Pharmacokinetic-interaction of Vitex negundo Linn. & paracetamol.

BACKGROUND & OBJECTIVES: Currently, herbal preparations are clinically used as functional food, food supplements or as add on therapy, which affects the bioavailability and also the net therapeutic potential of co-administered allopathic drugs. Therefore, it is important to assess the interaction among these two classes of drugs. Here we studied the interaction between orally-administered ethanolic extract of leaves of Vitex negundo Linn. (Verbenaceae) (VN extract) and paracetamol in albino rats. METHODS: Solvent free dried extract of VN leaves was orally given to experimental rats in different doses (62.5-1000 mg/kg/b.wt.), daily for six consecutive days. On days 3 and 6, paracetamol (100 mg/kg/b.wt.) was orally administered to these extract treated rats and control rats (drug vector). At various time intervals (5 min-120 min), blood was collected from each animal and paracetamol concentration was determined in plasma by using HPLC with UV detector at 249 nm. Various pharmacokinetic parameters were calculated by non compartmental model. RESULTS: A significant decline in plasma concentration of paracetamol with time-gap was recorded with the increasing dose of VN extract, without affecting its T(max) (maximum time to achieve peak plasma concentration). There was a significant decrease in the extent of absorption and decline in intensity of therapeutic response (as evidenced by reduced AUC value and decline in C(max)). Further, compared to control, the relative bioavailability of paracetamol, in presence of VN extract, decreased significantly. INTERPRETATION & CONCLUSIONS: VN extract or its ayurvedic formulation if co-administered with allopathic drug like paracetamol, the dose of allopathic drug needs to be adjusted in order to achieve desired therapeutic response of paracetamol.

Effects of G-CSF on serum cholesterol and development of atherosclerotic plaque in apolipoprotein E-deficient mice.

UNLABELLED: Macrophage colony stimulating factor (M-CSF) is known to have profound effects upon vascular pathologies, but potential roles of other colony stimulating factors (CSF) are not well understood. We treated apo E deficient (apo E-/-) mice with granulocyte colony stimulating factor (G-CSF) or vehicle daily for 9 weeks, during which time they were fed a Western-style diet. G-CSF treatment resulted in increased proportions of circulating monocytes (6.9 ± 2.2% vs. 3.8 ± 0.3%; p < 0.05), a trend towards increased neutrophils (33.5 ± 19.1% vs. 22.2 ± 7.8%; p = 0.17), and decreased serum levels of total cholesterol (981 ± 594 vs. 1495 ± 1009 mg/dL; p < 0.005) compared to control mice. There was a trend towards less low density lipoprotein (LDL) in G-CSF treated mice (24.6 ± 2.4% vs. 37.4 ± 12.3%; p = 0.10). A greater proportion of bone marrow cells from G-CSF treated mice expressed membrane type 1 matrix metalloprotease (MT1-MMP) (G-CSF: 14.5 ± 5.5%; CONTROL: 6.2 ± 5.0%; p < 0.05) compared to bone marrow cells from vehicle treated mice. G-CSF treatment was also associated with smaller atheromatous plaque, decreased Oil red O staining, and decreased infiltration of both Monocyte/Macrophage Marker Antibody (MOMA-2) and F4/80 dependent macrophage populations into aortic lesions. However, decreased plaque area appeared to be largely due to lower cholesterol levels in G-CSF-treated mice. Lesions in G-CSF treated mice appeared to be structurally distinct from control mice, containing relatively less lipid and macrophages. Our results suggest important roles for G-CSF in cholesterol metabolism, mobilization of bone marrow stem cells that might alter plaque development, and accumulation of lipids and macrophages into atherosclerotic lesions.

Nuclear localization of catalytically active MMP-2 in endothelial cells and neurons.

From microscopic organelles and sub-cellular domains to the level of whole tissues, organs, and body parts, living organisms must continuously maintain and renovate structural components. Matrix metalloproteinases (MMPs) comprise a family of over two dozen Zn-dependent endopeptidases thought to be primary effectors of extracellular tissue renewal and remodeling processes. Endogenous inhibitors, particularly the tissue inhibitors of MMPs (TIMPs), counteract MMP-2 proteolytic activity, but also participate in conversion of several pro-MMPs to proteolytically active forms. Numerous pathologies are characterized by imbalances in activities of MMPs relative to TIMPs. MMPs are synthesized and stored in cytoplasmic domains prior to secretion or expression in cell surface-associated form. Several proteases have been identified in cell nuclei, but their functions, regulation, and substrates remain largely unknown. Here we showed that the catalytically active gelatinase MMP-2 is expressed in nuclei of endothelial cells and neurons, but not in glial or Schwannoma cell lines, in a pattern resembling nuclear speckles, and colocalizes with TIMP-1.

