Assessment of artemisinin tolerance in Plasmodium falciparum clinical isolates in children with uncomplicated malaria in Ghana.

BACKGROUND: Artemisinin-based combination therapy (ACT) is the first-line treatment for uncomplicated malaria in Ghana. Artemisinin (ART) tolerance in Plasmodium falciparum has arisen in Southeast Asia and recently, in parts of East Africa. This is ascribed to the survival of ring-stage parasites post treatment. The present study sought to assess and characterize correlates of potential ART tolerance based on post-treatment parasite clearance, ex vivo and in vitro drug sensitivity, and molecular markers of drug resistance in P. falciparum isolates from children with uncomplicated malaria in Ghana. METHODS: Six months to fourteen years old children presenting with acute uncomplicated malaria (n = 115) were enrolled in two hospitals and a Health Centre in Ghana's Greater Accra region and treated with artemether-lumefantrine (AL) according to body weight. Pre- and post-treatment parasitaemia (day 0 and day 3) was confirmed by microscopy. The ex vivo ring-stage survival assay (RSA) was used to detect percent ring survival while the 72 h SYBR Green I assay was used to measure the 50% inhibition concentration (IC50s) of ART and its derivatives and partner drugs. Genetic markers of drug tolerance /resistance were evaluated using selective whole genome sequencing. RESULTS: Of the total of 115 participants, 85 were successfully followed up on day 3 post-treatment and 2/85 (2.4%) had parasitaemia. The IC50 values of ART, artesunate (AS), artemether (AM), dihydroartemisinin (DHA), amodiaquine (AQ), and lumefantrine (LUM) were not indicative of drug tolerance. However, 7/90 (7.8%) pre-treatment isolates had > 10% ring survival rates against DHA. Of the four isolates (2 RSA positive and 2 RSA negative) with high genomic coverage, P. falciparum (Pf) kelch 13 K188* and Pfcoronin V424I mutations were only present in the two RSA positive isolates with > 10% ring survival rates. CONCLUSIONS: The observed low proportion of participants with day-3 post-treatment parasitaemia is consistent with rapid ART clearance. However, the increased rates of survival observed in the ex vivo RSA against DHA, maybe a pointer of an early start of ART tolerance. Furthermore, the role of two novel mutations in PfK13 and Pfcoronin genes, harboured by the two RSA positive isolates that had high ring survival in the present study, remains to be elucidated.

Role of Micro-RNA for Pain After Surgery: Narrative Review of Animal and Human Studies.

One of the most prevalent symptoms after major surgery is pain. When postoperative pain treatment is unsatisfactory, it can lead to poor surgical recovery, decreased quality of life, and increased health care costs. Current analgesics, single or in combination, have limited efficacy due to low potency, limited duration of action, toxicities, and risk of addiction. The lack of nonaddictive strong analgesics along with the over prescription of opioids has led to an opioid epidemic in the United States. Therefore, there is an urgent need for the development of newer analgesics. Microribonucleic acids (miRNAs) are small noncoding RNA molecules that modulate protein synthesis in neurons and supporting cells (glia, leukocytes, and Schwann cells). The literature indicates that miRNA regulation is important in nociception. Here, we summarize the current evidence on the role of miRNAs on mechanisms involved in incisional, inflammatory, neuropathic, and cancer pain. We also discuss the role of modulating miRNA functions as potential therapeutic targets for analgesic use and opioid tolerance. Finally, we propose how the delivery of analog miRNAs (mimic-miRNAs or antago-miRNAs) could be introduced into clinical practice to provide analgesia in the perioperative period.

Assessment of Potentially Inappropriate Prescribing of Opioid Analgesics Requiring Prior Opioid Tolerance.

Importance: Opioid-tolerant only (OTO) medications, such as transmucosal immediate-release fentanyl products and certain extended-release opioid analgesics, require prior opioid tolerance for safe use, as patients without tolerance may be at increased risk of overdose. Studies using insurance claims have found that many patients initiating these medications do not appear to be opioid tolerant. Objectives: To measure prevalence of opioid tolerance in patients initiating OTO medications and to determine whether linked electronic health record (EHR) data contribute evidence of opioid tolerance not found in insurance claims data. Design, Setting, and Participants: This retrospective cohort study used a national database of deidentified longitudinal health information, including medical and pharmacy claims, insurance enrollment, and EHR data, from January 1, 2007, to December 31, 2016. Data included 131 756 US residents with at least 183 days of continuous enrollment in commercial or Medicare Advantage insurance (including medical and pharmacy benefits) who had received an OTO medication and who had no inpatient stays in the 30 days prior to starting an OTO medication; of these, 20 044 individuals had linked EHR data within the prior 183 days. Data were analyzed from July 1, 2017, to August 31, 2018. Exposures: Initiating an OTO medication. Main Outcomes and Measures: Prior opioid tolerance demonstrated through pharmacy fills or EHR data on prescriptions written. Results: Among 153 385 OTO use episodes identified, 89 029 (58.0%) occurred among women, 62 900 (41.0%) occurred among patients with Medicare Advantage insurance, 39 394 (25.7%) occurred in the Midwest, 17 366 (11.3%) occurred in the Northeast, 73 316 (47.8%) occurred in the South, and 23 309 (15.2%) occurred in the West. Less than half of use episodes (73 117 episodes [47.7%]) involved patients with evidence in claims data of opioid tolerance prior to initiating therapy with an OTO medication, including 31 392 of 101 676 episodes (30.9%) involving transdermal fentanyl, 1561 of 2440 episodes (64.0%) involving transmucosal fentanyl, 36 596 of 43 559 episodes (84.0%) involving extended-release oxycodone, and 3568 of 5710 episodes (62.5%) involving extended-release hydromorphone. Among 20 044 OTO use episodes with linked EHR and claims data, less than 1% of OTO episodes identified in claims had evidence of opioid tolerance in structured EHR data that was not present in claims data (108 episodes [0.5%]). After limiting the sample to OTO episodes identified in claims with a matching OTO prescription within 14 days in the structured EHR data, only 40 of 939 episodes (4.0%) occurred among patients with evidence of tolerance that was not present in claims data. Conclusions and Relevance: This cohort study found that most patients initiating OTO medications did not have evidence of prior opioid tolerance, suggesting they were at increased risk of opioid-related harms, including fatal overdose. Data from EHRs did not contribute substantial additional evidence of opioid tolerance beyond the data found in prescription claims. Future research is needed to understand the clinical rationale behind these observed prescribing patterns and to quantify the risk of harm to patients associated with potentially inappropriate prescribing.

