Clinical Pharmacology and Therapeutics

(UGT) and is a substrate of P-glycoprotein (P-gp), coded by UGT and the ATP-binding cassette (ABCB1) genes respectively Methods: We assessed the effect of genetic variability in UGT1A and ABCB1 on moxifloxacin pharmacokinetics in South African tuberculosis patients. Genotypes for selected UGT1A and ABCB1 SNPS were determined using a TaqMan ® Genotyping OpenArray™, except for rs8175347 where a high resolution melt (HRM) analysis was used to measure TA repeats. A nonlinear mixed-effects model was used to describe moxifloxacin pharmacokinetics. Results: We determined the frequency of genetic variability in UGT1A and ABCB1 in 172 patients. Genotypes of UGT1A SNP's, rs8175347 and rs3755319 were significantly associated with changes in moxifloxacin pharmacokinetic parameters (clearance (CL) and bioavailability). Individuals with the AC or AA genotype for rs3755319 had on average 12.6% higher moxifloxacin clearance and lower AUC compared to individuals with the CC genotype (p = 0.021). TA repeats within the TATA box of the promoter region, showed donors that had TA 5/6 repeats within rs8175347 SNP had a significantly lower clearance and higher bioavailability associated with an approximately 32% increase in AUC compared to TA 6/6, 6/7 and 7/8 repeats (p= 0.001). Genotypes of the ABCB1 SNP rs2032582 were significantly associated with 40% reduced pre-hepatic bioavailability lower AUC in individuals with the CA genotype.

Randomized controlled trials (RCTs) provide evidence for regulatory agencies, shape clinical practice, influence formulary decisions, and have important implications for patients. However, many patient groups that are major consumers of drugs are under-represented in randomized trials. We review three methods to extrapolate evidence from trial participants to different target populations following market approval and discuss how these could be implemented in practice to support regulatory and health technology assessment decisions. Although these methods are not a substitute for less restrictive pre-approval RCTS or rigorous observational studies when sufficient data are available in the post-approval setting, they can help to fill the evidence gap that exists in the early marketing period. Early evidence using real-world data and methods for extrapolating evidence should be reported with clear explanation of assumptions and limitations especially when used to support regulatory and health technology assessment decisions. Randomized controlled trials (RCTs) provide evidence for regulatory agencies, shape clinical practice, influence formulary decisions, and have important implications for patients. In the United States, when a new drug enters the market, evidence of its benefits and risks is often based solely on data from RCTs conducted for regulatory agency approval. For decades, it has been recognized that many patient groups, such as older adults, racial minorities, pregnant women, and others, have been under-represented in RCTs although also being major consumers of drugs. 1,2 For example, although ischemic heart disease is prevalent in older adults, over 50% of trials registered at clinicaltrials.gov between January

Purpose: The objective of this report was to determine the pharmacokinetic properties, safety, and tolerability of single and multiple doses of intravenous delafloxacin. In addition, the absolute bioavailability (BA) of the 450-mg tablet formulation of delafloxacin was determined. Methods: Three clinical trials are summarized. The first study was a randomized, double-blind, placebocontrolled, single-(300, 450, 600, 750, 900, and 1200 mg) ascending-dose study of IV delafloxacin in 62 (52 active, 10 placebo) healthy volunteers. The second study was a randomized, double-blind, placebo-controlled study of IV delafloxacin (300 mg) given as a single dose on day 1, followed by twicedaily dosing on days 2 through 14; 12 (8 active, 4 placebo) healthy volunteers were enrolled. The third study was an open-label, randomized, 2-period, 2-sequence crossover study in which 56 healthy volunteers were randomly assigned to 1 of 2 sequences of a single oral dose of delafloxacin (450-mg tablet) or IV delafloxacin (300 mg). Serial blood samples were collected, and plasma pharmacokinetic parameters of delafloxacin were calculated. Findings: Delafloxacin C max values increased proportionally with increasing single IV dose for the dose range of 300 to 1200 mg, whereas the AUC values increased more than proportionally to dose for the same dose range. The mean terminal half-life of delafloxacin was approximately 12 hours (ranging from 8 to 17 hours). The volume of distribution (V d ) at steady state was approximately 35 L, which is similar to the volume of total body water. There was minimal accumulation of delafloxacin after twice-daily IV administration of 300 mg with an accumulation ratio of 1.09. The delafloxacin total exposure after a single 1-hour IV infusion of 300 mg and a single oral dose of a 450-mg tablet were equivalent with geometric least square mean ratio (90% CI) of 0.8768 (0.8356-0.9200) for AUC 0-1 and 0.8445 (0.8090-0.8815) for AUC 0-t , respectively. The C max values of delafloxacin were not equivalent for the 2 formulations with a ratio (90% CI) of 0.5516 (0.5150-0.5908), respectively. The mean absolute bioavailability of delafloxacin was 58.8%. Implications: Delafloxacin was well tolerated in healthy volunteers after single and multiple IV doses. The total systemic exposure to IV (300 mg) and oral (450 mg) delafloxacin is comparable, supporting that a switch between the 2 formulations is appropriate.

Dihydroartemisinin (DHA)-piperaquine is promising for malaria chemoprevention in pregnancy. We assessed impacts of pregnancy and efavirenz-based antiretroviral therapy on exposure to DHA and piperaquine in pregnant Ugandan women. Intensive sampling was performed at 28 weeks gestation in 31 HIV-uninfected pregnant women, in 27 HIV-infected pregnant women receiving efavirenz, and in 30 HIV-uninfected non-pregnant women. DHA peak concentration and area under the concentration time curve (AUC0-8hr ) were 50% and 47% lower, respectively, and piperaquine AUC0-21d was 40% lower in pregnant women compared to non-pregnant women. DHA AUC0-8hr and piperaquine AUC0-21d were 27% and 38% lower, respectively in pregnant women receiving efavirenz compared to HIV-uninfected pregnant women. Exposure to DHA and piperaquine were lower among pregnant women and particularly in women on efavirenz, suggesting a need for dose modifications. The study of modified dosing strategies for these populations is ur...

