRB2) gene in an Omani cohort. METHODS: This study was carried out between May 2014 and March 2015 at the Sultan Qaboos University, Muscat, Oman. Blood samples were taken from 316 unrelated Omani subjects. Genotyping for rs1042713 (c.46A>G, p.Arg16Gly), rs1042714 (c.79C>G, p.Gln27Glu) and rs1800888 (c.491C>T, p.Thr164Ile) polymorphisms was performed by real-time polymerase chain reaction using single nucleotide polymorphism (SNP) genotyping assays. The allelic frequencies of these polymorphisms were estimated on the basis of the observed numbers of specific alleles from the genotype data for male and female subjects. The genotype frequencies for each polymorphism were tested for deviation from the Hardy-Weinberg equilibrium. RESULTS: Gly16 and Glu27 were the most frequent variants found among the cohort (63% and 75%, respectively). The Ile164 variant was not detected in the study population. There was a significant linkage disequilibrium between the rs1042713 and rs1042714 SNPs (r(2) = 0.209; P ≤0.001). The most observed haplotypes were Gly16-Gln27 and Arg16-Gln27 (0.37 and 0.38, respectively). The frequency of Gly16-Glu27 was 0.25, comprising all Glu27 carriers. CONCLUSION: The allelic distribution of variants in this Omani cohort was similar to distributions reported among Caucasian populations.

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.