Pharmacokinetics and safety of TBAJ-876, a novel antimycobacterial diarylquinoline, in healthy subjects.

TBAJ-876, a second-generation diarylquinoline with greater antimycobacterial activity and a potentially better safety profile compared with bedaquiline, is under development for the treatment of drug-susceptible and drug-resistant tuberculosis (TB). A phase 1, first-in-human study of TBAJ-876, comprising a single-ascending dose (SAD) part including a food effect cohort, a multiple-ascending dose (MAD) part, and a relative bioavailability part of tablets versus oral suspension, was conducted on 137 healthy adults. A drug-drug interaction study was conducted on 28 healthy adults to evaluate the effects of TBAJ-876 on a cytochrome P450 3A4 substrate (midazolam) and a P-glycoprotein substrate (digoxin). TBAJ-876 was well-tolerated at single doses up to 800 mg and multiple doses up to 200 mg for 14 days. No deaths or serious adverse events occurred. No episodes of clinically significant prolongation of the QTc interval were observed. TBAJ-876 exposures were dose proportional in the SAD and MAD studies. TBAJ-876 exhibited multicompartmental pharmacokinetics (PK) with a long terminal half-life yielding quantifiable concentrations up to the longest follow-up of 10 weeks after a single dose and resulting in accumulation with multiple dosing. In the fed state, TBAJ-876 exposures approximately doubled with the tablet formulation, whereas M3 metabolite exposures decreased by approximately 20%. The relative bioavailability of TBAJ-876 was similar between tablets and the oral suspension at 100-mg doses. With co-administration of TBAJ-876, the AUC0-inf of midazolam was unchanged and the Cmax was reduced by 14%; the AUC0-last of digoxin was increased by 51%, and the Cmax was increased by 18%. These results support further investigation of TBAJ-876 for the treatment of tuberculosis.

Glycated ACE2 receptor in diabetes: open door for SARS-COV-2 entry in cardiomyocyte.

RATIONALE: About 50% of hospitalized coronavirus disease 2019 (COVID-19) patients with diabetes mellitus (DM) developed myocardial damage. The mechanisms of direct SARS-CoV-2 cardiomyocyte infection include viral invasion via ACE2-Spike glycoprotein-binding. In DM patients, the impact of glycation of ACE2 on cardiomyocyte invasion by SARS-CoV-2 can be of high importance. OBJECTIVE: To evaluate the presence of SARS-CoV-2 in cardiomyocytes from heart autopsy of DM cases compared to Non-DM; to investigate the role of DM in SARS-COV-2 entry in cardiomyocytes. METHODS AND RESULTS: We evaluated consecutive autopsy cases, deceased for COVID-19, from Italy between Apr 30, 2020 and Jan 18, 2021. We evaluated SARS-CoV-2 in cardiomyocytes, expression of ACE2 (total and glycosylated form), and transmembrane protease serine protease-2 (TMPRSS2) protein. In order to study the role of diabetes on cardiomyocyte alterations, independently of COVID-19, we investigated ACE2, glycosylated ACE2, and TMPRSS2 proteins in cardiomyocytes from DM and Non-DM explanted-hearts. Finally, to investigate the effects of DM on ACE2 protein modification, an in vitro glycation study of recombinant human ACE2 (hACE2) was performed to evaluate the effects on binding to SARS-CoV-2 Spike protein. The authors included cardiac tissue from 97 autopsies. DM was diagnosed in 37 patients (38%). Fourth-seven out of 97 autopsies (48%) had SARS-CoV-2 RNA in cardiomyocytes. Thirty out of 37 DM autopsy cases (81%) and 17 out of 60 Non-DM autopsy cases (28%) had SARS-CoV-2 RNA in cardiomyocytes. Total ACE2, glycosylated ACE2, and TMPRSS2 protein expressions were higher in cardiomyocytes from autopsied and explanted hearts of DM than Non-DM. In vitro exposure of monomeric hACE2 to 120 mM glucose for 12 days led to non-enzymatic glycation of four lysine residues in the neck domain affecting the protein oligomerization. CONCLUSIONS: The upregulation of ACE2 expression (total and glycosylated forms) in DM cardiomyocytes, along with non-enzymatic glycation, could increase the susceptibility to COVID-19 infection in DM patients by favouring the cellular entry of SARS-CoV2.

Proteomics in Forensic Sciences: Identification of the Nature of the Last Meal at Autopsy.

A long-term psychiatric 40 years-old male patient was found dead at 9:00 a.m. in the clinic where he lived. Death was caused by traumatic injuries, which the sanitary staff imputed to a fall. Nurses declared that the patient refused having breakfast, whereas at autopsy the stomach contained 350 g of whitish semifluid material. Using both shotgun and gel-based proteomics, we demonstrated that the chyme contained partly digested milk- and bread-derived proteins, eaten during a recent breakfast. The conflict between evidence and assertions of the attending sanitary staff prompted the Legal Authority to undertake detailed investigations to ascertain facts and possible responsibilities. The herein characterization provides insights in the in vivo mechanisms of gastric breakdown of food proteins in a real meal. ß-lactoglobulin was partially resistant to gastric digestion as confirmed by Western blot analysis, in contrast to caseins and wheat gluten proteins, which had been degraded by gastric fluids. In addition to a complex pattern of gastric proteins (e.g., mucin-5AC, pepsin A-3, pepsinogen C, gastric lipase, gastrokine-2, trefoil factors), chyme contained intact proteins and variably sized food-derived polypeptides arising from peptic and nonpeptic proteolytic cleavage as well as heterodimeric disulfide-cross-linked peptides. These findings suggest that the current analytical workflows offer only a partial picture of the real complexity of the human "digestome".

