Protective and Ameliorative Effects of Hydroethanolic Extract of Piper nigrum (L.) Stem against Antiretroviral Therapy-Induced Hepatotoxicity and Dyslipidemia in Wistar Rats.

Antiretroviral therapy (ART) has revolutionized the lives of people living with HIV/AIDS by overall improving their quality of life and increasing life expectancy. However, ART-associated hepatotoxicity and metabolic disorders in HIV/AIDS patients are growing concerns to clinicians, especially due to the long-term use of the drugs. This study reported on the phytochemical and pharmacological profile of hydroethanolic extracts of Piper nigrum stem (PNS) and evaluated its protective effect against tenofovir/lamivudine/efavirenz (TLE)-induced hepatotoxicity and dyslipidemia in Wistar rats. Cytotoxic, antioxidant, and anti-inflammatory assays were performed on PNS. Thirty-six rats divided into 6 groups of 6 animals/group were administered: distilled water, 17 mg/kg TLE, 17 mg/kg TLE and 100 mg/kg silymarin, 17 mg/kg TLE, and Piper extract (200 mg/kg, 400 mg/kg, or 800 mg/kg) orally for 28 days. The body weight of animals was recorded every 7 days. On Day 29, the rats were sacrificed, and blood samples were collected for hematological and biochemical tests. Portions of the liver and kidneys were collected for histological evaluation, while liver homogenates were prepared from the rest to measure antioxidant enzymes. PNS possessed in vitro cytotoxic, antioxidant, and anti-inflammatory activities. A significant decrease (p < 0.05) in the body weight of rats treated with PNS was observed. A significant high platelet count (p < 0.05) was observed in the PNS800 mg/kg group. A considerable decrease in alkaline phosphatase and triglycerides was observed in the silymarin and PNS group compared to the TLE-only group. The findings also show a significant increase in catalase and glutathione in the TLE-only group compared to the normal group, while SOD decreased. Histological observations revealed normal hepatic and renal tissues in the silymarin, and PNS-treated groups compared to the normal control, while leucocyte infiltration was observed in the TLE-only group. These results suggest that PNS extract possessed antioxidant activity that alleviated TLE-induced toxicity. Further studies are necessary to understand the pharmacokinetic interactions between ART and PNS.

In Vitro Antioxidant, Anti-Inflammatory, and Digestive Enzymes Inhibition Activities of Hydro-Ethanolic Leaf and Bark Extracts of Psychotria densinervia (K. Krause) Verdc.

Psychotria densinervia hydro-ethanolic leaf extract (PHELE) and bark extract (PHEBE) were evaluated for antioxidant, anti-inflammatory, and inhibition of digestive enzymes activities. The antioxidant activity was characterized by 2,2-diphenyl-1-picrylhydrazyl (DPPH), 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS), ferric reducing antioxidant power (FRAP), total phenolic content (TPC), and total flavonoid content (TFC) assays. The anti-inflammatory activity was characterized by protein denaturation and antiproteinase tests, while the inhibition of the enzymes was assessed using α-amylase, α-glucosidase, lipase, and cholesterol esterase activities. PHELE presented low (p < 0.001) IC50 (59.09 ± 5.97 µg/ml) for DPPH compared with ascorbic acid (71.78 ± 6.37 µg/ml) and PHEBE (115.40 ± 1.21 µg/ml). The IC50 of PHELE (262.4 ± 4.46 µg/ml) and PHEBE (354.2 ± 1.97 µg/ml) was higher (p < 0.001) than that of catechin (33.48 ± 2.02 µg/ml) for ABTS. PHELE had high (p < 0.001) FRAP (341.73 ± 21.70 mg CE/g) than PHEBE (150.30 ± 0.32 mg CE/g). PHELE presented (p < 0.001) high TPC (270.05 ± 7.53 mg CE/g) and TFC (23.43 ± 0.032 mg CE/g) than PHEBE (TPC: 138.89 ± 0.91 and TFC: 20.06 ± 0.032 mg CE/g). PHELE showed antiprotein denaturation with IC50 (257.0 ± 7.51 µg/ml) (p < 0.001) and antiproteinase activity (74.37 ± 1.10 µg/ml) lower than PHEBE (316.1 ± 6.02 µg/ml and 177.6 ± 0.50 µg/ml), respectively. Orlistat inhibited lipase (p < 0.001) activity with IC50 (37.11 ± 4.39 µg/ml) lower than PHELE and PHEBE (50.57 ± 2.89 µg/ml and 62.88 ± 1.74 µg/ml, respectively). PHELE inhibited cholesterol esterase with IC50 (34.75 ± 3.87 µg/ml) lower than orlistat (54.61 ± 2.56) and PHEBE (80.14 ± 1.71 µg/ml). PHELE inhibited α-amylase IC50 (6.07 ± 4.05 µg/ml) lower than PHEBE (19.69 ± 6.27 µg/ml) and acarbose (20.01 ± 2.84 µg/ml). Acarbose inhibited α-glucosidase (p < 0.001) activity with IC50 (4.11 ± 3.47 µg/ml) lower than PHELE (24.41 ± 2.84 µg/ml) and PHEBE (38.81 ± 2.46 µg/ml). PHELE presented better antioxidant, anti-inflammatory, and enzyme inhibition activity than PHEBE.

