Cost-Effective Isolation of a Process Impurity of Pregabalin

Cost-effective isolation methods were developed on preparative HPLC, flash LC, and simulated moving bed (SMB) to prepare the process impurity, 3-(aminomethyl)-5-methylhex-4-enoic acid (4-ene impurity), of pregabalin. By a thorough experimental study on the different isolation techniques available, it was concluded that SMB was the most cost-effective. Hence, it was a continuous chromatography that utilized the advantage of SMB so that a high quantity of the impurity was generated in a short period of time. SMB was equipped with eight reversed-phased columns and was used to separate the process impurity of pregabalin. The effects of flow rate in zone 2 (Q2) and 3 (Q3), as well as switching time, on the operating performance parameters like purity, productivity, and desorbent consumption were studied. Operating conditions leading to more than 90% purity in the raffinate outlet stream were identified, together with those achieving optimal performance. All of these developed methods are novel, cost-effective, and can be applied to the isolation of other process- and stability-related impurities of pregabalin.     

Coronary endarterectomy for diffuse extensive coronary artery disease

Introduction Atherosclerotic coronary artery disease is in an increasing trend in India. With the advancement of non-surgical methods of revascularisation, the patients coming for surgery are of less attractive anatomy. The role of coronary endarterectomy along with coronary artery bypass grafting for a selected group of these patients is quite promising. Materials and Methods From March 2000 to March 2005, out of 362 CABGs performed, 42 patients had undergone coronary endarterectomy. The age range being from 35 to 76 years, M: F is 38∶4 Hypertension was present in 26 (61%), diabetes mellitus in 20 (47.6%), smoking in 26 (61%) and dyslipidemia in 12 (28.5%) cases. Old myocardial infarction was present in 52.3% cases, unstable angina in 16.6%, stable angina in 23.8% and cardiogenic shock in 7.1% cases. All cases had undergone coronary artery bypass grafting with endarterectomy. Out of 18 LAD endarterectomies 17 cases LIMA was used as onlay patch. Result The average number of grafts anastomosed was 3.7. Single-vessel endarterectomy was done in 37, double vessel in 4 and four vessel in one case. LAD endarterectomy was done in 18, RCA in 12, diagonal in 10, intermediate in 1 and marginals in 8 cases. Postoperatively 3 patients had arrhythmia, two perioperative MI, one recurrent angina and one congestive cardiac failure (CCF). There was 2 (4.76%) mortality. Conclusion Hypertension and smoking are major risk factors. LAD is the most common artery requiring endarterectomy. Usage of LIMA following endarterectomy of LAD is quite satisfactory and short term results are encouraging.     

Synthesis and biological evaluation of delavayin-C

The synthesis of a cyclic heptapeptide, delavayin-C, cyclo(gly-tyr-tyr-tyr-pro-val-pro) is described. The structure of this compound was established on the basis of analytical IR, (1)H NMR and FAB mass spectral data. The antibacterial and antifungal activities of this peptide are also described.     

Design and synthesis of taxane derivatives of valproic acid as potent and selective cytotoxic agents

Resistance to anticancer agents has important implications for cancer chemotherapy. Small changes in chemical structures of cytotoxic agents can alter their biological interactions that can be beneficial in overcoming the drug resistance problem. Valproic acid, a well-known antiepileptic drug is in advanced clinical studies for cancer treatment. In the present study, valproic acid was incorporated into the taxane moiety at various positions and the new analogs were evaluated for their in vitro cytotoxicity. The novel analog, Valprotaxel showed comparable cytotoxicity in head and neck, and colon cancer cell lines with remarkable improvement in selectivity for cancer cells compared to paclitaxel and docetaxel.     

Antiurolithiatic activity of ethanol leaf extract of Ipomoea eriocarpa against ethylene glycol-induced urolithiasis in male Wistar rats

Objective:The objective of this study was to investigate the prophylactic and curative effect of the ethanol leaf extract of Ipomoea eriocarpa (Convolvulaceae) (IEE) in ethylene glycol-induced urolithiasis in rats.Results:The IEE treatment (prophylactic and curative) significantly (P < 0.001) restored the parameters in urine, serum, and kidney homogenate to near-normal level. The histopathological examinations revealed that calcium oxalate crystal deposits in the renal tubules and congestion and dilation of the parenchymal blood vessels were significantly reverted after IEE treatment.Conclusions:The leaf extract of I. eriocarpa reduces and inhibits the growth of urinary stones showing its effect as an antiurolithiatic agent.KEY WORDS: Calcium oxalate, ethylene glycol, Ipomoea eriocarpa, urolithiasis     

Investigation of enhancement of solubility of norfloxacin beta-cyclodextrin in presence of acidic solubilizing additives