Generating comparative evidence on new drugs and devices after approval.

Certain limitations of evidence available on drugs and devices at the time of market approval often persist in the post-marketing period. Often, post-marketing research landscape is fragmented. When regulatory agencies require pharmaceutical and device manufacturers to conduct studies in the post-marketing period, these studies might remain incomplete many years after approval. Even when completed, many post-marketing studies lack meaningful active comparators, have observational designs, and might not collect patient-relevant outcomes. Regulators, in collaboration with the industry and patients, ought to ensure that the key questions unanswered at the time of drug and device approval are resolved in a timely fashion during the post-marketing phase. We propose a set of seven key guiding principles that we believe will provide the necessary incentives for pharmaceutical and device manufacturers to generate comparative data in the post-marketing period. First, regulators (for drugs and devices), notified bodies (for devices in Europe), health technology assessment organisations, and payers should develop customised evidence generation plans, ensuring that future post-approval studies address any limitations of the data available at the time of market entry impacting the benefit-risk profiles of drugs and devices. Second, post-marketing studies should be designed hierarchically: priority should be given to efforts aimed at evaluating a product's net clinical benefit in randomised trials compared with current known effective therapy, whenever possible, to address common decisional dilemmas. Third, post-marketing studies should incorporate active comparators as appropriate. Fourth, use of non-randomised studies for the evaluation of clinical benefit in the post-marketing period should be limited to instances when the magnitude of effect is deemed to be large or when it is possible to reasonably infer the comparative benefits or risks in settings, in which doing a randomised trial is not feasible. Fifth, efficiency of randomised trials should be improved by streamlining patient recruitment and data collection through innovative design elements. Sixth, governments should directly support and facilitate the production of comparative post-marketing data by investing in the development of collaborative research networks and data systems that reduce the complexity, cost, and waste of rigorous post-marketing research efforts. Last, financial incentives and penalties should be developed or more actively reinforced.

Efficacy of low-dose versus high-dose simethicone with polyethylene glycol for bowel preparation: A prospective randomized controlled trial.

BACKGROUND AND AIM: Additional simethicone (SIM) can improve adequate bowel preparation and adenoma detection rate (ADR). However, there is no consensus on the optimal dose of SIM. In this study, we compared the adequate bowel preparation rate with supplementation of split-dose 2 L polyethylene glycol (PEG) with low-dose SIM (200 mg) versus high-dose SIM (1200 mg). METHODS: This was a prospective, randomized, observer-blinded trial involving consecutive subjects undergoing colonoscopy. The primary outcome was adequate bowel preparation as assessed by Boston Bowel Preparation Scale (BBPS) score. RESULTS: Four hundred subjects were randomly allocated to low-dose SIM or high-dose SIM group. Baseline characteristics were comparable in the two groups (P > 0.05). No significant between-group differences were observed with respect to total bubble scale (BS) (8.49 ± 1.00 vs 8.39 ± 1.10, P = 0.07), total BBPS score (8.70 ± 0.81 vs 8.29 ± 1.18, P = 0.98), ADR (33.68% vs 31.79%, P = 0.69) or withdrawal time (13 [range, 10-16] min vs 13 [10-15] min, P = 0.96). The intubation time in low-dose SIM group was significantly shorter than that in high-dose SIM group (8 (4-16) min vs 10 [6-17] min, P = 0.04). In addition, BS scores as well as diminutive ADR in right colon were superior in the low-dose SIM group (2.68 ± 0.59 vs 2.52 ± 0.73, P = 0.03 and 54.29% vs 30.30%, P = 0.046, respectively). CONCLUSION: Addition of low-dose SIM to split-dose 2 L PEG was as effective as addition of high-dose SIM with respect to adequate bowel preparation, ADR and patient tolerance. However, low-dose SIM was superior with respect to intubation time, right colon BS scores, right colon diminutive ADR and cost savings.

