Formulation and evaluation of miconazole lipogel for enhanced drug permeation.

Hydrophilic drugs could be incorporated into the skin surface by manes of Lipogel. This study aimed to prepare miconazole lipogel with natural ingredients to enhance drug permeability using dimethyl Sulfoxide (DMSO). The miconazole lipogels, A1 (without DMSO) and A2 (with DMSO) were formulated and evaluated for organoleptic evaluation, pH, viscosity, stability studies, freeze-thawing, drug release profile and drug permeation enhancement. Results had stated that prepared lipogel's pH falls within the acceptable range required for topical delivery (4 to 6) while both formulations show good results in organoleptic evaluation. The A2 formulation containing DMSO shows better permeation of miconazole (84.76%) on the artificial skin membrane as compared to A1 lipogel formulation (50.64%). In in-vitro drug release studies, A2 for-mulation showed 87.48% drug release while A1 showed just 60.1% drug release from lipogel. Stability studies were performed on model formulations under environmental conditions and both showed good spreadibility, stable pH, free of grittiness and good consistency in formulation. The results concluded that A2 formulation containing DMSO shows better results as compared to DMSO-free drug lipogel.

Long-Term Proton Pump Inhibitor Therapy and its Effect on Endocrine Hormones in Selected Patient Population.

Proton pump inhibitors (PPI) are commonly prescribed medications for a variety of gastrointestinal disorders around the globe. Long-term utilization of proton pump inhibitors is linked with different adverse events. Although, short-term therapy has been demonstrated to have little or no impact on endocrine hormones in men, yet its safety with long-term use has poorly been studied. We aimed to evaluate the impacts of long-term utilization of proton pump inhibitors on male reproductive hormones and its clinical outcomes. A cross-sectional study was performed in two out-patients gastroenterology clinics in Khyber Pakhtunkhwa province. Male patients who were using PPIs regularly for≥3 months were enrolled in this study. Among 65 enrolled participants, patients with sexual complaints have significant variations in mean serum levels of prolactin (p<0.001), sex hormone binding globulins (p=0.043), total testosterone (p<0.001) and progesterone (p=0.001) as compared to patients without sexual complaints. Significantly high values of prolactin mean ranks were observed in patient with sexual complaints (p<0.001). There were statistically significant correlations of serum levels of sex hormone binding globulins (p=0.003), total testosterone (p=0.008) and progesterone (p<0.001) with serum prolactin levels. Similarly, statistically significant variation was observed for decreased libido (p=0.001), erectile dysfunction (p=0.001) and decreased semen mass ((p<0.001) between normal and hyperprolactinemic PPI users. Highly significant differences were observed in serum sex hormone binding globulins (p<0.001), total testosterone (p<0.001) and progesterone (p<0.001) values in normal and hyperprolactinemic groups. In conclusion, long-term utilization of PPI may induce endocrine hormone disruption with subsequent sexual complications.

Evaluation of different Pakistani medicinal plants for inhibitory potential against Echis carinatus induced Phospholipase A2 toxicity.

Medicinal plants of Pakistan are known for their curative properties against snake bite as rural people have been using natural herbs for such injuries for hundreds to thousands of years. People of rural areas of Pakistan are prone to snakebite, and on the whole death due to snakebite has been increasing worldwide. The objective of this study was to test the neutralizing potential of 17 Pakistani medicinal plant extracts against phospholipase A2 activity in Echis carinatus venom. Plant material was extracted by simple maceration and fractionation of active plant extracts. Venom was collected by manual massage of the venom glands. The PLA2 enzymatic assay was performed to map out the venomous activity of Echis carinatus envenomation. Snake venom released fatty acids at different concentrations (0.1-5 mg/ml) of venom in a dose-dependent manner. Reduction of pH by 01 correlated with 133 µmol of fatty acids released at 5mg/ml of venom. All plants extract inhibited PLA2 activity, however, Curcuma longa, Citrullus colocynthis and Rubia cordifolia inhibited maximum of PLA2 activity (⁓78%) comparable to the standard antidote (p>0.5). Medicinal plants possess secondary metabolites and many active compounds that may have neutralizing or inhibiting properties against the PLA2 activity of Echis venom. Further studies such as compound analysis could provide an alternative against snakebites injuries resulting from Echis carinatus venom.

