Search

Abstract: CuI facilitated three-component reaction of isatin derivatives, l-proline and terminal alkynes containing an amide or ester functional group. The multi-component reaction (MCR) afforded a faster and practical synthesis of spirooxindole derivatives. A range of novel spirooxindoles were synthesized by using this straightforward and one-pot efficient methodology. A representative compound showed significant inhibition of PDE4B enzyme in vitro and good interactions with this protein in silico. [Copyright &y& Elsevier]

Background: Few prospective data exist on incidence of post kala-azar dermal leishmaniasis (PKDL) and visceral leishmaniasis (VL) relapse after different treatment regimens. Methodology/Principal findings: A Phase IV trial included 1761 VL patients treated between 2012–2014 with single dose AmBisome (SDA; N = 891), miltefosine-paromomycin (Milt-PM; n = 512), or AmBisome-miltefosine (AmB-Milt; n = 358). Follow-up for PKDL and VL relapse was scheduled for 6, 12 and 24 months after treatment, lasting until 2017. Patients with lesions consistent with PKDL were tested by rK39 rapid test, and if positive, underwent skin-snip sampling, smear microscopy and PCR. Probable PKDL was defined by consistent lesions and positive rK39; confirmed PKDL required additional positive microscopy or PCR. PKDL and relapse incidence density were calculated by VL treatment and risk factors evaluated in Cox proportional hazards models. Among 1,750 patients who completed treatment, 79 had relapse and 104 PKDL. Relapse incidence density was 1.58, 2.08 and 0.40 per 1000 person-months for SDA, AmB-Milt and Milt-PM, respectively. PKDL incidence density was 1.29, 1.45 and 2.65 per 1000 person-months for SDA, AmB-Milt and Milt-PM. In multivariable models, patients treated with Milt-PM had lower relapse but higher PKDL incidence than those treated with SDA; AmB-Milt rates were not significantly different from those for SDA. Children <12 years were at higher risk for both outcomes; females had a higher risk of PKDL but not relapse. Conclusions/Significance: Active surveillance for PKDL and relapse, followed by timely treatment, is essential to sustain the achievements of VL elimination programs in the Indian sub-continent. Author summary: Efforts to eliminate visceral leishmaniasis (VL) in the Indian subcontinent have had an unprecedented impact on the number of cases over the past decade, however, the disease is known to be cyclical and previous periods of low incidence have been followed by a major resurgence. The disease is thought to be maintained between epidemics as post-kala-azar dermal leishmaniasis (PKDL), a skin disease affecting 5 to 15% of apparently cured VL patients in the Indian subcontinent. PKDL is difficult to cure and since PKDL patients are not systemically ill, they seldom seek treatment, meaning that PKDL is likely to be a major obstacle to elimination. A key question is how different VL treatment regimens affect the risk of subsequent PKDL. We followed-up a cohort of more than 1700 patients treated with three different drug regimens in an effectiveness trial in Bihar and found that patients treated with miltefosine-paromomycin had a lower risk of relapse but higher PKDL incidence, while AmBisome treated patients had the reverse pattern. In order to sustain the gains already made, active surveillance for PKDL and relapse is essential, along with timely treatment, and new VL treatment regimens that avoid future PKDL are needed. [ABSTRACT FROM AUTHOR]

starting from various aminophenols and epichlorhydrin [ABSTRACT FROM AUTHOR]

Derivatives (IIIc) and (IIId) show interesting inhibitory activity against MDA-MB231 (breast cancer) cells. [ABSTRACT FROM AUTHOR]

The first Cu-mediated one-pot three-component reaction of isatin derivatives (I), L-proline (II), and terminal alkynes (III) leading to spiropyrrolidine oxindols (IV) is reported. [ABSTRACT FROM AUTHOR]

A simple and efficient synthesis of (2S,5S)-5-Hydroxypipecolic acid hydrochloride is reported. The key features of the synthesis involve the asymmetric reduction of ketone using (S)-CBS oxazaborolidine and the use of commercially available methyl pyroglutamate as a starting material. [ABSTRACT FROM AUTHOR]

