Miracle-dz/UniFAR-FTUs huggingface dataset:
Cutaneous adverse drug reactions in Indian population: A systematic review

Background: Epidemiological data is limited for cutaneous adverse drug reactions (CADRs) in India. Most of the Indian studies have small sample size and are of limited duration. Aims: The aim of this study is to analyze CADRs with reference to the causative drugs and their clinical characteristics in Indian population. Materials and Methods: As per selection criteria, electronic databases were searched for publications describing CADRs from January-1995 to April-2013 by two independent investigators. Data of the causative drugs and clinical characteristics were extracted and summarized by absolute numbers, percentages, ranges, and means as presented by the authors. The subgroup analysis of causative drugs was performed for causality assessment, severe or nonsevere reactions and occurrence of common CADRs. Studies showing “definite” and “probable” categories of causality analysis were labeled as “definite and probable causality (DPC) studies”. The other included studies were labeled as “non-DPC studies”. Results: Of 8337 retrieved references, 18 prospective studies were selected for analysis. The pooled incidence was 9.22/1000 total among outpatient and inpatient cases. Commonly observed reactions were maculopapular rash (32.39%), fixed drug eruptions (FDEs) (20.13%), urticaria (17.49%) and Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) (6.84%). The major causative drug groups were antimicrobials (45.46%), nonsteroidal anti-inflammatory drugs (NSAIDs) (20.87%) and anti-epileptic drugs (14.57%). Commonly implicated drugs were sulfa (13.32%), β-lactams (8.96%) and carbamazepine (6.65%). High frequency of CADRs is observed with anti-epileptic drugs in DPC studies only. Carbamazepine, phenytoin and fluoroquinolones had higher severe to nonsevere cutaneous reaction ratio than other drugs. Antimicrobials were the main causative drugs for maculopapular rash, FDEs and SJS/TEN, and NSAIDs for the urticaria. The mortality for overall CADRs, SJS/TEN, and exfoliative dermatitis were 1.71%, 16.39%, and 3.57%, respectively. “Definitely preventable”, “probably preventable” and “not preventable” categories CADRs were 15.64%, 63.14%, and 34.64%, respectively. Conclusion: Antimicrobials, NSAIDs and antiepileptic are common causative agents of CADRs in India. Antiepileptic agents show high rates of severe cutaneous reactions.
Cost-effectiveness of implementing the interventions for diabetes prevention and control in the community and military settings

Diabetes is an increasingly prevalent and costly cause of morbidity and mortality, representing not only a major clinical care concern but an immense public health challenge. In 2010, diabetes affected 25.8 million Americans – 8.3% of the US population and 26.9% of those aged 65 years or older. People with diabetes are disproportionately affected by eye and renal disease, non-traumatic amputations, and cardiovascular disease, which result in significant health-care costs of $245 billion in the US in 2012. Although many interventions can reduce health burden of diabetes, health care resources are limited. Hence, evidence is needed to inform health care practitioners and policymakers of these interventions’ costs and benefits to practices, payers, and patients, and thus aid them in prioritizing the interventions for diabetes prevention and control. Through a decision-analytic approach using computational modeling, this dissertation proposed the cost-effectiveness analysis on implementing the Chronic Care Model (CCM) for diabetes control in the community and military settings and on implementing an Online adaptation of the Diabetes Prevention Program lifestyle intervention (ODPP) for weight management in an overweight/obese primary care population with high cardiovascular risk. Our analyses showed that from a health care system and a societal perspective, the CCM compared with usual care cost $42,179-$45,495 and $42,051-$113,280 per quality-adjusted life-year (QALY) gained; the CCM compared with provider continuing medical education (PROV) cost $17,186 and $50,718 per QALY gained; and the ODPP compared with usual care cost $7,777-$14,351 and $18,263-$29,331 per QALY gained. Generally, these results were robust in sensitivity analyses. This dissertation provided supporting evidence that compared with usual care or PROV, the CCM for secondary and tertiary diabetes prevention in the community and military settings as well as the ODPP for primary diabetes prevention in the primary care setting appear to be economically reasonable interventions for diabetes management. These findings are of public health significance as the economic evaluation conducted in this dissertation is an important component of evidence-based clinical and public health practices, which is a decision making aid to help assess the relative value of alternative interventions that can enhance clinical care and public health.
Pharmacokinetics of crizotinib in NSCLC patients