Sulfonyl hydrazones derived from 3-formylchromone as non-selective inhibitors of MAO-A and MAO-B: Synthesis, molecular modelling and in-silico ADME evaluation.

A series of sulfonyl hydrazones derived from 3-formylchromone was synthesized and discovered to be effective, non-selective inhibitors of monoamine oxidases (MAO-A and MAO-B). The compounds are easily (synthetically) accessible in high yields, by simple condensation of 4-methylbenzenesulfonohydrazide with different (un)substituted 3-formylchromones. All compounds had IC50 values in lower micro-molar range (IC50 = 0.33-7.14 µM for MAO-A, and 1.12-3.56 µM for MAO-B). The most active MAO-B inhibitor was N'-[(E)-(6-fluoro-4-oxo-4H-chromen-3-yl)methylidene]-4-methylbenzenesulfonohydrazide (3e) with IC50 value of 1.12 ±â€¯0.02 µM, and N'-[(E)-(6-chloro-4-oxo-4H-chromen-3-yl)methylidene]-4-methylbenzenesulfonohydrazide (3f) was the most active MAO-A inhibitor with IC50 value of 0.33 ±â€¯0.01 µM. From enzyme kinetic studies, the mode of inhibition against MAO-B was found to be competitive, whereas against MAO-A, it was found to be non-competitive. Molecular docking studies indicated a new binding pocket for non-competitive MAO-A inhibitors. The activity of these compounds is optimally combined with highly favorable ADME profile with predicted good oral bioavailability.

ASSESSMENT OF PRACTICE AT RETAIL PHARMACIES IN PAKISTAN: EXTENT OF COMPLIANCE WITH THE PREVAILING DRUG LAW OF PAKISTAN.

The main objective of this study was to assess the practice at retail pharmacies in Pakistan and to compare the same in rural and urban areas. The maintenance of pharmacy and drug inspectors' visit was also assessed. This cross sectional study was conducted in Abbottabad, Pakistan during October-November, 2012. A sample of 215 drug sellers or drug stores was selected by employing convenient sampling method. With a response rate of 91.6%, 197 drug sellers participated in this study. All the drug sellers were male. Overall, 35% (n = 197) of the drug sellers did not have any professional qualification. A majority of the drug sellers were involved in various malpractices like selling of medicines without prescription (80.7%), prescribing practice (60.9%), prescription intervention (62.4%) and selling of controlled substances (66%) without a license for selling it. These malpractices were significantly higher in rural area than that in urban area.

Quinoline-sulfonamides as a multi-targeting neurotherapeutic for cognitive decline: in vitro, in silico studies and ADME evaluation of monoamine oxidases and cholinesterases inhibitors.

Alzheimer's disease (AD) is a multifactorial irreversible neurological disorder with multiple enzymes involved. In the treatment of AD, multifunctional agents targeting cholinesterase (ChE) and monoamine oxidase (MAO) inhibitors have shown promising results. Herein, a series of novel quinoline-sulfonamides (a1-18) were designed and synthesized as a dual inhibitor of MAOs and ChEs. The in vitro results showed that compounds a5, a12, a11, and a6 exhibited the most potent compounds against specific enzymes. They had IC50 value 0.59 ± 0.04 for MAO-A, 0.47 ± 0.03 for MAO-B, 0.58 ± 0.05 for BChE and 1.10 ± 0.77 for AChE µM respectively. Furthermore, kinetic studies revealed that these compounds are competitive. Molecular docking studies enhanced the understanding of the in silico component, unveiling critical interactions, specifically the hydrogen bonding interaction, π-π, π-alkyl, π-amid and π-sulfur interactions between the ligand and enzymes. These findings suggest that compounds a5, a6, a11, a12, a15, and a18 may be potent multifunctional candidates for AD treatment.