Characterizing Absorption Properties of Dispersible Pretomanid Tablets Using Population Pharmacokinetic Modelling.

BACKGROUND AND INTRODUCTION: The dispersible tablet formulation (DTF) of pretomanid has been developed to facilitate future use in children. This work aimed to assess the pharmacokinetics (PK) and relative bioavailability of the DTF compared to the marketed formulation (MF) and the potential influence of dose. METHODS: Pretomanid DTF was investigated in a single-dose, randomized, four-period, cross-over study, with 7 days of washout between doses. Forty-eight healthy volunteers were enrolled and randomized into one of two panels to receive doses either in the fasted state or after a high-fat meal. Each volunteer received doses of 10, 50, and 200 mg DTF, and 200 mg MF pretomanid. Blood samples for pharmacokinetic assessment were drawn following a rich schedule up to 96 h after each single dose. The study data from the panel receiving the high-fat meal were analyzed using a nonlinear mixed-effects modeling approach, and all data were characterized with noncompartmental methods. RESULTS: A one-compartment model with first-order elimination and absorption through a transit compartment captured the mean and variability of the observed pretomanid concentrations with acceptable precision. No significant difference in bioavailability was found between formulations. The mean absorption time for the DTF was typically 137% (86-171%) of that for the MF. The bioavailability was found to be dose dependent with a small positive and larger negative correlation under fed and fasted conditions, respectively. CONCLUSION: Using data from a relative bioavailability study in healthy adult volunteers, a mathematical model has been developed to inform dose selection for the investigation of pretomanid in children using the new dispersible tablet formulation. Under fed conditions and at the currently marketed adult dose of 200 mg, the formulation type was found to influence the absorption rate, but not the bioavailability. The bioavailability of the DTF was slightly positively correlated with doses when administered with food. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04309656, first posted on 16 March 2020.

Odanacatib for the treatment of postmenopausal osteoporosis: results of the LOFT multicentre, randomised, double-blind, placebo-controlled trial and LOFT Extension study.

BACKGROUND: Odanacatib, a cathepsin K inhibitor, reduces bone resorption while maintaining bone formation. Previous work has shown that odanacatib increases bone mineral density in postmenopausal women with low bone mass. We aimed to investigate the efficacy and safety of odanacatib to reduce fracture risk in postmenopausal women with osteoporosis. METHODS: The Long-term Odanacatib Fracture Trial (LOFT) was a multicentre, randomised, double-blind, placebo-controlled, event-driven study at 388 outpatient clinics in 40 countries. Eligible participants were women aged at least 65 years who were postmenopausal for 5 years or more, with a femoral neck or total hip bone mineral density T-score between -2·5 and -4·0 if no previous radiographic vertebral fracture, or between -1·5 and -4·0 with a previous vertebral fracture. Women with a previous hip fracture, more than one vertebral fracture, or a T-score of less than -4·0 at the total hip or femoral neck were not eligible unless they were unable or unwilling to use approved osteoporosis treatment. Participants were randomly assigned (1:1) to either oral odanacatib (50 mg once per week) or matching placebo. Randomisation was done using an interactive voice recognition system after stratification for previous radiographic vertebral fracture, and treatment was masked to study participants, investigators and their staff, and sponsor personnel. If the study completed before 5 years of double-blind treatment, consenting participants could enrol in a double-blind extension study (LOFT Extension), continuing their original treatment assignment for up to 5 years from randomisation. Primary endpoints were incidence of vertebral fractures as assessed using radiographs collected at baseline, 6 and 12 months, yearly, and at final study visit in participants for whom evaluable radiograph images were available at baseline and at least one other timepoint, and hip and non-vertebral fractures adjudicated as being a result of osteoporosis as assessed by clinical history and radiograph. Safety was assessed in participants who received at least one dose of study drug. The adjudicated cardiovascular safety endpoints were a composite of cardiovascular death, myocardial infarction, or stroke, and new-onset atrial fibrillation or flutter. Individual cardiovascular endpoints and death were also assessed. LOFT and LOFT Extension are registered with ClinicalTrials.gov (number NCT00529373) and the European Clinical Trials Database (EudraCT number 2007-002693-66). FINDINGS: Between Sept 14, 2007, and Nov 17, 2009, we randomly assigned 16 071 evaluable patients to treatment: 8043 to odanacatib and 8028 to placebo. After a median follow-up of 36·5 months (IQR 34·43-40·15) 4297 women assigned to odanacatib and 3960 assigned to placebo enrolled in LOFT Extension (total median follow-up 47·6 months, IQR 35·45-60·06). In LOFT, cumulative incidence of primary outcomes for odanacatib versus placebo were: radiographic vertebral fractures 3·7% (251/6770) versus 7·8% (542/6910), hazard ratio (HR) 0·46, 95% CI 0·40-0·53; hip fractures 0·8% (65/8043) versus 1·6% (125/8028), 0·53, 0·39-0·71; non-vertebral fractures 5·1% (412/8043) versus 6·7% (541/8028), 0·77, 0·68-0·87; all p<0·0001. Combined results from LOFT plus LOFT Extension for cumulative incidence of primary outcomes for odanacatib versus placebo were: radiographic vertebral fractures 4·9% (341/6909) versus 9·6% (675/7011), HR 0·48, 95% CI 0·42-0·55; hip fractures 1·1% (86/8043) versus 2·0% (162/8028), 0·52, 0·40-0·67; non-vertebral fractures 6·4% (512/8043) versus 8·4% (675/8028), 0·74, 0·66-0·83; all p<0·0001. In LOFT, the composite cardiovascular endpoint of cardiovascular death, myocardial infarction, or stroke occurred in 273 (3·4%) of 8043 patients in the odanacatib group versus 245 (3·1%) of 8028 in the placebo group (HR 1·12, 95% CI 0·95-1·34; p=0·18). New-onset atrial fibrillation or flutter occurred in 112 (1·4%) of 8043 patients in the odanacatib group versus 96 (1·2%) of 8028 in the placebo group (HR 1·18, 0·90-1·55; p=0·24). Odanacatib was associated with an increased risk of stroke (1·7% [136/8043] vs 1·3% [104/8028], HR 1·32, 1·02-1·70; p=0·034), but not myocardial infarction (0·7% [60/8043] vs 0·9% [74/8028], HR 0·82, 0·58-1·15; p=0·26). The HR for all-cause mortality was 1·13 (5·0% [401/8043] vs 4·4% [356/8028], 0·98-1·30; p=0·10). When data from LOFT Extension were included, the composite of cardiovascular death, myocardial infarction, or stroke occurred in significantly more patients in the odanacatib group than in the placebo group (401 [5·0%] of 8043 vs 343 [4·3%] of 8028, HR 1·17, 1·02-1·36; p=0·029, as did stroke (2·3% [187/8043] vs 1·7% [137/8028], HR 1·37, 1·10-1·71; p=0·0051). INTERPRETATION: Odanacatib reduced the risk of fracture, but was associated with an increased risk of cardiovascular events, specifically stroke, in postmenopausal women with osteoporosis. Based on the overall balance between benefit and risk, the study's sponsor decided that they would no longer pursue development of odanacatib for treatment of osteoporosis. FUNDING: Merck Sharp & Dohme Corp, a subsidiary of Merck & Co, Inc, Kenilworth, NJ, USA.

