Study of Some Inflammatory Mediators in the Serum of Patients With Atherosclerosis and Acute Myocardial Infarction.

Background and aim of the study The aim of this study is to evaluate the changes in the inflammatory mediator's serum amyloid A (SAA), adiponectin, and resistin in the serum of patients with stable angina and acute myocardial infarction. Subjects and methods The study was done on 60 subjects divided into three groups: 20 healthy normal individuals as a control group, 20 patients with stable angina (atherosclerotic plaque), and 20 patients with myocardial infarction. Fasting blood samples were withdrawn from all subjects and serum was prepared. SAA, resistin, and adiponectin levels were quantitatively measured by enzyme-linked immunosorbent assay (ELISA). Results The SAA level was significantly higher in both stable angina and the acute myocardial infarction group than the control group (2.7179 ± 0.44501 mg/L) and the serum resistin level was significantly higher (p-value = 0.0) in the stable angina (8.368 ± 1.633 ng/ml) and the acute myocardial infarction (13.606 ± 2.067 ng/ml) groups (p-value= 0.0) than the control group. (2.4272±1.25210 ng/ml). Moreover, resistin levels in stable angina when compared to the AMI showed a significant difference between them (p-value = 0.0) while adiponectin was significantly lower in the acute myocardial infarction group. (6.641±2.6011 µg/mL, p-value = 0.019) than its level in the control group (11.873±1.798 µg/mL). While the adiponectin level showed no significant differences between stable angina in comparison to the AMI. Conclusion SAA can be used as a confirmatory marker for stable angina and a diagnostic tool for AMI patients. Both SAA and resistin may participate in the atherosclerosis process as an effectors molecule of inflammatory reactions. For adiponectin, we concluded that it has the antiatherogenic property and its levels were lower in both the stable angina and acute myocardial infarction groups.

Optimization of the Conditions for Plasmid DNA Delivery and Transfection with Self-Assembled Hyaluronic Acid-Based Nanoparticles.

Polymeric systems have been extensively studied as polyelectrolyte complexes to enhance the cellular delivery and transfection efficiency of genetic materials, such as plasmid DNA (pDNA). Here, self-assembled nanoparticles were formulated by complexation of hyaluronic acid (HA)-conjugated poly(ethylene glycol) (HA-PEG) and poly(ethylenimine) (HA-PEI), respectively, with pDNA creating relatively small, stable, and multifunctional nanoparticle complex formulations with high transfection efficiency. This formulation strategy offers high gene expression efficiency and negligible cytotoxicity in HeLa and A549 human lung cancer cell lines. To develop the ideal formulation, in vitro transfection efficiency was studied for three different nanoparticle formulations (HA-PEI/HA-PEG, HA-PEI, and HA-PEG) with different concentrations. The combination of the three polymers (HA, PEG, and PEI) was significant for the formulation to achieve the maximum gene expression results. The nanoparticles were found to be stable for up to a week at 4 °C conditions. Overall, these HA-based nanoparticles showed promising aspects that can be utilized in the designing of gene delivery vectors for cancer therapy.

Zingerone alleviates the delayed ventricular repolarization and AV conduction in diabetes: Effect on cardiac fibrosis and inflammation.

BACKGROUND: The study aims to analyse the action of zingerone in diabetes-related cardiac arrhythmias. METHODS: Diabetes was induced by streptozocin while treatment groups received 20 mg/kg zingerone daily. Following extra seven weeks, electrocardiography, extraction of blood, urine and heart for biochemical analysis, histopathology and immunofluorescence were undertaken. RESULTS: The suppression of QT and QTc prolongation in diabetic rats was indicative of prolonged cardiac repolarisation that was greatly reduced by zingerone treatment. In addition, the reduction in PR interval attested that zingerone improved AV delay in diabetic rats. The fibrogenic transforming growth factor ß1 upregulation in diabetic hearts was suppressed by zingerone. The marked glycogen deposition and muscle degeneration seen in diabetic heart sections were also alleviated by zingerone. Furthermore, zingerone prevented the decrease in of the serum anti-inflammatory cytokine adiponectin in diabetics. The heightened levels of oxidative stress markers 8-isoprostane and uric acid in diabetic rats were suppressed. In the diabetic heart, the reduced catalase activity was improved and the excessive expression of angiotensin receptor 1 was inhibited by zingerone. CONCLUSION: Cardiac delayed repolarisation and AV conduction in rats with diabetes were halted by zingerone. It appears that inhibition of cardiac fibrosis and associated inflammation-oxidative stress signalling underpins the zingerone effect.

