Pharmacokinetics and brain penetration study of chlorogenic acid in rats

1. The present study is designed to investigate the brain distribution and plasma pharmacokinetics profiles of chlorogenic acid (CGA) after intranasal administration in Charles–Foster rats to evaluate whether the CGA molecules are transported directly via the nose-to-brain path.

2. The CGA is administered intravenously (IV) and intranasally (IN) at the dose of 10?mg/kg. Further, its concentration in the plasma, cerebrospinal fluid (CSF) and the whole brain is analyzed by HPLC-UV method.

3. The study observes that CGA is rapidly absorbed in plasma with t_max of 1?min similar to IV route after IN administration. The peak plasma concentration and AUC_0–24 are higher by 3.5 and 4.0 times respectively in IV administration, compared to IN delivery that represents the significant less systemic exposure of CGA in IN route.

4. However, the concentration of CGA in the brain is 4, 6.5, 5.3, 5.2 and 4.5 times higher at 30, 60, 120, 240 and 360?min, respectively in IN administration compared to IV administration. The exposure of CGA in the brain after IN administration (AUC_{brain, IN}) was significantly greater (4 times) as compared to the exposure of CGA in the brain (AUC_{brain, IV}) after IV administration reflecting significant brain uptake of CGA through nasal route. Therefore, IN delivery of CGA can be a promising approach for the treatment of stroke and neurodegenerative disorders.     

Arsenic-induced hepatic mitochondrial toxicity in rats and its amelioration by diallyl trisulfide

The present investigation was aimed to investigate the possible protective role of diallyl trisulfide (DATS) against arsenic (As)-induced hepatic mitochondrial toxicity in rats. Mitochondria were isolated from the liver tissue of rats from all the groups. Lipid profile, lipid peroxidation, antioxidant enzyme activities, hepatic function enzymes, mitochondrial swelling, cytochrome c oxidase activity, mitochondrial Ca⁺-ATPase and Na⁺/K⁺-ATPase activity, mitochondrial calcium content and mitochondrial enzyme activities were measured. Short-term As exposure (5?mg/kg?bw/d for 28?d) caused liver damage as evidenced by changes in activities of liver enzymes. The effects of As were coupled with enhanced reactive oxygen species generation, mitochondrial swelling, inhibition of cytochrome c oxidase, complex I-mediated electron transfer, decreased Ca²⁺-ATPase and Na⁺/K⁺-ATPase activity, a reduction in mitochondrial calcium content, changes in indices of hepatic mitochondrial oxidative stress, significant increase in mitochondrial lipid peroxidation products and alterations in mitochondrial lipid profile. Significant decreases in mitochondrial antioxidants and tricarboxylic acid cycle enzymes were also found in the liver mitochondria of As-induced hepatic mitochondrial toxicity in rats. As also increased hepatic caspase-3 activity and DNA fragmentation. All these apoptosis-related molecular changes caused by As could be alleviated by supplementation with DATS, which likely suggests a protective role against As-induced hepatotoxic changes and hepatic mitochondrial toxicity. The protective effect of DATS on the liver mitochondria was evidenced by altering all the changes induced by As. Free radical scavenging and metal chelating activities of DATS may be the mechanism, responsible for the protective action against As-induced mitochondrial damage in liver.     

Targeting Janus tyrosine kinase 3 (JAK3) with an inhibitor induces secretion of TGF-β by CD4+ T cells

Regulatory T cells (Tregs) are critical for the peripheral maintenance of the autoreactive T cells in autoimmune disorders such as type 1 diabetes (T1D). Pharmacological inhibition of Janus tyrosine kinase 3 (JAK3) has been proposed as a basis for new treatment modalities against autoimmunity and allogeneic responses. Targeting JAK3 with an inhibitor has previously been shown to exhibit protective action against the development of T1D in non-obese diabetic (NOD) mice. As the mechanism of such preventative action has been unknown, we hypothesized that JAK3 inhibition induces generation of Tregs. Here, we show that the JAK3 inhibitor 4-(4′-hydroxyphenyl)-amino-6,7-dimethoxyquinazoline (WHI-P131) suppresses proliferation of short-term cultured NOD CD4⁺ T cells through induction of apoptosis, while promoting survival of a particular population of long-term cultured cells. It was found that the surviving cells were not of the CD4⁺CD25⁺FoxP3⁺ phenotype. They secreted decreased amounts of IL-10, IL-4 and interferon (IFN)-γ compared to the cells not exposed to the optimal concentrations of JAK3 inhibitor. However, an elevated transforming growth factor (TGF)-β secretion was detected in their supernatants. In vivo treatment of prediabetic NOD mice with WHI-P131 did not affect the frequency and number of splenic and pancreatic lymph node CD4⁺FoxP3⁺ Tregs, while generating an elevated numbers of CD4⁺FoxP3⁻ TGF-β-secreting T cells. In conclusion, our data suggest an induction of TGF-β-secreting CD4⁺ T cells as the underlying mechanism for antidiabetogenic effects obtained by the treatment with a JAK3 inhibitor. To our knowledge, this is the first report of the JAK3 inhibitor activity in the context of the murine Tregs.     