Efficacy of bisphosphonates for the control of alveolar bone loss in periodontitis.

Periodontal disease is characterized by periodontal bone loss. For this reason, we conducted a study to test the effect of alendronate (ALN), an inhibitor of bone resorption, on alveolar bone mass. A total of 335 patients with periodontal disease (men = 162, women = 173), aged 30 to 79, were randomized to either placebo or ALN 70 mg once weekly. All patients received prophylaxis at baseline, and at 6, 12, and 18 months. Smokers accounted for 62% of patients, and 71% of the patients had severe periodontal disease. The primary efficacy endpoint was the change in alveolar bone loss (ABL). When all subjects were analyzed, 2 years of treatment with alendronate 70 mg once weekly did not significantly change either ABL or alveolar bone density (ABD) relative to placebo. However, in the subgroup of patients with low mandibular bone mineral density (BMD) at baseline, alendronate significantly reduced bone loss relative to placebo (p < 0.01). No such effect was seen in patients with normal baseline mandibular BMD. The overall and upper gastrointestinal safety and tolerability profile of alendronate after 2 years of treatment was very favorable compared to placebo. No cases of osteonecrosis of the jaw were observed. In summary, in patients with periodontal disease receiving prophylaxis, alendronate 70 mg once weekly was well tolerated, but did not have a detectable effect on alveolar bone loss, except in those patients with low mandibular BMD at baseline.

Skeletal consequences of hormone therapy discontinuance: a systematic review.

UNLABELLED: Although hormone therapy protects against bone loss after menopause, currently it is not recommended once menopausal symptoms have subsided. We reviewed randomized clinical trials to quantify bone loss after stopping hormone therapy and summarize treatment options for women who discontinue hormone treatment. We conducted a search of MEDLINE and EMBASE for randomized, controlled trials measuring bone mineral density (BMD) after hormone therapy discontinuation. Other known published and unpublished data were also included. Eleven studies fulfilled the search criteria. In each, bone loss was rapid after stopping hormone therapy, with BMD declines ranging from 2.3% to 6.2% in the first year. Increases in bone turnover markers also occurred rapidly when hormone therapy was stopped. Limited data addressing treatment after hormone therapy is stopped exist; only 2 studies specifically evaluated therapy to protect bone after hormone discontinuation. Taken together, these 2 studies demonstrate that alendronate produced significant increases relative to placebo in spine, hip, and total body BMD in women with low bone density who had discontinued hormone therapy within the past 3 months, preventing the rapid bone loss seen on discontinuation of hormone therapy. Among treatment options for preventing bone loss on discontinuation of hormone therapy for which randomized clinical trial data are available, alendronate prevented bone loss or increased bone density in postmenopausal women with low bone density. Women who are discontinuing hormone therapy should be counseled about potential bone loss and effective treatment options. TARGET AUDIENCE: Obstetricians & Gynecologists, Family Physicians. LEARNING OBJECTIVES: After completion of this article, the reader should be able to state that discontinuation of replacement menopausal hormone therapy, which protects against bone loss, is not recommended after menopause symptoms have subsided; recall that it may accelerate bone loss; and explain that there is bone loss preventive treatment for women after discontinuation of hormone therapy.

Effects of continuing or stopping alendronate after 5 years of treatment: the Fracture Intervention Trial Long-term Extension (FLEX): a randomized trial.

