FDA/Arthritis Foundation osteoarthritis drug development workshop recap: Assessment of long-term benefit.

OBJECTIVE: To summarize proceedings of a workshop convened to discuss the current state of science in the disease of osteoarthritis (OA), identify the knowledge gaps, and examine the developmental and regulatory challenges in bringing these products to market. DESIGN: Summary of the one-day workshop held virtually on June 22nd, 2021. RESULTS: Speakers selected by the Planning Committee presented data on the current approach to assessment of OA therapies, biomarkers in OA drug development, and the assessment of disease progression and long-term benefit. CONCLUSIONS: Demonstrated by numerous failed clinical trials, OA is a challenging disease for which to develop therapeutics. The challenge is magnified by the slow time of onset of disease and the need for clinical trials of long duration and/or large sample size to demonstrate the effect of an intervention. The OA science community, including academia, pharmaceutical companies, regulatory agencies, and patient communities, must continue to develop and test better clinical endpoints that meaningfully reflect disease modification related to long-term patient benefit.

Correção histeroscópica de útero septado completo / Hysteroscopic correction of complete septate uterus

As anomalias congênitas do trato genital feminino são condições relativamente comuns que podem levar com frequência a problemas reprodutivos. Atualmente, a abordagem cirúrgica da maioria das malformações uterinas tem sido realizada por via endoscópica, tendo a histeroscopia, com sua segurança e baixa invasividade, substituído a correção cirúrgica por via abdominal, praticamente em desuso. Com o advento da cirurgia histeroscópica, a realização de metroplastia se tornou um procedimento simples, com ótimos resultados reprodutivos. O caso clínico apresentado relata o resultado de uma correção cirúrgica endoscópica de uma malformação uterina pouco comum: útero septado completo. A dificuldade cirúrgica na abordagem da doença está na presença de dupla vagina e, sobretudo, na presença de dois colos uterinos que implicam a utilização de estratégias endoscópicas especiais para superar os obstáculos. Os autores detalham sua experiência com esse tipo de metroplastia. Uma boa prática endoscópica aliada a modernas técnicas de imagem permitem, também nesses casos, uma completa restituição da integridade da cavidade uterina, melhorando o potencial reprodutivo dessas pacientes.(AU)

Congenital malformations of the female genital tract are relatively common conditions that can often lead to reproductive problems. Currently, the surgical approach to most uterine malformations has been performed endoscopically, and hysteroscopy, with its safety and low invasiveness, has been replacing abdominal surgical correction, practically in disuse. With the advent of hysteroscopic surgery, the realization of metroplasty became a simple procedure, with excellent reproductive results. The clinical case presented, reports the result of an endoscopic surgical correction of an uncommon uterine malformation: complete septate uterus. The surgical difficulty in approaching the disease is in the presence of double vagina, and, especially, in the presence of two uterine cervix that imply the use of special endoscopic strategies to overcome obstacles. The authors detail their experience with this type of metroplasty. A good endoscopic experience combined with modern imaging techniques also allows in these cases a complete restoration of the integrity of the uterine cavity, improving the reproductive potential of these patients.(AU)

Review of maintenance trials for major depressive disorder: a 25-year perspective from the US Food and Drug Administration.

OBJECTIVE: The maintenance efficacy of antidepressants is usually assessed in postmarketing studies with a randomized withdrawal design. This report explores differences in relapse rates, trial characteristics, and success rates in maintenance efficacy studies submitted to the US Food and Drug Administration (FDA) over a 25-year period. DATA SOURCES: Clinical data from all maintenance trials with antidepressants submitted to FDA between 1987 and 2012. STUDY SELECTION: Efficacy data were compiled from 15 maintenance clinical trials in adults diagnosed with major depressive disorder according to DSM-III or DSM-IV criteria. DATA EXTRACTION: Trial characteristics, relapse rates, and time to relapse in each study were examined. RESULTS: Relapse rates were significantly lower (P < .05) in the drug arm than in the placebo arm in every study, with a mean relapse rate difference of 18% and an average percent reduction in relapse rate of 52% compared to placebo. Only 6% of the relapse events occurred in the first 2 weeks of the double-blind phase. The separation between treatment arms continued to increase throughout the double-blind phase only in the trial with longest response stabilization period. CONCLUSIONS: Antidepressant maintenance trials have a high rate of success, indicating a benefit of continuing drug treatment after initial response to an antidepressant. This benefit appears to result mainly from a decreased rate of recurrent depression rather than from an effect of drug withdrawal in the placebo groups.