Introduction: For a subpopulation of NSCLC patients genetic rearrangement of the anaplastic lymphoma kinase (ALK) was found as driver mutation, which can be targeted by the selective inhibitor crizotinib. Areas covered: This article presents an overview of the clinical studies that provided the characterization of the pharmacokinetic parameters for the administration of crizotinib to cancer patients and the factors influencing the clinical profiles of this drug. Expert opinion: Crizotinib is administered orally as a capsule and clinical studies indicated 250 mg crizotinib BID continuously as the maximal tolerated dose in cancer patients. Bioavailability is ∼ 40% and pharmacokinetic parameters are influenced by food only to a minor degree. This dose of the drug corresponds to a significant inhibition of the mutated ALK, retards tumor growth and achieves clinical responses in the majority of patients. Crizotinib lactam is the single metabolite with minor inhibitory activity for the ALK fusion protein. Metabolization is executed mainly by CYP3A4/5 and is modulated by other drugs interacting with this cytochrome oxidase. Despite the one-fits-all approach in administration of crizotinib at a fixed dose the pharmacokinetic parameters indicate a stable steady state upon continuous administration, which achieves sufficient inhibition of the ALK drug target.
Physiologically based pharmacokinetic and pharmacodynamic modeling in cancer drug development: status, potential and gaps

Introduction: Modeling and simulation have become important means of answering questions relevant to the development of a drug, making it possible to assess risks early and to reduce costs. Physiologically based pharmacokinetic and pharmacodynamic (PBPK/PD) models contribute to a comprehensive understanding of the drug, covering specific questions from early discovery through lifecycle management stages. As for other disease areas, in oncology, PBPK and PD models are important topics that remain to be addressed. Areas covered: This review describes current PBPK and PD approaches, their applicability in drug development in general and specifically in the area of oncology. It discusses the current status and then focuses on key challenges and the potential for future use. It provides cases in which modeling currently cannot answer the questions and assesses the requirements to close gaps for PBPK/PD in oncology. Expert opinion: PBPK/PD models have led to improvements in identifying risks and reducing costs during the drug development process. Nevertheless, there is a lot of potential, where more rigorous integration of biological knowledge and specific experimental design would result in a more comprehensive biological picture. Ideally, such approaches would reveal the extent to which preclinical work can be extrapolated to clinical settings, thus enabling reliable prediction and, ultimately, reducing failed trials in clinical oncology.
An extensive pharmacokinetic, metabolic and toxicological review of elderly patients under intensive chemotherapy for acute myeloid leukemia

Introduction: Acute myeloid leukemia (AML) is a clonal hematological malignancy characterized by accumulation of poorly differentiated and immature blast cells in bone marrow and blood circulation. The initiation of intensive chemotherapy is necessary to control further progression of the disease. Therapeutic success is less common in older patients (> 65 years) than it is in younger patients with AML. Cytarabine in combination with an anthracycline has been the mainstays of AML therapy for many years and continues to serve as the foundation for the current standard therapeutic regimen. Areas covered: This review discusses the pharmacokinetic (PK), metabolic and toxicological issues associated with antileukemic agents used to treat elderly patients (> 60 years) with AML. Expert opinion: Profound and predictable changes often occur with age and can have effects on drug metabolism, PK and toxicity with consequences bearing on overall efficacy. Few studies focus specifically on elderly patients with AML, but modifications to intensive induction therapy may be beneficial as the current number and rate of individuals achieving complete remission of the disease remains low. Therapeutic options, for the treatment of AML, have remained static for many years, but it has become clear that among elderly patients with AML, improved antileukemic therapy is greatly needed.
Pharmacokinetic and pharmacodynamic considerations on the erythropoietin effect and adverse events of darbepoetin

