Biomedical subjects

Xiaoping Zhang

Publications and source records attributed to Xiaoping Zhang.

At least 37 records · Page 2Linked to original sources

PubMed2005

[Redistribution patterns of black soil in hillslope landform of Northeast China: a 137Cs study].

In the black soil region of Northeast China, soil and water loss is quite serious, but not fully investigated due to the lack of reliable methods. 137Cs technology is a good one to study the medium-and long term erosion and sedimentation rates and the spatial redistribution of soil. With this technology and the existing calibration models, this paper studied the redistribution patterns of black soil in a typical hillslope landform of Northeast China. The results showed that in the study area, the reference 137Cs value was 2232.75 Bq x m(-2), intervenient the background values in the Yangtse River Delta and Loess Plateau; and the 137Cs areal activity had a great differentiation in horizontal and vertical directions, being the lowest in the shoulder-slope positions, which suggested that the summits and back-slope positions suffered weak erosion, and some of the eroded soils were re-deposited in foot-slope and toe-slope positions. The vertical distribution of 137Cs in soil profile ranged from 20 cm on a shoulder-slope to 80 cm on a toe-slope position, indicating a significant erosion and deposition. Estimations with four existing calibration models showed that PM model underestimated while MBM1 model overestimated the soil erosion rates very obviously, and both MBM2 and MBM3 gave similar and reasonable estimations.

Cesium Radioisotopes↗

PubMed2005

[Population characteristics of Coptis chinensis var. brevisepala in Anhui Province and its endangering mechanism].

The study on the distribution pattern, population size, and age structure of C. chinensis var. brevisepala in Anhui Province showed that C. chinensis var. brevisepala mainly distributed in the southern mountain areas such as Mts. Jiuhuashan, Guniujiang, Huangshan and Qingliang Peak. The habitats had two kinds, i.e., under woods and beside water ditches, both of which were shady and humid, with loose and acidic soils containing abundant organic matter. The shading degree surpassed 70%, air humidity reached 70% approximately 90%, and soil water content was more than 30%. The distribution pattern of existing C. chinensis var. brevisepala populations was clustering, with illogical age structure and small population size. It was suggested that the populations of C. chinensis var. brevisepala in Anhui Province were in an unsteady stage. Serious destroy of natural habitat and excessive digging and gathering adult individuals were the main causes of the rapid decrease of the individuals in some populations, which threatened the existence of C. chinensis var. brevisepala populations seriously.

Biodiversity↗

PubMed2005

[Response of Vetiveria zizanioides to Pb2+ stress].

The study on the eco-physiological indices of V. zizanioides under Pb2+ stress showed that with the increase of Pb2+ concentration (0 approximately 8 mmol x L(-1)) in water culture, the growth of V. zizanioides seedlings was badly influenced. Their leaves' conductivity increased, while SOD activity increased first and decreased then, but still higher than control. There was a positive correlation between SOD activity and Pb2+ concentration. POD and CAT activities were also increased first and decreased then, but when the Pb2+ concentration was > 4 mmol x L(-1), these enzyme activities were lower than the control, and had a significantly negative correlation with Pb2+ concentration. It was considered that the increase of enzyme activities was resulted from the adaptability of V. zizanioides stressed by Pb2+, while high concentration Pb2+ had an inhibitory effect on enzyme activities.

Catalase↗

PubMed2004

CD4 phosphorylation partially reverses Nef down-regulation of CD4.

HIV Nef down-regulates CD4 from the cell surface in the absence of CD4 phosphorylation, whereas PMA down-regulates CD4 through a phosphorylation-dependent pathway. In this study we show that the down-regulation of CD4 in human Jurkat T cells expressing Nef was nearly complete (approximately 95%), whereas that induced by PMA was partial (approximately 40%). Unexpectedly, treating T cells expressing Nef with PMA restored the surface CD4 up to 35% of the steady state level. Both mutating the phosphorylation sites in the CD4 cytoplasmic tail (Ser408 and Ser415) and the use of a protein kinase C inhibitor, bisindolylmaleimide1, abolished the restoration of surface CD4, suggesting that the restoration required CD4 phosphorylation. CD4 and Nef could be cross-linked by a chemical cross-linker, 3,3-dithiobis[sulfosuccinimidyl-propionate], in control T cell membranes, but not in PMA-treated T cell membrane, suggesting that CD4 and Nef interacted with each other in T cells, and the phosphorylation disrupted the CD4-Nef interaction. We propose that this dissociation switches CD4 internalization from the Nef-mediated, nearly complete down-regulation to a phosphorylation-dependent, partial down-regulation, resulting in a net gain of CD4 on the T cell surface.