Novel tretinoin 0.05% lotion for the once-daily treatment of moderate-to-severe acne vulgaris: assessment of safety and tolerability in subgroups.

Background: Topical tretinoin's role in acne has been established through evidence-based guidelines. Cutaneous irritation and potential to cause or exacerbate postinflammatory hyperpigmentation (PIH) may limit use.Objective: Evaluate safety and tolerability of novel polymeric formulation of tretinoin 0.05% lotion in moderate-to-severe acne.Methods: One thousand six hundred and forty patients randomized to tretinoin 0.05% lotion or vehicle in two double-blind placebo-controlled 12-week studies. Investigator-evaluated cutaneous safety (erythema and scaling) and patient-reported tolerability (itching, burning/stinging) assessed using a scale of 0 (none) to 3 (severe). Hyper- and hypo-pigmentation evaluated at each study visit. A number of subpopulations were investigated.Results: Tretinoin 0.05% lotion was considered safe and very well tolerated. Only application site pain (3.1%), dryness (3.7%) and erythema (1.4%) were reported by >1% or patients. Treatment-related adverse events were particularly rare (≤2%) in Hispanic and male subpopulations, and lower in adult females. The severity of cutaneous safety and tolerability scores remained <0.5 (where 1 = mild) and were generally lower than baseline severity. Tretinoin 0.05% lotion did not appear to cause or exacerbate PIH.Conclusions: A novel polymeric formulation of tretinoin 0.05% lotion provides a highly favorable safety and tolerability profile, with an incidence of erythema, dryness, and skin burning lower than that previously reported with other formulations of tretinoin.

Chromametric assessment of drug skin tolerance: A comparative study between Africans and Caucasians skins.

BACKGROUND/AIMS: During dermatological forms development, one of the simplest non-invasive techniques used to evaluate cutaneous tolerance of formulations is to monitor the color changes using a tristimulus chromameter. Most published tolerance studies involving chromametric measurements are performed on Caucasian subjects. However, in the context of drug formulation for African-type populations, it is not always relevant to transpose tolerance results obtained on Caucasians populations to African-type ones due to histological ethnic differences of the skin. The goal of this work was to assess whether tristimulus chromameter can be used to highlight color variations following the application of dermatological topics on black skin in order to validate skin tolerance studies made on African-type subjects. MATERIALS AND METHODS: After application of two commercial creams with opposite side effects (skin irritation and skin blanching) in both Africans and Caucasians populations, color variations were evaluated using a tristimulus chromameter in L* a* b* color system and compared between both populations. L* indicating color brightness, a* represents green and red directions and b* represents blue and yellow directions. RESULTS: While skin irritation resulted in a significant increase of a* parameter in both studied populations, the skin blanching resulted in a decrease of a* associated with an increase of L* . CONCLUSION: We established that tristimulus chromameter can be used to achieve in vivo skin tolerance study of dermatologic formulations in Africans despite their dark skin even though it appeared less sensitive. This study can speed up the development of dermatological forms dedicated to Africans and/or Caucasians subjects.

Approaches to improve drug tolerance and target tolerance in the assessment of neutralizing anti-drug antibodies.

Aim: Neutralizing anti-drug antibody (NAb) assays are inherently prone to the interference from drug and its soluble target, potentially resulting in erroneous results. An effective approach to improve drug tolerance of an NAb assay is pretreatment of samples with acid to dissociate immune complexes of NAb and drug, followed by separating NAbs from circulating drug before testing them in the assay. Methods and Results: The acid pretreatment conditions were optimized to improve drug tolerance of cell-based and non-cell-based NAb assays. NAbs were further separated from circulating drug either through direct drug removal or purification of NAb from the sample. In addition, an integrated experimental strategy was implemented to simultaneously improve drug and its soluble target tolerance for reliable NAb assessment. Conclusion: The approaches described herein would enable the development of reliable NAb assays that overcome drug and its target interference for more precise and sensitive NAb assessment.

Assessment of Acute Motor Effects and Tolerance Following Self-Administration of Alcohol and Edible ∆9 -Tetrahydrocannabinol in Adolescent Male Mice.

BACKGROUND: Cannabinoids and their principle psychoactive target, the cannabinoid type 1 receptor (CB1R), impact a number of alcohol-related properties, and although alcohol and cannabis are often co-used, particularly in adolescence, few animal models of this phenomenon exist. We modeled the co-use of alcohol and ∆9 -tetrahydrocannabinol (THC) in adolescent mice using ingestive methods popular during this developmental period in humans, namely binge-drinking and edible THC. With this model, we assessed levels of use, acute effects, and tolerance to each substance. METHODS: Adolescent male C57BL/6J mice had daily, limited access to 1 of 2 edible doughs (THC or control), to 1 of 2 fluids (ethanol (EtOH) or water), and in 1 of 2 orders (dough-fluid or fluid-dough). Home cage locomotor activity was recorded both during access and after access. On the day following the final access session, a subset of mice were assessed for functional and metabolic tolerance to alcohol using accelerating rotarod and blood EtOH concentrations, respectively. The remaining mice were assessed for tolerance to THC-induced hypothermia, and whole-brain CB1R expression was assessed in all mice. RESULTS: EtOH intake was on par with levels previously reported in adolescent mice. Edible THC was well-consumed, but consumption decreased at the highest dose provided. Locomotor activity increased following EtOH intake and decreased following edible THC consumption, and edible THC increased fluid intake in general. The use of alcohol produced neither functional nor metabolic tolerance to an alcohol challenge. However, the use of edible THC impaired subsequent drug-free rotarod performance and was associated with a reduction in THC's hypothermic effect. CONCLUSIONS: Adolescent mice self-administered both alcohol and edible THC to a degree sufficient to acutely impact locomotor activity. However, only edible THC consumption had lasting effects during short-term abstinence. Thus, this adolescent co-use model could be used to explore sex differences in self-administration and the impact substance co-use might have on other domains such as mood and cognition.