The treatment of steroid-resistant minimal change nephropathy (SR-MCN) in adults remains a challenge to nephrologists. Although immunosuppressants such as cyclophosphamide (CTX), chlorambucil, and cyclosporin A have been used in these patients, their use has been limited by low remission rates and severe adverse effects. Alternative immunosuppressive treatments for SR-MCN are therefore needed. Objective: The aim of this study was to compare the efficacy of tacrolimus (TAC) with that of intravenous (IV) pulse CTX therapy in the management of SR-MCN and to assess the tolerability of those treatments. Methods: This was a nonrandomized, case-matched trial in Chinese adults with SR-MCN. Patients were self-assigned to either: (1) combination therapy with prednisone and oral TAC; or (2) combination therapy with prednisone and IV CTX. TAC was initiated at 0.05 mg/kg/d and was adjusted to maintain a trough blood level of 5 to 10 ng/mL for 1 year. CTX was initiated at 1 g/1.73 m 2 for a total dosage of 10 g/ 1.73 m 2 over 1 year. In both groups, oral prednisone was initiated at 0.5 mg/kg/d for 3 months but was tapered off to complete cessation by 6 months. Results: A total of 37 patients were enrolled (21 in the TAC group; 16 in the CTX group), of whom 33 (19 in the TAC group; 14 in the CTX group) completed the study. There were no significant difference in baseline demographic characteristics between the two treatment groups (The TAC group-mean age at onset, 28.8 [11.3]; mean age at trial, 29.6 [11.0]; male, 63.16%; The CTX groupmean age at onset, 34.4 [12.7]; mean age at trial, 35.9 [12.7]; male, 57.14%). The remission rates were 57.9%, 73.7%, and 78.9% in the TAC group and 14.3%, 42.9%, and 50.0% in the CTX group after 2, 4, and 6 months, respectively. The remission rate at 2 months was significantly higher in the TAC group than in the CTX group (P Ͻ 0.05). The remission rates during the 1-year therapy and the 1-year follow-up were higher in the TAC group than in the CTX group (Kaplan-Meier curve, log-rank test, P Ͻ 0.001). For patients who achieved remission, the mean (SD) time needed for remission was 48.7 (36.0) days in the TAC group and 85.3 (40.6) days in the CTX group (P Ͻ 0.05). During the 1-year therapy and 1-year follow-up periods, 6 of the 15 TAC-treated patients and 1 of the 7 CTX-treated patients relapsed (P ϭ 0.35). Conclusions: These findings suggest that TAC therapy was effective compared with IV pulse CTX therapy in treating this select group of Chinese adults with SR-MCN. Both agents were well tolerated although TAC seemed to induce remission more rapidly than IV pulse CTX therapy.

If you feel that you may have a mast cell disorder (MCD), a mast cell activation related issue or disorder, or environmental illness, contact a qualified medical healthcare professional to receive medical help. The information present here is not medical advice and is in no way a substitute for receiving medical advice and treatment from a qualified medical healthcare professional.

Drug ototoxicity limits the quality of life of patients after treatment, having serious consequences, especially for psychosocial development of children. Although the ototoxicity of many drugs resolves after treatment discontinuation, the use of platinum derivatives and aminoglycosides is associated with permanent hearing loss. In this review, we have listed ototoxic drugs and the mechanisms by which they damage the ears. Moreover, possible protective strategies and important methods for early detection of ototoxic effects are discussed.

Benoxaprofen is a benzoxazole derivative of propionic acid with anti-inflammatory, antipy- retic, and analgesic properties. Unlike other nonsteroidal anti-inflammatory drugs, it is only a weak inhibitor of prostaglandin synthetase.4 6, " Benoxaprofen is highly bound to plasma proteins and is little affected by first-pass hepatic metab- olism. Although only unchanged benoxaprofen is detected in plasma, about 60% is excreted in the urine as the p-glucuronide and about 40% is excreted in feces as the parent compound.9 The drug's relatively long half-life (0/2) in those with normal renal function allows it to be given as a single daily dose. This study was undertaken to determine benoxaprofen and benoxaprofen glucuronide kinetics in patients with impaired renal function and to establish dosage guidelines for these patients.

Purpose: To identify factors associated with the choice of type 2 diabetes mellitus (T2DM) therapy at the time of intensification of antidiabetic treatment across four European countries. Methods: For T2DM patients from the Netherlands (NL), Italy (IT), Spain (ES) (2007)(2008)(2009)(2010)(2011) and United Kingdom (UK) (2008)(2009)(2010)(2011)(2012) antidiabetic drug prescription/dispensing records and patient characteristics were obtained from electronic health-care records. Oral monotherapy was defined as 1 st line, oral dual therapy as 2nd line, >2 oral treatments or oral combined with an injectable as 3rd line and injectables only as 4th line treatment. Treatment intensification was defined as starting a higher line of treatment. Comedication, comorbidities, clinical parameters and other factors associated with treatment choice were identified using multivariable relative risk estimation by Poisson regression with robust error variance. Findings: In the study period 485,120 patients, i.e. 79% of the treated T2DM population underwent treatment intensification. Changes in treatment choice were clearly visible over the study period, such as decline of thiazolidinedione (TZD) use (NL, ES, UK), and increase of dipeptidyl peptidase-4 inhibitors (DPP4i) use (NL, ES, UK) and glucagon-like peptide-1 receptor agonist (GLP-1ra) use (UK). For 1st line treatment advanced age and renal comorbidity were associated with SU (all countries), whereas high BMI was inversely associated with SU in UK and ES. For 2nd line advanced age was associated with metformin + SU (all countries) and renal comorbidity with SU + dipeptidyl peptidase-4 inhibitors (DPP4i) in UK and NL. High BMI was associated with metformin + thiazolidinedione (TZD) in UK and ES, and with metformin + DPP4i (UK). For 3rd line advanced age and renal comorbidity were associated with SU + insulin (NL, ES, UK). HbA1c ≥8.5% was positively and high BMI inversely associated with any 3rd line combination containing insulin. For 4th line treatment women were more likely to receive GLP-1ra than men in UK and ES. Implications: The results suggest that the main factors driving treatment choice at any stage of intensification were age, HbA1c, BMI, renal and cardiac morbidity, and prior treatment history. These drivers were consistent with guidelines and contra-indications for specific medications. Differences between countries were generally consistent with, but not solely attributable to differences in local guidelines and reimbursement policies.