CD4 Antigens↗

PubMed2004

Persistent c-FLIP(L) expression is necessary and sufficient to maintain resistance to tumor necrosis factor-related apoptosis-inducing ligand-mediated apoptosis in prostate cancer.

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has been shown to induce apoptosis in a variety of tumorigenic and transformed cell lines but not in many normal cells. Hence, TRAIL has the potential to be an ideal cancer therapeutic agent with minimal cytotoxicity. FLICE inhibitory protein (c-FLIP) is an important regulator of TRAIL-induced apoptosis. Here, we show that persistent expression of c-FLIP(Long) [c-FLIP(L)] is inversely correlated with the ability of TRAIL to induce apoptosis in prostate cancer cells. In contrast to TRAIL-sensitive cells, TRAIL-resistant LNCaP and PC3-TR (a TRAIL-resistant subpopulation of PC3) cells showed increased c-FLIP(L) mRNA levels and maintained steady protein expression of c-FLIP(L) after treatment with TRAIL. Ectopic expression of c-FLIP(L) in TRAIL-sensitive PC3 cells changed their phenotype from TRAIL sensitive to TRAIL resistant. Conversely, silencing of c-FLIP(L) expression by small interfering RNA in PC3-TR cells reversed their phenotype from TRAIL resistant to TRAIL sensitive. Therefore, persistent expression of c-FLIP(L) is necessary and sufficient to regulate sensitivity to TRAIL-mediated apoptosis in prostate cancer cells.

Antineoplastic Agents↗

PubMed2004

Discrete signaling pathways participate in RB-dependent responses to chemotherapeutic agents.

The retinoblastoma (RB) tumor suppressor has been proposed to function as a key mediator of cell cycle checkpoints induced by chemotherapeutic agents. However, these prior studies have relied on embryonic fibroblasts harboring chronic loss of RB, a condition under which compensation of RB functions is known to occur. Here we utilized primary adult fibroblasts derived from mice harboring loxP sites flanking exon 3 of the Rb gene to delineate the action of RB in the chemotherapeutic response. In this system we find that targeted disruption of Rb leads to little overt change in cell cycle distribution. However, these cells exhibited deregulation of RB/E2F target genes and became aneuploid following culture in the absence of RB. When challenged with both DNA damaging and antimetabolite chemotherapeutics, RB was required for primary adult cells to undergo DNA damage checkpoint responses and loss of RB resulted in enhanced aneuploidy following challenge. In contrast, following spontaneous immortalization and the loss of functional p53 signaling, the antimetabolite 5-fluorouracil (5-FU) failed to induce arrest despite the presence of RB. In these immortal cultures RB/E2F targets were deregulated in a complex, gene-specific manner and RB was required for the checkpoint response to camptothecin (CPT). Mechanistic analyses of the checkpoint responses in primary cells indicated that loss of RB leads to increased p53 signaling and decreased viability following both CPT and 5-FU treatment. However, the mechanism through which these agents act to facilitate cell cycle inhibition through RB were distinct. These studies underscore the critical role of RB in DNA-damage checkpoint signaling and demonstrate that RB mediates chemotherapeutic-induced cell cycle inhibition in adult fibroblasts by distinct mechanisms.

Aneuploidy↗

PubMed2004

Human organic anion-transporting polypeptide OATP-A (SLC21A3) acts in concert with P-glycoprotein and multidrug resistance protein 2 in the vectorial transport of Saquinavir in Hep G2 cells.