Background: An earlier open label, prospective, non-randomized, non-comparative, multi-centric study conducted within public health facilities in Bihar, India (CTRI/2012/08/002891) measured the field effectiveness of three new treatment regimens for visceral leishmaniasis (VL): single dose AmBisome (SDA), and combination therapies of AmBisome and miltefosine (AmB+Milt) and miltefosine and paromomycin (Milt+PM) up to 6 months follow-up. The National Vector Borne Disease Control Program (NVBDCP) recommended an extended follow up at 12 months post-treatment of the original study cohort to quantify late relapses. Methods: The 1,761 patients enrolled in the original study with the three new regimens were contacted and traced between 10 and 36 months following completion of treatment to determine their health status and any occurrence of VL relapse. Results: Of 1,761 patients enrolled in the original study, 1,368 were traced at the extended follow-up visit: 711 (80.5%), 295 (83.2%) and 362 (71.5%) patients treated with SDA, AmB+Milt and Milt+PM respectively. Of those traced, a total of 75 patients were reported to have relapsed by the extended follow-up; 45 (6.3%) in the SDA, 25 (8.5%) in the AmB+Milt and 5 (1.4%) in the Milt+PM arms. Of the 75 relapse cases, 55 had already been identified in the 6-months follow-up and 20 were identified as new cases of relapse at extended follow-up; 7 in the SDA, 10 in the AmB+Milt and 3 in the Milt+PM arms. Conclusion: Extending follow-up beyond the standard 6 months identified additional relapses, suggesting that 12-month sentinel follow-up may be useful as a programmatic tool to better identify and quantify relapses. With limited drug options, there remains an urgent need to develop effective new chemical entities (NCEs) for VL. [ABSTRACT FROM AUTHOR]

Background: In 2010, WHO recommended the use of new short-course treatment regimens in kala-azar elimination efforts for the Indian subcontinent. Although phase 3 studies have shown excellent results, there remains a lack of evidence on a wider treatment population and the safety and effectiveness of these regimens under field conditions. Methods: This was an open label, prospective, non-randomized, non-comparative, multi-centric trial conducted within public health facilities in two highly endemic districts and a specialist referral centre in Bihar, India. Three treatment regimens were tested: single dose AmBisome (SDA), concomitant miltefosine and paromomycin (Milt+PM), and concomitant AmBisome and miltefosine (AmB+Milt). Patients with complicated disease or significant co-morbidities were treated in the SDA arm. Sample sizes were set at a minimum of 300 per arm, taking into account inter-site variation and an estimated failure risk of 5% with 5% precision. Outcomes of drug effectiveness and safety were measured at 6 months. The trial was prospectively registered with the Clinical Trials Registry India: CTRI/2012/08/002891. Results: Out of 1,761 patients recruited, 50.6% (n = 891) received SDA, 20.3% (n = 358) AmB+Milt and 29.1% (n = 512) Milt+PM. In the ITT analysis, the final cure rates were SDA 91.4% (95% CI 89.3–93.1), AmB+Milt 88.8% (95% CI 85.1–91.9) and Milt+PM 96.9% (95% CI 95.0–98.2). In the complete case analysis, cure rates were SDA 95.5% (95% CI 93.9–96.8), AmB+Milt 95.5% (95% CI 92.7–97.5) and Milt+PM 99.6% (95% CI 98.6–99.9). All three regimens were safe, with 5 severe adverse events in the SDA arm, two of which were considered to be drug related. Conclusion: All regimens showed acceptable outcomes and safety profiles in a range of patients under field conditions. Phase IV field-based studies, although extremely rare for neglected tropical diseases, are good practice and an important step in validating the results of more restrictive hospital-based studies before widespread implementation, and in this case contributed to national level policy change in India. Trial registration: Clinical trial is registered at Clinical trial registry of India (, Registered on 16/08/2012, Trial Registered Prospectively). [ABSTRACT FROM AUTHOR]