Spontaneous closure of the ductus arteriosus depends on gestational age (GA) and might be delayed in preterm infants, resulting in patent ductus arteriosus (PDA). Ibuprofen can be administered to enhance closure, but the exposure‐response relationship between ibuprofen and the closure of PDA remains uncertain. We investigated the influence of patient characteristics and ibuprofen exposure on ductus closure. A cohort of preterm infants with PDA and treated with ibuprofen was analyzed. Ibuprofen exposure was based on a previously developed population pharmacokinetic study that was in part based on the same study population. Logistic regression analyses were performed with ductus closure (yes/no) as outcome, to analyze the contribution of ibuprofen exposure and patient characteristics. In our cohort of 263 preterm infants (median GA 26.1 (range: 23.7–30.0) weeks, birthweight 840 (365–1,470) g) receiving ibuprofen treatment consisting of 3 doses that was initiated at a median postnatal ...

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is characterized primarily by severe, unexplained fatigue 1 accompanied by dysfunctional homeostasis with possible focal inflammation in the hypothalamus. Scientists have struggled to identify the pathogenesis of ME/CFS. In the April issue of Clinical Therapeutics, experts report their findings on the diagnosis and possible causes of ME/CFS. 3e10 However, effective treatments remain elusive, and the presence of comorbidities 13 further complicates the search for a cure. This continuation of the Specialty Update on ME/CFS focuses on interventions, including the molecular basis of the identification of patient subgroups that may be amenable to treatment. In the opening commentary, Dr. Broderick et al 14 review the limited efficacy of available pharmaceutical interventions and suggest combination therapies as well as individualized approaches based on the heterogeneity of ME/ CFS. Dr. Craddock et al 15 report the results from a pharmacogenomic study that identified candidate therapeutic targets in a subset of patients in whom differential geneeexpression profiles were associated with fatigue. Dr. Ariza and colleagues 16 report on the involvement of EpsteineBarr virus dUTPase, a viral protein implicated in some patients with ME/ CFS, using immortalized cell lines and an in vivo mouse study. Dr. Giannoccaro et al 17 investigate the presence of autoantibodies against neuronal proteins in a small group of patients with ME/CFS and control subjects. Finally, in their original research articles, Finally, Rekeland et al 18 report their findings on the use of rituximab in ME/CFS. In a future issue of Clinical Therapeutics, Tsilioni et al will present data on the use of a dietary supplement in patients with fibromyalgia and fatigue. Regardless of the importance of the work presented, it is obvious that the presentation of ME/CFS is highly heterogeneous and that no treatment approach is likely to address all symptoms in most patients. A focus on patient subgroups based on biomarkers and/or common symptomatology may be the best approach for now.

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This special themed update includes 6 articles by experts in the field covering the role of different classes of molecules and processes involved in alerting an organism of the presence of real or perceived, external or internal, dangers that threaten its survival. These reviews address the role of purinergic signaling and immune responses in sepsis, the alarmin properties of DNA and DNA-associated nuclear proteins, the key role of damage-associated molecular patterns in inflammation and tissue repair, the potential therapeutic aspects of alarmin cytokine interleukin (IL)-33 or its inhibitors in various diseases, the role of alarmins in antitumor immunity, and nanotube formation, a rapid form of alarm signaling. Better understanding of these danger signals, also known as alarmins, and their possible containment in case of false or sustained alarm would help prevent or treat a number of diseases. Selye 7 was the first to write about the stress response to explain how a mammal responds to danger to survive (the fight or flight response). Although he tried to identify a responsible hypothalamic factor, he missed corticotropin-releasing hormone (CRH), 8 which is considered a master alarmin that mediates the effect of stress on the body, especially the skin. It is interesting that CRH also promotes inflammation, 10 an evolutionary defense response 11 that preceded the development of the immune system. Inflammation is now known to depend on a unique, ancient, 12 multitasking cell 13 -the mast cell 14 -which has existed throughout the phylogenetic tree. The body has the ability to secrete hormonal, immune, and neural substances 14 resembling the behavior of unicellular organisms dating back some 500 million years. In fact, Selye 19 wrote in his comprehensive book The Mast Cells that "the so-called metachromatic corpuscles found in certain protozoa may be related to mast cells" and "the metachromatic volutin granules of yeast resemble mast cell granules." CRH can promote the development of skin mast cell progenitors 20 and stimulate skin mast cells. Human mast cells express the high affinity CRH receptor-1 (CRHR-1), activation of which leads to selective release of vascular endothelial growth factor without degranulation. Intradermal administration of CRH activates skin mast cells and increases vascular permeability through activation of CRHR-1 in humans. In fact, stress increases the expression of CRHR-1 in bone marrow mast cells. Moreover, CRH can be secreted from mast cells 25 and can stimulate the hypothalamic-pituitary axis, triggering the fight or flight reaction. Different life forms and tissues developed a variety of molecules to sound the alarm and keep them out of danger (Table ). The horseshoe crab, which resembles species that existed more than 500 million years ago, survived by using defenses that involved a close interplay between the coagulation and innate immune systems. It is, therefore, interesting that among the most potent triggers of mast cells is bradykinin, which is generated by the action of kallikrein on kininogen derived from Hageman factor XII of the clotting cascade, 29,30 and mast cells are the richest source of the anticoagulant heparin. Scan the QR Code with your phone to obtain FREE ACCESS to the articles featured in the Clinical Therapeutics topical updates or text GS2C65 to 64842. To scan QR Codes your phone must have a QR Code reader installed.