Saquinavir mesylate (SQV) is the first-in-class and prototypical HIV protease inhibitor (PI) used in the treatment of HIV infection. SQV undergoes extensive hepatic metabolism and intestinal and bile secretion, and has poor and variable oral bioavailability. In previous studies, our group and others have described the interactions between SQV and absorptive and secretory efflux transporters such as MRP1, MRP2, and P-gp. However, the potential role of absorptive influx transporters such as OATP-A (SLC21A3) has not yet been reported for SQV. In the study presented here, the role of OATP-A in the influx transport of SQV was studied using a hepatic cell model, Hep G2, and Xenopus laevis oocytes overexpressing human OATP-A. In Hep G2 cells, SQV transport was found to be (i) concentration-dependent and saturable, (ii) temperature-sensitive, and (iii) proton (pH)- and sodium-independent. While GF120918, a specific inhibitor of P-gp, and MK571, a MRP transporter family inhibitor, significantly enhanced SQV uptake, estrone 3-sulfate, a substrate of OATP-A, significantly inhibited SQV uptake by Hep G2 cells. The observation that inhibitors of P-gp, MRP, or OATP-A have opposite effects on SQV uptake in polarized Hep G2 cells is consistent with their functions as hepatic efflux or influx transporters. In X. laevis oocytes into which OATP-A cRNA had been injected, the level of uptake of SQV was significantly greater than the level of uptake by oocytes into which water had been injected and was concentration-dependent and saturable (Km = 36.4+/-21.8 microM). This is the first report showing that SQV influx transport is directly facilitated by OATP-A. Given the wide body distribution of OATP-A, the current results suggest a potentially important role for OATP-A in the absorption and disposition of SQV in vivo. The data also suggest that in human hepatocytes basolaterally located OATP-A (influx transporter) may act in concert with apically located P-gp and/or MRP2 (efflux transporters) for the vectorial transport and excretion of SQV into bile.

ATP Binding Cassette Transporter, Subfamily B↗

PubMed2004

Assessment of drug-drug interaction potential of enfuvirtide in human immunodeficiency virus type 1-infected patients.

INTRODUCTION: Enfuvirtide is the first drug to block human immunodeficiency virus type 1 (HIV-1) glycoprotein 41-mediated viral fusion to host cells. This study investigated whether enfuvirtide can influence the activities of cytochrome P450 (CYP) enzymes in HIV-1-infected patients. METHODS: An open-label, 1-sequence crossover study was conducted in 12 HIV-1-infected adults, by use of a 5-drug cocktail consisting of caffeine, chlorzoxazone, dapsone, debrisoquin (INN, debrisoquine), and mephenytoin to assess the activities of CYP1A2, CYP2E1, CYP3A4, CYP2D6, and CYP2C19, respectively. Dapsone was used to assess N-acetyltransferase activity. Patients received a single dose of the cocktail alone on day -15 and another together with enfuvirtide on day 6. Enfuvirtide (90 mg subcutaneously) was administered twice daily on days 1 to 7. Phenotypic index parameters were estimated and analyzed by ANOVA with factors subject and day (-15 and 6). RESULTS: The phenotypic index parameters, with and without enfuvirtide, for CYP3A4 (0.33 versus 0.34; 90% confidence interval [CI] for ratio of least squares means, 0.88-1.09), CYP2D6 (0.72 versus 0.71; 90% CI, 0.97-1.06), and N-acetyltransferase (0.35 versus 0.39; 90% CI, 0.82-0.98) were bioequivalent. The phenotypic index parameters, with and without enfuvirtide, for CYP1A2 (0.76 versus 0.81; 90% CI, 0.71-1.17), CYP2E1 (1.3 versus 1.2; 90% CI, 0.87-1.29), and CYP2C19 (93 versus 81.8; 90% CI, 0.98-1.28) were not bioequivalent but were not substantially different. CONCLUSIONS: Enfuvirtide had no clinically important effect on the metabolism of probe drugs mediated by CYP3A4, CYP2D6, or N-acetyltransferase and had little effect on the metabolism of drugs mediated by CYP1A2, CYP2E1, or CYP2C19. The potential for interactions between enfuvirtide and concomitantly administered drugs metabolized by the CYP enzymes tested in this study is low.

