Quinolines

Libraries of compounds are increasingly becoming commercially available for the use of individual academic laboratories. A high-throughput system based on a stably integrated transcriptional reporter was used to screen a library of random compounds to identify agents that conferred robust augmentation of a signal transduction pathway. A novel histone deacetylase (HDAC) inhibitor, termed scriptaid, conferred the greatest effect, a 12- to 18-fold augmentation. This facilitation of transcriptional events was generally applicable to exogenous gene constructs, including viral and cellular promoters, different cell lines and reporter genes, and stably integrated and transiently introduced sequences. Scriptaid did not interfere with a further induction provided by stimulation of the cognate signal transduction pathway (transforming growth factor beta/Smad4), which implied the functional independence of ligand-stimulated transcriptional activation and histone acetylation states in this syst...

Background The ACT recommended by WHO is very effective and well-tolerated. However, these combinations need to be administered for three days, which may limit adherence to treatment. The combination of dihydroartemisinin - piperaquine phosphate - trimethoprim (Artecom®, Odypharm Ltd), which involves treatment over two days, appears to be a good alternative, particularly in malaria-endemic areas. This study intends to compare the efficacy and tolerability of the combination dihydroartemisinin - piperaquine phosphate - trimethoprim (DPT) versus artemether - lumefantrine (AL) in the treatment of uncomplicated Plasmodium falciparum malaria in Cameroon, Ivory Coast and Senegal. Methods This was a randomized, controlled, open-label clinical trial with a 28-day follow-up period comparing DPT to AL as the reference drug. The study involved patients of at least two years of age, suffering from acute, uncomplicated Plasmodium falciparum malaria with fever. The WHO 2003 protocol was used. Results A total of 418 patients were included in the study and divided into two treatment groups: 212 in the DPT group and 206 in the AL group. The data analysis involved the 403 subjects who correctly followed the protocol (per protocol analysis), i.e. 206 (51.1%) in the DPT group and 197 (48.9%) in the AL group. The recovery rate at D14 was 100% in both treatment groups. The recovery rate at D28 was 99% in the DPT and AL groups before and after PCR results with one-sided 97.5% Confidence Interval of the rates difference > -1.90%. More than 96% of patients who received DPT were apyrexial 48 hours after treatment compared to 83.5% in the AL group (p < 0.001). More than 95% of the people in the DPT group had a parasite clearance time of 48 hours or less compared to approximately 90% in the AL group (p = 0.023). Both drugs were well tolerated. No serious adverse events were reported during the follow-up period. All of the adverse events observed were minor and did not result in the treatment being stopped in either treatment group. The main minor adverse events reported were vomiting, abdominal pain and pruritus. Conclusion The overall efficacy and tolerability of DPT are similar to those of AL. The ease of taking DPT and its short treatment course (two days) may help to improve adherence to treatment. Taken together, these findings make this medicinal product a treatment of choice for the effective management of malaria in Africa.

Pitavastatin (Livazo®, Livalo®), an inhibitor of HMG-CoA reductase (statin), is indicated for the reduction of elevated total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) levels, in adult patients with primary hypercholesterolaemia and mixed dyslipidaemia, when response to diet and other non-pharmacological measures is inadequate. Pitavastatin has a favourable pharmacological profile following oral administration, including its long half-life (up to 12 hours), selective uptake into hepatocytes and minimal metabolism by cytochrome P450 (CYP) enzymes. This latter property decreases the likelihood of drug-drug interactions with agents that are metabolized by, inhibit or induce CYP enzymes. Pitavastatin improved the lipid profile (including LDL-C, TC and high-density lipoprotein cholesterol levels) in patients with hypercholesterolaemia and mixed dyslipidaemia, according to large, pivotal phase III studies of up to 60 weeks' duration. In these trials, pitavastatin for 12 weeks was noninferior to simvastatin and atorvastatin in terms of the improvement from baseline in LDL-C levels. In similarly designed trials, pitavastatin improved lipid profiles and was noninferior to simvastatin in patients with high cardiovascular risk and demonstrated significantly greater LDL-C reduction than pravastatin in elderly patients. Furthermore, in patients with type 2 diabetes mellitus, although noninferiority criteria for the comparison with atorvastatin were not met in terms of the improvement from baseline in LDL-C levels, pitavastatin was associated with some improvements in the lipid profile. Pitavastatin also demonstrated substantial lipid-modifying effects in exclusively Asian populations in well designed clinical trials. Pitavastatin was generally well tolerated in clinical trials of up to 60 weeks' duration, with a tolerability profile generally similar to that of atorvastatin and simvastatin. Therefore, pitavastatin appears to be an attractive alternative for the treatment of patients with primary hyperlipidaemia or mixed dyslipidaemia who have not responded adequately to diet and other non-pharmacological measures, and may present a useful treatment option in patients requiring polypharmacy, such as those at high risk of cardiovascular disease. Further studies evaluating the effects of pitavastatin on clinical endpoints, such as cardiovascular morbidity and mortality, are required to confirm the longer-term benefits of pitavastatin.