Cafeteria Diet-Induced Metabolic and Cardiovascular Changes in Rats: The Role of Piper nigrum Leaf Extract.

BACKGROUND: Cafeteria diet is known to induce excessive body fat accumulation (obesity) that could cause metabolic and cardiovascular changes and even death. The increase in prevalence over time and the failure in treatment options make obesity a real public health problem. The present study assessed the preventive effect of the hydro-ethanolic extract of the Piper nigrum leaf on the development of metabolic and cardiovascular changes in cafeteria diet fed Wistar rats. METHODS: Thirty-six male rats were divided into 5 groups of 6 rats each: a normal control group (Nor.), a negative control group (Neg.), two groups administered different doses of extract in mg/kg (E250 and E500), and a group administered atorvastatin 10 mg/kg (Ator., reference drug). The animals were fed with experimental diets (standard and cafeteria) for a period of 5 weeks. Food and water intake were assessed daily, and the body weight assessed weekly. At the end of the feeding, plasma lipid profile and markers of hepatic and renal function were assessed. Furthermore, the relative weights of the adipose tissue and the organs were assessed. The liver, kidneys, and heart homogenates were assessed for markers of oxidative stress while the aorta was histopathologically examined. RESULTS: Cafeteria diet-induced weight gain of 30% and increased triglyceride, total cholesterol, and low-density lipoprotein cholesterol level of more than 50%. Equally, an increase in the relative weight of accumulated adipose tissues of more than 90%, oxidative stress, and alteration in the organ structure were visible in cafeteria diet fed rats (Neg). Treatment with P. nigrum extract significantly prevented weight gain, dyslipidemia, oxidative stress, and alteration in the architecture of the aorta. The effect of P. nigrum extract was comparable to that of the reference drug. CONCLUSION: Piper nigrum leaf may prevent weight gain and possess cardioprotective activity with a strong antioxidant activity.

[EFFICACY OF RADIOFREQUENCY ABLATION OF AORTORENAL SYMPATHETIC NODES IN PATIENTS IN ARTERIAL HYPERTENSION].

Efficacy of radiofrequency ablation (RFA) of prevertebral sympathetic nodes, concern- ing the arterial pressure lowering in 36 patients, suffering hypertonic disease and coex- istent heart diseases, was analyzed. In 12 mo after RFA a systolic arterial pressure lowering at average throughout the group by (3.24 ± 1.15) kPa, or (24.3 ± 8.6) mm Hg, diastolic arterial pressure--by (1.51 ± 0.45) kPa, or (11.3 ± 3.4) mm Hg was noted. RFA of prevertebral sympathetic nodes have had promoted a stable lowering of arterial pressure in patients, suffering chronic hypersympathicotony.

