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The emergence of multi- and extensively-drug resistant tubercular (MDR- and XDR-TB) strains of mycobacteria has limited the use of existing therapies, therefore new drugs are needed. Dihydrofolate reductase (DHFR) has recently attracted much attention as a target for the development of anti-TB agents. This study aimed to develop selective M. tuberculosis DHFR inhibitors using rationale scaffolding design and synthesis, phenotype-oriented screening, enzymatic inhibitory study, whole cell on-target validation, molecular modeling, and in vitro DMPK determination to derive new anti-TB agents. 2,4-diamino-1-phenyl-1,3,5-triazaspiro[5.5]undeca-2,4-dienes 20b and 20c were identified as selective M. tuberculosis DHFR inhibitors, showing promising antimycobacterial activities (MIC 50 : 0.01 μM and MIC 90 : 0.025 μM on M. tuberculosis H37Rv). This study provided compelling evidence that compound 20b and 20c exerted whole cell antimycobacterial activity through DHFR inhibition. In addition, these two compounds exhibited low cytotoxicity and low hemolytic activity. The in vitro DMPK and physiochemical properties suggested their potential in vivo efficacy., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

Background. Data on hypovitaminosis D in elderly patients admitted to rehabilitation units in tropical countries are scarce. Objective. To assess the prevalence of vitamin D deficiency and its associated risk factors in elderly patients admitted to a rehabilitation unit in tropical Singapore. Methods. Prospective, cohort study of 134 subjects ≥ 65 years old admitted to a tertiary rehabilitation centre. Serum 25-hydroxyvitamin D3 (25OHD3) was measured on rehabilitation admission. Results. Mean age was 72.0 ± 5.7 years, and stroke was the commonest rehabilitation diagnosis (49.3%). Low 25OHD3 levels were present in 115 patients (85.6%) and 59 patients (44%) were deemed to be vitamin D deficient. The mean PTH level was significantly higher in patients with low 25OHD3 levels. (p = 0.002) Age, gender, vitamin D supplementation, premorbid ambulatory status, and admission/discharge Functional Independence Measure scores were not significantly associated with vitamin D deficiency. Malays/Indians (p = 0.013) and recurrent fallers (p = 0.029) were at significantly higher risk of vitamin D deficiency. Conclusions. Despite the tropical weather, vitamin D deficiency is common in elderly subjects admitted to a rehabilitation unit in Singapore. Routine assessment of vitamin D levels is recommended especially in those with a history of recurrent falls and patients of Indian/Malay ethnicity.

Objectives: To assess the effects of botulinum toxin A (BT-A) on hemiplegic shoulder pain associated with spasticity., Design: Randomized, double-blind, placebo-controlled study., Setting: Outpatient clinic of a rehabilitation department., Participants: Patients, more than three months post stroke, with hemiplegic shoulder pain associated with shoulder adductor and elbow flexor spasticity, randomly assigned to BT-A or placebo., Intervention: One-time injection of BT-A (500 units) into the pectoralis major and biceps brachii on the hemiplegic side., Main Measures: Visual analogue scale of shoulder pain (0 -10), shoulder adductor and elbow flexor tone using the Ashworth Scale and passive range of shoulder abduction. These were assessed at baseline, four weeks, eight weeks and 12 weeks post injection., Results: Seventeen patients were enrolled, eight in the BT-A group and nine in the placebo group. At baseline, the median visual analogue scale score for shoulder pain was 6, the median Ashworth Scale shoulder adductor and elbow flexor spasticity score was 2 and the median range of shoulder abduction 76 degrees. Subjects who received BT-A showed significantly greater improvements in median shoulder adductor and elbow flexor Ashworth Scale scores than placebo at week 4 (P B / 0.01) but not at week 8 and 12. For shoulder pain and passive shoulder abduction range, all subjects showed postinjection improvements and no difference could be demonstrated between the two groups., Discussion: Possible reasons for the negative finding in this study include the small sample size and the presence of causes of shoulder pain not related to spasticity which could have confounded outcome.