The inflammatory state provokes sexual dimorphism in left ventricular and electrocardiographic effects of chronic cyclosporine in rats.

Although cardiotoxicity has been recognized as an adverse effect of cyclosporine A (CSA), no information exists regarding sex specificity of CSA cardiotoxicity. We tested the hypothesis that left ventricular (LV) and electrocardiographic (ECG) effects of CSA and related inflammatory/histopathological derangements are sex related. CSA reduced the LV slope of end-systolic pressure volume relationship and increased isovolumic relaxation constant. These effects were more pronounced in male compared to female rats, suggesting LV systolic and diastolic dysfunction. ECG recordings showed elevated ST segments and increased QTc and T peak trend intervals in CSA-treated male rats, markers of LV ischemia and arrhythmogenesis. In female rats, CSA delayed AV conduction, as reflected by prolonged PR interval. Other sex-related effects for CSA included (i) increased blood cholesterol, and reduced rates of rise and fall in LV pressure and nuclear factor kappa B and angiotensin receptors type 1 expressions in male rats, and (ii) increased LV adiponectin in females. Histopatholgically, CSA caused vascular congestion, blood extravasation, and pyknotic or even absent nuclei in both sexes. In conclusion, rats exhibit sex-independent susceptibility to negative LV and histopathological influences of CSA. These effects become more intensified in male rats, perhaps on account of aggravated ischemic and inflammatory milieus.

Geraniol alleviates diabetic cardiac complications: Effect on cardiac ischemia and oxidative stress.

The present study was planned to assess the possible protective effect of geraniol on cardiovascular complications in an animal model with diabetes. Diabetes was induced in rats by a single streptozotocin injection. In the treated group, geraniol (150mgkg-1day-1) was administered orally starting from the 15th day after induction of diabetes, and ending after 7 weeks; diabetic control rats were given vehicle for the same period. At the end of the study, cardiac contractility was assessed by using a Millar microtip catheter in anesthetised rats, and cardiac conductivity determined by a surface ECG. Serum levels of glucose, cholesterol, triglyceride and adiponectin as well as urine 8-isoprostane were determined. In addition, cardiac superoxide dismutase (SOD) and catalase activity were measured. Geraniol administration significantly alleviated the attenuated cardiac systolic function associated with diabetes as indicated by inhibiting the decrease in the rate of rise (dP/dtmax) in ventricular pressure and the increase in systolic duration observed in diabetic rats. In addition, geraniol alleviated impaired diastolic function as shown by inhibiting the decrease in the rate of fall (dP/dtmin) in ventricular pressure and increased isovolumic relaxation constant (Tau) observed in diabetic rats. ECG recordings showed that geraniol prevented any increase in QTc and T-peak-T-end intervals, and markers of LV ischemia and arrhythmogenesis, seen in diabetic animals. Geraniol suppressed the exaggerated oxidative stress as evidenced by preventing the increase in 8-isoprotane. In diabetic heart tissue, geraniol prevented the inhibition in catalase activity but did not affect the heart SOD. Geraniol partially reduced hyperglycemia, prevented the hypercholesterolemia, but did not affect the serum level of adiponectin in diabetic animals. Results obtained in this study suggest that geraniol provides a potent protective effect against cardiac dysfunction induced by diabetes. This ameliorative effect could be attributed to its suppression of oxidative stress.

Mangostanaxanthones III and IV: advanced glycation end-product inhibitors from the pericarp of Garcinia mangostana.

