Hepatoprotective Bile Acid Co-Drug of Isoniazid: Synthesis,Kinetics and Investigation of Antimycobacterial Potential

Pharmaceutical Chemistry Journal - The long-course treatment of tuberculosis with isoniazid (INH) leads to hazardous side effects on liver and poor patient compliance. To overcome these toxic...     

Protracted effects of chronic oral haloperidol and risperidone on nerve growth factor, cholinergic neurons, and spatial reference learning in rats

The primary therapeutic agents used for schizophrenia, antipsychotic drugs, ameliorate psychotic symptoms; however, their chronic effects on cognition (or the physiologic processes of the brain that support cognition) are largely unknown. The purpose of this rodent study was to extend our previous work on this subject by investigating persistent effects (i.e. during a 14 day drug-free washout period) of chronic treatment (i.e. ranging from 45 days to 6 months) with a representative first and second generation antipsychotic. Drug effects on learning and memory and important neurobiological substrates of memory, the neurotrophin, nerve growth factor (NGF) and its receptors, and certain components of the basal forebrain cholinergic system were investigated. Behavioral effects of oral haloperidol (2.0 mg/kg/day), or risperidone (2.5 mg/kg/day) were assessed in an open field, a water maze task, and a radial arm maze procedure and neurochemical effects in brain tissue were subsequently measured by enzyme-linked immunosorbent assays (ELISAs). The results indicated that both antipsychotics produced time-dependent and protracted deficits in the performance of a water maze procedure when compared with vehicle-treated controls, while neither drug was associated with significant alterations in radial arm maze performance. Interestingly, haloperidol, but not risperidone, was detectible in the rodent brain in appreciable levels for up to 2 weeks after drug discontinuation. Both antipsychotics were also associated with reduced levels of NGF protein in the basal forebrain and prefrontal cortex and significant (or nearly significant) decreases in phosphorylated tropomyosin-receptor kinase A (TrkA) protein and the vesicular acetylcholine transporter (depending on the brain region analyzed). Neither antipsychotic markedly affected TrkA or p75 neurotrophin receptor levels. These data in rats indicate that chronic treatment with either haloperidol or risperidone may be associated with protracted negative effects on cognitive function as well as important neurotrophin and neurotransmitter pathways that support cognition.     

Time-dependent cognitive deficits associated with first and second generation antipsychotics: cholinergic dysregulation as a potential mechanism

Although cognitive dysfunction is considered one of the more debilitating symptoms of schizophrenia, there is a fundamental gap in our knowledge of how the primary pharmacologic treatments of this disease, first- and second-generation antipsychotics (FGAs and SGAs, respectively), affect cognition, particularly over extended periods of time. Moreover, it has been known for decades that chronic treatment with FGAs can lead to imbalances in cholinergic function in the striatum that result in movement disorders; however, there is a growing body of evidence to suggest that both FGAs and SGAs can lead to cholinergic alterations in brain areas more traditionally considered as memory-related, such as cortical and hippocampal regions. Data from our laboratories in rodents indicate that some SGAs (if administered for sufficient periods of time) can be associated with impairments in memory-related task performance as well as alterations in the cholinergic enzyme choline acetyltransferase, the vesicular acetylcholine transporter, and nicotinic (alpha(7)) and muscarinic (M(2)) acetylcholine receptors. Given the well documented importance of central cholinergic function to information processing and cognitive function, it is important that the mechanisms for such chronic antipsychotic effects be identified. In this review, two potential mechanisms for long-term antipsychotic-related cholinergic alterations in the central nervous system are discussed: 1) antipsychotic antagonist activity at dopaminergic-D(2) receptors on cholinergic neurons and 2) antipsychotic effects on neurotrophins that support cholinergic neurons, such as nerve growth factor and brain derived growth factor. Novel strategies to optimize the therapeutics of schizophrenia and maintain cognitive function via adjunctive cholinergic compounds and antipsychotic crossover approaches are also discussed.     

