Inhibitory effect of the angiogenesis inhibitor o- (chloroacetyl-carbamoyl) fumagillol (TNP-470) on tumor growth and metastasis of murine mammary tumor cell line (JYG-B) inoculated in female nude mice

The effect of the potent angiogenesis inhibitor O-(chloroacetyl-carbamoyl) fumagillol(TNP-470), a semisynthetic analogue of fumagillin on tumor growth and metastasis was studied using murine mammary tumor cells (JYG-B) inoculated into female nude mice. Injection of TNP-470 at 10 and 30 mg/kg doses, 3 times a week, until the end of the experiment (41 days)inhibited the s.c.inoculated primary tumor growth in a dose-dependent manner (45%and 65% in volume, respectively). TNP-470 at 30 and 60 mg/kg doses, 3 times a week, until the end of the experiment (35 days), reduced the weight of the i.p. inoculated total tumor mass of abdominal dissemination in a dose-dependent manner (54% and 76%, respectively). Pulmonary metastasis was found in all mice but TNP-470 significantly reduced the lung weight reflecting the total volume of the metastatic foci, and the numbers of metastatic foci in the liver and kidneys was reduced by TNP-470 treatment. These findings show that the angiogenesis inhibitor (TNP-470)has a strong inhibitory effect on tumor grwoth and metastasis in vivo.     

Association between sperm quality, oxidative stress, and seminal antioxidant activity

Objectives

To determine seminal antioxidant capacity, oxidative stress markers, and their association with semen quality as oxidative stress is considered to be a major etiological factor in male infertility.

Subjects and methods

Semen samples were obtained from 138 men and categorized on the basis of sperm count, motility, and morphology. Seminal oxidative and antioxidant markers are as follows: lipid peroxidation (LPO), protein carbonyls (PC), superoxide dismutase (SOD), catalase (CAT), thiols, and ascorbic acid were determined.

Results

Sperm count significantly correlated positively with progressive sperm motility and normal morphology. Sperm count and normal morphology showed significant negative correlation with LPO and PC. Sperm count and progressive motility showed significant positive relationship with SOD. The SOD, CAT, and thiols positively whereas LPO and PC negatively associated with elevated sperm count.

Conclusion

Insufficient antioxidant enzymes and increased oxidative stress may attribute to the risk of declining semen quality and hence protective role for antioxidant enzymes against the oxidative damage cannot be ruled out.     

Neonatal seizures: controversies and challenges in translating new therapies from the lab to the isolette

Neonatal seizures have unique properties that have proved challenging for both clinicians and basic science researchers. Clinical therapies aimed at neonatal seizures have proven only partially effective and new therapies are slow to develop. This article will discuss neonatal seizures within the framework of the barriers that exist to the development of new therapies, and the challenges inherent in bringing new therapies from the bench to the bedside. With the European Union and USA creating national collaborative project infrastructure, improved collaborative resources should advance clinical research on urgently needed new therapies for this disorder.     

Dopamine release is involved in antinociceptive effect of theophylline

The methylxanthines, e.g., theophylline, are widely used for the treatment of bronchial asthma. Additionally, a pain relieving effect of theophylline has been reported in patients as well as in experimental animals. The mechanism of this antinociceptive action is not clear. In this study, involvement of dopaminergic system in theophylline-induced antinociception was evaluated using tail flick test model. Swiss albino mice, (either sex, weighing 25-30 g) with base line tail flick latencies (TFL) between 2.0 and 3.5 s, were used. TFL was recorded before and at intervals of 15, 30, 45, and 60 min. after drug treatment. The experimental protocol was duly approved by the Institutional Animal Ethics Committee, All India Institute of Medical Sciences, New Delhi, India. To determine the role of dopaminergic system, the mice were pretreated with either D1 or D2 dopaminergic receptor antagonists SCH 23390 and haloperidol, respectively, prior to treatment with theophylline. Another group of animals received apomorphine along with theophylline. The dose of theophylline used, i.e., 10 mg/kg, intraperitoneally (i.p.), had shown a significant increase in TFLs. The theophylline-induced antinociception, 10 mg/kg, i.p., was reversed by pretreatment with both D1 and D2 dopaminergic receptor antagonists SCH 23390 and haloperidol as well as with apomorphine (1 mg/kg) pretreatment. The results suggest that theophylline-induced antinociception is due to release of dopamine.     

Controlled release chitosan microspheres of mirtazapine: In vitro and in vivo evaluation

The purpose of the study was to formulate and evaluate controlled release chitosan microspheres of mirtazapine (MTZ) to improve the bioavailability by altering the pharmacokinetic profiles of the drug. Chitosan microspheres were prepared to prolong the release of the drug into the systemic circulation. Microspheres were prepared by a single water in oil (w/o) emulsion technique varying the chitosan/drug ratio, stirring speed and concentration of the crosslinking agent (glutaraldehyde). Drug-polymer compatibility studies were carried out using fourier transform infrared spectroscopy (FT-IR) and differential scanning calorimetry (DSC). The microspheres were evaluated for encapsulation efficiency, particle size, surface morphology, swelling index, in vitro release, as well as erosion and in vivo studies in rats. The FT-IR and DSC studies revealed no interaction between drug and polymer. The encapsulation efficiency of different formulation varied from 53 ± 1.2% to 78 ± 1.5%. The mean particle size of the optimized formulation F-14 was 106.4 ± 0.5 μm. Surface morphology revealed that chitosan microspheres were discrete and spherical in shape with a porous surface. The release of MTZ from chitosan microspheres was rapid up to 4 h, and then it was continuously and slowly released up to 48 h. Optimized formulation (F-14) was found to be stable under accelerated storage conditions based on International Conference on Harmonisation guidelines. Pharmacokinetic studies revealed that the optimized formulation showed significant increases in systemic exposure (AUC = 177.70 ± 7.39 μg·h/mL), half-life (4.72 ± 0.46 h) and reduced clearance (0.009 ± 0.0001 L/h) compared to pure drug administration. Hence, the present study demonstrates that controlled release formulation of MTZ microspheres using chitosan can improve pharmacokinetic profiles of MTZ.     

The Tamiflu fiasco and lessons learnt

Oseltamivir (Tamiflu), a neuraminidase inhibitor, was approved for seasonal flu by US Food and Drug Administration in 1999. A number of randomized controlled trials, systematic reviews, and meta-analysis emphasized a favorable efficacy and safety profile. Majority of them were funded by Roche, which also first marketed and promoted this drug. In 2005 and 2009, the looming fear of pandemic flu led to recommendation by prominent regulatory bodies such as World Health Organization (WHO), Centers for Disease Control and Prevention, European Medicines Agency and others for its use in treatment and prophylaxis of influenza, and it''s stockpiling as a measure to tide over the crisis. Serious Adverse Events, especially neuropsychiatric events associated with Tamiflu started getting reported leading to a cascade of questions on clinical utility of this drug. A recent Cochrane review and related articles have questioned the risk-benefit ratio of the drug, besides raising doubts about the regulatory decision of approving it. The recommendations for stockpiling the said drug as given by various international organizations viz WHO have also been put to scrutiny. Although many reviewers have labeled the Tamiflu saga as a “costly mistake,” the episode leaves us with some important lessons. This article takes a comprehensive relook on the subject, and we proceed to suggest some ways and means to avoid a similar situation in the future.KEY WORDS: Cochrane review, flu pandemic, H1N1, roche, stockpiling, Tamiflu