CONTEXT: The optimal duration of treatment of women with postmenopausal osteoporosis is uncertain. OBJECTIVE: To compare the effects of discontinuing alendronate treatment after 5 years vs continuing for 10 years. DESIGN AND SETTING: Randomized, double-blind trial conducted at 10 US clinical centers that participated in the Fracture Intervention Trial (FIT). PARTICIPANTS: One thousand ninety-nine postmenopausal women who had been randomized to alendronate in FIT, with a mean of 5 years of prior alendronate treatment. INTERVENTION: Randomization to alendronate, 5 mg/d (n = 329) or 10 mg/d (n = 333), or placebo (n = 437) for 5 years (1998-2003). MAIN OUTCOME MEASURES: The primary outcome measure was total hip bone mineral density (BMD); secondary measures were BMD at other sites and biochemical markers of bone remodeling. An exploratory outcome measure was fracture incidence. RESULTS: Compared with continuing alendronate, switching to placebo for 5 years resulted in declines in BMD at the total hip (-2.4%; 95% confidence interval [CI], -2.9% to -1.8%; P<.001) and spine (-3.7%; 95% CI, -4.5% to -3.0%; P<.001), but mean levels remained at or above pretreatment levels 10 years earlier. Similarly, those discontinuing alendronate had increased serum markers of bone turnover compared with continuing alendronate: 55.6% (P<.001) for C-telopeptide of type 1 collagen, 59.5% (P < .001) for serum n = propeptide of type 1 collagen, and 28.1% (P<.001) for bone-specific alkaline phosphatase, but after 5 years without therapy, bone marker levels remained somewhat below pretreatment levels 10 years earlier. After 5 years, the cumulative risk of nonvertebral fractures (RR, 1.00; 95% CI, 0.76-1.32) was not significantly different between those continuing (19%) and discontinuing (18.9%) alendronate. Among those who continued, there was a significantly lower risk of clinically recognized vertebral fractures (5.3% for placebo and 2.4% for alendronate; RR, 0.45; 95% CI, 0.24-0.85) but no significant reduction in morphometric vertebral fractures (11.3% for placebo and 9.8% for alendronate; RR, 0.86; 95% CI, 0.60-1.22). A small sample of 18 transilial bone biopsies did not show any qualitative abnormalities, with bone turnover (double labeling) seen in all specimens. CONCLUSIONS: Women who discontinued alendronate after 5 years showed a moderate decline in BMD and a gradual rise in biochemical markers but no higher fracture risk other than for clinical vertebral fractures compared with those who continued alendronate. These results suggest that for many women, discontinuation of alendronate for up to 5 years does not appear to significantly increase fracture risk. However, women at very high risk of clinical vertebral fractures may benefit by continuing beyond 5 years. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT 00398931.

Significant differential effects of alendronate, estrogen, or combination therapy on the rate of bone loss after discontinuation of treatment of postmenopausal osteoporosis. A randomized, double-blind, placebo-controlled trial.

BACKGROUND: Combination therapy with alendronate and estrogen for 2 years increases bone mineral density at the spine and hip more than does therapy with either agent alone. Changes in bone mineral density after discontinuation of therapy have not been compared directly. OBJECTIVE: To determine the rate of bone loss when therapy with alendronate, estrogen, or both agents is discontinued. DESIGN: Double-blind, placebo-controlled discontinuation trial. SETTING: 18 U.S. centers. PATIENTS: 244 postmenopausal, hysterectomized women 44 to 77 years of age. INTERVENTION: 2 years of therapy with alendronate, 10 mg/d (n = 92); conjugated estrogen, 0.625 mg/d (n = 143); alendronate and conjugated estrogen (n = 140); or placebo (n = 50). At year 3, women were allocated into five groups: Twenty-eight women continued to take placebo and 44 women continued to take combination therapy, but 50 women taking alendronate, 81 taking conjugated estrogen, and 41 taking combination therapy were switched to placebo. MEASUREMENTS: Bone mineral density and biochemical markers of bone turnover. RESULTS: Women taking alendronate or combination therapy who were switched to placebo for year 3 of the study maintained bone mass. Bone mineral density in these women was 4.1% (CI, 2.6% to 5.7%) and 6.6% (CI, 5.0% to 8.2%) higher, respectively, at the spine (P < 0.001 for both treatment comparisons) and 3.5% (CI, 2.3% to 4.6%) and 3.0% (CI, 1.8% to 4.2%) higher, respectively, at the trochanter (P < 0.001 for both treatment comparisons) than that in women previously taking estrogen who were switched to placebo. In contrast, women who were taking estrogen and were switched to placebo during year 3 experienced a 4.5% decrease at the spine (95% CI, -5.0% to -4.0%) and a 2.4% decrease at the trochanter (CI, -2.7% to -2.1%) (P < 0.001 for both changes). Compared with women who took placebo for 3 years, women who took estrogen for 2 years and were then switched to placebo had a bone mineral density that was 2.9% higher (CI, 1.2% to 4.6%) at the spine (P < 0.05) and 2.9% higher (CI, 1.6% to 4.2%) at the trochanter (P < 0.001). Changes in biochemical markers during year 3 did not differ among the groups that discontinued active treatment. CONCLUSIONS: Accelerated bone loss is seen after withdrawal of estrogen therapy but not after withdrawal of alendronate or combination therapy. The differential effects after withdrawal of therapy should be considered in the management of postmenopausal osteoporosis.