UV and Three Derivative Spectrophotometric Methods for Determination of Ezetimibe in Tablet Formulation

UV, first, second and third derivative spectrophotometric methods have been developed for the determination of ezetimibe in pharmaceutical formulation. The solutions of standard and sample were prepared in methanol. For the first method, UV spectrophotometry, the quantitative determination of the drug was carried at 233 nm and the linearity range was found to be 6-16 μg/ml. For the first, second and third derivative spectrophotometric methods the drug was determined at 259.5 nm, 269 nm and 248 nm with the linearity ranges 4-14 μg/ml, 4-14 μg/ml and 4-16 μg/ml. The calibration graphs constructed at their wavelength of determination were found to be linear for UV and derivative spectrophotometric methods. All the proposed methods have been extensively validated. The described methods can be readily utilized for the analysis of pharmaceutical formulation. There was no significant difference between the performance of the proposed methods regarding the mean values and standard deviations.     

Neonatal screening for congenital hypothyroidism in a developing country: problems and strategies

Neonatal screening in India poses more organisational and socio-economic rather than medical challenges. Based on the pilot study of 450 cord sera, the plan for screening considered cord TSH<30 μU/ml as normal, 30 to 80 as borderline with recall by letters and >80 as indicative of hypothyroid state, with recall by home visits. Of the 17,240 live births only 12,407 cord sera were collected. Envisaging follow-up difficulties, T₄ was assayed in cord sera when TSH was>30 μ U/ml. 2·81% (350) babies needed recall. Only 30% of 302 (2·43%) babies with cord TSG 30 to 80 responded, to recall letters and were normal; availability of both cord TSH and T₄ helped in excluding hypothyroidism in majority of non-respondents. Forty-eight (0·38%) newborns had TSH>90 μU/ml; 80% of this group and 100% with TSH> 100 μU/ml were traced by home visits. Hypothyroidism was confirmed in 5/48, biochemically and by thyroid scan. All five hypothyroids had cord TSH>300 μU/ml. The incidence in this nonendemic region of India was 1∶2481. Thus false elevation of cord TSH 30 to 300 μU/ml was noted in 0·34% with a chance of detecting a hypothyroid 1 in 10 when TSH>80 μU/ml. Screening strategies in a developing country must ensure meticulous clerical assistance, co-operation and education of nurses and parents, precise and cost effective technics and facilities for continued surveilance of detected hypothyroids.     

The ICH guidance in practice: stress degradation studies on indinavir sulphate and development of a validated specific stability-indicating HPTLC assay method

A sensitive, selective, precise and stability-indicating high-performance thin layer chromatography (HPTLC) method for analysis of indinavir sulphate both as a bulk drug and in formulations was developed and validated. The method employed TLC aluminium plates precoated with silica gel 60F-254 as the stationary phase. The solvent system consisted of carbon tetrachloride/chloroform/methanol/10% v/v ammonia (4:4.5:1.5:0.05, v/v/v/v). Densitometric analysis of indinavir sulphate was carried out in the absorbance mode at 260 nm. This system was found to give compact spots for indinavir sulphate (Rf value of 0.43 +/- 0.02, for six replicates). Indinavir sulphate was subjected to acid and alkali hydrolysis, oxidation, dry and wet heat treatment, and photo degradation. The drug undergoes degradation under acidic and basic conditions, oxidation, dry and wet heat treatment, and photo degradation. Also the degraded products were well resolved from the pure drug with significantly different Rf values. The method was validated for linearity, precision, robustness, limit of detection (LOD), limit of quantitation (LOQ), specificity and accuracy. Linearity was found to be in the range of 100-6000 ng/spot with significantly high value of correlation coefficient r2 = 0.997 +/- 0.64. The linear regression analysis data for the calibration plots showed good linear relationship with r2 = 0.999 +/- 0.002 in the working concentration range of 1000-6000 ng/spot. The LOD and LOQ were 40 and 120 ng/spot, respectively. Statistical analysis proves that the method is repeatable and specific for the estimation of the said drug. As the method could effectively separate the drug from its degradation products, it can be employed as a stability-indicating one. Moreover, the proposed HPTLC method was utilized to investigate the kinetics of acid degradation process. Arrhenius plot was constructed and activation energy was calculated.     