Based on promising preclinical data, we conducted a single arm phase II trial to assess the clinical benefit rate (CBR) of neratinib, defined  as complete/partial response (CR/PR) or stable disease (SD) ≥24 weeks, in HER2(mut) non-amplified metastatic breast cancer (MBC).  Secondary endpoints included progression-free survival (PFS), toxicity, and circulating tumor DNA (ctDNA) HER2(mut) detection.  &lt;p&gt;Experimental Methods:  Tumor tissue positive for HER2(mut) was required for eligibility.  Neratinib was administered 240mg daily with prophylactic loperamide.  ctDNA sequencing was performed retrospectively for 54 patients (14 positive and 40 negative for tumor HER2(mut)). &lt;/p&gt; &lt;p&gt;Results:  2.4% (9/381) tumors sequenced centrally harbored HER2(mut) (lobular 7.8% vs ductal 1.6%; p=0.026).  Thirteen additional HER2(mut) cases were identified locally.  21 of these 22 HER2(mut) cases were estrogen receptor positive.  Sixteen patients (median age 58 [31-74] years and 3 [2-...

The antimalarial drug piperaquine is associated with delayed ventricular depolarization, causing prolonged QT interval (time taken for ventricular de-polarisation and re-polarisation). There is a lack of safety data regarding dihydroartemisinin/piperaquine (DHA/PPQ) for the treatment of uncomplicated malaria, which has limited its use. We created a platform where electrocardiograms (ECG) were performed in public hospitals for the safety assessment of DHA/PPQ, at baseline before the use of dihydroartemisinin/piperaquine (Eurartesim®), and on day 3 (before and after administration of the final dose) and day 7 post-administration. Laboratory analyses included haematology and clinical chemistry. The main objective of the ECG assessment in this study was to evaluate the effect of administration of DHA/PPQ on QTc intervals and the association of QTc intervals with changes in blood biochemistry, full and differential blood count over time after the DHA/PPQ administration. A total of 1315 p...

This work describes recent results from our research program aiming at the synthesis and evaluation of new compounds acting as potential anti-inflammatory drugs. A series of novel acyl-hydrazones bearing 2-aryl-thiazole moiety were synthesized by the condensation between derivatives of 4-[2-(4-methyl-2-phenyl-thiazole-5-yl)-2-oxo-ethoxy]-benzaldehyde and 2, 3 or 4-(2-aryl-thiazol-4-ylmethoxy)-benzaldehyde, respectively and different carboxylic acid hydrazides. The structures of newly synthesized compounds were established by the combined use of IR, (1)H NMR, mass spectral data and elemental analysis. These compounds were tested in vivo for their anti-inflammatory activity, in an acute experimental inflammation. The acute phase bone marrow response, phagocytes&#39; activity and NO synthesis were evaluated. Compounds 10, 15, 17, 18 and 22 reduced the absolute leukocytes count due to the lower neutrophils percentage. Phagocitary index was decreased by all the compounds. Seven of them r...

Spectral emission properties of novel 4-aryloxy-1H-pyrazolo[3,4-b]quinolines were investigated. All of the compounds exhibit strong blue luminescence in the solution and in the solid state as well. Pyrazoloquinolines were used as dopants in PVK matrices in electroluminescent devices with ITO/PVK:PQ/Ca/Al light emitting diode configuration.