Effects of long-term proton pump inhibitor use on sexual hormones and sexual and reproductive health in female patients.

PURPOSE: Proton pump inhibitors (PPIs) are widely used to treat a range of gastrointestinal diseases around the world. Long-term use of PPIs has been associated to a variety of undesirable effects. Although short-term therapy has been shown to have little or no effect on endocrine hormone in women, however, its long-term safety has received little attention. We aimed at evaluating long-term use of PPIs and its effects on female reproductive hormones as well as related clinical consequences. METHODS: A cross-sectional study was conducted in two outpatient gastroenterology clinics in the province of Khyber Pakhtunkhwa. This study included female patients who had been using PPIs on a regular basis for 3 months or more. RESULTS: In total of 101 participants, patients with sexual complaints have significantly altered levels of prolactin (p = 0.05), estrogen (p < 0.001) and progesterone (p = 0.001) than patient without sexual complaints. The frequency of amenorrhea (p < 0.001), cyclic disturbances (p < 0.001), breast augmentation (p = 0.001) and painful breast (p = 0.004) were statistically significant in patients with raised serum prolactin values. Serum values of Sex hormone binding globulin SHBG (p < 0.001), estradiol (p = 0.002) and total testosterone (p < 0.001) were significantly altered between normal prolactin and hyperprolactinemic patients. CONCLUSION: These findings suggest that long-term PPI use may cause endocrine hormone disturbances leading to sexual difficulties in women.

Consumption of proton pump inhibitors in outpatients of Gastroenterology Clinics in Khyber Pakhtunkhwa: evidence of inexpedient use.

Introduction: Proton pump inhibitors (PPIs) are effective drugs used for multiple gastrointestinal complications. They are commonly used in both hospitalised and outpatients. However, little is known about its utilisation pattern in ambulatory patients. Aim: To evaluate the inexpedient continuous use of PPIs in patients with respect to treatment duration. Material and methods: A cross-sectional observational study was conducted from January 2018 to November 2019 in Khyber Pakhtunkhwa, Pakistan. Regular proton pump inhibitor users were identified through patient histories. Results: During the study period, 171 patients were included using a non-probability consecutive sampling technique, who were using regular proton pump inhibitors for a longer duration, i.e. from 3 months to 15 years. The highest proportion (42.8%) were using PPI regularly from 3 months to 1 year followed by 22.9% for 1-2 years, 12.0% for 2-3 years, 7.8% for 3-4 years, 4.2% for 4-5 years, and 10.24% for > 5 years. Omeprazole and esomeprazole were the most commonly used drugs, with 71.1% and 23.5% prevalence, respectively. A total of 33.73% of patients had continued PPI use on their own after initially being prescribed by the physician. Conclusions: It can be deduced that PPIs are used in outpatients beyond standard treatment guidelines. The inexpedient continuous use of proton pump inhibitors is of concern due to the risk of developing adverse effects. Therefore, patient counselling and periodic monitoring must be carried out to prevent the irrational use of PPIs.

Low pathogenic avian influenza A (H7N2) virus infection in immunocompromised adult, New York, USA, 2003.

In 2003, infection with low pathogenic avian influenza A (H7N2) virus was identified in an immunocompromised man with fever and community-acquired pneumonia in New York, USA. The patient recovered. Although the source of the virus was not identified, this case indicates the usefulness of virus culture for detecting novel influenza A viruses.

Exploring the factors and barriers of healthcare professionals in tertiary care hospitals toward pharmacovigilance: a multicenter study from Khyber Pakhtunkhwa, Pakistan.

