Lacidipine self-nanoemulsifying drug delivery system for the enhancement of oral bioavailability

Low bioavailability of Lacidipine (LD), an calcium channel blocker pose many challenges in the treatment of hypertension. The objective of this study was to formulate and characterize LD self-nanoemulsifying drug delivery systems (SNEDDS) to improve oral bioavailability of the drug. Formulations were evaluated for globule size, surface morphology, emulsification time, cloud point, drug content, in vitro dissolution, ex vivo permeation, stability and oral bioavailability studies. Captex 810D, TPGS, Tween-60, Transcutol P and PEG 400 was selected based on the solubility study results. The optimized SNEDDS readily gets nanoemulsified at 37 °C with droplet size of 41 nm when mixed with 200 times of its water. Transmission electron microscope photographs confirmed the spherical shape of the globules. In vitro dissolution of SNEDDS showed more than 80 % of drug release within 15 min. The ex vivo permeation of LD from SNEDDS is 4.8- and 9-fold higher compared to pure drug in the absence and presence of verapamil respectively. The stability study of the SNEDDS confirmed no environmental effect on the physical nature and drug content. Oral bioavailability of SNEDDS is 2.5 times higher than marketed tablet. The results suggest that, the SNEDDS formulation can be used as a possible alternative for the traditional oral formulations of LD to improve its oral bioavailability.     

Retinoblastoma associated with orbital pseudocellulitis and high-risk retinoblastoma: a study of 32 eyes

International Ophthalmology - To study the correlation between retinoblastoma (RB) associated with orbital pseudocellulitis and high-risk histopathology features. Retrospective study of 32 patients...     

Evaluation of anti-ulcer activity of Samanea saman (Jacq) merr bark on ethanol and stress induced gastric lesions in albino rats

Objective:

To evaluate the antiulcer activity of Samanea saman (Jacq) Merr bark on ethanol and stress induced gastric lesions in albino rats.

Materials and Methods:

Gastric lesions were induced in rats by oral administration of absolute ethanol (5 ml/kg) and stress induced by water immersion. The antiulcer activity of methanolic extract of Samanea saman (Jacq) Merr bark (100 mg/kg, 200 mg/kg, 400 mg/kg) was compared with standard drugs. The parameters studied were ulcer index, gastric juice volume, pH, free acidity and total acidity.

Result:

Samanea saman (Jacq) Merr showed a dose dependent curative ratio compared to ulcer control groups. The extract at 400 mg/kg showed significant anti ulcer activity which is almost equal to that of the standard drug in both models. The volume of acid secretion, total and free acidity was decreased and pH of the gastric juice was increased compared to ulcer control group.

Conclusions:

The present study indicates that Samanea saman (Jacq) Merr bark extracts have potential anti ulcer activity.     

Modeling chronic olanzapine exposure using osmotic minipumps: pharmacological limitations

Animal models can face unique challenges in mirroring what occurs in humans. This is the case for antipsychotics in rodents, where these drugs are metabolized much more rapidly. One strategy to address this issue has been the use of osmotic minipumps to ensure continuous antipsychotic exposure over prolonged intervals, which is routinely the case when these same drugs are administered to humans. More recently, it has been identified that with olanzapine this approach may be compromised by oxidative degradation, a process that can be observed within days. Further, in vivo evidence has reported progressive decreases in plasma levels over a 1-month interval. To address this issue in vitro, osmotic minipumps (n = 4), with olanzapine at a concentration resulting in a dose of 7.5 mg/kg/day in vivo, were placed in saline-filled Falcon tubes and immersed in a water bath. Olanzapine concentrations were assessed in the minipumps as well as the surrounding water bath at baseline, 1 h, and days 1, 7, 14, 21, and 28. Minipump results indicated a monophasic exponential decay and a half-life of 14.8 days (95% CI = 13.1-17.1 days). Results from the water bath demonstrated a linear increase in olanzapine up to and including day 21, followed thereafter by a decrease to day 28. It is concluded that administration of olanzapine via osmotic minipump is viable in animal models to mirror what occurs in humans, although the interval should be confined to 2 weeks. As well, strategies in dissolving olanzapine to diminish oxidation are discussed.     

Evaluation of a new p16(INK4A) ELISA test and a high-risk HPV DNA test for cervical cancer screening: results from proof-of-concept study

p16(INK4a), a cell cycle regulation protein, accumulates in abnormal epithelial cells infected with high-risk human papilloma virus (HPV). In immunostaining studies, p16(INK4a) has shown potential as a marker of high grade cervical intraepithelial neoplasia (CIN) and invasive cervical cancer. To evaluate its potential use in cervical cancer screening, we conducted a feasibility study to compare the performance of a new enzyme linked immunosorbant assay (ELISA) for p16(INK4a) (mtm laboratories, Heidelberg, Germany) to that of the Hybrid Capture 2 (hc2) test for high-risk HPV DNA for the detection of CIN3. Three hundred and nineteen women were referred from Western Washington Planned Parenthood clinics for colposcopy examination and cervical biopsy because of abnormal Pap test results. Cervical samples were obtained from study participants for p16(INK4a) ELISA, liquid-based cytology and hc2. The order (first and second) for obtaining samples for cervical cytology and p16(INK4a) ELISA changed with every other subject. Concentrations of p16(INK4a) protein were higher when the sample was taken before the cytology. The sensitivity of p16(INK4a) ELISA (concentration > or = 8 units/ml) taken as first sample was 90.0% for CIN3, and the sensitivity of HC2 taken as a second sample was 85%. In the same group, the specificity of p16(INK4a) ELISA (46.9%) was slightly better than hc2 (35.4%) Results from this proof-of-concept study suggest that p16(INK4a) ELISA has a similar sensitivity and slightly better specificity for CIN3 compared to hc2. These findings support proceeding with a larger study with samples from a population of women presenting for routine cytology screening.     