Advanced glycation end-products (AGEs) are associated with a non-enzymatic reaction between the amino group of a protein and the carbonyl group of a sugar during hyperglycemia. The precipitation of AGEs in different tissues leads to many complications, such as endothelial dysfunction, cardiovascular complications, atherosclerosis, retinopathy, neuropathy, and Alzheimer's disease. Garcinia mangostana L. (Clusiaceae) (GM) was selected owing to the ability of its polar and non-polar fractions to inhibit AGE formation. For the first time, the bioguided fractionation of its pericarp MeOH extract (GMT) gave rise to two new xanthones, namely, mangostanaxanthones III (1) and IV (3), in addition to six known compounds, ß-mangostin (2), garcinone E (4), rubraxanthone (5), α-mangostin (6), garcinone C (7), and 9-hydroxycalabaxanthone (8), from the non-polar faction. Their structures were verified by various spectroscopic methods, including 1D and 2D NMR studies and high-resolution MS data. All of the isolated xanthones significantly inhibited both sugar (ribose) and dicarbonyl compound (methylglyoxal)-induced protein glycation in a dose-dependent manner. This is explained by the ability of the isolated xanthones to inhibit protein oxidation, as indicated by the decreases in dityrosine and N'-formylkynurenine formation.

Phenolics from Garcinia mangostana alleviate exaggerated vasoconstriction in metabolic syndrome through direct vasodilatation and nitric oxide generation.

BACKGROUND: Exaggerated vasoconstriction plays a very important role in the hypertension, a major component of metabolic syndrome (MetS). In the current work, the potential protective effect of methanol extract of fruit hulls of Garcinia mangostana L. on the exaggerated vasoconstriction in MetS has been investigated. In addition, the bioactive fraction and compounds as well as the possible mechanism of action have been illustrated. METHODS: The effect of methanol extract of G. mangostana (GMT) fruit hulls on the vascular reactivity of aorta isolated from animals with MetS was investigated through bioassay-guided fractionation procedures. GMT was partitioned with chloroform (I) and the remaining mother liquor was fractionated on a Diaion HP-20 with H2O, 50 and 100 % methanol to give fractions II, III, and IV, respectively. The effect of total extract (GMT), bioactive fraction and the bioactive compounds on the vasoconstriction were examined in aortae isolated from animals with MetS by incubation for 30 min before exposing aortae to cumulative concentrations of phenylephrine (PE). The direct relaxant effect was also examined by adding cumulative concentrations of the bioactive fraction and its bioactive compounds to PE precontracted vessels. In addition, aortic nitric oxide (NO) and reactive oxygen species (ROS) production was investigated. RESULTS: Bioassay-guided fractionation of GMT revealed isolation of garcimangosone D (1), aromadendrin-8-C-ß-D-glucopyranoside (2), 2,4,3'-trihydroxy benzophenone-6-O-ß-D-glucopyranoside (3), maclurin-6-O-ß-D-glucopyranoside (rhodanthenone) (4), epicatechin (5), and 2,3',4,5',6-pentahydroxy benzophenone (6). Only compounds 2, 4, and 5 significantly alleviated the exaggerated vasoconstriction of MetS aortae and in the same time showed significant vasodilation of PE pre-contracted aortae. To further illustrate the mechanism of action, the observed vasodilation was completely blocked by the nitric oxide (NO) synthase inhibitor, Nω-nitro-L-arginine methyl ester hydrochloride and inhibited by guanylate cyclase inhibitor, methylene blue. However, vasodilation was not affected by the potassium channel blocker, tetraethylammonium or the cyclooxygenase inhibitor, indomethacin. In addition, compounds 2, 4, and 5 stimulated NO generation from isolated aortae to levels comparable with acetylcholine. Furthermore, 4 and 5 inhibited reactive oxygen species generation in MetS aortae. CONCLUSION: The phenolic compounds 2, 4, and 5 ameliorated the exaggerated vasoconstriction in MetS aortae through vasodilatation-NO generation mechanism.

Cardioprotection by 6-gingerol in diabetic rats.

The current study was conducted to evaluate the effect of 6-gingerol (6G) on cardiac complications in streptozotocin (STZ)-induced diabetic (DM) rats. STZ-induced DM rats (single 50 mg/kg i.p. injection, 15 days prior to drug treatment) or time-matched controls were treated with 6G (75 mg/day route orally). After a further 8 weeks, blood was collected for biochemical analysis and 8-isoprostenol was measured in urine. Cardiac hemodynamics and ECG was assessed. 6G significantly attenuated the increased level of blood glucose in diabetic rats and improved cardiac hemodynamics in including RR interval, max dP/dt, min dP/dt and Tau. In addition, 6G alleviated the elevated ST segment, T amplitude and R amplitude with no significant effect on disturbed levels of adiponectin, TGF-ß or 8-isoprostenol induced by diabetes. The results showed that treatment with 6G has an ameliorative effect on cardiac dysfunction induced by diabetes. Which may be not related to its potential antioxidant effect.