Purpose: Psychological stress worsens many diseases, especially those with inflammatory components, such as atopic dermatitis (AD) and autism spectrum disorder (ASD), conditions that are significantly correlated in large epidemiologic studies. However, how stress contributes to these conditions is still poorly understood. This narrative review of the relevant literature advances the premise that stress affects inflammatory processes in AD and ASD via stimulation of mast cells (MCs). Methods: MEDLINE was searched between 1980 and 2019 using the terms allergies, atopic dermatitis, autism spectrum disorder, brain, corticotropinreleasing hormone, inflammation, hypothalamicpituitary-adrenal axis, mast cells, neuropeptides, stress, neurotensin, and substance P. Findings: Exposure to psychological stress is associated with onset and/or exacerbation of AD and ASD. This association could be attributable to activation of MCs, which are ubiquitous in the body, including the brain, and could contribute to inflammation. Implications: Understanding and addressing the connection between stress and MCs is important in clarifying the pathogenesis and developing effective treatments for diseases that worsen with stress and involve inflammation, such as AD and ASD.

There are 300 trillion bacteria (0.3 n 10 15 ) in our large intestine and 100 trillion (0.1 n 10 15 ) on our skin. The human body contains 5000 trillion cells (5 n 10 15 ), with 100 mitochondria per cell. Given the bacterial origin of mitochondria, 2 there are 5400 trillion intracellular "bacteria," outnumbering those of the gut and skin microbiomes 10-fold. 3 Therefore, the total human microbiome, together with the bacteria-derived mitochondria, comprises 410 15 bacteria. This number is approximately the same as the total number of synapses in a toddler: the human brain has 10 11 neurons with 7000 synaptic connections for each neuron, and the brain of a 3-year-old child has been estimated to have 10 15 synapses. Barring food poisoning, some unforeseen communicable infection, or epidemic, these bacteria thrive and generally keep us healthy. 5 However, change in diet habits, environmental pollutants, preservatives, antibiotics, and stress 6,7 have derailed this symbiosis. This disconnect has possibly led to a host of disorders, such as autism, chronic fatigue syndrome, fibromyalgia, and many neuropsychiatric diseases that so far elude precise pathogenesis and effective treatment. 9 Unfortunately, our understanding of the gut-brain axis is still rudimentary, and treatment approaches are scarce. In this issue of Clinical Therapeutics, colleagues address the critical role of the gut microbiota in the gut-brain axis and its contribution to a variety of disorders that involve the immune, endocrine, and nervous systems. The microbiota gutbrain axis is known to be involved in functional gastrointestinal disorders. However, increasing evidence supports the notion that the microbiota gut-brain axis regulates immunity and may also influence cognitive function as well as mood and behavior. 17,18 A possible key mediator of the microbiota gut-brain axis is histamine, which is critical for learning, memory, cognition, and motivation. Histamine has also been involved in the pathogenesis of neuropsychiatric disorders. Most of the histamine in the gut and the brain is found in mast cells, which have emerged as "master control" cells 26 and communicate with the microbiome, 27 but they may either promote or limit pathogenic processes. Mast cells 30 and histamine 31 regulate mucosal immunity, as well as the endocrine 32,33 and the nervous 34,35 systems. In fact, histamine from brain mast cells promotes wakefulness and modulates behavior. 36 These divergent actions of mast cells may be possible because of their unique ability to selectively secrete their numerous mediators. Microbiota may also modulate inflammation, which is now considered important in the pathogenesis of many of the disorders mentioned earlier, especially autism. The gut microbiome has its own endocrine system, and inflammatory peptides such as substance P are important in the gut-brain cross talk. The peptide neurotensin, in particular, is noteworthy because of its abundance in the gut 45 and the brain. Moreover, neurotensin acts synergistically with corticotropin-releasing hormone (CRH), which is secreted under stress, to stimulate mast cells. In fact, both neurotensin and CRH are increased in the serum of children with autism, especially those who also have intestinal issues. It is of further interest that mitochondrial DNA is also increased in the serum of these children. Mitochondrial DNA acts synergistically with CRH to trigger mast cells 50 and is

In many trials, interim analyses are often performed to decide whether the trial should be terminated early, for a variety of reasons. These reasons may include an imbalance in adverse events in one group versus the other(s), a situation in which, given the sample size, it would be impossible to demonstrate superiority of one treatment (futility) or a significant difference between groups. This commentary argues that ending a trial prematurely for the latter reason is fraught with problems and often results in an overestimation of the effect that would have been obtained were the trial allowed to continue. It concludes that stopping a trial early for apparent superiority of a treatment should be avoided.

Dengan ini menyatakan bahwa dalam skripsi ini tidak terdapat karya yang pernah diajukan untuk memperoleh gelar kesarjanaan di suatu perguruan tinggi dan sepanjang pengetahuan penulis juga tidak terdapat karya atau pendapat yang pernah ditulis atau diterbitkan oleh orang lain kecuali yang secara tertulis diacu dalam naskah dan disebutkan dalam daftar pustaka.

Latar Belakang: Inflamasi merupakan respon protektif lokal yang berpotensial menimbulkan bahaya. Jahe (Zingiber officinale) mengandung flavonoid yang dapat berefek antiinflamasi. Penelitian yang telah ada menggunakan rimpang Jahe sebagai bahan uji. Padahal kandungan flavonoid dalam Daun Jahe lebih besar daripada rimpangnya. Penelitian ini bertujuan untuk mengetahui efek antiinflamasi ekstrak etanol Daun Jahe terhadap tikus putih jantan (Rattus novergicus). Metode Penelitian: Penelitian ini bersifat eksperimental laboraturik dengan the post test only controlled group design. Penelitian dilakukan di Universitas Setia Budi. Sampel berupa tikus putih jantan berumur ± 3 bulan, berat badan ± 150 gram, sebanyak 25 ekor yang diambil secara purposive sampling. Subyek dibagi rata dalam 5 kelompok secara acak, yakni kelompok Kontrol Negatif (KN) diberi normal salin, Kontrol Positif (KP) diberi indometasin, Perlakuan I (KU1) diberi 20 mg ekstrak etanol Daun Jahe/100 grBB tikus, Perlakuan II (KU...

Volume 37 Number 8S Results: It is expected, from preliminary data and based in other similar studies that from the sample of women enquired around 80% had received at least a medical prescription during pregnancy, being most of these medicines (15%) harmful to the fetus. Women who suffer from chronic disease(s) are the major medicine consumers and this consumption is highly related to gestational symptoms relief. About 60% of the pregnant have a mild level of knowledge on of medicine use during pregnancy; there is also a statistic relationship between age, social class, education field, qualifications, wanted or unwanted pregnancy, and first pregnancy or following, the third trimester of pregnancy and medicine use level. The study concluded that the consumption of harmful medicines to the fetus is still very common being frequently associated with the lack of women's knowledge and other social demographic factors, therefore leading to fetal malformations and the use of selfmedication without control.

