Effect of polydimethylsiloxane and ethylcellulose on in vitro permeation of centchroman from its transdermal patches.

This research aims at the development of controlled release contraceptive transdermal patches of centchroman using ethylcellulose (EC) as film-forming polymer, polydimethylsiloxane (PDMS) as pressure sensitive adhesive with propylene glycol and Di-n-butyl-phthalate for their penetration enhancer and plasticizing properties, respectively. The physicochemical compatibility of the drug and the polymers was performed by differential scanning calorimetry and Fourier transform infrared (FTIR) spectroscopic technique. Effects of EC and PDMS ratios on moisture uptake, moisture content, tensile strength (TS), Young's modulus, adhesive strength, water vapor transmission rate (WVTR) and in vitro permeation of centchroman through Sprague-Dawley rats abdominal skin using Franz's diffusion cell were evaluated. A 3(2) full factorial design was employed to observe the effect of independent variables; concentration of ethyl cellulose and PDMS on drug permeated after 32 h, which was selected as dependent variable. Compatibility studies suggested that there were no significant interaction between the drug and polymers used. It was found that incorporation of only EC resulted in too hard patches and addition of PDMS produced patches with lower TS, increased percentage elongation, WVTR and Young's modulus. Statistical analyses suggested that independent variables have a significant effect on the dependent variable. All formulation follows zero-order release kinetics with r(2) > 0.990. In conclusion, drug in adhesive transdermal patches can be successfully fabricated for non-steroidal contraceptive centchroman to obtain a zero-order release systems.

Withania somnifera shows a protective effect in monocrotaline-induced pulmonary hypertension.

CONTEXT: Withania somnifera (Linn.) Dunal (Solanaceae), a clinically used herbal drug in Ayurveda, shows potent antioxidant, anti-inflammatory, pro-apoptotic, and cardioprotective effects. However, the efficacy of W. somnifera in pulmonary hypertension (PH), a cardiopulmonary disorder, remains unexplored. OBJECTIVE: The present study investigates the effect of W. somnifera root powder on monocrotaline (MCT)-induced PH in rats. MATERIALS AND METHODS: In preventive studies, W. somnifera root powder (50 and 100 mg/kg/d, p.o.) was administered from day 1 following single administration of MCT (60 mg/kg, s.c.) in Sprague-Dawley (SD) rats. After 35 d, right ventricular pressure (RVP) was measured in anesthetized rats. Various physical markers of right ventricular hypertrophy (RVH) were measured in isolated hearts. Markers of endothelial function, inflammation, and oxidative stress were estimated in lung homogenate. Vasoreactivity of pulmonary arteries was also studied. In therapeutic treatment, W. somnifera (50 and 100 mg/kg/d, p.o.) was administered from day 21 to 35 post-MCT administration. RESULTS: Preventive treatment with 50 and 100 mg/kg W. somnifera significantly reduced the RVP (32.18 ± 1.273 mm Hg and 29.98 ± 1.119 mm Hg, respectively, versus 42.96 ± 1.789 mm Hg of MCT) and all markers of RVH in MCT-challenged rats. There was an improvement in inflammation, oxidative stress and endothelial dysfunction, and attenuation of proliferative marker and apoptotic resistance in lungs. Therapeutic treatment with W. somnifera (100 mg/kg) also reduced RVP and RVH. DISCUSSION: This study demonstrated that W. somnifera significantly protected against MCT-induced PH due to its antioxidant, anti-inflammatory, pro-apoptotic, and cardioprotective properties.

Stability indicating studies on NMITLI 118RT+ (standardized extract of withania somnifera dunal).

BACKGROUND: Withania somnifera Dunal (Ashwagandha) is an Indian medicinal plant of great medicinal value; used in many clinically proven conditions. NMITLI-118RT+ is a candidate drug under a Council of Scientific and Industrial Research (CSIR) networking project. It is a chemotype of W. somnifera's root extract, which has been used for the present study. OBJECTIVES: The present investigation aims to develop and validate a simple isocratic reverse phase-high performance liquid chromatography (RP-HPLC) system for the detection and estimation of Withanolide A (marker compound) and its analytical application for stability indicating studies on NMITLI-118RT+. MATERIAL AND METHODS: A validated RP-HPLC method for Withanolide A was established on a Waters HPLC system and the same was used on NMITLI-118RT+ for quantification and fingerprinting purposes, and for establishing forced degradation, isothermal stress tests, and drug-excipient testing protocols as per International Conference on Harmonization (ICH) guidelines. RESULTS: A validated method was established, which could detect the marker at a retention time of around 6.3 minutes, with a linearity range of 2-100 µg/mL, by varying the amounts of the said marker, which were estimated in four different batches of NMITLI-118RT+. Photostability as per ICH guidelines suggested a slight loss of the active constituent and maximum degradation was afforded with alkali followed by acid, and then peroxide, in the forced degradation studies. In the drug-excipient studies, the maximum amount of active constituent could be detected in the samples with ethyl cellulose and the least with hydroxy propyl cellulose. CONCLUSION: The method developed here was simple and rapid. The various stability indicating studies carried out in the present investigation would be useful for formulation development and were suggestive of deciding the recommended storage conditions for NMITLI-118RT+.

Design and synthesis of γ-butyrolactone derivatives as potential spermicidal agents.