Dynamic assessment of the pupillary reflex in patients on high-dose opioids.

Background and aims Pupil size and reaction are influenced by opioids, an effect that is not considered to be affected by opioid tolerance. As clinicians have observed patients on high-dose opioids who exhibited seemingly normal pupil sizes, we wanted to dynamically assess the pupillary reflex in cancer patients on high-dose opioids. Methods We performed a dynamic assessment of the pupillary reflex in cancer patients on high-dose opioids and a control group of healthy volunteers using a portable, monocular, infrared pupillometer. We also performed a clinical examination and measured blood concentrations of opioids and their active metabolites. Results Sixty three patients who were on opioids for 2 months (median time) and on an oral morphine equivalent dose of 250 mg (median dose) were investigated. Most patients used more than one opioid. When correcting for age, pupil size in the group that had received no increase of opioid dose over the last 14 days was not significantly different from pupil size in the healthy volunteer group (p = 0.76), while the group that had increased the dose of opioids differed significantly from healthy volunteers (p = 0.006). We found no statistically significant correlation between total oral morphine equivalents and pupillary reactions or between blood opioid or opioid metabolite concentrations and baseline pupillary changes. Conclusion Pupillary changes do take place in patients on opioids. However, tolerance to these changes occurs when medication is not increased over time. Dynamic pupillometry can give additional information about the degree of tolerance to opioids. Implications These findings elucidate previous misconceptions regarding pupillary effects and tolerance to opioids.

Secuquinumabe para o tratamento de artrite psoriásica em pacientes adultos com resposta inadequada a medicamentos modificadores do curso da doença sintéticos ou biológicos da classe anti-TNF / Secuquinumab for the treatment of psoriatic arthritis in adult patients with inadequate response to synthetic or biological disease course modifying drugs of the anti-TNF class