Introduction: In the TREAT and RED-HF trials, patients who received a high darbepoetin dose had an increased risk of adverse events. To find an explanation, the published literature was analyzed on the pharmacokinetics and pharmacodynamics of darbepoetin. Areas covered: Based on the sigmoid Emax model, the concentration producing 50% of the maximum erythropoietin effect is reported as CE50 = 0.41 ng/ml and the Hill coefficient as H = 3.0 for darbepoetin. Accordingly, a pharmacodynamics-based threshold concentration can be estimated with CE05 = 0.153 ng/ml producing 5% of Emax and a ceiling concentration with CE95 = 1.098 ng/ml producing 95% of Emax, respectively. Expert opinion: Darbepoetin trough levels should not be less than the threshold concentration but peak levels above the ceiling concentration could be associated with an increased risk of adverse events. The time span associated with the concentration fluctuation between the ceiling and the threshold concentration is estimated with 236 h (= 2.84 times elimination half-life of 83 h) and shorter than the 336 h when dosing every other week. According to such time-dependent pharmacodynamics, a weekly dosing regimen might be more effective and associated with less adverse events than higher doses every other week in patients with suboptimal response to a normal darbepoetin dose.
Analytical requirements and standardization of CA 15—3

The CA 15—3 assay could play, probably in combination with cytokeratin markers, a role in the detection of early recurrence and in monitoring therapy in metastatic breast cancer patients. The CA 15—3 assay is, however, not useful for early detection of breast cancer and has no prognostic significance. The analyte is not clearly defined and a primary reference material cannot be synthesized. A reference measurement procedure is not available and many commercial assays use the original Centocor IRMA as such. The comparability of different CA 15—3 assays is not sufficient according to the results of EQAS. The general recommendations of analytical requirements for tumour marker determinations specified by the working group “Quality Control and Standardization” (Hamburger Symposia on Tumour Markers) includes intra-assay and inter-assay precision, drift, carry-over, dilution effect and high-dose hook effect. From a medical point of view reference limits should be established. Specificity/sensitivity profiles sh.
Endocrine emergencies in critically-ill patients: Challenges in diagnosis and management: Comment

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CYP3A activity: towards dose adaptation to the individual

ABSTRACT Introduction: Co-medication, gene polymorphisms and co-morbidity are main causes for high variability in expression and function of the CYP3A isoenzymes. Pharmacokinetic variability is a major source of interindividual variability of drug effect and response of CYP3A substrates. While CYP3A genotyping is of limited use, direct testing of enzyme function (‘phenotyping’) may be more promising to achieve individualized dosing of CYP3A substrates. Areas covered: We will discuss available phenotyping strategies for CYP3A isoenzymes and causes of intra- and interindividual variability of CYP3A. The impact of phenotyping on the dose selection and pharmacokinetics of CYP3A substrates (docetaxel, irinotecan, tyrosine kinase inhibitors, ciclosporin, tacrolimus) are reviewed. Pubmed searches were conducted during March–November 2015 to retrieve articles related to CYP3A enzyme, phenotyping, drug interactions with CYP3A probe substrates, and phenotyping-guided dosing algorithms. Expert opinion: While ample data is available on the choice appropriate phenotyping drugs (midazolam, alfentanil, aplrazolam, buspirone, triazolam), less clinical trial data is available concerning strategies to usefully guide dosing in the clinical practice. Implementation into the clinical routine necessitates further research to identify (1) an easy-to-use and cheap test for CYP3A activity that (2) adequately predicts drug exposure to (3) allow a sound decision on dose adaptation and hence (4) improve clinical outcome and/or reduce the intensity or frequency of adverse drug effects.
Targeting the intestinal L-cell for obesity and type 2 diabetes treatment

Degradation-resistant glucagon-like peptide-1 (GLP-1) mimetics and GLP-1 enhancers (inhibitors of dipeptidyl peptidase-4, the enzyme which degrades and inactivates GLP-1) have been used for treatment of type 2 diabetes mellitus since 2005–2006. Cutting-edge research is now focusing on uncovering the secretory mechanisms of the GLP-1-producing cells (L-cells) with the purpose of developing agonists that enhance endogenous hormone secretion. Since GLP-1 co-localizes with other anorectic peptides, cholecystokinin, oxyntomodulin/glicentin and peptide YY, L-cell targeting might cause release of several hormones at the same time, providing additive effects on appetite and glucose regulation. In this review, we explore the role of proglucagon-derived peptides and other L-cell co-localizing hormones, in appetite regulation and the mechanism regulating their secretion.
First episode psychosis and employment: A review

