Efficacy and safety of the novel glycine transporter inhibitor BI 425809 once daily in patients with schizophrenia: a double-blind, randomised, placebo-controlled phase 2 study.

BACKGROUND: Cognitive impairment associated with schizophrenia predicts poor functional outcomes, but currently no approved pharmacotherapy is available. This study investigated whether the glycine transporter-1 inhibitor BI 425809 improves cognition in patients with schizophrenia. METHODS: This phase 2, randomised, double-blind, placebo-controlled, parallel-group trial (81 centres, 11 countries), randomly assigned outpatients (aged 18-50 years) with schizophrenia on stable treatment to add-on once-daily oral BI 425809 2 mg, 5 mg, 10 mg, or 25 mg or placebo (1:1:1:1:2) for 12 weeks. Treatment was assigned in blocks using interactive response technology; patients, investigators, and all trial personnel were masked to group assignment. The primary endpoint was change from baseline in MATRICS Consensus Cognitive Battery (MCCB) overall composite T-score at week 12. Six predefined dose-response models were evaluated using a multiple comparison procedure and modelling approach with mixed model repeated measures to assess evidence for a non-flat dose-response relationship for cognitive improvements with BI 425809. Adverse events were monitored. Safety analyses included all randomly allocated patients who received one or more doses of trial medication; efficacy analyses included patients from this set who also had available baseline data and at least one post-baseline on-treatment measurement for the primary or secondary endpoint. This study is registered with ClinicalTrials.gov, number NCT02832037. FINDINGS: 509 patients were randomly assigned between April 25, 2018, and Oct 4, 2019 (BI 425809 2 mg, n=85; 5 mg, n=84; 10 mg, n=85; 25 mg, n=85; placebo, n=170 444 (87%) completed the 12-week treatment. Five of six dose-response models showed a statistically significant benefit of BI 425809 over placebo (linear [t=2·55, p=0·015], linear in log [t=2·56, p=0·015]; Emax [t=2·75, p=0·0089], sigmoid Emax [t=2·98, p=0·0038], logistic [t=2·77, p=0·0085]). Pairwise comparisons showed greater mean improvement from baseline in MCCB overall composite T-score at week 12 with BI 425809 10 mg and 25 mg versus placebo (adjusted mean difference 1·98 [95% CI 0·43-3·53] for 10 mg and 1·73 [0·18-3·28] for 25 mg; standardised effect size 0·34 for 10 mg and 0·30 for 25 mg). Adverse events were balanced across groups, reported in 50 (59%) of 85 patients on BI 425809 2 mg, 44 (52%) of 84 on 5 mg, 35 (41%) of 85 on 10 mg, 36 (42%) of 85 on 25 mg, and 74 (44%) of 170 on placebo. INTERPRETATION: BI 425809 improved cognition after 12 weeks in patients with schizophrenia; doses of 10 mg and 25 mg showed the largest separation from placebo. If these encouraging results are confirmed in phase 3 trials, BI 425809 could provide an effective treatment for cognitive impairment associated with schizophrenia. FUNDING: Boehringer Ingelheim.

Hypocholesterolemia is associated with immune dysfunction in early human immunodeficiency virus-1 infection.

PURPOSE: Patients with the acquired immunodeficiency syndrome exhibit marked disturbances in lipid metabolism. Because altered lipid metabolism may affect immune processes, this study characterized the lipid profile of asymptomatic individuals infected with the human immunodeficiency virus (HIV-1), in relationship to immune function. PATIENTS AND METHODS: Serum levels of triglycerides and cholesterol were determined in 94 asymptomatic HIV-1-infected (Centers for Disease Control stage II, III) homosexual men and 42 healthy seronegative control subjects. Immune assessment included measurements of lymphocyte subpopulations (CD4), immune activation (beta 2-microglobulin), natural killer cell function, and lymphocyte proliferation in response to mitogens phytohemagglutinin and pokeweed. Dietary intake was determined using a semiquantitative food frequency questionnaire. RESULTS: Despite greater consumption of saturated fat and cholesterol, significantly lower levels of total, high-density, and low-density lipoprotein cholesterol were observed in HIV-1-seropositive men, relative to seronegative controls (p < 0.05), with 40% of the HIV-1-infected group demonstrating hypocholesterolemia (less than 150 mg/dL). Low values of total, high-density, and low-density cholesterol were associated with elevated levels of beta 2-microglobulin in HIV-1-seropositive men. No difference between the groups was noted for serum triglycerides. HIV-1-infected subjects did not demonstrate the significant inverse relationship between cholesterol and mitogen response observed in seronegative controls. CONCLUSIONS: These findings indicate that low levels of cholesterol are prevalent during the early stages of HIV-1 infection and associated with specific alterations in immune function, suggesting that hypocholesterolemia may be a useful marker of disease progression.

Nutritional status of institutionalized elderly in south Florida

To assess the nutritional status of an elderly nursing home population of South Florida, forty-seven persons with ages ranging from 65 to 96 years were studied. Complete clinical examination and anthropometric measures were performed, along with blood cell count, biochemical blood parameters and assessment of water-soluble vitamins levels. The most common clinical finding were edentulous (67%), general pallor (44%), hyperpigmentation (33%), dry skin (26%) and arcus corneitis (26%). Thirty-five percent of the studied population had cholesterol levels greater than 220 mg/dl. Triglyceride levels were also significantly elevated in a considerable subset of our subjects, with 30% having levels above threshold value of 150 mg/dl. Small proportions of subjects showed low levels of albumin (6%), total protein (28%), ascorbic acid (2%), and thiamin (9%). Forty-five percent of males were pyridoxine deficient, while 63% of the females presented such deficiency. This study underscores the need to define, with greater precision, the nutritional status of aged populations as well as improve our inadequate standards associated with the normal aging process. Nutritional intervention--only possible when appropriate standards are defined--can potentially serve not only to prevent the occurrence of significant morbidity and mortality, but can also be employed to enhance quality of life in the elderly individuals