Influência dos stents farmacológicos na seleção de pacientes diabéticos tratados por meio de intervenção coronária percutânea / Influence of drug-eluting stents in the selection of diabetic pacients treated by percutaneous coronary intervention

Introdução: Os diabéticos representam um desafio para as intervenções coronárias percutâneas (ICP) em decorrência das elevadas taxas de reestenose, limitando a utilização desse procedimento em situações com grande perspectiva de recidiva, restringindo o emprego da técnica e predispondo à revascularização incompleta. Os stents farmacológicos contribuíram para a atenuação expressiva dessas limitações, podendo ter causado mudanças nas características dos casos tratados contemporaneamente. Assim, nosso objetivo foi comparar o perfil dos diabéticos tratados por ICP em dois momentos distintos desta década. Método: Estudo de coorte envolvendo 2.530 pacientes diabéticos revascularizados de forma consecutiva, divididos em dois grupos: grupo A, 1.309 pacientes revascularizados no período de 2006 a 2008; e grupo B, 1.221 pacientes tratados entre 2003 e 2005. Excluíram-se apenas os pacientes em que foram utilizados stents farmacológicos não disponíveis para uso comercial...

Background: Diabetic patients represent a challenge for percutaneous coronary interventions (PCI) due to the highrestenosis rates, which limit the use of the procedure in cases prone to recurrences, predisposing patients to incomplete revascularization. Drug-eluting stents (DES) have contributed for a significant improvement of these limitations and may have caused changes in the characteristics of patients treated contemporaneously. Thus, our objective was to compare the profile of diabetic patients treated intwo different periods of this decade. Method: This was a consecutive cohort study including 2,530 diabetic patientswho were divided into two groups: group A, 1,309 patients revascularized from 2006 to 2008; and group B, 1,221patients treated from 2003 to 2005. Only patients using DES not commercially available were excluded. Results: DES were more frequently used in group A (23% vs. 9%; P < 0.0001), which has a higher prevalence of insulin requiring patients (14% vs. 10%; P = 0.0001), chronic renal failure (20% vs. 10.1%; P < 0.0001), B2/C lesions(68% vs. 63%; P = 0.003), total occlusions (17% vs. 10%; P < 0.0001), stent diameter < 2.5 mm (26% vs. 22%; P = 0.01) and stent length > 24 mm (31% vs. 22%; P < 0.0001).Multivessel interventions (12% vs. 6%; P < 0.001) and complete revascularization (65% vs. 59%; P = 0.002) also prevailed in group A. Clinical hospital results were not different between groups. Conclusion: The greater availability of DES has led to significant changes in the profile ofdiabetic patients treated currently, expanding the indications for more complex patients and providing a more complete myocardial revascularization.

A penalized mixture model approach in genotype/phenotype association analysis for quantitative phenotypes.

A mixture normal model has been developed to partition genotypes in predicting quantitative phenotypes. Its estimation and inference are performed through an EM algorithm. This approach can conduct simultaneous genotype clustering and hypothesis testing. It is a valuable method for predicting the distribution of quantitative phenotypes among multi-locus genotypes across genes or within a gene. This mixture model's performance is evaluated in data analyses for two pharmacogenetics studies. In one example, thirty five CYP2D6 genotypes were partitioned into three groups to predict pharmacokinetics of a breast cancer drug, Tamoxifen, a CYP2D6 substrate (p-value = 0.04). In a second example, seventeen CYP2B6 genotypes were categorized into three clusters to predict CYP2B6 protein expression (p-value = 0.002). The biological validities of both partitions are examined using established function of CYP2D6 and CYP2B6 alleles. In both examples, we observed genotypes clustered in the same group to have high functional similarities. The power and recovery rate of the true partition for the mixture model approach are investigated in statistical simulation studies, where it outperforms another published method.

