Floating Tablet of Trimetazidine Dihydrochloride: An Approach for Extended Release with Zero-Order Kinetics

Trimetazidine dihydrochloride is an effective anti-anginal agent; however, it is freely soluble in water and suffers from a relatively short half-life. To solve this encumbrance, it is a prospective candidate for fabricating trimetazidine extended-release formulations. Trimetazidine extended-release floating tablets were prepared using different hydrophilic matrix forming polymers including HPMC 4000 cps, carbopol 971P, polycarbophil, and guar gum. The tablets were fabricated by dry coating technique. In vitro evaluation of the prepared tablets was performed by the determination of the hardness, friability, content uniformity, and weight variation. The floating lag time and floating duration were also evaluated. Release profile of the prepared tablets was performed and analyzed. Furthermore, a stability study of the floating tablets was carried out at three different temperatures over 12 weeks. Finally, in vivo bioavailability study was done on human volunteers. All tablet formulas achieved <0.5 min of floating lag time, more than 12 h of floating duration, and extended t _1/2. The drug release in all formulas followed zero-order kinetics. T4 and T8 tablets contained the least polymer concentration and complied with the dissolution requirements for controlled-release dosage forms. These two formulas were selected for further stability studies. T8 exhibited longer expiration date and was chosen for in vivo studies. T8 floating tablets showed an improvement in the drug bioavailability compared to immediate-release tablets (Vastrel® 20 mg).     

Synthesis of AZT analogues: 7-(3-azido-2-hydroxypropyl)-, 7-(3-amino-2-hydroxypropyl)-,7-(3-triazolyl-2-hydroxypropyl)theophylline

Nucleophilic displacement of the tosyloxy group in 7-(2-hydroxy-3-p-toluenesulfonyloxypropyl)theophylline (1) with azide anion afforded 7-(3-azido-2-hydroxypropyl)theophylline (2). Reduction of the 3-azido group in 2 with Ph3P/Py/NH4OH afforded the 3-amino derivative 4, alternatively obtained by regioselective amination of 7-(2,3-epoxypropyl)theophylline (3). Selective acetylation of 4 gave the N-acetyl derivative 5. 1,3-Dipolar cycloaddition of the azide group in 2 with N1-propargyl thymine (6) afforded the regioisomeric triazole 7.     

Potential misidentification of cyclooxygenase-2 by western blot analysis and prevention through the inclusion of appropriate controls

Cyclooxygenase (COX)-2 plays an important role in the development of cancer and has been recognized as a potential therapeutic target. Because nonsteroidal anti-inflammatory drugs (NSAIDs) are able to inhibit the activity of this enzyme, the potential efficacy of such drugs for purposes of cancer prevention or therapy is an area of intense research. Therefore, it is of critical importance to unequivocally determine the expression levels of COX-2 protein in tumor cells. In this regard, there are several conflicting reports in the literature where the same type of tumor cell lines were reported as COX-2 positive and as COX-2 negative. We found that during Western blot analysis of COX-2 positive and COX-2 negative cells, different antibodies to COX-2 protein are able to generate strong signals, which are false-positives and can be confused with COX-2. Thus, we believe that some of the conflicting reports on COX-2 expression in tumor cell lines could be the result of improper interpretation of the Western blot signals. Here, we present some of these pitfalls and suggest the inclusion of appropriate controls to unequivocally identify COX-2 protein levels.     

Reference ranges of copper and zinc and the prevalence of their deficiencies in an Arab population aged 15-80 years

Serum concentrations of copper and zinc were measured by flame atomic absorption spectrophotometry in 560 Kuwaitis aged from 15 to 80 yr who were in apparent good health to establish reference ranges and determine the prevalence of the deficiency of the trace metals. Zinc/copper ratios were derived by calculation. Because the mean +/- SD (microM) for copper in females (24.9 +/- 7) was significantly higher (p<0.0001) than in males (21.0 +/- 5.8) and vice versa for zinc (17.0 +/- 3.5 [males] vs 15.5 +/- 3.4 [females]) and zinc/copper ratios (0.87 +/- 0.28 [males] vs 0.67 +/- 0.27 [females]), gender-specific reference ranges were established in addition to reference ranges for the total population. The reference range for zinc was closer to those reported for other populations than was copper. Body mass index (BMI) and copper values were lower and the zinc/copper ratio was higher in the young (15-24 yr) compared to the older subjects. Copper concentrations were positively associated with BMI values (r=0.302, p<0.0001). Smokers had significantly lower (p=0.011) BMI than nonsmokers. The prevalence of copper and zinc deficiency, 0.36% and 0.53%, respectively, was low. Generally, the values for serum copper and zinc obtained for the Kuwaiti population studied suggest adequate dietary intake of the trace metals.     

