PITX1, a specificity determinant in the HIF-1α-mediated transcriptional response to hypoxia

Hypoxia is an important developmental cue for multicellular organisms but it is also a contributing factor for several human pathologies, such as stroke, cardiovascular diseases and cancer. In cells, hypoxia activates a major transcriptional program coordinated by the Hypoxia Inducible Factor (HIF) family. HIF can activate more than one hundred targets but not all of them are activated at the same time, and there is considerable cell type variability. In this report we identified the paired-like homeodomain pituitary transcription factor (PITX1), as a transcription factor that helps promote specificity in HIF-1α dependent target gene activation. Mechanistically, PITX1 associates with HIF-1β and it is important for the induction of certain HIF-1 dependent genes but not all. In particular, PITX1 controls the HIF-1α-dependent expression of the histone demethylases; JMJD2B, JMJD2A, JMJD2C and JMJD1B. Functionally, PITX1 is required for the survival and proliferation responses in hypoxia, as PITX1 depleted cells have higher levels of apoptotic markers and reduced proliferation. Overall, our study identified PITX1 as a key specificity factor in HIF-1α dependent responses, suggesting PITX1 as a protein to target in hypoxic cancers

A study of serum psedocholinesterase levels following diazinon poisoning in relation to liver function-prognostic and therapeutic value

Background: To study serum pseudo-cholinesterase (PChE) levels as an index of liver injury in individuals with diazinon poisoning with or without alcoholism. It gives the knowledge of the therapeutic efficacy and severity of liver dysfunction.Methods: Blood samples were taken from normal male adults as control and PChE is estimated. Blood samples were taken from diazinon poisoning patients from local hospitals on the 1st day and on 5th day for pseudocholinesterase estimation. Another group of blood samples were taken on the 1st day and on the 5th day from diazinon poisoning patients with history of alcoholism serum PChE is estimated.Results: Serum PChE was estimated among the normal healthy male adults as the normal value of enzyme for the various levels for comparison. Among 30 normal adults, the control value of PChE ranged between 125 and 321 µmol/ml with 212 as the mean. Following the treatment with atropine, PAM and blood transfusion, blood samples were estimated by 5th day among patients with diazinon. Their mean value was found to be 200 µmol/ml. Among individuals with alcohol and diazinon poisoning, following the treatment, the serum PChE levels were raised comparatively on 1st day. The value is 100 µmol/ml.Conclusions: In diazinon poisoning without alcoholism, the prognostic and therapeutic efficacy of the drugs is better unlike in alcoholics. Hence a scope of necessitating the hepatoprotective measures is of consideration in the organophosphorous poisoning cases

A questionnaire-based exploratory study on self medication among second year MBBS students

Background: The practice of self-medication is expected to be higher in health science students due to their exposure to knowledge about different diseases and drugs. This study was done to assess the knowledge, attitude and practice of self-medication and to compare the impact of knowledge of Pharmacology on it, among second-year MBBS students.Methods: A semi-structured questionnaire consisting of both open-ended and close-ended questions was prepared and given to second-year medical students of Kurnool medical college, Kurnool. Data was analysed and entered in Microsoft Excel (version 2019), and associations were tested using the Chi-square test. The results are expressed as counts and percentages. Statistical significance was p<0.05.Results: Among the respondents, 37.33% are practising self- medication, 54.66% think knowledge of Pharmacology aids students to practice without any dire consequences. Most of the students take for fever (95.33%), (97.33%) for cough, cold, sore throat.84% were aware that it’s not safe to take drugs pertaining to alternate systems of medicine like Ayurveda, homoeopathy. A statistically significant association between knowledge, attitude, practice and gender and residence has been observed.Conclusions: The study shows that students are aware that self-medication is dangerous when followed by lay people. On the other hand, health professionals with knowledge about medications can take self-medication for common conditions without any dire consequences. They are also aware that it’s not safe to take medications that come under alternate systems of medicines, and WhatsApp consultation is not to be encouraged

An observational study on dapagliflozin as an add-on therapy in type-2 diabetes mellitus patients in a tertiary care teaching hospital