Protective effect of zingerone on increased vascular contractility in diabetic rat aorta.

The aim of the present study was to investigate the effect and possible mechanism of action of zingerone, the main constituent of ginger, on vascular reactivity in isolated aorta from diabetic rats. The results show that incubation of aortae with zingerone alleviates the exaggerated vasoconstriction of diabetic aortae to phenylephrine, as well as the impaired relaxatory response to acetylcholine in a concentration-dependent manner. Furthermore, Zingerone directly relax phenylephrine-precontracted aortae. The vasorelaxatory response is significantly attenuated by the nitric oxide synthase inhibitor Nω-nitro-l-arginine methyl ester hydrochloride and the guanylate cyclase inhibitor methylene blue but no effect of either the potassium channels blocker tetraethylammonium chloride, or the cyclooxygenase inhibitor indomethacin was observed. Zingerone had no effect on advanced glycation end product formation as well. In conclusion, zingerone ameliorates enhanced vascular contraction in diabetic aortae which may be mediated by its vasodilator effect through NO- and guanylate cyclase stimulation.

New Cerebroside and Nucleoside Derivatives from a Red Sea Strain of the Marine Cyanobacterium Moorea producens.

In the course of our ongoing efforts to identify marine-derived bioactive compounds, the marine cyanobacterium Moorea producens was investigated. The organic extract of the Red Sea cyanobacterium afforded one new cerebroside, mooreaside A (1), two new nucleoside derivatives, 3-acetyl-2'-deoxyuridine (2) and 3-phenylethyl-2'-deoxyuridine (3), along with the previously reported compounds thymidine (4) and 2,3-dihydroxypropyl heptacosanoate (5). The structures of the compounds were determined by different spectroscopic studies (UV, IR, 1D, 2D NMR, and HRESIMS), as well as comparison with the literature data. Compounds 1-5 showed variable cytotoxic activity against three cancer cell lines.

Phenolics from Garcinia mangostana Inhibit Advanced Glycation Endproducts Formation: Effect on Amadori Products, Cross-Linked Structures and Protein Thiols.

Accumulation of Advanced Glycation Endproducts (AGEs) in body tissues plays a major role in the development of diabetic complications. Here, the inhibitory effect of bioactive metabolites isolated from fruit hulls of Garcinia mangostana on AGE formation was investigated through bio-guided approach using aminoguanidine (AG) as a positive control. Including G. mangostana total methanol extract (GMT) in the reaction mixture of bovine serum albumin (BSA) and glucose or ribose inhibited the fluorescent and non-fluorescent AGEs formation in a dose dependent manner. The bioassay guided fractionation of GMT revealed isolation of four bioactive constituents from the bioactive fraction; which were identified as: garcimangosone D (1), aromadendrin-8-C-glucopyranoside (2), epicatechin (3), and 2,3',4,5',6-pentahydroxybenzophenone (4). All the tested compounds significantly inhibited fluorescent and non-fluorescent AGEs formation in a dose dependent manner whereas compound 3 (epicatechin) was found to be the most potent. In search for the level of action, addition of GMT, and compounds 2-4 inhibited fructosamine (Amadori product) and protein aggregation formation in both glucose and ribose. To explore the mechanism of action, it was found that addition of GMT and only compound (3) to reaction mixture increased protein thiol in both glucose and ribose while compounds 1, 2 and 4 only increased thiol in case of ribose. In conclusion, phenolic compounds 1-4 inhibited AGEs formation at the levels of Amadori product and protein aggregation formation through saving protein thiol.

6-Gingerol alleviates exaggerated vasoconstriction in diabetic rat aorta through direct vasodilation and nitric oxide generation.