Composite functional genetic and comedication CYP2D6 activity score in predicting tamoxifen drug exposure among breast cancer patients.

Accurate assessment of CYP2D6 phenotypes from genotype is inadequate in patients taking CYP2D6 substrate together with CYP2D6 inhibitors. A novel CYP2D6 scoring system is proposed that incorporates the impact of concomitant medications with the genotype in calculating the CYP2D6 activity score. Training (n = 159) and validation (n = 81) data sets were obtained from a prospective cohort tamoxifen pharmacogenetics registry. Two inhibitor factors were defined: 1 genotype independent and 1 genotype based. Three CYP2D6 gene scoring systems, and their combination with the inhibitor factors, were compared. These 3 scores were based on Zineh, Zanger, and Gaedigk's approaches. Endoxifen/NDM-Tam plasma ratio was used as the phenotype. The overall performance of the 3 gene scoring systems without consideration of CYP2D6-inhibiting medications in predicting CYP2D6 phenotype was poor in both the training set (R(2) = 0.24, 0.22, and 0.18) and the validation set (R(2) = 0.30, 0.24, and 0.15). Once the CYP2D6 genotype-independent inhibitor factor was integrated into the score calculation, the R(2) values in the training and validation data sets were nearly twice as high as the genotype-only scoring model: (0.44, 0.43, 0.38) and (0.53, 0.50, 0.41), respectively. The integration of the inhibitory effect of concomitant medications with the CYP2D6 genotype into the composite CYP2D6 activity score doubled the ability to predict the CYP2D6 phenotype. However, endoxifen phenotypes still varied substantially, even with incorporation of CYD2D6 genotype and inhibiting factors, suggesting that other, as yet unidentified factors must be involved in tamoxifen activation.

Terapia celular no infarto do miocárdio: mito ou realidade? / Cell therapy in myocardial infarction: myth or reality?

A doença isquêmica do coração ainda permance como uma das causas de maior morbidade e mortalidade no mundo atual. Embora suas opções terapêuticas tenham-se desenvolvido muito nos últimos anosl, o infarto agudo do miocárdio, além das elevadas morbidade e mortalidade, associa-se ao desenvolvimento de quadros de cardiomiopatia isquêmica crônica, insuficiência ventricular e baixa qualidade de vida para muitos pacientes. A terapia celular para recuperação da função ventricular, para esses pacientes traz consigo uma nova perspectiva de vida. Os autores se propõem a revisar os principaisavanços, técnicas de realização e promessas em terapia celular para pacientes acometidos por infarto agudo do miocárdio com grande perda de função ventricular...

Terapia celular no infarto agudo do miocárdio Mito ou realidade? / Terapia celular no infarto agudo do miocárdio Mito ou realidade?

A doença isquêmica do coração ainda permanece como uma das causas de maior morbidade e mortalidade no mundo atual. Embora suas opções terapêuticas tenham se desenvolvido muito nos últimos anos, o Infarto Agudo do Miocárdio, além da elevada morbimortalidade associa-se ao desenvolvimentode quadros de miocardiopatia isquêmica crônica, insuficiência ventricular e baia qualidade de vida para muitos pacientes. Para estes pacientes, a terapia celular para recuperação da função ventricular traz consigo uma nova perspectiva de vida. Os autores se propõem a revisar os principais avanços, ténicas de realização e promessas na terapia celular para pacientes acometidos por infarto agudo do miocárdio com grande perda da função ventricular...

Quantitative effect of CYP2D6 genotype and inhibitors on tamoxifen metabolism: implication for optimization of breast cancer treatment.