BACKGROUND: Spontaneous Adverse drug reactions (ADRs) reporting is a cornerstone for a successful pharmacovigilance program as under-reporting of ADRs remains a major issue around the globe. The current study aimed to assess the knowledge attitude and practices of health care professionals regarding pharmacovigilance along with barriers and factors to encourage ADR reporting at tertiary care hospitals of Khyber-Pakhtunkhwa, Pakistan. METHODS: A questionnaire-based cross-sectional survey was conducted, using the convenience sampling method to collect the data from doctors, nurses, and pharmacists working in seven tertiary care hospitals from seven districts of Khyber-Pakhtunkhwa province, Pakistan, between July 2019 and March 2020. RESULTS: During the study, a total of 830 questionnaires were distributed, out of which 669 were returned (response rate 80.6%). Overall, Healthcare professionals exhibited poor knowledge (79.5%) about ADR reporting and pharmacovigilance however, 73.5% of pharmacists were more knowledgeable as compared to 18.7% doctors and 13.8% nurses (p < .001). Moreover, poor reporting practices were displayed by 95.6% doctors, 94.4% nurses, 94.4 and 75.5% pharmacists (p < .001). However, the majority of healthcare professionals showed an overall positive attitude (94%) toward ADR reporting. The most frequently cited barriers were unavailability of reporting forms (92.5%), absence of a professional environment to discuss ADRs (82.5%), and lack of training (81.8%) whereas, most common factors to encourage ADR reporting were obligatory reporting (85.9%) and provision of ADR management guidelines and training (84.3%). A significant relation was found between the healthcare professionals and their professional status with the overall knowledge, attitude, and practice (KAP) scores (p < .001) whereas a medium, positive correlation was found between the knowledge and practice of pharmacovigilance and ADR reporting by the healthcare professionals (r = 0.321, n = 669, p < .001). CONCLUSION: There is an overall lack of knowledge and poor reporting practices among health care professionals on ADR reporting and pharmacovigilance. Hence the study suggests that strategies should be devised by all the stakeholders to properly educate and train the healthcare professionals in this area to enhance overall patient safety and safe use of medicines.

Identification and Expression Analysis of CD73 Inhibitors in Cervical Cancer.

AIMS: The present study was conducted to examine the inhibitory effects of synthesized sulfonylhydrazones on the expression of CD73 (ecto-5'-NT). BACKGROUND: CD73 (ecto-5'-NT) represents the most significant class of ecto-nucleotidases, which are mainly responsible for the dephosphorylation of adenosine monophosphate to adenosine. Inhibition of CD73 played an important role in the treatment of cancer, autoimmune disorders, precancerous syndromes, and some other diseases associated with CD73 activity. OBJECTIVE: Keeping in view the significance of CD73 inhibitor in the treatment of cervical cancer, a series of sulfonylhydrazones (3a-3i) derivatives synthesized from 3-formylchromones were evaluated. METHODS: All sulfonylhydrazones (3a-3i) were evaluated for their inhibitory activity towards CD73 (ecto-5'-NT) by the malachite green assay and their cytotoxic effect was investigated on the HeLa cell line using MTT assay. Secondly, the most potent compound was selected for cell apoptosis, immunofluorescence staining, and cell cycle analysis. After that, CD73 mRNA and protein expression were analyzed by real-time PCR and Western blot. RESULTS: Among all compounds, 3h, 3e, 3b, and 3c were found to be the most active against rat-ecto- 5'-NT (CD73) enzyme with IC50 (µM) values of 0.70 ± 0.06 µM, 0.87 ± 0.05 µM, 0.39 ± 0.02 µM, and 0.33 ± 0.03 µM, respectively. These derivatives were further evaluated for their cytotoxic potential against cancer cell line (HeLa). Compounds 3h and 3c showed the cytotoxicity at IC50 value of 30.20 ± 3.11 µM and 86.02 ± 7.11 µM, respectively. Furthermore, compound 3h was selected for cell apoptosis, immunofluorescence staining, and cell cycle analysis, which showed a promising apoptotic effect in HeLa cells. Additionally, compound 3h was further investigated for its effect on the expression of CD73 using qRT-PCR and western blot. CONCLUSION: Among all synthesized compounds (3a-3i), Compound 3h (E)-N'-((6-ethyl-4-oxo-4Hchromen- 3-yl) methylene)-4-methylbenzenesulfonohydrazide was identified as the most potent compound. Additional expression studies conducted on the HeLa cell line proved that this compound successfully decreased the expression level of CD73 and thus, inhibited the growth and proliferation of cancer cells.

