Tropical ecosystems are central to the global focus on halting and reversing habitat destruction as a means of mitigating carbon emissions. Brazil has been highlighted as a vital part of global ...climate agreements because, whilst ongoing land-use change causes it to be the world's fifth biggest greenhouse gas emitting country, it also has one of the greatest potentials to implement ecosystem restoration. Global carbon markets provide the opportunity of a financially viable way to implement restoration projects at scale. However, except for rainforests, the restoration potential of many major tropical biomes is not widely recognised, with the result that carbon sequestration potential may be squandered. We synthesize data on land availability, land degradation status, restoration costs, area of native vegetation remaining, carbon storage potential and carbon market prices for 5475 municipalities across Brazil's major biomes, including the savannas and tropical dry forests. Using a modelling analysis, we determine how fast restoration could be implemented across these biomes within existing carbon markets. We argue that even with a sole focus on carbon, we must restore other tropical biomes, as well as rainforests, to effectively increase benefits. The inclusion of dry forests and savannas doubles the area which could be restored in a financially viable manner, increasing the potential CO2e sequestered >40 % above that offered by rainforests alone. Importantly, we show that in the short-term avoiding emissions through conservation will be necessary for Brazil to achieve it’s 2030 climate goal, because it can sequester 1.5 to 4.3 Pg of CO2e by 2030, relative to 0.127 Pg CO2e from restoration. However, in the longer term, restoration across all biomes in Brazil could draw down between 3.9 and 9.8 Pg of CO2e from the atmosphere by 2050 and 2080.
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•Problem: Focusing mostly on tropical forests for climate mitigation projects•We model CO2e costs-effective restoration and conservation across Brazil.•Restoring dry biomes is vital to increasing cost-effective restoration opportunities in Brazil.•Restoration is the most effective way to achieve long-term climate mitigation.•Conservation is the most relevant to achieving Brazil's 2030 climate goals.
Objective
To evaluate the efficacy of synovial fluid culture in obtaining the causative organism from dogs with suspected septic arthritis.
Methods
In this retrospective evaluation, synovial fluid ...cytology and microbiology submissions from dogs with suspected septic arthritis from March 2007 to August 2011 were reviewed. Synovial fluid cytology consistent with joint sepsis was identified. Cultures of synovial fluid from dogs with clinical histories and abnormalities consistent with septic arthritis were used to evaluate the efficacy of bacterial isolation.
Results
In total, 36 dogs met the inclusion criteria. Initial aerobic cultures of joint fluid yielded bacterial growth in 44% of these dogs. All anaerobic cultures were negative. In 19% of the dogs with positive cultures, antibiotics had been administered prior to arthrocentesis compared with 10% of dogs with negative cultures. There was no association between culture efficacy and the administration of antimicrobial treatment prior to synovial fluid culture or recent surgery involving the affected joint (P = 0.637 and P = 0.106, respectively).
Conclusion
Culture of synovial fluid from dogs with suspected septic arthritis has a low yield, necessitating a more effective means of identifying bacteria from suspected septic joints in dogs.
Endothelin 1, a powerful endogenous vasoconstrictor and mitogen, might be a cause of pulmonary hypertension. We describe the efficacy and safety of bosentan, a dual endothelin-receptor antagonist ...that can be taken orally, in patients with severe pulmonary hypertension.
In this double-blind, placebo-controlled study, 32 patients with pulmonary hypertension (primary or associated with scleroderma) were randomly assigned to bosentan (62.5mg taken twice daily for 4 weeks then 125 mg twice daily) or placebo for a minimum of 12 weeks. The primary endpoint was change in exercise capacity. Secondary endpoints included changes in cardiopulmonary haemodynamics, Borg dyspnoea index, WHO functional class, and withdrawal due to clinical worsening. Analysis was by intention to treat.
In patients given bosentan, the distance walked in 6 min improved by 70 m at 12 weeks compared with baseline, whereas it worsened by 6 m in those on placebo (difference 76 m 95% CI 12-139, p=0.021). The improvement was maintained for at least 20 weeks. The cardiac index was 1.0 L min(-1) m(-2) (95% CI 0.6-1.4, p<0.0001) greater in patients given bosentan than in those given placebo. Pulmonary vascular resistance decreased by 223 dyn s cm(-)(5) with bosentan, but increased by 191 dyn s cm(-5) with placebo (difference -415 -608 to -221, p=0.0002). Patients given bosentan had a reduced Borg dyspnoea index and an improved WHO functional class. All three withdrawals from clinical worsening were in the placebo group (p=0.033). The number and nature of adverse events did not differ between the two groups.