Adult↗

PubMed2004

Endocardial endothelium in the avascular frog heart: role for diffusion of NO in control of cardiac O2 consumption.

We investigated the role of nitric oxide (NO) in the control of myocardial O(2) consumption in the hearts of female Xenopus frogs, which lack a coronary vascular endothelium and in which the endocardial endothelium is the only source of NO to regulate cardiac myocyte function. Hence, frogs are an ideal model in which to explore the role of diffusion of NO from the endocardial endothelium (EE) without vascular endothelial or cardiac cell NO production. In Xenopus hearts we examined the regulation of cardiac O(2) consumption in vitro at 25 degrees C and 37 degrees C. The NO-mediated control of O(2) consumption by bradykinin or carbachol was significantly (P < 0.05) lower at 25 degrees C (79 +/- 13 or 73 +/- 11 nmol/min) than at 37 degrees C (159 +/- 26 or 201 +/- 13 nmol/min). The response to the NO donor S-nitroso-N-acetyl penicillamine was also markedly lower at 25 degrees C (90 +/- 8 nmol/min) compared with 37 degrees C (218 +/- 15 nmol/min). When Triton X-100 was perfused into hearts, the inhibition of myocardial O(2) consumption by bradykinin (18 +/- 2 nmol/min) or carbachol (29 +/- 4 nmol/min) was abolished. Hematoxylin and eosin slides of Triton X-100-perfused heart tissue confirmed the absence of the EE. Although endothelial NO synthase protein levels were decreased to a variable degree in the Triton X-100-perfused heart, NO(2) production (indicating eNOS activity) decreased by >80%. It appears that the EE of the frog heart is the sole source of NO to regulate myocyte O(2) consumption. When these cells are removed, the ability of NO to regulate O(2) consumption is severely limited. Thus our results suggest that the EE produces enough NO, which diffuses from the EE to cardiac myocytes, to regulate myocardial O(2) consumption. Because of the close proximity of the EE to underlying myocytes, NO can diffuse over a distance and act as a messenger between the EE and the rest of the heart to control mitochondrial function and O(2) consumption.

Animals↗

PubMed2004

Lack of interaction between enfuvirtide and ritonavir or ritonavir-boosted saquinavir in HIV-1-infected patients.

Enfuvirtide (Fuzeon) is an HIV fusion inhibitor, the first drug in a new class of antiretrovirals. The HIV protease inhibitors ritonavir and saquinavir both inhibit cytochrome P450 (CYP450) isoenzymes, and low-dose ritonavir is often used to boost pharmacokinetic exposure to full-dose protease inhibitors. These two studies were designed to assess whether ritonavir and ritonavir-boosted saquinavir influence the steady-state pharmacokinetics of enfuvirtide. Both studies were single-center, open-label, one-sequence crossover clinical pharmacology studies in 12 HIV-1-infected patients each. Patients received enfuvirtide (90 mg twice daily [bid], subcutaneous injection) for 7 days and either ritonavir (200 mg bid, ritonavir study, orally) or saquinavir/ritonavir (1000/100 mg bid, saquinavir/ritonavir study, orally) for 4 days on days 4 to 7. Serial blood samples were collected up to 24 hours after the morning dose of enfuvirtide on days 3 and 7. Plasma concentrations for enfuvirtide, enfuvirtide metabolite, saquinavir, and ritonavir were measured using validated liquid chromatography tandem mass spectrometry methods. Efficacy and safety were also monitored. Bioequivalence criteria require the 90% confidence interval (CI) for the least squares means (LSM) of C(max) and AUC(12h) to be between 80% and 125%. In the present studies, analysis of variance showed that when coadministered with ritonavir, the ratio of LSM for enfuvirtide was 124% for C(max) (90% confidence interval [CI]: 109%-141%), 122% for AUC(12h) (90% CI: 108%-137%), and 114% for C(trough) (90% CI: 102%-128%). Although the bioequivalence criteria were not met, the increase in enfuvirtide exposure was small (< 25%) and not clinically relevant. When administered with ritonavir-boosted saquinavir, the ratio of LSM for enfuvirtide was 107% for C(max) (90% CI: 94.3%-121%) and 114% for AUC(12h) (90% CI: 105%-124%), which therefore met bioequivalence criteria, and 126% for C(trough) (90% CI: 117%-135%). The pharmacokinetics of enfuvirtide are affected to a small extent when coadministered with ritonavir at a dose of 200 mg bid but not when coadministered with a saquinavir-ritonavir combination (1000/100 mg bid). However, previous clinical studies have shown that such increases in enfuvirtide exposure are not clinically relevant. Thus, no dosage adjustments are warranted when enfuvirtide is coadministered with low-dose ritonavir or saquinavir boosted with a low dose of ritonavir.