A associação entre os transtornos de linguagem receptivo e expressivo e os transtornos de aprendizagem / The association between receptive and expressive language disorders and learning disorders

O aprendizado e a linguagem são processos neuronais complexos, os quais possuem íntima ligação entre si. Diante disso, o transtorno de linguagem (TL) também está fortemente correlacionado aos transtornos de aprendizagem (TA), uma associação inicialmente observada no projeto de extensão "Construindo Histórias...", da PUC Minas, e confirmada pela literatura. Foi realizada uma busca de publicações dos últimos 15 anos, nas bases PubMed, LILACS, Up to Date e MedLine, utilizando os descritores Language Development Disorders, Child Languages, Language Development, Learning e Learning Disorders e suas traduções em português. Foram selecionadas 18 publicações e também o foi utilizado o livro Transtornos da aprendizagem. Os TL por definição são mudanças nos padrões normais do aprendizado da linguagem e podem ser classificados em expressivo e receptivo. Como resultado desse quadro, a criança apresenta dificuldades em compreender e de se expressar, o que está diretamente relacionado ao processo de aprendizagem e pode resultar em um TA. O diagnóstico desses transtornos deve ser realizado de maneira individualizada e observando a interação de fatores genéticos, fisiológicos, socioculturais e escolares. Conclui-se que os transtornos de linguagem e de aprendizado não afetam apenas a vida acadêmica, mas também a vida social, comportamental e psicológica e, por isso, é de extrema importância que ocorra um foco maior na detecção precoce desses transtornos, para que, assim, a criança receba um tratamento adequado e, consequentemente, tenha um prognóstico melhor. (AU)

Learning and language are complex neuronal processes, which have an intimate connection with each other. Therefore, language development disorder (LDD) or language impairment is also strongly correlated with learning disorders (LD), an association initially observed in the extension project "Constructing stories" at PUC Minas and confirmed by the literature. A search for publications from the last 15 years was carried out in the following outlets: PubMed, LILACS, Up to Date and MedLine using the descriptors Language Development Disorders, child languages, Language Development, Learning and Learning Disorders and their Portuguese version. Eighteen publications were selected and the book Transtornos da aprendizagem, 2016 was also used. LDD by definition are changes in normal language learning patterns and can be classified as expressive and receptive. Because of this situation, children have difficulties in understanding and expressing themselves, this is directly related to the learning process, which can result in an LD. The diagnosis of these disorders must be done individually and observing the interaction of genetic, physiological, sociocultural and school factors. It is worth noting that language and learning disorders not only affect academic life, but also social, behavioral and psychological life, and therefore it is extremely important that there is a greater focus on the early detection of these disorders, thus, children receive an appropriate treatment and, consequently, have a better prognosis. (AU)

Randomized trial of effect of alendronate continuation versus discontinuation in women with low BMD: results from the Fracture Intervention Trial long-term extension.

UNLABELLED: To determine the effects of continuation versus discontinuation of alendronate on BMD and markers of bone turnover, we conducted an extension trial in which 1099 older women who received alendronate in the FIT were re-randomized to alendronate or placebo. Compared with women who stopped alendronate, those continuing alendronate for 3 years maintained a higher BMD and greater reduction of bone turnover, showing benefit of continued treatment. However, among women who discontinued alendronate and took placebo in the extension, BMD remained higher, and reduction in bone turnover was greater than values at FIT baseline, showing persistence of alendronate's effects on bone. INTRODUCTION: Prior trials including the Fracture Intervention Trial (FIT) have found that therapy with alendronate increases BMD and decreases fracture risk for up to 4 years in postmenopausal women with low BMD. However, it is uncertain whether further therapy with alendronate results in preservation or further gains in BMD and if skeletal effects of alendronate continue after treatment is stopped. MATERIALS AND METHODS: We conducted a follow-up placebo-controlled extension trial to FIT (FIT long-term extension [FLEX]) in which 1099 women 60-86 years of age who were assigned to alendronate in FIT with an average duration of use of 5 years were re-randomized for an additional 5 years to alendronate or placebo. The results of a preplanned interim analysis at 3 years are reported herein. Participants were re-randomized to alendronate 10 mg/day (30%), alendronate 5 mg/day (30%), or placebo (40%). All participants were encouraged to take a calcium (500 mg/day) and vitamin D (250 IU/day) supplement. The primary outcome was change in total hip BMD. Secondary endpoints included change in lumbar spine BMD and change in markers of bone turnover (bone-specific alkaline phosphatase and urinary type I collagen cross-linked N-telopeptide). RESULTS: Among the women who had prior alendronate therapy in FIT, further therapy with alendronate (5 and 10 mg groups combined) for 3 years compared with placebo maintained BMD at the hip (2.0% difference; 95% CI, 1.6-2.5%) and further increased BMD at the spine (2.5% difference; 95% CI, 1.9-3. 1%). Markers of bone turnover increased among women discontinuing alendronate, whereas they remained stable in women continuing alendronate. Cumulative increases in BMD at the hip and spine and reductions in bone turnover from 8.6 years earlier at FIT baseline were greater for women continuing alendronate compared with those discontinuing alendronate. However, among women discontinuing alendronate and taking placebo in the extension, BMD remained higher and reduction in bone turnover was greater than values at FIT baseline. CONCLUSIONS: Compared with women who stopped alendronate after an average of 5 years, those continuing alendronate maintained a higher BMD and greater reduction of bone turnover, showing benefit of continued alendronate treatment on BMD and bone turnover. On discontinuation of alendronate therapy, rates of change in BMD at the hip and spine resumed at the background rate, but discontinuation did not result in either accelerated bone loss or a marked increase in bone turnover, showing persistence of alendronate's effects on bone. Data on the effect of continuation versus discontinuation on fracture risk are needed before making definitive recommendations regarding the optimal length of alendronate treatment.