Protective effect of Pueraria tuberosa DC. embedded biscuit on cisplatin-induced nephrotoxicity in mice.

Recently, the nephroprotective property of Pueraria tuberosa DC. tuber (PT) has been reported by our group. Here, PT-embedded biscuits were prepared and tested on cisplatin-induced nephrotoxicity in Swiss albino mice. The PT powder was characterized by RAPD (random amplified polymorphic DNA) to ascertain its authenticity and PT biscuits were prepared in different concentrations (1, 2, or 4 g of PT powder). These biscuits were given as diet for a total of 10 days, but on the 7th day cisplatin injection (8 mg/kg bw, i.p.) was given. On the 10th day animals were killed to collect kidneys for assessment of antioxidant status. Blood samples were collected on both the 7th and 10th days for assessment of liver and kidney functions. In mice, PT biscuit showed significant protection against cisplatin-induced nephrotoxicity, but there was a transient rise in alanine aminotransferase and aspartate aminotransferase at the dose of 4 g PT biscuit. Therefore, it is suggested that PT biscuit might be an effective food supplement for cancer patients undergoing cisplatin-chemotherapy. However, periodical liver function monitoring is required, especially when PT is used for longer periods or at higher doses.

Amelioration of cisplatin induced nephrotoxicity by PTY: a herbal preparation.

Cisplatin, a chosen drug for cancer treatment, is associated with severe nephrotoxicity, that limits its clinical use. Cisplatin involves enhanced oxidative stress, mitochondrial dysfunction and death of tubular cells. Nephroprotective role of PTY, prepared from methanolic extract of tubers of Pueraria tuberosa D.C., has been studied. PTY was orally given to rats in different doses for seven consecutive days, along with cisplatin (8 mg/kg B.W., i.p.) on 4th day. PTY significantly prevented the rise in serum creatinine, blood urea nitrogen. It prevented the decline in glutathione content, activities of superoxide dismutase and catalase and also prevented DNA damage, tubular swelling, cellular necrosis and protein cast deposition as compared to experimental control group in kidney. These changes were restored to near normal levels by PTY in dose of 40 mg/100 g B.W. Thus, it is proposed that the PTY possesses dose-dependent protective effect against cisplatin induced kidney damages, primarily through its free radical scavenging property.

Decal bone matrix as a local antibiotic delivery vehicle in a MRSA-infected bone model: An experimental study.

BACKGROUND: Polymethyl methacrylate (PMMA) antibiotic beads though have proved their utility as a local antibiotic delivery system, however, there are limitations. Decalcified bone matrix (DBM) as a vehicle of antibiotics can serve the purpose, provided a minimum inhibitory concentration is sustained. Healing of the defect and avoiding the second surgery is another advantage. We studied the DBM as the delivery vehicle for vancomycin in controlling the methicillin-resistant Staphylococcus aureus (MRSA) osteomyelitis as well as healing of the cavity simultaneously in an experimental study. MATERIALS AND METHODS: An in vitro study was conducted to optimize vancomycin impregnation in the DBM. For the in vivo study, a unicortical defect was created in the metaphysis of the distal femur in 18 rabbits. After contaminating the defect with MRSA, rabbits were divided into three groups. Group I (eight limbs) received no graft. Defects in group II (11 limbs) were filled with plain DBM chips and in group III (14 limbs), cavities were implanted with vancomycin-impregnated decal bone chips. Rabbits were assessed by clinical, radiological, histological, gross examination and bacterial load assay. High Performance Liquid Chromatography HPLC analysis of vancomycin in group III was done to assess the concentration in DBM chips. RESULTS: In group I, the infection persisted throughout the period of the study. Group II showed the fulminated infection at the grafted site with DBM chips sequestrating out. Vancomycin-impregnated decal chips in group III did not show any sign of infection and eventually incorporated. The bacterial load study showed a progressive load change and HPLC revealed an effective antibiotic concentration up to 3 weeks in both in vitro and in vivo. CONCLUSION: Decal bone chips were effective as the local antibiotic delivery vehicle in preventing the MRSA osteomyelitis model. It eluted vancomycin significantly and the graft uptake was also excellent. Allogeneic decal grafts eliminated the need for second surgery and acted as an excellent delivery vehicle for antibiotics.