CONTEXTO: A artrite psoriásica (AP) é uma artrite inflamatória crônica, autoimune, que acomete entre 0,06 e 0,25% da população. O tratamento envolve medidas não farmacológicas e o uso de anti-inflamatórios não esteroidais (AINEs), glicocorticoides e medicamentos modificadores do curso da doenças (MMCD) sintéticos e biológicos, segundo o tipo de acometimento predominate (AP periférica ou axial). Os medicamentos biológicos são indicados em caso de falha ao tratamento prévio com os AINES e MMCD sintéticos (AP periférica) ou AINES (AP axial), constituindo a última linha de tratamento da doença. TECNOLOGIA: SECUQUINUMABE (COSENTYX®). PERGUNTA: Secuquinumabe é eficaz e seguro para o tratamento da artrite psoriásica ativa, quando a resposta à terapia prévia com medicamentos modificadores do curso da doença (MMCD), sintéticos ou biológicos, for inadequada? EVIDÊNCIAS CIENTÍFICAS: Foram incluídos três ensaios clínicos e quatro revisões sistemáticas de comparação direta de secuquinumabe contra placebo e indireta com relação aos demais biológicos disponíveis no SUS. Comparações indiretas demonstraram eficácia equivalente entre secuquinumabe e os medicamentos anti-TNF disponíveis no SUS, porém estes estudos apresentaram baixa qualidade metodológica. Dados dos ensaios clínicos randomizados FUTURE 1 e FUTURE 2 demonstraram que secuquinumabe 150 mg é eficaz em 24 semanas, comparado a placebo, para os desfechos de AP periféricos (ACR20, ACR50, ACR 70, DAS28 e entesite), de pele (PASI75, PASI 90), e para redução da progressão radiográfica. Para pacientes com falha ao anti-TNF, apenas sequinumabe 300 mg foi mais eficaz que placebo (FUTURE II). Para pacientes com psoríase e artrite psoriásica concomitante, sequinumabe 300 mg foi mais eficaz que placebo e que etanercepte (ERASURE e FIXTURE). Com relação aos resultados de segurança, as taxas de eventos adversos, eventos adversos sérios e descontinuação por eventos adversos foram semelhantes entre os grupos secuquinumabe e placebo até 16 semanas de acompanhamento, porém a ocorrência de infecções ou infestações foi maior entre pacientes que receberam secuquinumabe. Ao final de 104 semanas, 84,5% dos pacientes que utilizaram secuquinumabe relataram pelo menos um evento adverso, sendo a ocorrência de infecções ou infestações os mais comuns. AVALIAÇÃO ECONÔMICA: A análise de custo minização sugere que secuquinumabe na dose de 150 mg é mais barato em comparação com os medicamentos anti-TNF disponíveis no SUS em todos os cenários propostos. Secuquinumabe 300 mg é mais caro que adalimumabe, etanercepte e golimumabe no primeiro ano de uso e mais caro que golimumabe a partir do segundo ano. Esta análise foi sensível à redução de 10% no preço de aquisição dos medicamentos disponíveis no SUS, favorecendo os medicamentos já incorporados. AVALIAÇÃO DE IMPACTO ORÇAMENTÁRIO: A análise de impacto orçamentário apresentada sugere economia de até R$ 60 milhões de reais com a incorporação de secuquinumabe em cinco anos, o que representa 4% do total gasto com AP. Entretanto, parâmetros estimados no modelo estão inadequados e podem influenciar o resultado final, tais como: baixo índice de troca entre os medicamentos biológicos; constante e elevado market share para o secuquinumabe; taxa de descontinuação sem troca de 0%. MONITORAMENTO DO HORIZONTE TECNOLÓGICO: Alguns medicamentos estão em fase de desenvolvimento clínico para o tratamento da artrite psoriásica (abatacepte, apremilaste, brodalumabe, guselkumabe, ixequizumabe, tofacitinibe e upadacitinibe). Essas novas tecnologias ainda não tiveram seu registro aprovado pela Anvisa para a AP. CONSIDERAÇÕES FINAIS: Não existem estudos que avaliem o secuquinumabe com outros medicamentos disponíveis pelo SUS por comparação direta. Os ensaios clínicos randomizados FUTURE 1, FUTURE 2, FIXTURE e ERASURE mostraram que secuquinumabe foi melhor do que o placebo para os desfechos de eficácia. Não houve diferenças entre secuquinumabe e placebo para a segurança. A revisão sistemática de comparação indireta relatou que secuquinumabe apresenta eficácia semelhante aos anti-TNF para o desfecho ACR 20. Secuquinumabe 150 mg possui menor custo do que as outras alternativas disponíveis no SUS. O mesmo não ocorre quando a dose de 300 mg é necessária, em casos de falha a um anti-TNF e na presença de psoríase moderada a grave. RECOMENDAÇÃO PRELIMINAR DA CONITEC: A CONITEC, em sua 58ª reunião ordinária, realizada no dia 03 de agosto de 2017, recomendou que a matéria fosse submetida à consulta pública com recomendação inicial favorável à incorporação no SUS do secuquinumabe 150mg para artrite psoriásica moderada a grave com falha terapêutica inicial ao AINE e/ou MMCD sintético e do secuquinumabe 300mg para pacientes com atrite psoriásica com falha terapêutica inicial ao anti-TNF ou para pacientes com psoríase e artrite psoriásica concomitante. Entretanto, a incorporação está condicionada à redução de preço do secuquinumabe 300mg ao menor preço de anti-TNF disponível no SUS, pois considerou-se que o secuquinumabe tem equivalência terapêutica com os medicamentos anti-TNF já disponíveis no SUS. CONSULTA PÚBLICA: Foram recebidas 66 contribuições de experiência ou opinião e 25 contribuições de cunho técnico-científico, onde 95% e 96% concordaram com a recomendação preliminar da CONITEC, respectivamente. Todas as contribuições foram avaliadas quantitativamente e qualitativamente. As contribuições destacaram a importância da incorporação de mais uma opção terapêutica para o tratamento da artrite psoriásica. As contribuições científicas enviadas não apresentaram evidências adicionais sobre a eficácia, efetividade e segurança do secuquinumabe em comparação aos medicamentos disponíveis no SUS. DELIBERAÇÃO FINAL: Os membros da CONITEC presentes na 62ª reunião ordinária da plenária, realizada no dia 07/12/2017, deliberaram por unanimidade recomendar a incorporação de secuquinumabe para o tratamento de artrite psoriásica em pacientes adultos com resposta inadequada a medicamentos modificadores do curso da doença sintéticos ou biológicos da classe anti-TNF. Foi assinado o Registro de Deliberação nº 317/2017 (Retificado e substituído pelo Registro de deliberação n° 402/2018). DECISÃO: (Portaria revogada) Incorporar o secuquinumabe para o tratamento de artrite psoriásica em pacientes adultos com resposta inadequada a medicamentos modificadores do curso da doença sintéticos ou biológicos da classe anti-TNF no âmbito do Sistema Único de Saúde ­ SUS. Dada pela Portaria nº 3 de 25 de janeiro de 2018, publicada no Diário Oficial da União nº 18, seção 1, página 123.

Assessment of prior opioid tolerance among new users of fentanyl transdermal system in FDA's Sentinel System.