The aging population routinely has comorbid conditions requiring complicated medication regimens, yet non-adherence can preclude optimal outcomes. This study explored the association of adherence in the elderly with demographic, socio-economic and disease burden measures. Data were from the fifth visit (2011-2013) for 6,538 participants in the Atherosclerosis Risk in Communities Study, conducted in four communities. The Morisky Green Levine Scale measured self-reported adherence. Forty percent of respondents indicated some non-adherence, primarily due to poor memory. Logit regression showed, surprisingly, that persons with low reading ability were more likely to report being adherent. Better self-reported physical or mental health both predicted better adherence, but the magnitude of the association was greater for mental than for physical health. Compared to persons with normal or severely impaired cognition, mild cognitive impairment was associated with lower adherence. Attention to mental health measures in clinical settings could provide opportunities for improving medication adherence.

Stevens-Johnson Syndrome, toxic epidermal necrolysis (SJS/TEN), DRESS (drug reaction with eosinophilia and systemic symptoms), and acute generalized exanthematous pustulosis (AGEP). Objective: To identify serious cases of (CADR) and the main suspected drugs.

Introduction: Upon activation, blood platelets release two types of extracellular vesicles (EV), namely microparticles characterised by the presence at their surface of phosphatidylserine (PS), which supports their role in haemostasis and in thrombosis (1), and exosomes characterised by their small size (50-100 nm) and the presence of CD63 on their surface (2). However, a clear distinction between microparticles and exosomes is hampered by the difficulty of EV characterisation, which results from their heterogeneity and from the lack of reliable methods allowing their isolation and quantification. Using cryo-electron microscopy (EM) and immuno-gold labelling (3), we have revisited the question of EVs released by activated platelets with the objective to provide a quantitative description of the size, phenotype and relative amounts of the main EV populations, focusing mainly on PS+ EVs CD41+ EVs and CD63+ EVs (4). Methods: Peripheral blood was collected over citrate from four healthy adult donors after informed consent. Platelets from platelet rich plasma (PRP) samples were activated with thrombin, TRAP or CRP-XL. Gold nanoparticles conjugated with annexin-5, anti-CD41-or anti-CD63-mAbs were synthesised to label PS+ EVs, platelet-derived EVs and CD63+ EVs, respectively (3). Cryo-EM was performed as described in (3). Results: We found that EVs activated by the three agonists presented a similar size distribution, about 50% of them ranging from 50 to 400 nm. About 60% EVs were found to expose CD41, a majority of them exposing also PS. Several mechanisms of EV formation are proposed to explain the presence of large amounts (40%) of CD41-negative or PSnegative EVs of large size, as well as large EVs containing organelles, principally mitochondria or granules. We found also that the majority of EVs in activated platelets expose CD63. Two populations of CD63+ EVs were distinguished, namely large EVs with low labelling density and small EVs, likely the exosomes, with high labelling density. Conclusion: This study provides a quantitative description of EVs from activated platelets and opens new insight on EV formation mechanisms.

The anticoagulant response to bishydroxycoumarin II. The effect of D-thyroxine, clofibrate, and norethandrolone D-thyroxine, clofibrate, and norethandrolone influence the pharmacologic effect of bishydroxycoumarin. In mice, D-thyroxine inhibits the metabolism of bishydroxycoumarin as well as that of meperidine and pentobarbital; in man, the anticoagulant response to bishydroxycoumarin is increased at doses which do not change the rate of metabolism of the drug. Clofibrate does not affect bishydroxycoumarin metabolism in mice or in man but does increase the anticoagulant response to the drug in man. N orethandrolone also increases the anticoagulant response to bishydroxycoumarin in man without affecting the rate of metabolism of the drug. Since clinically effective doses of these three drugs do not decrease the concentration of vitamin K-dependent clotting factors or affect the absorption, distribution, or metabolism of bishydroxycoumarin in man, it seems likely that they potentiate the pharmacologic effect of bishydroxycoumarin by increasing the affinity of the receptor site for the anticoagulant.

To the Editor: The article by JE Rossouw titled ''Postmenopausal hormone therapy for disease prevention: have we learned any lessons from the past'' 1 describes the history of estrogen therapy proceeding through the stages of uncritical adoption, acute concerns about safety and a current more nuanced view of selective timing and duration of therapy. As briefly noted in the article, the warning signs that raised concern about the cardiovascular safety of estrogens were first noticed more than 40 years ago. Laboratory and epidemiological studies 2-4 describing the occurrence of thrombosis in women on oral contraceptives, and increased nonfatal myocardial infarction and thromboembolism in men receiving conjugated estrogens for the secondary prevention of cardiovascular disease, 5 were reported then. Subsequent numerous evaluations defined the multiple prothrombotic effects of estrogens on the coagulation system and the role of genetic factors in modulating this risk. 6 Thus, estrogens produce prothrombotic effects in susceptible patients, regardless of gender and indication for use (contraception, cardiovascular disease prevention, menopausal symptoms). Current users of estrogens need to be mindful of this possibility in their benefit/ risk assessments.