Odanacatib in the treatment of postmenopausal women with low bone mineral density: five years of continued therapy in a phase 2 study.

Odanacatib (ODN) is a selective inhibitor of the collagenase cathepsin K that is highly expressed by osteoclasts. In this 2-year, phase 2, dose-ranging trial, postmenopausal women with bone mineral density (BMD) T-scores -2.0 to -3.5 at spine or hip were randomized to weekly placebo or ODN 3, 10, 25, or 50 mg plus vitamin D(3) and calcium. Prespecified trial-extensions continued through 5 years. In year 3, all women were re-randomized to ODN 50 mg or placebo. For years 4 and 5, women who received placebo or ODN 3 mg in years 1 and 2 and placebo in year 3 received ODN 50 mg; others continued year 3 treatments. Endpoints included lumbar spine (primary), hip, 1/3 radius, and total body BMD; markers of bone metabolism; and safety. Women in the year 4 to 5 extension receiving placebo (n = 41) or ODN 50 mg (n = 100) had similar baseline characteristics. For women who received ODN (10-50 mg) for 5 years, spine and hip BMD increased over time. With ODN 50 mg continually for 5 years (n = 13), mean lumbar spine BMD percent change from baseline (95% confidence interval [CI]) was 11.9% (7.2% to 16.5%) versus -0.4% (-3.1% to 2.3%) for women who were switched from ODN 50 mg to placebo after 2 years (n = 14). In pooled results of women receiving continuous ODN (10-50 mg, n = 26-29), year 5 geometric mean percent changes from baseline in bone resorption markers cross-linked N-telopeptide of type I collagen (NTX)/creatinine and cross-linked C-telopeptide (CTX) were approximately -55%, but near baseline for bone formation markers bone-specific alkaline phosphatase (BSAP) and amino-terminal propeptide of type I procollagen (P1NP). In women switched from ODN 10 to 50 mg to placebo after 2 years (n = 25), bone turnover markers were near baseline. In summary, women receiving combinations of ODN (10-50 mg) for 5 years had gains in spine and hip BMD and showed larger reductions in bone resorption than bone formation markers. Discontinuation of ODN resulted in reversal of treatment effects. Treatment with ODN for up to 5 years was generally well-tolerated.

A Síndrome da Exclusão Social: compreensão das origens da violência/ contraviolência no Brasil / The social exclusion syndrome: comprehension of the violence/counter-violence origins in Brazil

A indiferença humana no Brasil desde o início da colonização tem produzido e perpetuado o fenômeno da exclusão social. Um exemplo é a escravidão que durou cerca de 350 anos. Esse fenômeno excludente materializa-se ao produzir uma diversidade de fatores de risco biopsicossociais impactantes desde a gestação e em todos os períodos do ciclo de vida, acumulando e deixando sequelas profundas. Na década de 80 ocorreu interação sinérgica perversa entre o fenômeno da exclusão social e a entrada das drogas no nosso meio. A criança maior, o adolescente e o adulto jovem, muitas vezes socialmente vulneráveis, encontraram nas drogas duas possibilidades: a primeira, usar e abusar de drogas por várias razões, entre elas, baixa autoestima, para aliviar ansiedade e depressão, raiva; devido a uma personalidade extrovertida, impulsividade e inclinação ao comportamento de risco. E a segunda possibilidade, "empoderadora", entrar para o tráfico como meio de subir na vida e também por razões subjetivas. Esses caminhos quase sempre resultam em dependência química, "overdose", hospitalizações, práticas de atos infracionais, prisões, mortes e homicídios. O estudo indica que primariamente ocorreu violência histórica contra esse contingente populacional e que, muitas vezes, essa violência desencadeia um fenômeno também complexo, a contraviolência. A abordagem da violência/contraviolência deve focar, simultaneamente, sua origem (cultura da indiferença) e as consequências (fatores de risco e impactos biopsicossociais).(AU)

The human indifference in Brazil since the beginning of colonization has produced and perpetuated the phenomenon of social exclusion. The example is the slavery, which lasted about 350 years. This exclusive phenomenon has materialized itself as it has produced a diversity of biopsychosocial risk factors, which has impacted the individuals in all their life cycle periods from the gestation, accumulating and leaving their effects. In the 80's there was a perverse synergic interaction between the phenomenon of social exclusion and the entrance of drugs in our environment. The older child, the teenager and the young adult, socially vulnerables, find in drugs two possibilities: first, use and abuse of drugs for many reasons such as low self-esteem, to alleviate depression, anxiety and anger; due to an outgoing personality, impulsivity and more inclined to take risks; second possibility, "empowering", entering the drug trade as a way of getting ahead in life and also for subjective reasons. These pathways often always result in addiction, "overdose", hospitalization, infraction acts practice and also, arrests, deaths and homicides. The study of these cases in our history context shows that we face a primary historical violence against a huge population group that often this violence triggers a complex phenomenon, the counter-violence. The approach of violence/counter-violence should focus, simultaneously, on both the origin (culture of indifference) and the consequences (risk factors and biopsychosocial impacts).(AU)

Odanacatib in the treatment of postmenopausal women with low bone mineral density: three-year continued therapy and resolution of effect.