PURPOSE: Fentanyl transdermal system (FTS) is intended only for patients with prior opioid tolerance. The purpose of this study is to identify the proportion of new FTS users who had evidence of prior opioid tolerance, by dosage strength, in FDA's Sentinel System. METHODS: We identified new FTS episodes (183-day washout) from 2009 through 2013. Members were <65 years and enrolled in medical and pharmacy coverage for 183 days prior to initial FTS dispensing (index). We assessed the proportion of users with prior tolerance stratified by dosage strength of FTS using four definitions of opioid tolerance: ≥30-mg oxycodone equivalents/day in each of 7 consecutive days immediately prior to index; ≥30-mg oxycodone equivalents/day for any 7 days in the 30 days prior to index (secondary); any dose in each of 7 days in the 7 consecutive days immediately prior to index (tertiary); and any dose for any 7 days in the 30 days prior to index (quaternary). RESULTS: Of 44 450 episodes of 25 mcg/hr FTS, 37% met the primary definition, and 77% met the quaternary definition. Of 3507 episodes of 100 mcg/hr FTS, 57% and 74% met the primary and quaternary definitions, respectively. Those aged 25 to 34 years had the highest proportion of episodes with prior tolerance; those aged 55 to 64 accounted for more of the episodes overall. CONCLUSIONS: In Sentinel, many new users of FTS did not have evidence of prior opioid tolerance by the primary definition, ie, the product label definition, which is the minimum standard for the lowest FTS dose (12 mcg/hr), especially at the highest strength (100 mcg/hr). Validation of this metric is warranted, but our findings suggest the need for further prescriber education regarding appropriate prescribing of FTS.

High-Throughput Screening to Identify Anesthetic Ligands Using Xenopus laevis Tadpoles.

General anesthetics are considered among the most significant advances in modern medicine; however, they are also some of the most dangerous commonly administered drugs. Despite this, the discovery of novel anesthetics has been slow, with few clinically used agents regardless of their nearly 200-year history. Xenopus laevis frogs have a long history as a model organism and provide a vital bridge between in vitro and preclinical mammalian assays. The provided protocols are efficient and cost-effective and therefore readily amendable for high-throughput evaluation of novel anesthetic ligands. By using the X. laevis bioassay, a researcher is capable of determining relative general anesthetic tolerance and/or cross-tolerance for candidate nonvolatile and/or volatile ligands.

Therapeutic Drug Monitoring of Biologics for Inflammatory Bowel Disease: An Answer to Optimized Treatment?

Therapeutic drug monitoring (TDM), or the measurement of drug concentrations in blood and antidrug antibodies, for biologic therapies used to treat inflammatory bowel disease (IBD) is an area of growing interest within the IBD community. When there is a definable relationship between drug concentration and clinical effect, blood concentration of biologics (and antidrug antibodies assessment) could be used to predict patient response and to titrate the biologics to maximize therapeutic benefit. This dose individualization has been proven to be more efficacious and cost-effective than empiric dose adjustment and can better guide therapeutic decisions regarding therapy withdrawal or switch. Appropriate implementation and interpretation of drug concentration measurement in TDM are essential to ensure full clinical benefit. Factors that need to be considered include sources of variability, timing of blood sampling, dosing history, analytical performance, immunogenicity, comedications, and clinical status of the patients. Desired target concentrations for biologics used in IBD have not been clearly determined yet. Published concentration thresholds differed widely for a given biologic, indicating a lack of consistent information. Factors other than drug concentration that may contribute to the dose-response variation are largely missing in the current TDM setting. A target range is likely preferable to a single value for TDM of biologics in IBD, and additional prospective research needs to be conducted in order to establish these ranges. Moving forward, TDM may be combined with pharmacodynamic end points and modeling and simulation tools for improved therapeutic benefit in IBD.

The DARK Side of Total Synthesis: Strategies and Tactics in Psychoactive Drug Production.

Humankind has used and abused psychoactive drugs for millennia. Formally, a psychoactive drug is any agent that alters cognition and mood. The term "psychotropic drug" is neutral and describes the entire class of substrates, licit and illicit, of interest to governmental drug policy. While these drugs are prescribed for issues ranging from pain management to anxiety, they are also used recreationally. In fact, the current opioid epidemic is the deadliest drug crisis in American history. While the topic is highly politicized with racial, gender, and socioeconomic elements, there is no denying the toll drug mis- and overuse is taking on this country. Overdose, fueled by opioids, is the leading cause of death for Americans under 50 years of age, killing ca. 64,000 people in 2016. From a chemistry standpoint, the question is in what ways, if any, did organic chemists contribute to this problem? In this targeted review, we provide brief historical accounts of the main classes of psychoactive drugs and discuss several foundational total syntheses that ultimately provide the groundwork for producing these molecules in academic, industrial, and clandestine settings.

Anti-TNF Re-induction Is as Effective, Simpler, and Cheaper Compared With Dose Interval Shortening for Secondary Loss of Response in Crohn's Disease.