Adult↗

PubMed2004

[Conservation tillage systems in North America and their significance for China].

Soil degradation through erosion and desertification reduces soil productivity, and is a serious problem in agricultural production of China. To avert our arable land from further degradation, soil management must be shifted from degrading tillage to conservation practices. Over viewing the technology used in the 20th century for controlling soil degradation from erosion, conservation tillage developed in the United States and adopted in South America and Africa is one of the most successful measures to overcome soil degradation problems. This paper reviewed the historical development and the current situation of conservation tillage systems used in North and South America, with special reference to their effects on soil erosion control and soil quality. The increasing adoption of conservation tillage systems in North and South America and Africa followed an enhanced awareness of the increasing risk of soil erosion and the high cost of fuel associated with conventional tillage. Many crucial points for successfully adopting conservation tillage systems were emphasized, such as equipment/tool development and chemical weed control. Adopting conservation tillage could provide China with low-priced means of reducing soil degradation and improving soil and water quality.

Agriculture↗

PubMed2004

[Treatment for erectile dysfunction patients with obstructive sleep apnea syndrome by nasal continual positive airway pressure].

OBJECTIVE: To investigate the influence of nasal continual positive airway pressure (nCPAP) on the erectile function of erectile dysfunction (ED) patients with obstructive sleep apnea syndrome(OSAS). METHODS: Twenty-seven patients with ED and OSAS were randomly divided into treatment (n = 15) and control (n = 12) groups, the former treated by nCPAP from 22:00 to 6:00 per night for 1 month. And the apnea-hypopnea index(AHI), the lowest oxygen saturation (SaO2) and IIEF were compared before and after treatment. RESULTS: AHI, the lowest SaO2, erectile function and IIEF showed no significant difference before treatment in the two groups, but displayed a significant improvement after treatment in the treated group compared with the control (P > 0.05), in which no significant changes were observed before and after treatment (P > 0.05). CONCLUSION: nCPAP therapy can improve the erectile function of ED patients with OSAS.

Adult↗

PubMed2004

[Histopathological changes of the cryptorchid testis and epididymis of mice exposed to DEHP].

OBJECTIVE: To investigate the effects of DEHP on the incidence of cryptorchidism and the histopathological changes of the testis and epididymis in mice. METHODS: Forty KM mice were divided into 5 groups randomly: normal control group (n=8), corn oil group (n=8), DES group (n=8), low DEHP group (n=9), and high DEHP group (n=7). DEHP[100 or 500 mg/(kg x d)], DES[100 microg/(kg x d)] and corn oil were administrated respectively to the pregnant mice from gestation day 12 (GD 12) until postnatal day 3 (PND3). The incidence of cryptorchidism with testicular morphologic and histological changes in the male pups was observed. RESULTS: Significantly increased incidence of cryptorchidism was seen in the male pups with increasing exposure to DEHP. Cryptorchid testicular volumes and weights significantly decreased compared with the control. Abnormal pathological and ultrastructural alternations of seminiferous epithelium and Leydig cells were also observed. Meanwhile less or no sperm was found in the lumen of the epididymis. CONCLUSION: During the critical period of male sexual differentiation, exposure to DEHP may lead to a significantly high incidence of cryptorchidism, testicular damage and fertility impairment in the male offspring. The effects of DEHP are dosage-dependent.