The aim of the present study is to investigate the effect and potential mechanism of action of 6-gingerol on alterations of vascular reactivity in the isolated aorta from diabetic rats. Male Wistar rats were divided into two experimental groups, control and diabetics. Diabetes was induced by a single intraperitoneal injection of streptozotocin (50 mg kg(-1)), and the rats were left for 10 weeks to develop vascular complications. The effect of in vitro incubation with 6-gingerol (0.3-3 µM) on the vasoconstrictor response of the isolated diabetic aortae to phenylephrine and the vasodilator response to acetylcholine was examined. Effect of 6-gingerol was also examined on aortae incubated with methylglyoxal as an advanced glycation end product (AGE). To investigate the mechanism of action of 6-gingerol, the nitric oxide synthase inhibitor Nω-nitro-l-arginine methyl ester hydrochloride (100 µM), guanylate cyclase inhibitor methylene blue (5 µM), calcium-activated potassium channel blocker tetraethylammonium chloride (10 mM), and cyclooxygenase inhibitor indomethacin (5 µM) were added 30 minutes before assessing the direct vasorelaxant effect of 6-gingerol. Moreover, in vitro effects of 6-gingerol on NO release and the effect of 6-gingerol on AGE production were examined. Results showed that incubation of aortae with 6-gingerol (0.3-10 µM) alleviated the exaggerated vasoconstriction of diabetic aortae to phenylephrine in a concentration-dependent manner with no significant effect on the impaired relaxatory response to acetylcholine. Similar results were seen in the aortae exposed to methylglyoxal. In addition, 6-gingerol induced a direct vasodilation effect that was significantly inhibited by Nω-nitro-l-arginine methyl ester hydrochloride and methylene blue. Furthermore, 6-gingerol stimulated aortic NO generation but had no effect on AGE formation. In conclusion, 6-gingerol ameliorates enhanced vascular contraction in diabetic aortae, which may be partially attributed to its ability to increase the production of NO and stimulation of cyclic guanosine monophosphate.

Quality by design coupled with near infrared in formulation of transdermal glimepiride liposomal films.

This study is aimed at developing glimepiride (GMD) liposomal films using quality by design (QbD) and process analytical technology (PAT) principles. Risk analysis and Plackett-Burman design were utilized to evaluate formulation variables in two paths. Internal path included liposomal parameters (phosphatidylserine, cholesterol and drug concentrations, and pH of hydration medium). External path constituted films parameters, namely, polymer, plasticizer, and permeation enhancer percentages. As a PAT tool, near infrared (NIR)-based chemometric analysis was used in quantifying GMD contents. Liposomal formulations showed maximum GMD entrapment capacity of 41.9% with vesicular size of 0.51 µm at phospholipid to cholesterol to drug weight ratio of 2:1:0.8. Its transdermal films showed elongation ratio of 75%, folding endurance of 700-fold, 16.6% and 26.8% drug release after 1 and 12 h, respectively. Moreover, 3D response spaces for GMD entrapment and release characteristics were established. Regarding NIR analysis, partial-least-square regression model was accurate in quantifying drug content as indicated by the low root-mean-squared error of calibrations and prediction of 0.031 and 0.032, and bias values of 0.0015 and 0.0021, respectively. In conclusion, this study highlights the level of understanding that can be accomplished through a well-designed research based on QbD and PAT paradigms.

Solid lipid nanoparticles loaded with iron to overcome barriers for treatment of iron deficiency anemia.

According to the World Health Organization, 46% of the world's children suffer from anemia, which is usually treated with iron supplements such as ferrous sulfate. The aim of this study was to prepare iron as solid lipid nanoparticles, in order to find an innovative way for alleviating the disadvantages associated with commercially available tablets. These limitations include adverse effects on the digestive system resulting in constipation and blood in the stool. The second drawback is the high variability in the absorption of iron and thus in its bioavailability. Iron solid lipid nanoparticles (Fe-SLNs) were prepared by hot homogenization/ultrasonication. Solubility of ferrous sulfate in different solid lipids was measured, and effects of process variables such as the surfactant type and concentration, homogenization and ultrasonication times, and charge-inducing agent on the particle size, zeta potential, and encapsulation efficiency were determined. Furthermore, in vitro drug release and in vivo pharmacokinetics were studied in rabbits. Results indicated that Fe-SLNs consisted of 3% Compritol 888 ATO, 1% Lecithin, 3% Poloxamer 188, and 0.2% dicetylphosphate, with an average particle size of 25 nm with 92.3% entrapment efficiency. In vivo pharmacokinetic study revealed more than fourfold enhanced bioavailability. In conclusion, Fe-SLNs could be a promising carrier for iron with enhanced oral bioavailability.