Background: Diabetes mellitus is one of the prevalent morbid conditions all over the world and no exception for India. Day by day, increase in its prevalence is attributed to lifestyle derangements. To treat this condition many drugs and treatment modalities are developed. Dapagliflozin is an oral antidiabetic drug which acts by sodium-glucose cotransport-2 (SGLT-2) inhibition. Its effectiveness seen in type-2 diabetes mellitus makes it an option for Add-On therapy. Methods: This study is a retrospective observational study conducted at tertiary care hospital, GGH, Kurnool. The study proposal has been reviewed and approved by institutional ethics committee. All adult diabetic patients who were prescribed Dapagliflozin during the period of January 2021 to February 2022, total 45 were included in the study. FBG, HbA1c collected through hospital records from General Medicine and Endocrinology. Patients who stopped drug before 3 months period were excluded. Results: Administration of dapagliflozin as an add-on therapy was found 26.63% decrease in base line mean FBG 184 mg/dl to 135 mg/dl after 3mnoths which is significant (p=0.001). Mean HbA1c significantly reduced by 0.96 percentage point after 3 months (p=0.001). Dapagliflozin effectively reduced the FBG and HbA1c when used in combination with other OHAs or insulin within 3 months. Conclusions: Dapagliflozin as an add-on therapy significantly reduced the HbA1c level and fasting blood glucose of Type-2DM patients, in a 3-month treatment period. Due to the frequency of Genitourinary tract infections, caution is indicated while treating the patients

Taxanes induced hypersensitivity reactions in cancer chemotherapy patients reported at adverse drug reaction monitoring centre at a tertiary care hospital

Background: Cancer chemotherapy involves highly complex regimens using antineoplastic agents like taxanes (paclitaxel, docetaxel) etc. Taxanes cause hypersensitivity reactions (HSRs) like redness, rashes, dyspnoea, severe anaphylaxis and death. In this study, adverse drug reactions (ADRs) associated with taxanes are described &amp; analysed on their severity and preventability. The present study aims to analyse and determine the prevalence of ADRs, especially HSRs in patients treated with taxanes.Methods: After getting IEC approval, the present study is done retrospectively by assessing the HSRs in suspected ADR reporting forms from December 2019 to February 2022 in ADR monitoring centre (AMC) in the Department of Pharmacology at Kurnool Medical College, Kurnool. Descriptive statistics used to analyse patient demography, frequency, various carcinomas under treatment &amp; organ involved, causality assessment using WHO-UMC Scale and Naranjo's Algorithm, severity assessment using modified Hartwig &amp; Siegel’s scale and preventability by modified Schumock &amp; Thornton scale.Results: A total of 258 ADRs were recorded, of which 30 cases reported HSRs with taxanes-paclitaxel (22) and docetaxel (8). The most commonly occurred HSR is shortness of breath. Naranjo’s algorithm showed 52.5% possible (score 1-4) HSRs. WHO-UMC causality assessment scale showed 56.4% as probable HSRs. Modified Hartwig &amp; Siegel severity scale showed 46.6% moderate (level 3). Modified Schumock and Thornton scale showed 76.9% as not preventable.Conclusions: Chemotherapy-related ADRs among cancer patients urges the oncologists to be actively involved in ADR reporting, in the need of the hour in order to mitigate, avoid their occurrence and reducing morbidity and mortality, when practiced with diligence

Evaluation of knowledge, attitude and practice towards drug-drug interactions among postgraduates in tertiary care hospital, Kurnool

Background: Drug-drug interactions (DDIs) are changes in a drug’s effects due to concurrent use of another drug. Clinically significant interactions lead to undesired adverse effects, therapeutic failure, toxicity or may even cause death of the patients. The Aim is to evaluate the Knowledge, Attitude and Practice of Postgraduates regarding DDIs and implementation of educational program may enhance patient’s safety.Methods: A cross-sectional study was conducted among postgraduates in all clinical departments of Government general hospital, Kurnool in the month of October 2021. Pre-validated questionnaire was used to assess the KAP. It contains demographic data, knowledge and practice questions related to DDIs and attitude towards the preferable sources of drug interaction information. Data analysis was done by using SPSS version 26.Results: Out of 220 questionnaires distributed, 126 postgraduates submitted with complete answers(n=126). Overall response rate is 57%. By using the Bloom’s cut-off points, most of the respondents (43.5%) had low level of knowledge towards DDIs. Even respondents with high knowledge level (19%) are not practicing the drug interaction screening during the admission of patients. Majority of PGs with low level knowledge agreed to ask doctors than pharmacist about DDIs and prefer to search for DDIs using reference book than online mode as the source of drug information.Conclusions: In my study, most of the respondents had insufficient knowledge to prevent life threatening DDI’s. So, there is a need to increase medical educational program regarding the importance of screening and assessing of DDI’s before prescribing medicines