To the Editor: The April 2010 issue of Clinical Pharmacology & Therapeutics focuses on the role of inflammation in the pathogenesis of cancer, obesity, and cardiovascular disease. However, another important disease with an inflammatory component, Alzheimer's disease (AD), receives only limited attention. Epidemiologic studies indicate an inverse association between the incidence of AD and that of cancer; 2 on the other hand, there is a direct association between the incidence of both diabetes and cardiovascular disease and that of AD. The contribution of immune processes to the pathogenesis of these diseases is now becoming more fully appreciated. For instance, the progression of AD has been correlated with immune processes that promote or inhibit disease progression involving the innate immune system through alterations in the clearance of amyloid by the complement protein C1q, elevation of levels of inflammatory cytokines that worsen amyloid deposition, activation of amyloid protein processing, 4 and alteration of

Реферат. Зміни рівня галектину-3, β-2-мікроглобуліну, альбумінурії та продуктів кінцевого глікірування у хворих з хронічною серцевою недостатністю і фібриляцією передсердь під впливом лікування. Курята О.В., Мухаммад Мухаммад, Митрохіна О.С. Поєднання хронічної серцевої недостатності і фібриляції передсердь вважається одним з найбільш прогностично несприятливих поєднань серед серцево-судинних захворювань. Зараз активно обговорюється потреба в нових маркерах як потенційних мішенях для терапевтичного впливу. На сьогоднішній день продовжується активне вивчення кардіоренального синдрому, що в свою чергу веде до активного пошуку препаратів, що зменшують нефрологічний ризик, особливо в категорії осіб, що має комбіновану серцево-судинну патологію. Метою дослідження було порівняти вплив ірбесартану й інгібіторів АПФ на рівень галектину-3, β-2-мікроглобуліну, альбумінурії і продуктів кінцевого глікірування (AGE) у хворих з хронічною серцевою недостатністю з фібриляцією передсердь і порушенням функції нирок. Представлені і проаналізовані результати впливу препаратів у пацієнтів з хронічною серцевою недостатністю з фібриляцією передсердь. Дані свідчать про необхідність більш ретельної уваги до цієї групи хворих, а саме про необхідність діагностики функціонального стану нирок, що має дуже важливе значення для розробки ефективних заходів, спрямованих на запобігання прогресування цих захворювань.

Novel biomarkers of kidney toxicity are powerful tools not only with respect to their clinical applications but also because of their impact on drug development. These biomarkers can influence the assessment of efficacy of new drugs for kidney diseases as well as the risk management for new drugs. The science behind these novel biomarkers reflects the evolution over the past decade of genomic and proteomic platforms that have transformed the discovery and development of new biomarkers for preclinical and clinical applications in drug development. Several of these biomarkers are in use as transcriptomic biomarkers in animal models as well as translational proteomic biomarkers in animal models and in humans. Their ability to detect kidney damage earlier than is possible with currently accessible biomarkers is being given qualification through regulatory biomarker-qualification programs, which will help establish consensus for their widespread use.

mediates the effect has not been resolved due to high linkage disequilibrium (LD). We used ENCODE data on regulatory transcription factor binding sites, and heterozygous positions in a liver cell line to determine variants that regulate VKORC1. Methods: We sequenced the liver cell line HepG2 to locate all heterozygous positions in LD r 2 > 0.8 with the GWAS top hits, and used ENCODE data to find variants that bind transcription factors in an allele-specific way. The functional effect of these variants was evaluated using luciferase assays and over-expression of candidate transcription factors. Results: VKORC1 rs9923231 was not located in an ENCODE regulatory element, and luciferase assays did not show any difference in transcriptional activity between the two alleles. One allele-specific SNP, rs56314408, was on the same haplotype as rs9923231, and rs2032915 was located in the same liver enhancer 24 bp away. The C alleles of rs56314408 and rs2032915 showed higher transcriptional activity, which was further increased after over-expression of the transcription factors YY1 and USF1. We are currently evaluating the potential regulatory effect of rs56314408 and rs2032915 using CRISPR/Cas9. Conclusions: The conventionally analyzed VKORC1 -1639 G> A (rs9923231) is not located in a regulatory element in the liver, and has no evidence of being functional. The LD between rs9923231 and both functional candidates rs56314408 and rs2032915 is known to be high in Europeans. We propose that rs9923231 predicts warfarin dose adequately only in populations where it is in high LD with functional variants such as the candidates rs56314408 and rs2032915.

Guidelines for opioid prescribing in noncancer pain have proliferated since the opioid crisis in the United States became widely recognized. The recently published Centers for Disease Control (CDC) guidelines for opioid prescribing have been controversial. Many of these concerns arise from underestimation of the scale of the opioid crisis, as well as misunderstanding what the guidelines actually say. Strict guidelines should be welcomed as a constructive approach to managing a thorny public health issue.

The plasma concentration versus antihypertensive effect relationship for the calcium antagonist felodipine was investigated in 67 patients with hypertension and 21 healthy subjects by use of the Em, model. No consistent effect of felodipine on blood pressure was observed in the healthy subjects. In patients with hypertension the plasma drug concentration and blood pressure versus time curves mirrored each other, indicating a close relationship between concentration and effect. The maximum effect (Em,) model fitted the diastolic blood pressure data of most patients, but the model was less often applicable in patients with low initial diastolic blood pressure levels. The average Em, values and the plasma felodipine concentration needed to obtain 50% of Em, for the patients with hypertension were 29 mm H g and 8 nmol/L, respectively. The Em, values increased with increasing initial diastolic blood pressure levels but were similar in patients with high and low plasma felodipine concentrations. Age had negligible influence on the antihypertensive response to felodipine when compensation was made for the plasma concentrations. (CLIN PHARMACOL THER 1992;52:80-9.

In a randomized, crossover study, the absorption, distribution, and elimination of intravenous and oral felodipine were investigated in eight healthy men 22 to 31 years old. Felodipine was given as a 2.5 mg iv infusion over 30 minutes and as a 27.5 mg oral solution. Both doses were labeled with 25 1iCi '4C- felodipine. Given as an oral solution, felodipine is rapidly (mean time to peak concentration 64 minutes; range 30 to 90 minutes) and completely absorbed. Presystemic elimination reduced the availability to 16% (range 10% to 25%). Felodipine kinetics can be described by a multicompartmental model with three distinct phases. The ti,2 for the initial phase was 6.4 minutes (range 1.7 to 10.4 minutes) and felodipine was distributed to a volume of 0.6 L/kg (range 0.4 to 0.9 L/kg), which approximately corresponds to the total body water. The second distribution phase reached pseudoequilibrium with a ti,2 of 1.6 hours (range 1.3 to 2.2 hours). The volume of distribution at the end of this phase was 9.7 L/ kg (range 6.0 to 18.2 L/kg). The terminal phase had t1/2 of 10.2 hours (range 6.7 to 20.7 hours). The contribution of the three phases to the AUC was 15%, 40%, and 45% in the order of increased t1/2. Total body clearance of felodipine was 1.2 L/min (range 0.9 to 1.6 L/min). Within 72 hours after drug dosing, 62% to 81% of the felodipine doses were excreted in the urine and feces as metabolites. The rate of excretion by the kidneys had a biphasic pattern, with ti,2 values of 4 and 18 hours. Approximately 10% of the doses was excreted in the feces. (CLINT PHARIVIACOL THER 38:205-211, 1985.