BACKGROUND AND OBJECTIVES: N-Desmethyltamoxifen (NDM), a major primary metabolite of tamoxifen, is hydroxylated by cytochrome P450 (CYP) 2D6 to yield endoxifen. Because of its high antiestrogenic potency, endoxifen may play an important role in the clinical activity of tamoxifen. We conducted a prospective trial in 158 patients with breast cancer who were taking tamoxifen to further understand the effect of CYP2D6 genotype and concomitant medications on endoxifen plasma concentrations. METHODS: Medication history, genotype for 33 CYP2D6 alleles, and plasma concentrations of tamoxifen and its metabolites were determined at the fourth month of tamoxifen treatment. RESULTS: By use of a mixture model approach, endoxifen plasma concentration identified 2 phenotypic groups, whereas 4 were defined by the endoxifen/NDM plasma concentration ratio. Three distinct genotype groups were identified in the distribution of endoxifen/NDM ratio: (1) low ratios composed of patients lacking any functional allele (mean, 0.04 +/- 0.02); (2) intermediate ratios represented by patients with 1 active allele (mean, 0.08 +/- 0.04); and (3) high ratios composed of patients with 2 or more functional alleles (mean, 0.15 +/- 0.09). Endoxifen/NDM plasma ratios were significantly different between these groups (P < .001). The mean endoxifen plasma concentration was significantly lower in CYP2D6 extensive metabolizers who were taking potent CYP2D6 inhibitors than in those who were not taking CYP2D6 inhibitors (23.5 +/- 9.5 nmol/L versus 84.1 +/- 39.4 nmol/L, P < .001). CONCLUSION: CYP2D6 genotype and concomitant potent CYP2D6 inhibitors are highly associated with endoxifen plasma concentration and may have an impact on the response to tamoxifen therapy. These iterative approaches may be valuable in the study of other complex genotype-phenotype relationships.

A opinião de estudantes sobre o afastamento e as relações familiares após o ingresso em um colégio interno / La opinión de estudiantes sobre la separación e las relaciones familiares después del ingreso a um colegio interno / Students' opinion about family detachment and relationships after getting into a boarding school: a descriptive study

This is a descriptive-exploratory study of quali-quantitative nature accomplished with students living in a boarding school, with the objective of identifying the family characteristics, how the option for the boarding school was made, and to know what the separation from the family meant to the student. Thirty students from the three stages of High School, distributed in two groups were studied. Group I consisted of 15 students that sought three or more times the institution health clinic for assistance. Group II consisted of students of the same sex, age and classroom and that had not sought the clinic. The results revealed that the participants were between 14 and 18 years of age, arriving mainly from Southeast (36.7%) and Midwest (23.3%), and distributed equally in the three years of the High School program. In the two groups there was predominance of nuclear families, formed with three to six members and most of the students lived with the parents before coming to the institution. In 2 cases (1 in each group), the decision for the boarding school was made by the parents, in 10 cases it was made by the adolescents, and in 18 cases it was a joint decision (61.1% in Group I and 38.9% in Group II). Half of the students reported that their relationship with the family was very good, and that the arrival to the boarding school turned it even better. It also applies to the students that had referred negative aspects in their family relationship. In spite of the separation from the family, of the coexistence with different people and of the existence of norms and rules, the experience in a boarding school regime was evaluated positively. It is concluded that the option for boarding school involved mainly the possibility of living a new experience associated to the offer of better studies and that the boarding school is seen by the students as an alternative for their individual growth.

Este é um estudo descritivo-exploratório de natureza qualiquantitativa, realizado com estudantes internos de uma instituição de ensino, com o objetivo de identificar as características familiares e como se deu a opção pelo internato, além de conhecer o significado do afastamento familiar para o aluno. Foram estudados 30 alunos dos três anos do ensino médio, distribuídos em dois grupos. O grupo I se constituiu de 15 alunos que procuraram três ou mais vezes a clínica de saúde da instituição para atendimento de intercorrências, e o grupo II, de alunos do mesmo sexo, idade e sala que não haviam procurado a clínica. Os resultados revelaram que os participantes se situavam na faixa etária entre 14 e 18 anos, eram oriundos principalmente das regiões Sudeste (36,7%) e Centro-Oeste (23,3%) e distribuídos igualitariamente nos três anos do ensino médio. Nos dois grupos houve predominância de alunos provindos de famílias nucleares, constituídas de três a seis membros, nas quais os pais viviam juntos e os filhos, antes de virem para o internato, moravam com os pais. A decisão pelo internato, em dois casos (um em cada grupo) foi dos pais, em 10 foi dos adolescentes e em 18 casos foi conjunta (61,1% no grupo I e 38,9% no grupo II). 50% dos alunos avaliam sua relação com a família como muito boa e acham que a vinda para o internato a tornou melhor, o que vale inclusive para os alunos que haviam referido aspectos negativos. A experiência no regime de internato foi avaliada positivamente, apesar do afastamento familiar, da convivência com pessoas diferentes e da existência de normas e regras, por permitir desenvolvimento pessoal e amadurecimento como indivíduo. Conclui-se que a opção pelo internato envolveu principalmente a possibilidade da vivência de uma nova experiência, associada à oferta de melhores estudos, e que o internato é percebido pelos alunos como uma alternativa para o crescimento individual do aluno.