2,3-seco-2,3-dioxo-lyngbyatoxin A from a Red Sea strain of the marine cyanobacterium Moorea producens.

Chemical investigation of the organic extract of a Red Sea strain of the cyanobacterium Moorea producens has afforded 2,3-seco-2,3-dioxo-lyngbyatoxin A (1). Five known compounds including lyngbyatoxin A (2), majusculamides A and B (3 and 4), aplysiatoxin (5) and debromoaplysiatoxin (6) were also isolated. Their structures were elucidated by using HR-FAB-MS, 1D and 2D NMR analyses. The compounds were evaluated for antiproliferative activity against HeLa cancer cells. Lyngbyatoxin A (2) showed potent activity, with an IC50 of 9.2 nM, while 5 and 6 displayed modest activity with IC50 values of 13.3 and 3.03 µM, respectively. In contrast, compounds 1, 3 and 4 were inactive, with IC50 values greater than 50 µM. The lack of cytotoxicity for 2,3-seco-2,3-dioxo-lyngbyatoxin A (1) demonstrates that the indole moiety in lyngbyatoxin (2) is essential for its cytotoxicity, and suggests that detoxification of 2 may be carried out by biological oxidation of the indole moiety to yield 1.

Optimization of self-nanoemulsifying systems for the enhancement of in vivo hypoglycemic efficacy of glimepiride transdermal patches.

OBJECTIVES: To optimize and use of glimepiride (GMD)-loaded self-nanoemulsifying delivery systems (SNEDs) for the preparation of transdermal patches. METHODS: Mixture design was utilized to optimize GMD-loaded SNEDs in acidic and aqueous pH media. Optimized GMD-loaded SNEDs were used in the preparation of chitosan (acidic) and hydroxypropyl methyl cellulose (HPMC) (aqueous) films. The prepared optimized formulations were investigated for ex vivo skin permeation, for in vivo hypoglycemic activity and for their pharmacokinetic parameters using animal model. RESULTS: The optimized formulations showed flux value of (2.88 and 4.428 µg/cm(2)/h) through rat skin for chitosan and HPMC films, respectively. The pattern of GMD release from both formulations was in favor of Higuchi and approaching zero order models. The n values for Korsmeyer-Peppas equation were characteristic of anomalous (non-Fickian) release mechanism. Moreover, HPMC patches have shown significant reductions (p < 0.05) in blood glucose levels; (213.33 ± 15.19) mg/100 ml from the base-line measurement after 12 h of application. CONCLUSIONS: Optimized GMD SNEDs patches were found to improve GMD skin permeability and the essential pharmacokinetic parameters. Further extensive pre/clinical studies are necessary prior to use transdermal GMD as a valuable alternative to peroral dosage forms with improved bioavailability, longer duration of action and more patient convenience.

The formulation of a nasal nanoemulsion zaleplon in situ gel for the treatment of insomnia.

BACKGROUND: Zaleplon is a drug used for the treatment of insomnia and is available in tablet form; however, it has two major problems. First, the drug undergoes extensive first pass metabolism, resulting in only 30% bioavailability, and second, the drug has a poor aqueous solubility, which delays the onset of action. OBJECTIVE: The objective of this study is to utilise nanotechnology to formulate zaleplon into a nasal in situ nanoemulsion gel (NEG) to provide a solution for the previously mentioned problems. METHODS: The solubility of zaleplon in various oils, surfactants and co-surfactants was estimated. Pseudo-ternary phase diagrams were developed and various nanoemulsion (NE) formulations were prepared; these formulations were subjected to visual characterisation, thermodynamic stability study and droplet size and conductivity measurements. Carbopol 934 was used as an in situ gelling agent. The gel strength, pH, gelation time, in vitro release and ex vivo nasal permeation were determined. The pharmacokinetic study of the NEG was carried out in rabbits. RESULTS: Stable NEs were successfully developed with a droplet size range of 35 to 73 nm. A NEG composed of 15% Miglyol, 30% Labrasol and 10% PEG 200 successfully provided the maximum in vitro and ex vivo permeation and enhanced the bioavailability in the rabbits by eightfold, when compared with the marketed tablets. CONCLUSION: The nasal NEG is a promising novel formula for zaleplon that has higher nasal tissue permeability and enhanced systemic bioavailability.