Study of serum levels of superoxide dismutase in preeclampsia and eclampsia: role of the test as a predictive tool

AIM: To report serum levels of superoxide dismutase in women with preeclampsia and eclampsia. To document the use of the value as a predictive tool for deciding the time of onset of subsequent convulsions with fulminating eclampsia and use of the value as a marker for obstetric intervention in clinical severe preeclampsia and eclampsia. METHODS: Superoxide dismutase concentration was measured in a consecutive study in sera of women admitted in obstetric ward for preeclampsia and eclampsia, and compared with sera of normotensive, healthy pregnant women in third trimester. Three mL venous blood was subjected to superoxide dismutase estimation by pyrogallol autoxidation method. RESULTS: We found statistically significant difference (P < 0.05) in mean superoxide dismutase levels of normotensive pregnant women; and preeclamptic and eclamptic subjects, no statistically significant difference was found in between value of enzyme in preeclampsia and eclampsia (P > 0.05). Superoxide dismutase levels in two pregnancy outcomes; live births and still births, shows significant difference (P < 0.05), being 1.03 U/mL and 0.52 U/mL, respectively. The comparison of values before delivery and after delivery showed highly statistically significant difference (P < 0.001) in both groups separately. The cut-off value of serum superoxide dismutase 0.52 U/mL has sensitivity 68.5%, specificity 59.5% and negative predictive value of 78.6%, for predicting the fetal death as outcome of pregnancy with severe grade of disease. CONCLUSION: We found low levels of serum superoxide dismutase, less than 0.52 U/mL, being the predecessor of fulminating eclampsia. Our results support this predictive value of serum superoxide dismutase level as important in deciding the time of intervention as termination of pregnancy.     

Acute effects of GM1 ganglioside: Reduction in both behavioral asymmetry and loss of Na,K-ATPase after nigrostriatal transection

GM1 ganglioside injections (i.p.) reduce amphetamine-induced asymmetric rotation in rats 48 h after a partial unilateral transection of the nigrostriatal pathway. We found that this reduction was maximal when rats received their first GM1 injection within 2 h after surgery. Rats injected 4-12 h after surgery, or rats only pretreated with GM1, showed no significant effect on rotation. Striatal membrane Na+,K+-ATPase in rats injected with GM1 0-2 h after hemitransection showed only a 10% loss in activity (versus the untransected hemisphere) as compared to control losses of 38%. The maintenance of membrane Na+,K+-ATPase activity in GM1-treated rats may be one mechanism by which a balance between hemispheres in striatal dopaminergic transmission is preserved, resulting in reduced asymmetric rotation. The observation that there is a critical postsurgical period when GM1 administration results in optimal functional recovery supports our hypothesis that gangliosides are exerting an acute effect on damaged CNS tissue. This acute effect is further evidenced by the reduced loss of membrane Na+,K+-ATPase following injury.     

ApoE3 mediated polymeric nanoparticles containing curcumin: Apoptosis induced in vitro anticancer activity against neuroblastoma cells

Curcumin, a natural phytoconstituent, is known to be therapeutically effective in the treatment of various cancers such as, breast cancer, lung cancer, pancreatic cancer, brain cancer, etc. However, low bioavailability and photodegradation of curcumin hampers its overall therapeutic efficacy. Anionic polymerization method was employed for the preparation of apolipoprotein-E3 mediated curcumin loaded poly(butyl)cyanoacrylate nanoparticles (ApoE3-C-PBCA) and characterized for size, zeta potential, entrapment efficiency, photostability, morphology, and in vitro release study. ApoE3-C-PBCA were found to be effective against SH-SY5Y neuroblastoma cells compared to curcumin solution (CSSS) and curcumin loaded PBCA nanoparticles (C-PBCA) from in vitro cell culture investigations. Flow cytometry techniques employed for the detection of anticancer activity revealed enhanced activity of curcumin against SH-SY5Y neuroblastoma cells with ApoE3-C-PBCA compared to CSSS and C-PBCA, and apoptosis being the underlying mechanism. Present study revealed that ApoE3-C-PBCA has tremendous potential to develop into an effective therapeutic treatment modality against brain cancer.