Este es um estúdio descriptivo – exploratório de naturaliza cualiauantativa, realizado com estudiantes internos de uma instituición de enseñanza, com el objetivo de identificar las características familiares y como se dio la opción por el internato además de conocer o significado de la separación familiar para el alumno. Fueran estudi dos 30 alumnos de los tres años de la enseñanza média, distribuídos en dos grupos. El grupo I se constituyó de 15 alumnos que buscaram la clínica de salud de la instituición, tres o más veces, para atendimientos de entercurrencias y el grupo II, de aumnos del mesmo sexo, edad y sala de aula, que habían buscado la clínica. Los resultados revelaron que los participantes se situaban en la edad media entre 14 y 18 años, eram oriundos principalmente de las regiones sudeste (36,7%) y centro-oeste (23,3%) distribuídos igualitariamente en los tres años de la enseñanza media. En los dos grupos hubo predominancia de alumnos provenientes de familias nucleares, constituídas entre tres a seis miembros, en las cuales los padres viven juntos y con los hijos, antes de ir al internato. La de decisión por ser internos, em dos casos (uno em cada grupo) fue de los padres, en 10 fue de los adolescentes y en 18 casos fue conjunta (61,1% em el grupo I y 38,9% en el grupo II). 50% de los alumnos avaliaron su relación familiar con la familia, como muy buena y les pareció que después de ir al internato pasó a ser mejor, lo que vale inclusive para los alumnos que habian referido aspectos negativos. La experiencia en el régimen de internato fue avaliada positivamente, a pesar de la separación familiar, de la convivencia con personas diferentes y de la experiência de normas y reglas, por permitir desenvolvimiento personal y el amadurecimento como indivíduos...

Dextromethorphan to dextrorphan urinary metabolic ratio does not reflect dextromethorphan oral clearance.

Dextromethorphan urinary metabolic ratio is widely used to determine the CYP2D6 phenotype, but its utility to reflect subtle differences in catalytic activity is unclear. We evaluated the capability of dextromethorphan urinary metabolic ratio to predict dextromethorphan oral clearance as a measure of CYP2D6 activity. Data from 10 healthy extensive metabolizers of CYP2D6 were given 30 mg of dextromethorphan hydrobromide orally on two occasions. Blood and urine samples were collected for 72 h. Dextromethorphan and dextrorphan were determined in urine by high-performance liquid chromatography with fluorescence detection and in serum by liquid chromatography-mass spectrometry. The urinary metabolic ratio was very weakly correlated with dextromethorphan oral clearance (r = 0.24; p = 0.04). In contrast, the dextromethorphan oral clearance was highly correlated with the dextromethorphan to dextrorphan area under the concentration-time curve ratio (r = 0.84; p = 0.005) and the 3-h (r = 0.60; p = 0.003), 4-h (r = 0.72, p < 0.001), 6-h (r = 0.67; p < 0.001), and 8-h (r = 0.74; p < 0.001) dextromethorphan to dextrorphan serum ratios. Assuming an effect size of 30%, the number of volunteers required for crossover and cross-sectional studies using the urinary metabolic ratio as the CYP2D6 index was calculated to be 56 and 524, respectively, whereas 14 and 60 subjects are needed if oral clearance is used. Considering the required sample size and the low correlation with oral clearance, urinary metabolic ratio is not recommended as the primary outcome variable in studies requiring the detection of modest changes in CYP2D6 activity.