The Pharmacogene Variation Consortium (PharmVar) catalogs star (*) allele nomenclature for the polymorphic human CYP2B6 gene. Genetic variation within the CYP2B6 gene locus impacts the metabolism or bioactivation of clinically important drugs. Of particular importance are efficacy and safety concerns regarding: efavirenz, which is used for the treatment of HIV type‐1 infection; methadone, a mainstay in the treatment of opioid use disorder and as an analgesic; ketamine, used as an antidepressant and analgesic; and bupropion, which is prescribed to treat depression and for smoking cessation. This GeneFocus provides a comprehensive overview and summary of CYP2B6 and describes how haplotype information catalogued by PharmVar is utilized by the Pharmacogenomics Knowledgebase (PharmGKB) and the Clinical Pharmacogenetics Implementation Consortium (CPIC).

The diagnosis and management of drug‐induced liver injury (DILI) remains a challenge in clinical trials in drug development. The qualification of emerging biomarkers capable of predicting DILI soon after the initiation of treatment, differentiating DILI from underlying liver disease, identifying the causal entity, and assigning appropriate treatment options after DILI is diagnosed are needed. Qualification efforts have been hindered by lack of properly stored and consented biospecimens that are linked to clinical data relevant to a specific context of use. Recommendations are made for biospecimen collection procedures, with the focus on clinical trials, and for specific emerging biomarkers to focus qualification efforts.

Harmonizing clinical pharmacology and therapeutics (CPT) education in Europe is necessary to ensure that the prescribing competency of future doctors is of an uniform high standard. As there are currently no uniform requirements, our aim was to achieve consensus on key learning outcomes for undergraduate CPT education in Europe. We used a modified Delphi method consisting of three questionnaire rounds and a panel meeting. 129 experts from 27 European countries were asked to rate 307 learning outcomes. 92 experts (71%) completed all three questionnaire rounds, and 33 experts (26%) attended the meeting. 232 learning outcomes from the original list, 15 newly suggested and 5 rephrased outcomes were included. These 252 learning outcomes should be included in undergraduate CPT curricula to ensure that European graduates are able to prescribe safely and effectively. We provide a blueprint of a European core curriculum describing when and how the learning outcomes might be acquired. This ar...

This study assessed the acute physiologic effects over time of (co)administration of Delta9-tetrahydrocannabinol (Delta9-THC) (the main psychoactive compound of cannabis) and 3,4-methylenedioxymethamphetamine (MDMA or "ecstasy") in 16 healthy volunteers. Pharmacokinetics and cardiovascular, temperature, and catecholamine responses were assessed over time. Both single-drug conditions robustly increased heart rate, and coadministration showed additive effects. MDMA increased epinephrine and norepinephrine concentrations, whereas THC did not affect the catecholamine response. Coadministration of MDMA and THC attenuated the increase of norepinephrine concentrations relative to administration of MDMA alone. These results show that THC mediates heart rate increase independent of sympathetic (catecholaminergic) activity, probably through direct cannabinoid receptor type 1 (CB(1)) agonism in cardiac tissue. Furthermore, THC coadministration did not prevent MDMA-induced temperature...

Adaptive, seamless, multi-sponsor, multi-therapy platform clinical trials, designs executed on a large scale could create superior evidence more efficiently than single- sponsor, single- drug trials. Extending these adaptive platform trials also could diminish barriers to trial participation, increase the representation of real-world populations, and create systematic evidence development for learning throughout a therapeutic life cycle, to continually refine its use. Comparable evidence could arise from multi-arm design, shared comparator arms, and standardized endpoints- aiding sponsors in demonstrating the distinct value of their innovative medicines; facilitating providers and patients in selecting the most appropriate treatments; assisting regulators in efficacy and safety determinations; helping payers make coverage and reimbursement decisions; and spurring scientists with translational insights. Reduced trial times and costs could enable more indications, reduced development ...

Although intravenous proton pump inhibitors (PPIs) are considered at least as effective as H2-receptors antagonists for stress ulcer prophylaxis (SUP) in critically ill patients, there is no data on whether there is also the proof of no difference among these agents. The clinical material was the same as that reported in previous meta-analyses and included all trials comparing intravenous PPIs vs. H2-receptor antagonists for SUP in critically ill patients. Our methodology was a combination of meta-analysis and equivalence testing based on confidence intervals (CIs). The end-point was the rate of overt bleeding. All PPIs evaluated in the included trials were separately studied. The equivalence margins were derived from power calculation data of the original trials. Our analysis involved 8 randomized trials for 851 patients. Two comparisons were made (pantoprazole vs. H2-receptor antagonists and omeprazole vs. H2-receptor antagonists). The following RDs were estimated: pantoprazole, R...

Objective: To present the case of warfarin-cloxacillin interaction that resulted in an increased international normalized ratio (INR). Case summary: A 70-year-old man had been treated with warfarin for atrial fibrillation. He was hospitalized because of superficial thrombophlebitis of the left median cubital vein, which developed after venipuncture. An antibiotic therapy with cloxacillin was initiated immediately after the admission. Two days later, INR value increased from baseline 1.9 to 4.6. Anticoagulation therapy was discontinued and INR value was measured daily. His INR remained high for the entire duration of antibiotic therapy. Three days after the cloxacillin therapy was discontinued, the INR decreased to the baseline value. Discussion: In the presented case, the temporal relationship between the administration of cloxacillin and increased INR suggests that the cloxacillin was responsible for the enhanced warfarin activity. According to the Drug Interaction Probability Scale, a causal relationship between the warfarin-cloxacillin interaction and increased INR value was rated "probable". Conclusion: Interactions between warfarin and cloxacillin can result in serious adverse reactions. INR value should be closely monitored when patients are prescribed this combination of drugs.