Profile of women substance users seeking treatment at tertiary care treatment center in India: A retrospective chart review study

Introduction: Among substance users, women represent a small, unique subpopulation. Studying their socio-demographic and substance-use profile helps us understand their concerns and formulate management strategies. Materials and Methods: In this retrospective chart review, all the available records of outpatient treatment seekers at National Drug Dependence Treatment Centre (NDDTC), All India Institute of Medical Sciences (AIIMS), Ghaziabad, from 1 January 2011 to 31 December 2015 were screened. Data from the women substance users were entered into a specially designed MS Excel format and analyzed. Results: In these 5 years, 217 women (mean age 36.75 ± 11.84 years) sought treatment. Majority were married (75.6%), housewife (53.5%), educated (59.4%), from an urban background (70.0%). Most common primary substance used was opioid (61.3%), including heroin (30.0%) and pentazocine (16.1%). About 20.3% reported injectable opioid use. The mean duration of opioid use was 5.44 ± 4.68 years. History of prior treatment seeking was reported by 4.6% and no prior significant abstinence attempts by 77.4%. Discussion and Conclusion: Majority of female treatment seekers, are young, married urban women and seek treatment for opioid use, particularly heroin (as opposed to pentazocine, suggested by previous studies). Prior treatment seeking and abstinence rates are low. Data indicates the need of specialized services for this population.     

Tumor like swellings arising from Hoffa's fat pad: A report of three patients

We report three rare cases of tumor-like conditions arising from Hoffa''s fat pad (HFP). Patients were having persistent knee pain, the cause of which was not diagnosed by the general physician, and then were referred to us for knee pain. Magnetic resonance imaging revealed the lesions to be arising from HFP (ganglion cysts and hemangioma), as was suggested by clinical findings. Anatomy, pathology, and radiological features of the Hoffa''s disease are described here to increase awareness in orthopedic community of this rare but interesting disease which is often misdiagnosed as meniscal pathology. These cases illustrate that increased cognizance can facilitate timely intervention which will prevent morbidity of the patient.     

High proportion of pentazocine dependence among treatment-seeking female injecting drug users (FIDUs) in India: A distinct population?

Background. Adverse consequences of injecting are greater among female injecting drug users (FIDUs), yet treatment-seeking is low because of stigma, poor social support, and unavailability of gender-specific services. FIDUs, despite being a distinct subpopulation of women substance users, are sparsely studied.

Aims. We aimed to study the sociodemographic and clinical profile of treatment-seeking FIDUs at a tertiary drug treatment center in North India.

Methods. In this retrospective study, we reviewed medical records of all the FIDUs who sought outpatient treatment from January 1, 2011, to December 31, 2015.

Results. Out of a total of 217 records of female patients, 44 were current IDUs (20.27%), with mean age 35.48 ± 10.13 years. Majority were Hindu (84.1%), married (81.8%), homemakers (52.3%) educated up to 12 years (65.9%). Primary drug of dependence was injection pentazocine for 33 patients (75.0%) and injection smack (street heroin) for 8 (18.2%). Commonest reason for initiation of drug use was iatrogenic (n = 25; 56.8%). Major physical complications were reported by 29 (65.9%), while 12 (22.8%) reported psychiatric comorbidity.

Conclusion. A typical treatment-seeking FIDU is middle-aged, educated, homemaker using injecting pentazocine. High rate of injecting with iatrogenic onset highlights the need for women-specific services as well as awareness-building among physicians.     

Extensive cross-reactive neutralizing antibody response in Indian patients with limited genetic diversity of HIV-1

Genome sequence analysis of HIV-1 subtype C viruses from India shows monophyletic lineage and relatively limited genetic diversity. To understand its immunological implication, cross-reactivity of neutralizing antibody response was investigated. In primary screening, neutralizing antibody response to single heterologous primary HIV-1 subtype C isolate was assessed in plasma samples from 235 HIV-1 infected, anti-retroviral treatment naive individuals from Pune, India. Plasma samples that showed > or =90% neutralization and two randomly selected plasma samples that showed 50-60% neutralization were tested against a panel of primary HIV-1 subtype C isolates obtained from epidemiologically unlinked individuals from India. The neutralizing antibody response showed extensive cross-neutralization, suggesting presence of shared neutralization determinants among circulating HIV-1 subtype C viruses in India.