Complicated megaureter with aganglionosis in an adult lady.

Dilated ureters are often due to mechanical obstruction. This case report describes a young adult lady with primary megaureter due to aganglionosis finally managed with extravesical Leech-Gregor Uretroneocystostomy.

Anemia in the Long-Term Care Setting.

Anemia has a higher prevalence among residents of long-term care setting. Signs and symptoms of anemia in this group are more insidious and can be overlooked and attributed to other disease manifestations or old age. Available data on the consequences of anemia suggest worse outcomes in heart failure; cognitive and functional decline; and increased rates of falls, hospitalizations, and mortality. Diagnosis and treatment of anemia in long-term care residents should be considered based on cost and benefit to the patient and patient's and/or caregiver's preferences.

Quinolinic Carboxylic Acid Derivatives as Potential Multi-target Compounds for Neurodegeneration: Monoamine Oxidase and Cholinesterase Inhibition.

BACKGROUND: Parkinson's disease (PD), a debilitating and progressive disorder, is among the most challenging and devastating neurodegenerative diseases predominantly affecting the people over 60 years of age. OBJECTIVES: To confront PD, an advanced and operational strategy is to design single chemical functionality able to control more than one target instantaneously. METHODS: In this endeavor, for the exploration of new and efficient inhibitors of Parkinson's disease, we synthesized a series of quinoline carboxylic acids (3a-j) and evaluated their in vitro monoamine oxidase and cholinesterase inhibitory activities. The molecular docking and in silico studies of the most potent inhibitors were performed to identify the probable binding modes in the active site of the monoamine oxidase enzymes. Moreover, molecular properties were calculated to evaluate the druglikeness of the compounds. RESULTS: The biological evaluation results revealed that the tested compounds were highly potent against monoamine oxidase (A & B), 3c targeted both the isoforms of MAO with IC50 values of 0.51 ± 0.12 and 0.51 ± 0.03 µM, respectively. The tested compounds also demonstrated high and completely selective inhibitory action against acetylcholinesterase (AChE) with IC50 values ranging from 4.36 to 89.24 µM. Among the examined derivatives, 3i was recognized as the most potent inhibitor of AChE with an IC50 value of 4.36 ± 0.12 ±µM. CONCLUSION: The compounds appear to be promising inhibitors and could be used for the future development of drugs targeting neurodegenerative disorders.

A quality improvement intervention to enhance performance and perceived confidence of new internal medicine residents.

Background: Orientation for new medical residents is challenging due to the diversity of prior experiences and cultural backgrounds and is compounded by a lack of orientation curricula that adequately addresses the needs of the medical residents to allow them to perform their duties in an efficient manner from the start. The beginning of residency training is associated with reduced quality of healthcare widely referred to as the 'July effect'. Objective: To assess the impact of a peer-led orientation for new interns on (a) self-reported confidence level, (b) improvement in performance of first-year residents in appropriate clinical documentation and efficient discharge procedures and protocols. Design/methods: In June 2016, a hybrid of interactive teaching and simulation exercises was used to teach documentation of critical information, such as discharge medication reconciliation and discharge summary. A handout of an intern guide/manual was also provided. The previous year's data served as comparison/control data. Comparison data were obtained for both groups from hospital's utilisation review department. Results: Twenty-one of 23 expected new interns (91%) participated in the intervention. There was a significant decrease in non-compliance for clinical documentation in the intervention group compared to the control group. The self-reported confidence level in the intervention group increased 34%. Conclusions: Such peer-to-peer orientation has the potential to effectively improve appropriate documentation and discharge process by new residents and may help to reduce the 'July effect'.