Penggunaan jangka panjang terapi antipsikotik merupakan beban biaya yang ditanggung pasien skizofrenia. Penelitian ini bertujuan untuk mengetahui perbedaan efektivitas biaya dan efektivitas terapi kombinasi oral haloperidol-klorpromazin (tipikal) dibanding terapi kombinasi oral risperidol-klozapin (atipikal) pada pasien skizofrenia di ruang Unit Perawatan Intensif Psikiatrik (UPIP) di salah satu rumah sakit jiwa yang ada di Provinsi Riau. Penelitian dilakukan secara prospektif menggunakan rekam medik periode Februari hingga Mei 2016, dengan teknik accidental sampling. Dimana didapatkan yaitu nilai ACER (obat) kelompok terapi haloperidol-klorpromazin Rp 402,90 sedangkan terapi risperidon-klozapin Rp 4.848,53 dan nilai ACER (total) kelompok terapi haloperidol-klorpromazin Rp 302.073,43 sedangkan terapi risperidon-klozapin Rp 339.476,85. Sehingga dapat disimpulkan bahwa terapi kombinasi haloperidol-klorpromazin lebih cost-effective.

Clinical trials look into how medications affect people and try to find both the efficiency and safety of the treatment as well as any negative side effects. Clinical trial quality assurance is mostly determined by data consistency and subject safety, which calls for comprehensive quality control. This paper aims to evaluate the significance of Quality assurance practices in clinical trials particularly in the U.S. pharmaceutical industry. The objectives are to assess the role of quality assurance in maintaining data integrity, to examine regulatory requirements of quality assurance in the U.S., and to evaluate the impact of quality assurance on clinical trial outcomes. The paper used a comprehensive literature review and analysis of current quality assurance practices in clinical trials within the U.S. pharmaceutical industry including case studies, and expert insights. The findings revealed that effective quality assurance processes are critical for ensuring data integrity and regulatory compliance which significantly enhances the reliability of clinical trial results concerning drug safety and efficacy. It also showed that establishing clinical trial quality management plans is essential for outlining methodologies to uphold study quality particularly as clinical trials increasingly shift to developing nations where ethical and procedural disparities pose challenges. The paper concludes that the trend of outsourcing trial management necessitates robust quality assurance oversight to maintain standards while advancements in technology such as Electronic Data Capture Systems, enhance the efficiency of Quality assurance activities. Overall, the paper underscores that effective quality assurance practices are indispensable for maintaining participants' safety, ensuring data integrity, and contributing to the success of clinical trials.

According to the Centers for Disease Control and Prevention, 1 in the United States, 90% of pregnant women take medication during pregnancy. Nearly every pregnant woman faces the decision about whether to take medication and requires information to determine how to best protect her own health and the health of the fetus. Guidance on the safety of medications utilized during pregnancy was once scarce, and the consequences of this lack of information were sometimes devastating. The infamous "thalidomide disaster" in 1961 is one example. Thalidomide was marketed in Europe as a mild hypnotic and after its release, a dramatic increase was seen in the frequency of a severe and previously rare birth defect known as phocomelia, the absence of limbs or parts of limbs. 2 Epidemiologic studies associated its cause with in utero exposure to thalidomide, 3e9 which led to regulatory changes in both the United States and Europe. In the United Kingdom, the Committee on the Safety of Medicines was established in 1968, and in the United States the Kefauver-Harris Amendments strengthened the requirements for the proof of drug safety. These legislative changes led to what has become the current drug-approval process. The field of pharmacoepidemiology, the study of the use of and the effects of drugs in large numbers of people, emerged in response to the need for research on the impact of medication usage on the public's health. The advent of pharmacoepidemiology followed a long period during which information regarding medication safety was provided solely by preapproval clinical trials, and medication use in clinical practice settings was not incorporated into regulatory direction. The reliance on preapproval clinical studies, which generally excluded large proportions of the population, such as pregnant women, resulted in inadequate safety data as study-inclusion criteria limited generalizability. Even with the expanded inclusion of pregnant women in clinical research, safety data are limited as the small samples observed are often inadequate for the detection of rare outcomes. Today, large-scale pharmacoepidemiologic studies spanning continents guide the World Health Organization's recommendations on the safe use of medications in pregnancy, such as the use of the highly effective artemisinin antimalarial treatments previously precluded from use in pregnant women based solely on embryotoxicity studies in animals. We chose to introduce the field of pharmacoepidemiology to the readers of Clinical Therapeutics with two papers that illustrate the development of the field through seminal research on medication safety in pregnancy. The historical importance of early studies on in utero exposure to medications and adverse pregnancy and birth outcomes is described, as is the development of new and evolving data sources and methods that can be applied to other research areas as well. Multiple robust administrative data sources exist for use in performing population-based studies in pregnant women, with linkage to outcomes among their infants. The paper by Wood et al 14 provides an overview of these various data sources, such as spontaneous reporting systems, teratology-information services, primary caseecontrol or birth-cohort studies, pregnancy-exposure registries, and electronic health data. Refinements and technologic improvements in observational-data sources, such as combining data sources across institutional or

Recent advances in antiretroviral therapy (ART) have drastically improved the quality of life for people with HIV infection. However, owing to the persistence of latent HIV in the presence of therapy, patients must remain on therapy indefinitely. Currently, the solution to the HIV pandemic rests on the prevention of new infections and many decades of ART for the steadily expanding number of people infected worldwide. ART is costly, requires ongoing medical care, and can have side effects, thereby preventing its universal availability. Therefore, to escape the ironic burdens of therapy, efforts have begun to develop treatments for latent HIV infection. Current approaches propose either complete eradication of infection or induction of a state of stringent control over viral replication without ART. This review will discuss these strategies in detail and their potential for clinical development.

The development of CNS drugs is associated with high failure rates. It is postulated that too much focus has been put on BBB permeability and too little on understanding BBB transport, which is the main limiting factor in drug delivery to the brain. An integrated approach to collecting, understanding, and handling pharmacokinetic-pharmacodynamic information from early discovery stages to the clinic is therefore recommended in order to improve translation to human drug treatment.