Cavernous nerve reconstruction to preserve erectile function following non-nerve-sparing radical retropubic prostatectomy: a prospective study

Erectile dysfunction following radical prostatectomy for treatment of clinically localized prostate cancer remains a problem that deters many men from seeking surgical treatment. Sparing the cavernous nerves has been popularized as a method of preserving potency, but men with locally advanced disease may be at increased risk for positive margins with this technique. In this study, sural nerve grafting of the cavernous nerve bundles, to preserve postoperative potency while potentially maximizing cancer control, was examined. Thirty men were enrolled in this prospective phase I study and underwent non-nerve-sparing radical prostatectomy performed by one of two protocol surgeons. Preoperative erectile function was assessed both objectively, using a RigiScan (Timm Medical Technologies, Inc., Eden Prairie, Minn.), and subjectively. The cavernous nerves were identified and resected during the operation with the use of an intraoperative mapping device (CaverMap; Alliant Medical Technologies, Norwood, Mass.). Bilateral autologous sural nerve grafting to the cavernous nerve stumps was performed by one of two protocol plastic surgeons. Postoperative erectile dysfunction therapy, using intracorporeal injection, a vacuum pump, and/or oral sildenafil therapy, was instituted 6 weeks after the operation. Spontaneous erectile activity was subjectively and objectively measured every 3 months after the operation. Follow-up periods ranged from 13 to 33 months (mean, 23 months). Overall, 18 of 30 patients (60 percent) demonstrated both objective and subjective evidence of spontaneous erectile activity. Of those 18 men, 13 (72 percent) were able to have intercourse (seven unassisted and six with the aid of sildenafil). No disease or biochemical recurrences have been noted in this group of patients with locally advanced disease. In conclusion, autologous sural nerve grafting after non-nerve-sparing radical prostatectomy is an effective means of preserving spontaneous erectile activity after the operation while maximizing cancer control potential.     

Breast reconstruction in older women: advantages of autogenous tissue

As the population ages, the treatment of breast cancer among elderly women is becoming increasingly common. Decisions with regard to breast reconstruction require not only consideration of patient age and comorbidities but also a need to balance life expectancy with quality of life. Although it is often assumed that implant-based breast reconstruction is the least disruptive method, especially among patients who may be facing limited survival times, it was hypothesized that autogenous tissue breast reconstruction is a well-tolerated and perhaps preferable means of reconstruction for older women who choose to undergo reconstruction following mastectomy. No large series of autogenous tissue reconstructions in this age group has been presented. A retrospective study of 84 postmastectomy reconstructions (66 unilateral and 18 bilateral; 78.6 percent immediate) performed at the authors' institution for 81 women 65 years of age or older, between April of 1987 and December of 2000, was undertaken. Reconstructions were implant-based ( = 26), latissimus dorsi flap-based ( = 24), or transverse rectus abdominis myocutaneous (TRAM) flap-based ( = 34). Of the 34 TRAM flaps, 21 were free or supercharged. Breast complications were more frequent ( < 0.05) among recipients of implant-based reconstructions (76.9 percent) than among recipients of latissimus dorsi flap (41.7 percent) or TRAM flap (35.3 percent) reconstructions. In multivariate logistic regression analyses, comorbidities, smoking, radiotherapy, and body mass index had no effect. Medical complications without long-term sequelae were observed for two patients who underwent latissimus dorsi flap reconstructions and two patients who underwent free TRAM flap reconstructions; the difference in the rates of medical complications was not significant. At the mean follow-up time of 4.2 years, 92.8 percent of all study patients exhibited no evidence of disease. Notably, despite being free of disease, seven of the 26 patients (27 percent) who underwent implant-based reconstructions abandoned further reconstructive efforts after complications necessitated implant removal. It was concluded that age alone should not determine the type of breast reconstruction and that autogenous tissue breast reconstruction can be a safe successful alternative for women 65 years of age or older.     

A convenient method for the synthesis of 2-(beta-D-glycopyranosylthio) pyridines

Treatment of piperidinium salts of dihydropyridinethiolates 3 with glycosyl bromides 4 in dry acetone provides a convenient and high yielding synthesis of 1,4-dihydro-3-cyanopyridine thioglycosides 5. The structures of 5 were confirmed by oxidation as well as by 1H NMR and 13C NMR spectral analysis.     

