3-aryl-[1,2,4]triazino[4,3-a]benzimidazol-4(10H)-one: a novel template for the design of highly selective A₂B adenosine receptor antagonists

In an effort to identify novel ligands possessing high affinity and selectivity for the A(2B) AR subtype, we further investigated the class of 3-aryl[1,2,4]triazino[4,3-a]benzimidazol-4(10H)-ones V, previously disclosed by us as selective A(1) AR antagonists. Preliminary assays on a number of triazinobenzimidazoles derived from our "in-house" collection revealed that all the derivatives selected showed significant affinity at A(2B) AR, no affinity at A(3) AR, and various degrees of selectivity toward A(1) and A(2A) ARs. Investigation of a new series featuring modified substituents at the 10-position (4'-chlorophenyl or phenylethyl groups), and a chlorine atom at the 7-position (X) of the triazinobenzimidazole nucleus, yielded highly potent and selective A(2B) AR antagonists. The presence of a pendant 3-phenyl ring appears to hamper the interaction with A(2A) AR, conferring high A(2B)/A(2A) AR selectivity. Derivative 13 (X = Cl, R = C(6)H(5)) is the most potent and selective compound, with an IC(50) of 3.10 nM at A(2B) AR and no affinity at A(1), A(2A), and A(3) ARs.     

Water-soluble pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidines as human A₃ adenosine receptor antagonists

A relevant problem of the pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidine nucleus, an attractive scaffold for the preparation of adenosine receptor antagonists, is the low water solubility. We originally functionalized the C(5) position with a salifiable 4-pyridylcarbamoyl moiety that conferred good water solubility at low pH (<4.0) but poor solubility at physiologic pH, indicative of the dissociation of the pyridinium species. Here we replaced the pyridin-4-yl moiety with a 1-(substituted)piperidin-4-yl ring to exploit the higher basicity of this nucleus and for the the possibility to generate stable, water-soluble salts. The hydrochloride salt of the 1-(cyclohexylmethyl)piperidin-4-yl derivative (10, K(i)(hA(3)) = 9.7 nM, IC(50)(hA(3)) = 30 nM, K(i)(hA(1)/hA(3)) = 351, K(i)(hA(2A)/hA(3)) > 515, IC(50)(hA(2B)) > 5 μM) showed a solubility of 8 mg/mL at physiological pH and gave a stable aqueous system suitable for intravenous infusion. Molecular modeling studies were helpful in rationalizing the available structure-activity relationships and the selectivity profile of the new ligands.     

Nutritional status of HIV-infected women with tuberculosis in Dar es Salaam,Tanzania

Setting:

Tuberculosis (TB) treatment clinics in Dar es Salaam, Tanzania.

Objective:

To quantify anthropometrics and intake of en-ergy and protein among human immunodeficiency virus (HIV) positive women with TB.

Design:

HIV-positive women with newly diagnosed TB were assessed on their anthropometric characteristics and dietary intake. Energy and protein intake were determined using Tanzania food composition tables and compared with standard recommendations. Patients were re-evaluated after 4–6 months of anti-tuberculosis treatment.

Results:

Among 43 women, the baseline median CD4 count was 209 cells/µl (range 8–721); 19 (44%) had a CD4 count of <200; 20 (47%) were on antiretroviral therapy. Body mass index was <18.5 kg/m² in 25 (58%); the median food insecurity score was 6. The median level of kcal/day was 1693 (range 1290–2633) compared to an estimated need of 2658; the median deficit was 875 kcal (range −65–1278). The median level of protein/day was 42 g (range 27–67) compared to 77 g estimated need; the median protein deficit was 35 g (range 10–50). The median weight gain among 29 patients after 4–6 months was 6 kg.

Conclusion:

HIV-positive women with TB have substantial 24-h deficits in energy and protein intake, report significant food insecurity and gain minimal weight on anti-tuberculosis treatment. Enhanced dietary education together with daily supplementation of 1000 kcal with 40 g protein may be required.     

Anterior Cruciate Ligament Reconstruction with Bone Patellar Tendon Bone Graft through a Mini Arthrotomy

Instability after rupture of anterior cruciate ligament (ACL) may lead to recurrent episodes of giving way, an increased risk of meniscal injury and premature degenerative changes. A total of 25 cases with ACL injuries were evaluated after reconstruction with bone patellar tendon bone graft through a mini-arthrotomy. All patients were male. Maximum number of patients were between 25-30 years of age (40%). The most common modality of injury was contact sports (44%). Most common complaint was instability of knee (100%). Average Lysholm score increased from pre-operative of 47 (27-75) to post-operative of 87 (68-95). Two patients (8%) had retropatellar pain. Moderate to severe graft site tenderness was present in 4 (21%). After an average follow up of one year three months, the results were comparable with the results of arthroscopic reconstruction.Key Words: Anterior cruciate ligament reconstruction, Mini arthrotomy