The selective cathepsin K inhibitor odanacatib (ODN) progressively increased bone mineral density (BMD) and decreased bone-resorption markers during 2 years of treatment in postmenopausal women with low BMD. A 1-year extension study further assessed ODN efficacy and safety and the effects of discontinuing therapy. In the base study, postmenopausal women with BMD T-scores between -2.0 and -3.5 at the lumbar spine or femur received placebo or ODN 3, 10, 25, or 50 mg weekly. After 2 years, patients (n = 189) were rerandomized to ODN 50 mg weekly or placebo for an additional year. Endpoints included BMD at the lumbar spine (primary), total hip, and hip subregions; levels of bone turnover markers; and safety assessments. Continued treatment with 50 mg of ODN for 3 years produced significant increases from baseline and from year 2 in BMD at the spine (7.9% and 2.3%) and total hip (5.8% and 2.4%). Urine cross-linked N-telopeptide of type I collagen (NTx) remained suppressed at year 3 (-50.5%), but bone-specific alkaline phosphatase (BSAP) was relatively unchanged from baseline. Treatment discontinuation resulted in bone loss at all sites, but BMD remained at or above baseline. After ODN discontinuation at month 24, bone turnover markers increased transiently above baseline, but this increase largely resolved by month 36. There were similar overall adverse-event rates in both treatment groups. It is concluded that 3 years of ODN treatment resulted in progressive increases in BMD and was generally well tolerated. Bone-resorption markers remained suppressed, whereas bone-formation markers returned to near baseline. ODN effects were reversible: bone resorption increased transiently and BMD decreased following treatment discontinuation.

The cathepsin K inhibitor odanacatib suppresses bone resorption in women with breast cancer and established bone metastases: results of a 4-week, double-blind, randomized, controlled trial.

BACKGROUND: Metastatic bone disease (MBD) is a frequent complication in patients with breast cancer and is associated with significant morbidity. This study assessed the pharmacokinetics, efficacy, and safety of odanacatib, a selective Cat K inhibitor, in reducing markers of bone resorption in women with breast cancer and MBD. PATIENTS AND METHODS: Women with breast cancer and MBD were randomized 2:1 (double-blind) to oral odanacatib 5 mg daily for 4 weeks or intravenous (I.V.) zoledronic acid (ZA) 4 mg given once at study initiation. Plasma samples were collected for pharmacokinetic analysis. Bone resorption was assessed by measuring urinary N-telopeptide of type I collagen corrected for creatinine (uNTx; primary objective, pmol BCE/µmol creatinine). Adverse events (AEs) were monitored throughout the 4-week study and up to 14 days after last dose. RESULTS: A total of 43 patients (mean age, 60 years) received odanacatib (n = 29) or ZA (n = 14); 40 patients completed 4 weeks of treatment. The mean percent change in uNTx values at week 4 was -77% (95% CI, -82 to -71; odanacatib) and -73% (95% CI, -80 to -62; ZA). Mean (standard deviation) plasma concentration of odanacatib was 511.7 (202.9) nM; the range was 63.7-844.8 nM. The most common AEs were nausea, vomiting, headache, and bone pain, which were generally not attributed to study drug. CONCLUSION: Odanacatib suppressed uNTx similarly to ZA after 4 weeks of treatment in women with breast cancer and MBD. Odanacatib was generally safe and well tolerated. These results suggest that Cat K inhibition is a potentially important, novel therapeutic approach for treating MBD.

Evaluation of the safety, pharmacokinetics and treatment effects of an alpha(nu)beta(3) integrin inhibitor on bone turnover and disease activity in men with hormone-refractory prostate cancer and bone metastases.

AIM: This study aimed to evaluate the safety, pharmacokinetics and treatment effects of an alpha(nu)beta(3) integrin inhibitor on bone turnover and disease activity in men with hormone-refractory prostate cancer (HRPC) and bone metastases. METHODS: A total of 21 patients with bone metastases and HRPC were randomized to receive MK-0429 200 mg b.i.d. or 1600 mg b.i.d. for 4 weeks. Toxicity, pharmacokinetics and markers of bone turnover and tumor activity were examined. RESULTS: Nausea was the most common adverse event: one (200-mg group) and 11 (1600-mg group) patients. At 4 weeks, mean AUC(0-12 h) was 210 mmol*h (200-mg group) and 673 mmol*h (1600-mg group); mean C(max) values were 42 mmol/L (200-mg group) and 154 mmol/L (1600-mg group). Urinary cross-linked N-telopeptides of type I collagen to creatinine ratio (uNTx), a bone turnover biomarker, showed a change from baseline of -43.4 percent (200-mg group) and -34.1 percent (1600-mg group). There was an increase in serum prostate specific antigen (PSA), a marker for disease activity, of 54.1 percent (200-mg group) and 44.5 percent (1600-mg group). CONCLUSION: MK-0429 was generally well tolerated, with the most common side-effect being nausea. There was some evidence of an early reduction of bone turnover, indicating a potential for clinical use in the treatment of MBD although serum PSA was unexpectedly increased during the study.

Efficacy of continued alendronate for fractures in women with and without prevalent vertebral fracture: the FLEX trial.