Protective effect of arabic gum against cardiotoxicity induced by doxorubicin in mice: a possible mechanism of protection

Arabic gum (AG) is a naturally occurring compound that has been proposed to possess potent antioxidant activity. In this study, the possible effects whereby AG could protect against cardiotoxicity induced by doxorubicin (DOX) in mice were carried out. Administration of single dose of DOX (15 mg/kg, i.p.) induced cardiotoxicity 72 h, manifested biochemically by a significant elevation of serum creatine kinase (CK) (EC 2.7.3.2). In addition, cardiotoxicity was further confirmed by the significant increase in lipid peroxides measured as malondialdehyde (MDA). Administration of AG (25 g/kg) orally for 5 days before and 72 h after DOX injection produced a significant protection against cardiotoxicity induced by DOX. This was evidenced by significant reductions in serum CK and cardiac lipid peroxides. The effect of AG was examined on the superoxide anion radical generated by enzymatic and nonenzymatic methods. The results indicate that AG is a potent superoxide scavenger. The superoxide scavenging effect of AG may explain, at least in part, the protective effect of AG against cardiotoxicity induced by DOX.     

Yield and activity of Autographa californica multicapsid nucleopolyhedrovirus and Phthorimaea operculella granulosis virus in cloned and uncloned cell lines of P. operculella

Three selected uncloned Pop 2, Pop 3, Pop 4 and two cloned cell lines Pop cl1A and Pop cl2B were derived from the original cell line established from Phthorimaea operculella (ORS-Pop-93). Three new non-selected cell lines ORS-Pop-94A, ORS-Pop-94B and ORS-Pop-95 were also established from embryos of the same insect. Differences in morphology, growth rate and polypeptide profile were determined between these cell lines. All the cell lines were susceptible to the Autographa californica nucleopolyhedrovirus (AcMNPV). The cloned cell lines produced higher levels of AcMNPV (TCID-50 and PIB) than the parental cells and at the same rate as the Sf9 reference cell line. Substantial amounts of viral DNA were synthesized in the clone Pop cl 2B after infection with the granulosis virus of the potato tuber moth P. operculella (PTMGV) and a complete multiplication was obtained in the ORS-Pop-95 cell line. The comparison between Pop cell lines which support limited or complete replication of certain baculoviruses can offer insights into some of the molecular barriers which restrict the host range of these viruses. These cell lines with variable susceptibility to baculoviruses could also be used for in vitro recombinations, increasing their virus host range to be used for the control of this pest. This revised version was published online in August 2006 with corrections to the Cover Date.     

Pre-Breeding Genetic Diversity Assessment of Tomato (<i>Solanum lycopersicum</i> L.) Cultivars Based on Molecular,Morphological and Physicochemical Parameters

Appropriate knowledge of the parental cultivars is a pre-requisite for a successful breeding program. This study characterized fruit yield, quality attributes, and molecular variations of ten tomato cultivars during three consecutive generations under greenhouse conditions. Peto 86, Castle Rock, and Red Star cultivars showed the highest fruit yield (kg/plant), total phenolic compounds (TPC), and sap acidity. Principal component analysis categorized the evaluated fruit yield into three groups based on their quality attributes. A robust positive correlation appeared among traits inside each group. A positive correlation was likewise noticed between the first and the second groups. However, a negative correlation was detected between the first, the second and the third group. Molecular profiling, using seven inter-simple sequence repeat (ISSR) primers, produced 60 loci, including 49 polymorphic loci. The molecular analysis also pinpointed the highest genetic similarity (0.92) between P73 and Moneymaker, while the lowest genetic similarity (0.46) was observed between Castle Rock and Moneymaker. The cultivars P73 and Moneymaker showed the lowest genetic distance (2.24), while the highest genetic distance (5.92) was observed between Super Marmand and Peto86, on the one hand, and between Castle Rock and Moneymaker, on the other hand. The chemical analysis of fruit sap indicated the highest levels of TPC, total flavonoids, anthocyanin, ascorbic acid and total soluble solids in Peto 86 and Castle Rock cultivars. Phylogeny analysis of tomato cultivars based on morphological and molecular attributes indicated four distinct clades. Peto 86, Castle Rock, and Red star cultivars can be recommended for the tomato hybridization breeding programs in the future, with other tomato cultivars as potentially high-yielding parents.