Pyrazolobenzothiazine-based carbothioamides as new structural leads for the inhibition of monoamine oxidases: design, synthesis, in vitro bioevaluation and molecular docking studies.

Two new series of pyrazolobenzothiazine-based carbothioamides (3a-o and 4a-o) were synthesized using saccharin as the starting material. The synthesized derivatives were investigated for their ability to inhibit monoamine oxidases (MAO). Compound 3b was found to be a very potent MAO-A inhibitor with an IC50 value of 0.003 ± 0.0007 µM, while compound 4d was the most effective inhibitor of MAO-B having an IC50 value of 0.02 ± 0.001 µM. Molecular docking studies were performed to identify the probable binding modes in the active site of the monoamine oxidase enzymes. The synthetic and computational investigations in the current work suggested that these newly identified inhibitors may serve as a powerful starting point for the exploration and optimization of potential therapeutic agents targeting Parkinson's disease.

Quinolinyl-thienyl chalcones as monoamine oxidase inhibitors and their in silico modeling studies.

Mitochondrial enzymes monoamine oxidases were thought to be an emerging and useful therapeutic target for neurodegenerative disorders. Monoamine oxidases have two isoforms, A and B. MAO-A is related with metabolism of amine neurotransmitters in the brain whereas MAO-B is concerned with aging related neurodegenerative disorders. Therefore the identification, characterization and discovery of potent MAO-A and B inhibitors is very crucial in research. A series of quinolyl-thienyl chalcones were tested against MAO-A and B. Among the screened compounds, most of them revealed potent MAO-A and B inhibition. Compound 5i presented most potent MAO-A inhibition having IC50 values 0.047 µM, while 4l showed excellent inhibitory potency against MAO-B among all the tested compound having IC50 values 0.063 µM. Molecular modelling studies were performed against human MAO-A and MAO-B for the explanation of binding site interactions.

Metastatic Follicular Thyroid Carcinoma Secreting Thyroid Hormone and Radioiodine Avid without Stimulation: A Case Report and Literature Review.

Introduction. This is an extremely rare case of a patient with metastatic follicular thyroid cancer who continued to produce thyroid hormone and was iodine scan positive without stimulation after thyroidectomy and radioiodine (I-131) therapy. Patient Findings. A 76-year-old Caucasian male was diagnosed with metastatic follicular thyroid carcinoma on lung nodule biopsy. Total thyroidectomy was performed and he was ablated with 160 mCi of I-131 after recombinant human thyrotropin (rhTSH) stimulation. Whole body scan (WBS) after treatment showed uptake in bilateral lungs, right sacrum, and pelvis. The thyroglobulin decreased from 2,063 to 965 four months after treatment but rapidly increased to 2,506 eleven months after I-131. Thyroid stimulating hormone (TSH) remained suppressed and free T4 remained elevated after I-131 therapy without thyroid hormone supplementation. He was treated with an additional 209 mCi with WBS findings positive in lung and pelvis. Despite I-131, new metastatic lesions were noted in the left thyroid bed and large destructive lesion to the first cervical vertebrae four months after the second I-131 dose. Conclusions. This case is exceptional because of its rarity and also due to the dissociation between tumor differentiation and aggressiveness. The metastatic lesions continued to secrete thyroid hormone and remained radioiodine avid with rapid progression after I-131 therapy.

Prospective evaluation of 2009 H1N1 influenza A in patients admitted with fever to an oncology unit.

We prospectively evaluated all oncology inpatients for 2009 H1N1 influenza virus. All patients recovered completely. Evaluating all oncology patients with fever for influenza involved overtreatment of influenza-negative patients and involved a significant infection control burden. However, early antiviral intervention could have contributed to a favorable outcome.