In the Fracture Intervention Trial (FIT) Long Term Extension (FLEX) Trial, 10 years of alendronate (ALN) did not significantly reduce the risk of nonvertebral fractures (NVFs) compared with 5 years of ALN. Continuing ALN reduced the risk of clinical but not morphometric vertebral fractures regardless of baseline vertebral fracture status. In previous studies, ALN efficacy for NVF prevention in women without prevalent vertebral fracture was limited to those with femoral neck (FN) T-scores of -2.5 or less. To determine whether the effect of long-term ALN on fracture differs by vertebral fracture status and femoral neck (FN) T-score, we performed a post hoc analysis using FLEX data, a randomized, double-blind, placebo-controlled trial among 1099 postmenopausal women originally randomized to ALN in the FIT with mean ALN use of 5 years. In the FLEX Trial, women were randomized to placebo (40%) or ALN 5 mg/day (30%) or ALN 10 mg/day (30%) for an additional 5 years. Among women without vertebral fracture at FLEX baseline (n = 720), continuation of ALN reduced NVF in women with FLEX baseline FN T-scores of -2.5 or less [relative risk (RR) = 0.50, 95% confidence interval (CI) 0.26-0.96] but not with T-scores of greater than -2.5 and -2 or less (RR 0.79, 95% CI 0.37-1.66) or with T-scores of greater than -2 (RR 1.41, 95% CI 0.75-2.66; p for interaction = .019). Continuing ALN for 10 years instead of stopping after 5 years reduces NVF risk in women without prevalent vertebral fracture whose FN T-scores, achieved after 5 years of ALN, are -2.5 or less but does not reduce risk of NVF in women whose T-scores are greater than -2.

A síndrome da exclusão social / The syndrome of social exclusion

Quero apresentar-lhe o livro ?A Síndrome da Exclusão Social? fruto do meutrabalho no período de 1978 a 2010 no Departamento de Pediatria da Faculdade de Medicina da Universidade Federal de Minas Gerais (FM-UFMG). O trabalho que originou o livro começou na segunda metade da década de 80. Naquela ocasião criei um ambulatório de Psiquiatria infantil, que funcionou certo período de tempo no ambulatório São Vicente de Paula do complexo do Hospital das Clínicas da FM-UFMG. Percebi, após alguns meses de funcionamento daquele ambulatório, que a maioria das crianças encaminhadas (de aglomerados, vilas, bairros distantes e mesmo do interior de minas) apresentava como queixas principais problemas relacionados à escola. Concluí que problemas escolares não deveriamser abordados em um ambulatório localizado no centro de Belo Horizonte,mas sim próximo do domicílio das pessoas onde melhor integração entre saúde e educação poderia ser mais promissora.

Changes in bone mineral density following discontinuation or continuation of alendronate therapy in glucocorticoid-treated patients: a retrospective, observational study.

OBJECTIVE: To evaluate the effects of discontinuing or continuing alendronate (ALN) therapy on bone mineral density (BMD) after patients on a long-term regimen of glucocorticoids (GCs) completed a 1-year treatment period with ALN. METHODS: Eligible patients were individuals with GC-induced osteoporosis who had received ALN (5 or 10 mg) for 1 year in a prior clinical trial and, at the end of the year, were still taking GCs at an average daily dose of > or =7.5 mg of prednisone or equivalent. Patients were contacted 3-5 years after completion of the prior ALN trial for followup measurements of the lumbar spine BMD and hip BMD, and retrospective information was collected about serious or drug-related adverse experiences and concomitant medication use. Some patients remained on GCs, and some remained on ALN, either alone or in combination with other drugs. The primary response parameter was the percentage change in lumbar spine BMD from the end of year 1 to the followup visit. Change in BMD at the hip was a secondary response parameter. RESULTS: Ninety (49.2%) of the eligible 183 patients participated in the retrospective study. The followup period, which began at the end of year 1 of the original clinical trial, ranged from 3.3 years to 4.6 years. The mean number of days of treatment with ALN was 507. Fifty patients were included in the analysis because they had received supraphysiologic doses of GCs (doses above the lowest tertile of GC use for the study population; that is, higher than approximately 6 mg/day), and they had not taken (defined as <6 months of use) other bone-affecting agents except ALN. Eleven of the 50 patients discontinued taking ALN (duration of use <90 days), 8 took ALN between 90 days and 300 days, and 31 continued to take ALN for >300 days after year 1 of the clinical trial. GC users who discontinued treatment with ALN (<90 days of therapy) had numerically greater decreases in BMD at the lumbar spine, femoral neck, and total hip from the end of year 1 (mean change -5.1%, -9.2%, and -6.6%, respectively), compared with patients who continued to take ALN for >300 days (mean change 0.1%, -0.9%, and 1.8%, respectively). CONCLUSION: Substantial loss of BMD in the lumbar spine and hip was seen in patients who discontinued treatment with ALN but who continued to take >6 mg/day of GCs. However, patients receiving GCs who remained on the ALN regimen appeared to benefit from continued ALN treatment, since BMD was maintained in this latter group.

Quiste óseo traumático: presentación inusual en cóndilo mandibular / Traumatic bone cyst: a rare case in the mandibular condyle

Objetivo. Presentar un caso de un quiste óseo traumático localizado en el cóndilo mandibular. Caso clínico. Informamos de un caso de un quiste óseo traumático en el cóndilo mandibular de un paciente masculino de 24 años de edad que presentaba una lesión radiolúcida en la región que causaba expansión y perforación de ambas corticales óseas. Se realizó la exéresis de la lesión mediante un abordaje preauricular y otro submandiular. Conclusiones. Para su confirmación diagnóstica este peusodquiste, raramente encontrado en el cóndilo, requiere de la combinación de los datos de la anamnesis, de los hallazgos clínico-radiográficos y del estudio histopatológico de la pieza obtenida por la exploración quirúrgica.