Laparoscopic management of remnant cystic duct calculi: a retrospective study

INTRODUCTION

Even though cholecystectomy relieves symptoms in the majority of cases, a significant percentage suffer from ‘postcholecystectomy syndrome’. Cystic duct/gall bladder remnant calculi is a causative factor. We present our experience with the laparoscopic management of cystic duct remnant calculi.

PATIENTS AND METHODS

We managed 15 patients with cystic duct remnant calculi from 1996 to 2007 in our institute. All these patients had earlier undergone laparoscopic subtotal cholecystectomy at our centre. They were successfully managed by laparoscopic excision of the remnant.

RESULTS

The mean duration between first and second surgery was 8.35 months (range, 6–10.7 months). The mean operating time was 103.5 min (range, 75–132 min). Duration of hospital stay was 4–12 days. There was a higher incidence of remnant duct calculi following laparoscopic subtotal cholecystectomy than conventional laparoscopic cholecystectomy 13/310 (4.19%) versus 2/9590 (0.02%). The morbidity was 13.33%, while there were no conversions and no mortality.

CONCLUSIONS

Leaving behind a cystic duct stump for too long predisposes stone formation, while dissecting too close to the common bile duct and right hepatic artery in acute inflammatory conditions is dangerous. We believe that the former is a wiser policy to follow, as cystic duct remnant calculi are easier to manage than common bile duct or vessel injury. Laparoscopic excision of the remnant is effective, especially when performed by experienced laparoscopists. ‘T’-tube is used to canulate the common bile duct in case the tissue is friable. Magnetic resonance cholangiopancreaticography is the imaging modality of choice, and is mandatory.     

The effects of carbamazepine on sperm morphology in wistar rats

Carbamazepine (5 H-dibenz (b, f) azepine-5-carboxamide), is an antiepileptic drug which is expected to be administered regularly over a substantial part of patients lifetime. As the gender focus in epilepsy the later years has primarily been on women, there certainly is a lack of studies focused on the effects particular to men. The present study was aimed to investigate its effects on germ cell's by employing the sperm morphology assay. Twelve groups of male wistar rats were treated with sterile water 0.5 ml, cyclophosphamide (CP) 20 mg/kg, carbamazepine 9, 18, 36 mg/kg (i.p) and 2% gumacasia 0.25 ml/100 g respectively for 5 consecutive days at intervals of 24 hrs. Following the last exposure, on days 14 and 35 sperm morphology assay was conducted as per the standard procedure. Mann-Whitney 'U' test was used for statistical analysis and the level of significance was P<0.01. Neither carbamazepine nor cyclophosphamide induced formation of abnormally shaped sperms at 14 day time interval. Whereas on day 35, with 18 mg/kg dose level of carbamazepine there was an increase in the number of sperms with heads defects (P<0.01); Whereas in the other two dose levels the number of abnormally shaped sperms had decreased. 2% gumacasia increased the number of sperms with tail defects at day 35. (Mann-Whitney 'U' test). CONCLUSION: Carbamazepine and 2% gumacasia could be germ cell mutagens and could cause infertility on prolonged use therefore further studies with serum drug level estimations are needed.     

Antitumor Activity of the Methanol Extract of Hypericum hookerianum Stem Against Ehrlich Ascites Carcinoma in Swiss Albino Mice

A large number of plants belonging to the Hypericum family are known to possess strong antitumor properties. The methanol extract of H. hookerianum Wight and Arnott stem (MEHH) exhibited potent in vitro cytotoxic activity against various cancerous cell lines. In the present study, the high performance liquid chromatography (HPLC) standardized MEHH was tested for in vivo antitumor properties against Ehrlich ascites carcinoma (EAC) tumor bearing mice at 100, 200, and 400 mg/kg body weight doses given orally once daily for 14 days. The results indicate that administration of the extract not only increased the survival of animals with ascites tumor, decreased the body weight induced by the tumor burden, and reduced packed cell volume and viable tissue cell count, but also altered many hematological parameters changed during tumor progression, indicating the potent antitumor nature of the extract. Among the three doses tested, the 200 mg/kg body weight dose was found to be the most potent.     

In vitro–in vivo correlation of voriconazole resistance due to G448S mutation (cyp51A gene) in Aspergillus fumigatus

Invasive pulmonary aspergillosis continues to be associated with a high mortality despite timely and appropriate therapy. Although host immunity plays a major role in poor clinical response, antifungal drug resistance cannot be ignored. Our studies were aimed 1) to study the mechanism of drug resistance in voriconazole strains of Aspergillus fumigatus, 2) to establish a causal relationship between cyp51A mutation and voriconazole resistance (VRC-R), and 3) to determine whether VRC-R due to cyp51A mutation correlated with in vivo resistance. A point mutation (G448S) involving cyp51A gene in VRC-R isolate was associated with resistance to VRC but not to posaconazole (POS); POS had superior activity to VRC in reducing lung fungal burden and mortality in mice infected with a VRC-R mutant of A. fumigatus. Our study demonstrated that azole resistance is based on specific site of cyp51A mutation and that in vitro VRC-R correlates with in vivo resistance.