Biodisponibilidad comparativa de tres formulaciones orales de un antiinflamatorio no esteroideo / Comparative bioavailability of three oral formulations of a non steroidal antiinflammatory

Los estudios de biodisponibilidad/bioequivalencia tienen como objetivo evaluar el desempeño biofarmacéutico de productos genéricos en relación al producto original. Estas diferencias entre productos pueden determinar tanto problemas de eficacia como de seguridad en el uso de los mismos. La autoridad sanitaria es la encargada de controlar la intercambiabilidad de genéricos. Si bien en países de la región existe un marco legal para la realización de estos estudios, Uruguay aún carece de este tipo de regulación. Este estudio se presenta con el objetivo de contribuir al desarrollo de esta área en nuestro país. Se comparó la biodisponibilidad oral de tres preparados farmacéuticos de nimesulida en 12 voluntarios sanos. Se concluye que los productos A y B tienen una biodisponibilidad similar, diferenciándose del producto C, que tiene una fracción biodisponible menor. Se describe la metodología utilizada, el procesamiento farmacocinético y estadístico de los datos, el análisis de los resultados y sus posibles repercusiones clínicas. Las consecuencias de estas diferencias en la biodisponibilidad varían con el fármaco considerado. Se presenta una lista de fármacos en la que este hecho tiene particular importancia

Programa ACHEI: Atençäo ao Chagásico com Educaçäo Integral no município de Maringá e regiäo noroeste do Paraná, Brasil / The ACHEI Program: Chagas' diseases awareness through comprehensive education in the municipality of Maringá, northwest Paraná, Brazil

Participaram deste trabalho 131 pacientes chagásicos procedentes de diferentes áreas endêmicas atendidos pelo Laboratório de Doença de Chagas da Universidade Esiadual de Maringá (UEM). Estes pacientes descobriram que estavam infectados principalmente porque apresentaram sintomatologia (58, 1 por cento) ou porque se dispuseram a doar sangue (29,4 por cento). Durante o tratamento etiológico contra o Trypanosoma cruzi, 45,2 por cento apresentaram queixas relacionadas a efeitos colaterais do benznidazol. Com base nestes dados foi criado o Programa ACHEI: Atençäo ao Chagásico com Educaçäo Integral. Implantado como um projeto de extensäo, tem caráter multiprofissional/interdisciplinar. Foi programado com uma reuniäo mensal composta de uma primeira parte informativa específica, quando é também distribuído um folder explicando transmissäo, sintomatologia e tratamento da doença de Chagas. Na segunda parte é trabalhado o apoio psico-social, enfocando auto-estima e cidadania. E um espaco onde pacientes chagásicos podem compartilhar com seus iguais a dúvida sobre a sua qualidade de vida após diagnóstico, o medo, a ansiedade, o estigma, o diagnóstico positivo e a convivência com a família/grupo social criando a oportunidade e ambiente para que cada paciente reflita sobre sua própria história e açöes frente ao processo da doença

Estudo da prevalência da hipertensäo arterial entre servidores de FUEM/Maringá/PR / Study on the prevalence of arterial hypertension in personnel of the FUEM/Maringa/PR

O presente trabalho tem por objetivo apresentar o estudo da previdência de hipertensäo arterial entre os servidores da FUEM/Maringá, Paraná. Trata-se de um estudo exploratório realizado em 1989, cujos dados foram obtidos através de pressäo arterial de todos os indivíduos que se encontravam no local de trabalho, no momento da coleta de dados. A amostra foi constituída de 734 indivíduos (33,4 por cento do total de servidores). A prevalência de hipertensäo arterial foi crescente com o aumento da faixa etária, em ambos os sexos. As médias diastólicas e sistólicas também crescentes com o aumento da faixa etária. Com relaçäo à categoria profisional, a prevalência de hipertensäo arterial foi maior entre os docentes (12,15) do que entre os técnicos administrativos (7,3 por cento )