The present study is aimed at improving the solubility of a poorly water-soluble drug, norfloxacin by incorporating solubilizing additives such as ascorbic acid and citric acid into the beta-cyclodextrin complexes. Norfloxacin, being amphoteric in nature, exhibits a higher solubility at pH below 4 and above 8. Addition of substances like ascorbic acid and citric acid in beta-cyclodextrin complexes reduces the pH of the immediate microenvironment of the drug below pH 4. In the present work, beta-cyclodextrin complexes of norfloxacin were prepared along with solubilizing additives such as citric acid and ascorbic acid in various proportion and the dissolution profile was performed in both HCl buffer, pH 1.2 and phosphate buffer, pH 7.4. The results have shown an enhanced dissolution rate in both media. DSC and IR spectral studies performed on the solid complexes have shown that there is no interaction of the drug with the additives and beta-cyclodextrin. Disc diffusion studies have shown larger diameters of zone of inhibition indicating a greater diffusivity of the drug into the agar medium.     

CT perfusion for determination of pharmacologically mediated blood flow changes in an animal tumor model

PURPOSE: To prospectively compare single- and multisection computed tomographic (CT) perfusion for tumor blood flow determination in an animal model. MATERIALS AND METHODS: All animal protocols and experiments were approved by the institutional animal care and use committee before the study was initiated. R3230 mammary adenocarcinoma was implanted in 11 rats. Tumors (18-20 mm) were scanned with dynamic 16-section CT at baseline and after administration of arsenic trioxide, which is known to cause acute reduction in blood flow. The concentration of arsenic was titrated (0-6 mg of arsenic per kilogram of body weight) to achieve a defined blood flow reduction (0%-75%) from baseline levels at 60 minutes, as determined with correlative laser Doppler flowmetry. The mean blood flow was calculated for each of four 5-mm sections that covered the entire tumor, as well as for the entire tumor after multiple sections were processed. Measurements obtained with both methods were correlated with laser Doppler flowmetry measurements. Interobserver agreement was determined for two blinded radiologists, who calculated the percentage of blood flow reduction for the "most representative" single sections at baseline and after arsenic administration. These results were compared with the interobserver variability of the same radiologists obtained by summing blood flow changes for the entire tumor volume. RESULTS: Overall correlations for acute blood flow reduction were demonstrated between laser Doppler flowmetry and the two CT perfusion approaches (single-section CT, r=0.85 and r(2)=0.73; multisection CT, r=0.93 and r(2)=0.87; pooled data, P=.01). CT perfusion disclosed marked heterogeneity of blood flow, with variations of 36% +/- 13 between adjacent 5-mm sections. Given these marked differences, interobserver agreement was much lower for single-section CT (standard deviation, 0.22) than for multisection CT (standard deviation, 0.10; P=.01). CONCLUSION: Multisection CT perfusion techniques may provide an accurate and more reproducible method of tumor perfusion surveillance than comparison of single representative tumor sections.     

Combination of radiofrequency ablation with antiangiogenic therapy for tumor ablation efficacy: study in mice

PURPOSE: To prospectively determine whether modulation of renal cell carcinoma (RCC) tumor microvasculature by using the antiangiogenic drug sorafenib could increase the extent of radiofrequency (RF)-induced coagulation in an RCC animal tumor model. MATERIALS AND METHODS: All investigations received animal care and utilization committee approval. RCC (human 786-0) was implanted subcutaneously into 27 nude mice. Sixteen mice were randomly assigned into one of three groups when tumors reached 12 mm in diameter: Six mice received 80 mg of sorafenib, a Raf kinase and vascular endothelial growth factor receptor inhibitor, per kilogram of body weight; five mice received 20 mg/kg sorafenib; and five mice received a control carrier vehicle alone. Antiangiogenic therapy was administered until a mean 1-mm reduction in tumor diameter was noted in one group. These 16 mice received a standard dose of RF ablation. Ablation size was visualized by using 2% triphenyltetrazolium chloride. An additional 11 tumors in mice treated with sorafenib alone were stained with CD31 to determine microvascular density (MVD). Resultant size of ablation was compared among groups; statistical significance was determined with analysis of variance. Differences in MVD were assessed with the Kruskal-Wallis test. RESULTS: Over the 9-day administration of sorafenib, mean tumor size in the control group reached 15.2 mm +/- 0.8 (standard deviation). Tumors in mice receiving 20 mg/kg and 80 mg/kg sorafenib measured 12.2 mm +/- 0.6 and 11.1 mm +/- 0.5, respectively (P < .05). RF-induced coagulation diameter was 8.5 mm +/- 0.4 and 11.1 mm +/- 0.3 in the 20 mg/kg and 80 mg/kg sorafenib groups, respectively, but was only 6.7 mm +/- 0.7 for animals that underwent RF ablation alone (P < .01). Likewise, significant decreases in MVD were noted in the sorafenib-treated animals (P < .01). CONCLUSION: Treatment of RCC in nude mice with the antiangiogenic agent sorafenib resulted in markedly decreased MVD and significantly larger zones of RF-induced coagulation necrosis.