BACKGROUND AND AIMS: The optimal duration of dose-intensified therapy following secondary loss of response [LOR] to anti-tumour necrosis factor [TNF] therapy remains unclear. Anti-TNF re-induction involves a finite period of intensified therapy and may be a cost-effective means of re-capturing response. This study aimed to compare the efficacy, durability, and cost of anti-TNF re-induction and dose interval shortening [DIS] for secondary LOR in Crohn's disease [CD]. METHODS: This was a retrospective observational study in CD patients who developed secondary LOR to maintenance anti-TNF therapy, requiring subsequent re-induction and/or DIS. The primary outcome was treatment failure within 12 months. Secondary outcomes included factors associated with time to failure, disease activity, and incremental anti-TNF costs. RESULTS: Of 423 patients with CD on anti-TNF therapy, 80 [19%] developed secondary LOR, with 33 and 55 patients undergoing subsequent anti-TNF re-induction and DIS, respectively. There was no significant difference in the incidence of treatment failure at 12 months following re-induction and DIS, respectively [p = 0.27]. Factors predictive of a longer time to failure included a higher baseline serum albumin, male sex, and thiopurine co-therapy [each p < 0.05], whereas higher baseline faecal calprotectin was associated with shorter time to failure. There was no significant difference in clinical remission or objective disease activity across both groups. The median incremental cost of re-induction and DIS was AUD 4 838 and AUD 13 190, respectively. CONCLUSIONS: In patients with CD who develop secondary LOR, re-induction may represent an effective and less expensive first-line strategy, reserving dose intensification strategies such as DIS for non-responders.

Eficacia y seguridad de tapentadol en comparación con terapia de soporte en pacientes con dolor neuropático crónico severo, refractario o intolerante a tratamiento convencional físico y farmacológico / Efficacy and safety of tapentadol compared to supportive therapy in patients with chronic severe neuropathic pain, refractory or intolerant to conventional physical and pharmacological treatment

El dolor neuropático puede definirse como un dolor que aparece debido a uma lesión o enfermedad del sistema somatosensorial, por lo que, consiste en um conjunto de síntomas y no en un diagnóstico per se. La prevalencia de dolor neuropático se encuentra entre 7 % y 10 % a nivel global. Las personas manifiestan presentar alodinia, hiperalgesia, anestesia dolorosa y alteración positiva o negativa de la sensibilidad. Para el tratamiento del dolor neuropático crónico severo, refractario o intolerante a tratamiento convencional físico y farmacológico, incluyendo opioides débiles (tramadol) y fuertes (oxicodona y morfina), EsSalud sólo cuenta con terapias de soporte invasivas, como las infiltraciones locales, bloqueos nerviosos, estimulaciones eléctricas, entre otras opciones. Sin embargo, dada la poca evidencia de su eficacia y su agresividad, las terapias de soporte invasivas se consideran el último escalón (cuarto escalón) en el manejo del dolor según la escalera analgésica de la Organización Mundial de la Salud (OMS), por lo que, se plantea el uso de tapentadol como una alternativa farmacológica, más

Eficacia y seguridad de ácido zoledrónico para el tratamiento de pacientes con diagnóstico de osteoporosis con contraindicación a uso de bifosfonatos orales por compromiso esofágico / Efficacy and safety of zoledronic acid for the treatment of patients diagnosed with osteoporosis with contraindication to the use of oral bisphosphonates due to esophageal involvement