Comparative evaluation of H1 receptor blocking activity and safety of newer H1antagonist mizolastine with loratadine and placebo: a randomized double blind three way crossover study

Background: Histamine is a naturally occurring body constituent synthesized from L-histidine by histidine decarboxylase enzyme that is expressed throughout the body including central nervous system neurons, gastric mucosa, mast cells and basophils. The objective of this study was to compare the pharmacological activity and safety of 10 mg mizolastine, 10 mg loratadine and placebo in healthy human volunteers.Methods: After randomly allocating the 3 drugs, a battery of psychometric tests was done. Histamine prick test for wheal and flare reaction, VAS for sedation and itch followed by salivary flow test were done. Vitals were recorded. The subjects were randomized to receive either of the treatment in a cross-over manner with washout period of 7 days. The wheal and flare areas were recorded before and after 1,2,4,8, and 24 hours.Results: Mean inhibition on histamine induced wheal and flare response with mizolastine was highly significant as compared to placebo from 1 hour onwards (p<0.001) with maximum inhibition of 98.1±1.8% at 4 hours and of 85.1±24.8percent at 8 hours, for wheal and flare, respectively. The mean inhibition on histamine induced response with loratadine was significant from 2 hours (p<0.05) for wheal area and 1 hour onwards up to 24 hours (P<0.01) for flare area with the maximum inhibition of 56.2±31.6 percent and 60.1±14.2percent at 8hours, respectively. Mean inhibition on histamine induced itch with mizolastine was also significant from 4 hours onwards and persisted up to 24 hours (p<0.05) with maximum inhibition of 58.6±54.2% at 8 hours for the itch response, unlike loratidine. There was no significant change in mean effect on sedation assessed on a VAS of 0-100 mm. There was no significant change in psychomotor functions, salivary flow or vital parameters. All were well tolerated.Conclusions: Mizolastine has good antihistaminic activity than loratadine. Neither drug causes any psychomotor impairment or has anti-cholinergic action

Review of methods for measuring β-cell function: Design considerations from the Restoring Insulin Secretion (RISE) Consortium

The Restoring Insulin Secretion (RISE) study was initiated to evaluate interventions to slow or reverse the progression of β-cell failure in type 2 diabetes (T2D). To design the RISE study, we undertook an evaluation of methods for measurement of β-cell function and changes in β-cell function in response to interventions. In the present paper, we review approaches for measurement of β-cell function, focusing on methodologic and feasibility considerations. Methodologic considerations included: (1) the utility of each technique for evaluating key aspects of β-cell function (first- and second-phase insulin secretion, maximum insulin secretion, glucose sensitivity, incretin effects) and (2) tactics for incorporating a measurement of insulin sensitivity in order to adjust insulin secretion measures for insulin sensitivity appropriately. Of particular concern were the capacity to measure β-cell function accurately in those with poor function, as is seen in established T2D, and the capacity of each method for demonstrating treatment-induced changes in β-cell function. Feasibility considerations included: staff burden, including time and required methodological expertise; participant burden, including time and number of study visits; and ease of standardizing methods across a multicentre consortium. After this evaluation, we selected a 2-day measurement procedure, combining a 3-hour 75-g oral glucose tolerance test and a 2-stage hyperglycaemic clamp procedure, augmented with arginine

Fidelity monitoring across the seven studies in the Consortium of Hospitals Advancing Research on Tobacco (CHART)