Animals↗

PubMed2003

Coronary microvascular endothelial stunning after acute pressure overload in the conscious dog is caused by oxidant processes: the role of angiotensin II type 1 receptor and NAD(P)H oxidase.

BACKGROUND: Few studies have examined the effect of acute pressure overload on endothelial function in the coronary microcirculation. METHODS AND RESULTS: In instrumented conscious dogs with heart rate held constant, veratrine caused a cholinergic nitric oxide (NO)-dependent increase in coronary blood flow by 23+/-3 mL/min (Bezold-Jarisch reflex). Ten minutes after release of constriction of the ascending aorta to increase left ventricular (LV) systolic pressure to 214+/-5 mm Hg for 30 minutes, the veratrine-induced increase in coronary blood flow (7+/-1 mL/min) was reduced by 66% and remained depressed for 2 hours (ie, endothelial stunning [ES]). Nitrite production from isolated coronary microvessels during ES was not different from normal. Ascorbic acid (AA), losartan, or apocynin prevented ES. Myocardial oxygen consumption (MVO2) of LV tissue was measured in vitro in response to bradykinin with preincubation of angiotensin II for 30 minutes. Bradykinin (10(-4) mol/L)-induced reduction in MVO2 was reversed in a concentration-dependent manner by angiotensin II (38+/-1% versus 19+/-2% at 10(-8) mol/L) and restored by coincubation of AA (37+/-2%), tempol (33+/-2%), losartan (34+/-2%), or apocynin (36+/-1%). Exogenous NO-induced reduction in MVO2 was not altered by angiotensin II. Angiotensin II increased lucigenin-detectable superoxide anion in LV tissue in a manner that was inhibited by bradykinin, AA, tempol, losartan, or apocynin. CONCLUSIONS: Endothelial stunning is caused by oxidant processes inhibited by ascorbate, and the activation of NAD(P)H oxidase by increased angiotensin II plays an important role in this process.

Acetophenones↗

PubMed2003

Lipid raft distribution of CD4 depends on its palmitoylation and association with Lck, and evidence for CD4-induced lipid raft aggregation as an additional mechanism to enhance CD3 signaling.

By mutagenesis, we demonstrated that the palmitoylation of the membrane-proximal Cys(396) and Cys(399)of CD4, and the association of CD4 with Lck contribute to the enrichment of CD4 in lipid rafts. Ab cross-linking of CD4 induces an extensive membrane patching on the T cell surface, which is related to lipid raft aggregation. The lipid raft localization of CD4 is critical for CD4 to induce the aggregation of lipid rafts. The localization of CD4 in lipid rafts also correlates to the ability of CD4 to enhance receptor tyrosine phosphorylation. Thus, our data suggest that CD4-induced aggregation of lipid rafts may play an additional role in CD4 signaling besides its adhesion to MHC molecules and association with Lck.

Amino Acid Motifs↗

PubMed2003

Influence of subcutaneous injection site on the steady-state pharmacokinetics of enfuvirtide (T-20) in HIV-1-infected patients.