INTRODUCCIÓN: El presente dictamen expone la evaluación de la eficacia y seguridad de ácido zoledrónico en pacientes con diagnóstico de osteoporosis y contraindicación a uso de bifosfonatos orales por compromiso esofágico. La osteoporosis es un desorden esquelético progresivo. Se caracteriza por una disminución de la masa ósea y el deterioro de la estructura del tejido óseo que conduce a un aumento de la fragilidad ósea y riesgo de fractura. Las consecuencias de sufrir una fractura pueden ser graves e incluyen un mayor riesgo de fracturas posteriores, hospitalización o internación, disminución de la calidad de vida y mortalidad prematura, generando una carga económica importante para los sistemas de salud (National Institute for Health and Care Excellence 2017). Los principales mecanismos que provocan la osteoporosis son la falta de masa ósea suficiente durante el proceso de crecimiento, la reabsorción excesiva de hueso mediada por los osteoclastos y la formación inadecuada de hueso nuevo por los osteoblastos durante el proceso continuo de renovación ósea (Raisz 2005). Dentro de los factores de riesgo claves y mejores predictores de fractura relacionada a la osteoporosis se encuentran: la densidad mineral ósea (DMO) disminuida, la historia de fracturas por fragilidad, la edad avanzada y la historia familiar de osteoporosis (National Institute for Health and Care Excellence 2017). TECNOLOGÍA SANITARIA DE INTERÉS: El ácido zoledrónico (Reclast®, Aclasta®) es un bifosfonato nitrogenado que inhibe la acción de los osteoclastos, que son las células del organismo responsables de la degradación del tejido óseo (resorción ósea). La absorción del fármaco por parte de los osteoclastos, genera la inhibición de la enzima farnesil pirofosfato sintetasa, necesaria para la actividad biológica de éstas células (European Medicines Agency 2017). METODOLOGÍA: Se realizó una búsqueda sistemática de literatura con el objetivo de identificar evidencia sobre la eficacia y seguridad de ácido zoledrónico, con respecto a la mejor terapia de soporte o placebo, en pacientes con diagnóstico de osteoporosis y contraindicación a uso de bifosfonatos orales por compromiso esofágico. Se utilizó las bases de datos The Cochrane Library, Medline y el metabuscador TRIP Database, priorizándose evidencia proveniente de revisiones sistemáticas o meta-análisis de ensayos clínicos controlados aleatorizados. Asimismo, se realizó una búsqueda dentro de bases de datos pertenecientes a grupos que realizan evaluación de tecnologías sanitarias y guías de práctica clínica, incluyendo Scottish Medicines Consortium (SMC), The National lnstitute for Health and Care Excellence (N ICE), The Canadian Agency for Drugs and Technologies in Health (CADTH) y páginas web de organizaciones reumatológicas elaboradoras de guías. Se hizo una búsqueda adicional en la página web de www.clinicaltrials.qov, para poder identificar ensayos clínicos en curso o que no hayan sido publicados. La búsqueda sistemática se basó en una metodología escalonada, la cual consistió en la búsqueda inicial de estudios secundarios (tipo revisiones sistemáticas de ensayos clínicos) que respondan a la pregunta PICO, seguido de la búsqueda de estudios primarios (tipo ensayos clínicos controlados aleatorizados). RESULTADOS: Con respecto a las GPCs, tanto NOGG como RACGP, recomiendan el uso de ácido zoledrónico en el tratamiento de la osteoporosis en pacientes con riesgo elevado de fracturas y contraindicación al uso de bifosfonatos orales. Estas recomendaciones se basan en los tres ECAs incluidos en el presente dictamen. Con respecto a la ETS, NICE recomienda el uso de ácido zoledrónico como opción de tratamiento de la osteoporosis en pacientes adultos con riesgo elevado de fracturas y contraindicación al uso de bifosfonatos orales, como es el caso de la población de interés de nuestra pregunta PICO. Esta recomendación también se basa en los tres ECAs incluidos en el presente dictamen. Si bien, NICE catalogó al ácido zoledrónico como una intervención costo-efectiva en nuestra población de interés, no fue posible extrapolar dichos resultados a nuestro contexto local. El meta-análisis con los tres ECAs realizados por Liu et al. incluidos en el presente dictamen. Los resultados mostraron que el ácido zoledrónico reducía significativamente la incidencia de fracturas vertebrales (RR 0.24, IC 95% 0.15 a 0.40, p p<0.001) no vertebrales (RR 0.76, IC 95% 0.67 a 0.86, p<0.001) y de cadera (RR 0.73, IC 95% 0.63 a 0.84, p=0.001), con respecto al placebo, en pacientes con osteoporosis con un periodo de seguimiento de 2 a 5 años. 0.30, IC 95% 0.24 a 0.38, p<0.001) y de fractura de cadera (1.4% versus 2.5%, HR 0.59, IC 95% 0.42 a 0.83, p=0.002) a los 36 meses de seguimiento, en mujeres postmenopáusicas con osteoporosis de 65 a 89 años. Lyles et al. mostraron que el ácido zoledrónico reducía la ocurrencia de nuevas fracturas clínicas (8.6% versus 13.9%, HR 0.65, IC 95% 0.50 a 0.84, p=0.001) y mejoraba la sobrevida (9.6% versus 13.3%, HR 0.72, IC 95%, 0.56 a 0.93, p=0.01) después de una media de seguimiento de 1.9 años, en mujeres y hombres mayores de 50 años con reparación quirúrgica reciente de una fractura de cadera. Boonen et al. mostraron una reducción en la ocurrencia de nuevas fracturas vertebrales en los pacientes tratados con ácido zoledrónico respecto a los tratados con placebo (1.6% versus 4.9%, RR 0.33, IC 95% 0.16 a 0.70, p=0.002) a los 24 meses de seguimiento, en hombres con osteoporosis de 50 a 85 años. Con respecto a la seguridad de ácido zoledrónico, los eventos adversos (EAs) reportados con más frecuencia en los tres ECAs fueron las reacciones a los pocos días de haber recibido una dosis, incluyendo pirexia, mialgia, síntomas parecidos a los de la influenza, cefalea, y artralgia. La tasa de EAs serios y la tasa de discontinuación debido a EAs no difirieron significativamente en comparación al placebo. Ningún estudio evaluó el efecto de ácido zoledrónico sobre la calidad de vida. En general, la calidad metodológica de los ECAs previamente descritos fue considerada como alta. No se identificaron estudios en pacientes con osteoporosis secundaria, como la osteoporosis inducida por el uso de glucocorticoides, que evaluará el efecto de ácido zoledrónico sobre los desenlaces de relevancia clínica incluidos en la pregunta PICO del presente dictamen. CONCLUSIONES: La evidencia científica de alta calidad metodológica disponible a la actualidad muestra consistencia sobre el beneficio clínico otorgado por el uso de ácido zoledrónico 5 mg administrado intravenosamente una vez al año en la prevención de nuevas fracturas en mujeres postmenopáusicas y hombres mayores de 50 años. Por lo expuesto el Instituto de Evaluación de Tecnologías en Salud e Investigación (IETSI) aprueba el uso de ácido zoledrónico para el tratamiento de los pacientes con diagnóstico de osteoporosis con contraindicación a uso de bifosfonatos orales por compromiso esofágico, según lo establecido en el anexo 1. La vigencia del presente dictamen preliminar es de dos años.