Crystallization of a new polymorph of acetohexamide from 2-hydroxybutyl-ß-cyclodextrin solution: form VI with a high aqueous solubility.

A new polymorph of acetohexamide (Form VI) was prepared via the formation of a complex with 2-hydoxybutyl-ß-cyclodextrin (HB-ß-CD) in aqueous solution. An alkaline solution of acetohexamide and HB-ß-CD was adjusted to pH 4.0 by titration with hydrochloric acid. The resulting opaque solution was filtered through paper and allowed to stand at 4°C for 24h. The resulting precipitate was isolated on a filter and analyzed for polymorph content by powder X-ray diffractometry and thermal analysis. The diffraction pattern and thermal behavior of the precipitate was different from those of previously reported acetohexamide polymorphs (Forms I, III, IV and V), indicating that a new polymorph of the drug, i.e. Form VI was produced. This new polymorph was fairly stable against conversion to a stable form even at accelerated storage conditions. Crystalline Form VI was highly soluble in water and dissolved more rapidly than the other known polymorphs. This property was reflected in the blood concentrations of the drug after oral administration to rats.

Effect of nonylphenol on male reproduction: analysis of rat epididymal biochemical markers and antioxidant defense enzymes.

The mechanism by which nonylphenol (NP) interferes with male reproduction is not fully elucidated. Therefore, the present study was conducted to evaluate the effect of NP on male reproductive organ's weight, sperm characteristics, and to elucidate the nature and mechanism of action of NP on the epididymis. Adult male Wistar rats were gavaged with NP, dissolved in corn oil, at 0, 100, 200 or 300mg/kg/day for 30 consecutive days. Control rats were gavaged with vehicle (corn oil) alone. Body weight did not show any significant change while, absolute testes and epididymides weights were significantly decreased. Sperm count in cauda and caput/corpus epididymides, and sperm motility was significantly decreased. Daily sperm production was significantly decreased in a dose-related manner. Sperm transit time in cauda epididymis was significantly decreased by 300mg/kg, while in the caput/corpus epididymis it was significantly decreased by 200 and 300mg/kg of NP. Plasma LDH was significantly increased while; plasma testosterone was significantly decreased in a dose-related pattern. In the epididymal sperm, NP decreased acrosome integrity, Δψm and 5'-nucleotidase activity. Hydrogen peroxide (H(2)O(2)) production and LPO were significantly increased in a dose-related pattern. The activities of SOD, CAT and GPx were significantly decreased in the epididymal sperm. In conclusion, this study revealed that NP treatment impairs spermatogenesis and has a cytotoxic effect on epididymal sperm. It disrupts the prooxidant and antioxidant balance. This leads oxidative stress in epididymal sperms of rat. Moreover, the reduction in sperm transit time may affect sperm quality and fertility potential.

Mitochondrial dysfunction induced impairment of spermatogenesis in LPS-treated rats: modulatory role of lycopene.

The current study investigates the potential toxicity of lipopolysaccharide (LPS) on the mitochondrial fraction of rat testis and the possible protective efficacy of lycopene. Adult male Wistar rats were categorized into four groups. Two groups were administered LPS (0.1mg/kg/day for 7 days i.p.); one of these groups received lycopene treatment (4 mg/kg/day by oral gavage, 24h before LPS treatment) (Group IV) and the other received LPS alone (Group III). A vehicle-treated group (Group I) and a lycopene drug control group (Group II) were also included. Sperm count and motility were significantly decreased in Group III. The testicular mitochondrial fraction of Group III showed significant increase in basal and Fe(2+)-induced lipid peroxidation, along with a significant increase in hydrogen peroxide (H(2)O(2)) level. Moreover, the activities of mitochondrial enzymic (SOD, CAT, GPx, GR and ADH) and non-enzymic (GSH and ascorbate) antioxidants levels were decreased. Group III also showed decline in the activities of TCA enzymes such as SDH, MDH and ICDH. Pretreatment with lycopene showed normal sperm parameters, lipid peroxidation, H(2)O(2) level, antioxidant defenses and TCA enzyme activities. In conclusion, this study indicates that LPS-induced oxidative stress leads to functional damages in the testicular mitochondria. Lycopene pretreatment provided a marked normalization in these parameters.