Background This paper describes fidelity monitoring (treatment differentiation, training, delivery, receipt and enactment) across the seven National Institutes of Health-supported Consortium of Hospitals Advancing Research on Tobacco (CHART) studies. The objectives of the study were to describe approaches to monitoring fidelity including treatment differentiation (lack of crossover), provider training, provider delivery of treatment, patient receipt of treatment, and patient enactment (behavior) and provide examples of application of these principles. Methods Conducted between 2010 and 2014 and collectively enrolling over 9500 inpatient cigarette smokers, the CHART studies tested different smoking cessation interventions (counseling, medications, and follow-up calls) shown to be efficacious in Cochrane Collaborative Reviews. The CHART studies compared their unique treatment arm(s) to usual care, used common core measures at baseline and 6-month follow-up, but varied in their approaches to monitoring the fidelity with which the interventions were implemented. Results Treatment differentiation strategies included the use of a quasi-experimental design and monitoring of both the intervention and control group. Almost all of the studies had extensive training for personnel and used a checklist to monitor the intervention components, but the items on these checklists varied widely and were based on unique aspects of the interventions, US Public Health Service and Joint Commission smoking cessation standards, or counselor rapport. Delivery of medications ranged from 31 to 100 % across the studies, with higher levels from studies that gave away free medications and lower levels from studies that sought to obtain prescriptions for the patient in real world systems. Treatment delivery was highest among those studies that used automated (interactive voice response and website) systems, but this did not automatically translate into treatment receipt and enactment. Some studies measured treatment enactment in two ways (e.g., counselor or automated system report versus patient report) showing concurrence or discordance between the two measures. Conclusions While fidelity monitoring can be challenging especially in dissemination trials, the seven CHART studies used a variety of methods to enhance fidelity with consideration for feasibility and sustainability. Trial registration - Dissemination of Tobacco Tactics for hospitalized smokers. Clinical Trials Registration No. NCT01309217. - Smoking cessation in hospitalized smokers. Clinical Trials Registration No. NCT01289275. - Using “warm handoffs” to link hospitalized smokers with tobacco treatment after discharge: study protocol of a randomized controlled trial. Clinical Trials Registration No. NCT01305928. - Web-based smoking cessation intervention that transitions from inpatient to outpatient. Clinical Trials Registration No. NCT01277250. - Effectiveness of smoking-cessation interventions for urban hospital patients. Clinical Trials Registration No. NCT01363245. - Comparative effectiveness of post-discharge interventions for hospitalized smokers. Clinical Trials Registration No. NCT01177176. - Health and economic effects from linking bedside and outpatient tobacco cessation services for hospitalized smokers in two large hospitals. Clinical Trials Registration No. NCT01236079

Use of Immortalized Human Hepatocytes to Predict the Magnitude of Clinical Drug-Drug Interactions Caused by CYP3A4 Induction

ABSTRACT: Cytochrome P4503A4 (CYP3A4) is the principal drug-metabolizing enzyme in human liver. Drug-drug interactions (DDIs) caused by induction of CYP3A4 can result in decreased exposure to coadministered drugs, with potential loss of efficacy. Immortalized hepatocytes (Fa2N-4 cells) have been proposed as a tool to identify CYP3A4 inducers. The purpose of the current studies was to characterize the effect of known inducers on CYP3A4 in Fa2N-4 cells, and to determine whether these in vitro data could reliably project the magnitude of DDIs caused by induction. Twenty-four compounds were chosen for these studies, based on previously published data using primary human hepatocytes. Eighteen compounds had been shown to be positive for induction, and six compounds had been shown to be negative for induction. In Cytochrome P4503A4 (CYP3A4) is the major drug-metabolizing enzyme in human liver and is responsible for the clearance of many commonly used drugs, including benzodiazepines, statins, calcium channel blockers, and HIV protease inhibitors. Certain drugs can modulate the level of CYP3A4 activity, thereby causing changes in clearance of coadministered drugs that are CYP3A4 substrates. Levels of CYP3A4 activity can be decreased by inhibition of enzyme activity, or increased by induction of new protein synthesis. Changes in CYP3A4 activity, either through inhibition or induction, can result in potentially serious drug-drug interactions (DDIs). Whereas assays for evaluating inhibition of CYP3A4 are routine and the relationship between in vitro data and in vivo effects relatively well understood Induction of CYP3A4 is thought to occur primarily through transcriptional activation of the gene. The 5Ј-regulatory region of the CYP3A4 gene contains elements that bind various transcription factors that can up-or down-regulate transcription. One such transcription factor is the pregnane X receptor (PXR). PXR is a ligand-activated transcription factor that is activated by a variety of drugs and endogenous compounds to increase transcription of CYP3A4 as well as other drug-metabolizing enzymes and transporter