BACKGROUND: Enfuvirtide is the first in a new class of antiretrovirals (ARVs), the fusion inhibitors, and the first ARV to be administered by subcutaneous (s.c.) injection. OBJECTIVES: The primary objective of this study was to determine the steady-state pharmacokinetics and relative bioavailability of enfuvirtide following sc injection at three separate anatomical sites: abdomen (A), thigh (B) and arm (C). STUDY DESIGN: A single-center, open-label, multiple-dose, three-way randomized, crossover study. Twelve HIV-1-infected adults were recruited from three ongoing Phase II enfuvirtide clinical trials and randomized into three groups. Each group continued to receive s.c. injection of enfuvirtide, at a dose of 90 mg twice daily (bid), according to one of three treatment sequences: ABC, BCA or CAB; over three consecutive periods of approximately 7 days each. Plasma concentrations of enfuvirtide and its metabolite (Ro 50-6343) were measured using a validated liquid chromatography-tandem mass spectrometry method. RESULTS: The relative bioavailability of enfuvirtide, based on AUC12h and abdomen as a reference site, was 101% for thigh and 117% for arm. The AUC12h of Ro 50-6343 ranged from 14 to 16% of that for enfuvirtide. Although injection site reactions (ISRs) were common, the overall grading (based on pain or discomfort) of all reported ISRs was Grade 1 (mild). The incidence of ISRs varied according to the site of injection, as did the signs and symptoms associated with them. No patient required treatment for an ISR. CONCLUSIONS: Comparability among the three injection sites, in terms of both absorption and the ISR profile, allows HIV-1-infected patients the freedom to choose and to rotate, if necessary, the site of enfuvirtide injection among the three anatomical sites.

Dose-Response Relationship, Drug↗

PubMed2003

Acute and chronic endothelial dysfunction: implications for the development of heart failure.

Heart failure has been characterized by a reduction in cardiac contractile function resulting in reduced cardiac output. The clinical symptoms including mild tachycardia, reduced arterial pressure, increased venous or filling pressure and exercise intolerance have conceptually, to a large degree, been attributed to cardiac myocyte dysfunction. More recently, a vascular component has been recognized to contribute to heart failure. Among the most studied vascular mechanisms that might contribute to the development of heart failure has been the reduced production of nitric oxide or the reduced bioactivity of NO associated with both basic models of heart failure and disease in patients. The still evolving concept that heart failure is a cytokine activated state has, in addition, focused attention on the possibility that the cytokine driven isoform of NO synthase (NOS), iNOS, may produce sufficient quantities of NO to actually suppress cardiac myocyte function contributing to the reduced inotropic state in the failing heart. Thus, our view of the role of NO in the development of heart failure has evolved from simply a reduction in production of NO in blood vessels, to altered substrate availability (i.e. L-arginine), to increased scavenging of NO by superoxide anion, to increased production of NO from iNOS. As these concepts develop, our approach to the therapeutics of heart failure has also progressed with the recognition of the need to develop treatments directed towards addressing one or more of these etiologies. This review will focus on these aspects of the involvement of NO in the development of heart failure and some of the treatments that have developed from our understanding of the basic biology of NO to address these pathohysiologic states.

Acute Disease↗

PubMed2003

Lack of enzyme-inducing effect of rifampicin on the pharmacokinetics of enfuvirtide.

The primary objective was to determine whether rifampicin influences the pharmacokinetics of enfuvirtide in HIV-1-infected patients. In a single-center, open-label, one-sequence crossover, clinical pharmacology study, 12 HIV-1-infected adults received enfuvirtide (90 mg, twice daily) on days 1 to 3 and days 11 to 13 (morning dose only on days 3 and 13) and rifampicin (600 mg, once daily) from days 4 to 13. Plasma concentrations were measured for enfuvirtide and its metabolite (days 3 and 13) and rifampicin (day 13 only). The ratios of least squares means (LSM) and 90% confidence intervals for enfuvirtide and enfuvirtide metabolite pharmacokinetic parameters (AUC12h, Cmax, Ctrough) were estimated in the presence and absence of rifampicin. Treatments were compared using an analysis of variance for natural log-transformed variables, with factors patient and treatment. Efficacy and safety were also monitored. Steady-state rifampicin had no appreciable effect on any of the pharmacokinetic parameters assessed for either enfuvirtide or its metabolite. The ratio of LSM for AUC12h, Cmax, and Ctrough for enfuvirtide was 97.5%, 103%, and 84.9%, respectively, and 108%, 112%, and 92.9%, for the enfuvirtide metabolite. Rifampicin did not affect the t1/2 of enfuvirtide or its metabolite. There were no unexpected effects of rifampicin on the short-term antiviral effect or safety of the administered antiretroviral treatment. The pharmacokinetics of enfuvirtide are not induced by a 10-day pretreatment with rifampicin.

Adult↗