Despite considerable growth in treatments, interventions, services and research of young people with a first episode of psychosis, little attention has been given to the priorities of these young people, in particular, gaining employment. A literature review was undertaken with the aim of investigating: 1) whether young people with a first episode of psychosis want to work, 2) what challenges they experience regarding work, 3) what is understood about employment outcomes, 4) what the most effective interventions to enable them to gain employment may be, and 5) what the associated costs may be. The review found that these young people appear to want to work yet face a range of psychological and social challenges to achieving this. Typically by the time they first come into contact with mental health services a proportion are already falling out of education and employment, and this decline continues with contact with services. However, there are specific interventions that can support them to gain employment. The Individual Placement and Support approach, adapted to include support to fulfil educational goals, has demonstrated that a mean of 69% of young people with a first episode of psychosis can gain education and employment compared to 35% of controls.
The Clinical Effect of Androgen Replacement Therapy for Female Sexual Dysfunction

Objectives: Androgen plays an important role in female sexual function, and its insufficiency causes a clinically significant sexual dysfunction. This study examines the association between sex hormones and the clinical effect of testosterone replacement therapy in female sexual dysfunction. Methods: This study examined 75 female patients who visited our hospital from March 2002 to June 2008 to treat sexual dysfunction. For the rest of the patients, we performed primary treatment and physiotherapy in accordance with the main cause of their sexual dysfunction. We also performed combination treatment of androgen replacement therapy for the patients who did not make medical progress after two months of primary treatment and for the patients whose free testosterone level is in the bottom group out of three normal range groups. Results: The mean age of target patients was 39.6±8.7 years (range, 35∼66 years) old. 10 patients out of 75 patients were postmenopausal women, and estrogen replacement therapy had been performed without androgen replacement therapy. We performed a combination treatment of androgen replacement therapy for the patients with sexual desire disorder, and 60% of them answered that they had an increased sexual response after they were given combination treatment of androgen replacement therapy. Conclusion: The results support the concepts that sex hormones significantly affect sexual response in women with sexual dysfunction. Clinically, it is effective and safe to perform a combination treatment of androgen replacement therapy in treating sexual dysfunction if medication is administered properly and carefully. (Ewha
Effect of low glycemic load diet with and without wheat bran on glucose control in gestational diabetes mellitus: A randomized trial

Background: A low-glycemic index diet is effective in blood glucose control of diabetic subjects, reduces insulin requirement in women with gestation diabetes mellitus (GDM) and improves pregnancy outcomes when used from beginning of the second trimester. However there are limited reports to examine the effect of low glycemic load (LGL) diet and fiber on blood glucose control and insulin requirement of women with GDM. Therefore, the aim of this study was to examine the effect of low glycemic load diet with and without fiber on reducing the number of women with GDM requiring insulin. Materials and Methods: All GDM women (n = 31) were randomly allocated to consume either a LGL diet with Fiber or LGL diet. Results: We found that 7 (38.9%) of 18 women with GDM in Fiber group and 10 (76.9%) in “Without Fiber” group required insulin treatment. Conclusion: The LGL diet with added fiber for women with GDM dramatically reduced the number needing for insulin treatment.
Quantum mechanical effect in protein–ligand interaction

Importance of the field: The development of quantum mechanics (QM) was perhaps the greatest intellectual achievement of the 20th century. Recently, QM-based methods have come to attention with the applications of studying QM effects in protein–ligand interactions. The QM-based methods give molecular-level insights into protein–ligand interactions and these can play a major role in the elucidation of the structure or reactivity of a biomolecular system. Areas covered in this review: In this review article, we present three examples to illustrate applications of QM-based methods in protein–ligand interactions. First, the QM calculation based on the density functional theory has been used to study the simplified active site model of CYP450 with an ethanol molecule. Second, a combined QM and molecular mechanical method, the generalized hybrid orbital approach, was applied to explore the identity of the fourth ligand of zinc in metalloproteins. Third, by the molecular fractionation with conjugate caps approach with full QM calculations; we obtained the interaction energies of thrombin–inhibitor complexes. What the reader will gain: Readers will gain an overview of development of QM-based methods. We summarize results from three applications of QM-based methods, each using a different method for a different system. These results show that studies of protein–ligand interactions based on QM calculations provide further descriptions of biochemical mechanisms, structures and particular interaction energies. Take home message: For the structure-based drug design, the QM-based methods will have significant applications. QM-based methods have been, and will continue to be, important tools in the study of biological systems; moreover, development of a more accurate and more efficient QM-based method is still worth waiting for.