[INTERVENTIONAL AND SURGICAL TREATMENT OF THE ANGINA PECTORIS RECURRENCE AFTER CORONARY SHUNTING OPERATION].

There were examined 134 patients, in whom in the clinic in 2005-2014 yrs a coronary shunting operation was performed. In patients with the angina pectoris recurrence a reoperation is indicated. The data of repeated coronaroventriculography and shuntography were analyzed. Efficacy of the surgical and interventional methods application in the patients was proved.

[A coronary atherosclerosis course in patients after interventions on coronary arteries].

Retrospective analysis of primary and secondary coronaroventriculography was conducted in 283 patients, to whom coronary stenting and coronary shunting were performed. Further course of coronary atherosclerosis was investigated in patients after intervention on coronary arteries.

Pharmacological inhibition of c-Abl compromises genetic stability and DNA repair in Bcr-Abl-negative cells.

Imatinib inhibits the kinase activity of Bcr-Abl and is currently the most effective drug for treatment of chronic myeloid leukemia (CML). Imatinib also blocks c-Abl, a physiological tyrosine kinase activated by a variety of stress signals including damaged DNA. We investigated the effect of pharmacological inhibition of c-Abl on the processing of irradiation-induced DNA damage in Bcr-Abl-negative cells. Cell lines and peripheral blood mononuclear cells (PBMCs) from healthy volunteers were treated with imatinib or dasatinib before gamma-irradiation. Inhibition of c-Abl caused an enhanced irradiation-induced mutation frequency and slowdown of DNA repair, whereas imatinib was ineffective in cells expressing a T315I variant of c-Abl. Mutation frequency and repair kinetics were also studied in c-Abl-/- murine embryonic fibroblasts (MEFs) retransfected with wild-type c-Abl (wt-Abl) or a kinase-defect variant of Abl (KD-Abl). Enhanced mutation frequency as well as delayed DNA repair was observed in cells expressing KD-Abl. These data indicate that pharmacological inhibition of c-Abl compromises DNA-damage response.

Developmental pharmacokinetics of ciclosporin--a population pharmacokinetic study in paediatric renal transplant candidates.

AIMS: To use population pharmacokinetic modelling to characterize the influence of developmental and demographic factors on the pharmacokinetic variability of ciclosporin. METHODS: Pharmacokinetic modelling was performed in NONMEM using a dataset comprising 162 pretransplant children, aged 0.36-17.5 years. Ciclosporin was given intravenously (3 mg kg(-1)) and orally (10 mg kg(-1)) on separate occasions followed by blood sampling for 24 h. RESULTS: A three-compartment model with first-order absorption without lag-time best described the pharmacokinetics of ciclosporin. The most important covariate affecting systemic clearance (CL) and distribution volume (V) was body weight (BW; scaled allometrically), responsible for a fourfold difference in uncorrected ciclosporin CL and a sixfold difference in ciclosporin V. The other significant covariates, haematocrit, plasma cholesterol and creatinine, were estimated to explain 20-30% of interindividual differences in CL and V of ciclosporin. No age-related changes in oral bioavailability or in BW-normalized V were seen. The BW-normalized CL (CL/BW) declined with age and prepubertal children (<8 years) had an approximately 25% higher CL/BW than did older children. Normalization of CL for allometric BW (BW(3/4)) removed its relationship to age. CONCLUSION: The relationship between CL and allometric BW is consistent with a gradual reduction in relative liver size, until adult values, and a relatively constant CYP3A4 content in the liver from about 6-12 months of age to adulthood. Ciclosporin oral bioavailability, known previously to display large interindividual variability, is not influenced by age. These findings can enable better individualization of ciclosporin dosing in infants, children and adolescents.