A series of γ-butyrolactone derivatives has been designed and synthesized from commercially available 2-acetyl butyrolactone (3-acetyldihydrofuran-2(3H)-one, 1) by aminoalkylating its active methylene followed by condensation with different aldehydes. Compounds having amino group were further converted to their respective tartrate salts and were evaluated for spermicidal activity against human sperm in vitro. Compounds showing appreciable spermicidal activity at ⩽0.5% [3c, 4d (0.5%); 2c, 3d (0.1%); 2d, 4c (0.05%)] were tested for safety studies against human cervical (HeLa) cell line. These compounds were found safer than, Nonoxynol-9. One of the two most active compounds was also found to be the safest (IC50=961 µg/ml; 4c), while the second compound exhibited lower safety against HeLa (IC50=269 µg/ml; 2d). The compound 4c significantly reduced the number of free thiols on human sperm. All the compounds were inactive against Trichomonas vaginalis.

Assay method for quality control and stability studies of a new antimalarial agent (CDRI 99/411).

CDRI compound no. 99/411 is a potent 1,2,4-trioxane antimalarial candidate drug under development at our Institute. An HPLC method for determination of CDRI 99/411 with its starting material and intermediates has been developed and validated for in process quality control and stability studies. The analytical performance parameters such as linearity, precision, accuracy, specificity, limit of detection (LOD) and lower limit of quantification (LLOQ) were determined according to International Conference on Harmonization ICH Q2(R1) guidelines. HPLC separation was achieved on a RP-select B Lichrosphere® column (250 mm×4 mm, 5 µm, Merck) using water containing 0.1% glacial acetic acid and acetonitrile as the mobile phase in a gradient elution. The eluents were monitored by a photo diode array detector at 245 and 275 nm. Based on signal to noise ratio of 3 and 10 the LOD of CDRI 99/411 was 0.55 µg/mL, while the LLOQ was 1.05 µg/mL. The calibration curves were linear in the range of 1.05-68 µg/mL. Precision of the method was determined by inter- and intra-assay variations within the acceptable range.

Effect of angiotensin II on spatial memory, cerebral blood flow, cholinergic neurotransmission, and brain derived neurotrophic factor in rats.

RATIONAL: Studies have shown the involvement of angiotensin II (Ang II) in neurobehavioral aspects, but the exact role of Ang II in memory is still ambiguous. OBJECTIVE: This study explored the effect of central Ang II on spatial memory along with cholinergic neurotransmission, brain energy metabolism, cerebral blood flow (CBF), and brain-derived neurotrophic factor (BDNF) in rats. METHODS: Spatial memory was evaluated by Morris water maze (MWM) after Ang II (ICV) administration in male Sprague-Dawley rats. CBF was measured by laser Doppler flowmetry. Oxidative stress adenosine triphosphate (ATP), BDNF, acetylcholinesterase (AChE), and acetylcholine (ACh) were estimated in the cortex and hippocampus at 1, 24, and 48 h after Ang II administration. The effect of AT1 and AT2 receptor blocker (candesartan and PD123,319, respectively), AChE inhibitor (donepezil), and antioxidant melatonin was studied on memory, CBF, and biochemical parameters. RESULTS: Ang II caused spatial memory impairment by affecting acquisition, consolidation, and recall in the MWM test along with a significant reduction in CBF. Ang II significantly reduced ACh level and caused oxidative stress in the rat brain 1 h post-injection. No significant change was observed in BDNF, AChE, and ATP level. Candesartan and donepezil prevented Ang II-induced memory impairment, reduction in CBF and ACh level. However, PD123,319 and melatonin failed to prevent Ang II-induced memory impairment but improved CBF partially. CONCLUSION: This study suggests that Ang II, via the AT1 receptor, affects spatial memory formation, CBF, and ACh level while AT2 receptor has no significant role.

Protective effect of fruits of Morinda citrifolia L. on scopolamine induced memory impairment in mice: a behavioral, biochemical and cerebral blood flow study.

ETHNOPHARMACOLOGICAL RELEVANCE: Noni (Morinda citrifolia L.) is widely used for different illnesses including CNS disorders. Recently Noni has been reported to prevent amyloid beta induced memory impairment in mice. However, the influence of Noni on cholinergic system has not been explored so far. Therefore, present study was designed to investigate effect of Noni fruit on memory, cerebral blood flow (CBF), oxidative stress and acetylcholinesterase (AChE) activity in scopolamine induced amnesia model. MATERIALS AND METHODS: Mice were orally treated with ethanolic extract of Noni fruit and chloroform, ethyl acetate and butanol fractions of ethanolic extract for three days. Scopolamine was administered 5 min prior to acquisition trial and memory function was evaluated by passive avoidance test. CBF was measured by laser doppler flowmetry. AChE activity and oxidative stress parameters were estimated in mice brain at the end of behavioral studies. Further, effect of ethanolic extract and its fractions (5-400 µg/ml) on AChE activity was measured in vitro. RESULTS: Scopolamine caused memory impairment along with reduced CBF, increased AChE activity and oxidative stress in mice brain. Ethanolic extract of Noni fruits and its chloroform and ethyl acetate fractions significantly improved memory and CBF. However, butanol fraction had no effect. Further, increased oxidative stress and AChE activity following scopolamine was significantly attenuated by ethanolic extract of Noni and its fractions. Moreover ethanolic extract and its fractions showed dose dependent inhibition of AChE activity in vitro. CONCLUSION: These observations suggest that Noni may be useful in memory impairment due to its effect on CBF, AChE and oxidative stress.