Bosentan increases exercise capacity and improves haemodynamics in patients with pulmonary hypertension, suggesting that endothelin has an important role in pulmonary hypertension.
Pulmonary hypertension is a progressive and often fatal complication of the scleroderma spectrum of disease for which no treatment has been proven effective in a randomized trial.
To determine the ...effect of epoprostenol on pulmonary hypertension secondary to the scleroderma spectrum of disease.
Randomized, open-label, controlled trial.
17 pulmonary hypertension referral centers.
111 patients with moderate to severe pulmonary hypertension.
Epoprostenol plus conventional therapy or conventional therapy alone.
The primary outcome measure was exercise capacity. Other measures were cardiopulmonary hemodynamics, signs and symptoms of pulmonary hypertension and scleroderma, and survival.
Exercise capacity improved with epoprostenol (median distance walked in 6 minutes, 316 m at 12 weeks compared with 270 m at baseline) but decreased with conventional therapy (192 m at 12 weeks compared with 240 m at baseline). The difference between treatment groups in the median distance walked at week 12 was 108 m (95% CI, 55.2 m to 180.0 m) (P < 0.001). Hemodynamics improved at 12 weeks with epoprostenol. The changes in mean pulmonary artery pressure for the epoprostenol and conventional therapy groups were -5.0 and 0.9 mm Hg, respectively (difference, -6.0 mm Hg CI, -9.0 to -3.0 mm Hg), and the mean changes in pulmonary vascular resistance were -4.6 and 0.9 mm Hg/L per minute, respectively (difference, -5.5 mm Hg/L per minute CI, -7.3 to -3.7 mm Hg/L per minute). Twenty-one patients treated with epoprostenol and no patients receiving conventional therapy showed improved New York Heart Association functional class. Borg Dyspnea Scores and Dyspnea-Fatigue Ratings improved in the epoprostenol group. Trends toward greater improvement in severity of the Raynaud phenomenon and fewer new digital ulcers were seen in the epoprostenol group. Four patients in the epoprostenol group and five in the conventional therapy group died (P value not significant). Side effects of epoprostenol therapy included jaw pain, nausea, and anorexia. Adverse events related to the epoprostenol delivery system included sepsis, cellulitis, hemorrhage, and pneumothorax (4% incidence for each condition).
Continuous epoprostenol therapy improves exercise capacity and cardiopulmonary hemodynamics in patients with pulmonary hypertension due to the scleroderma spectrum of disease.
Primary pulmonary hypertension is a progressive disease for which no treatment has been shown in a prospective, randomized trial to improve survival.
We conducted a 12-week prospective, randomized, ...multicenter open trial comparing the effects of the continuous intravenous infusion of epoprostenol (formerly called prostacyclin) plus conventional therapy with those of conventional therapy alone in 81 patients with severe primary pulmonary hypertension (New York Heart Association functional class III or IV).
Exercise capacity was improved in the 41 patients treated with epoprostenol (median distance walked in six minutes, 362 m at 12 weeks vs. 315 m at base line), but it decreased in the 40 patients treated with conventional therapy alone (204 m at 12 weeks vs. 270 m at base line; P < 0.002 for the comparison of the treatment groups). Indexes of the quality of life were improved only in the epoprostenol group (P < 0.01). Hemodynamics improved at 12 weeks in the epoprostenol-treated patients. The changes in mean pulmonary-artery pressure for the epoprostenol and control groups were -8 percent and +3 percent, respectively (difference in mean change, -6.7 mm Hg; 95 percent confidence interval, -10.7 to -2.6 mm Hg; P < 0.002), and the mean changes in pulmonary vascular resistance for the epoprostenol and control groups were -21 percent and +9 percent, respectively (difference in mean change, -4.9 mm Hg/liter/min; 95 percent confidence interval, -7.6 to -2.3 mm Hg/liter/min; P < 0.001). Eight patients died during the study, all of whom had been randomly assigned to conventional therapy (P = 0.003). Serious complications included four episodes of catheter-related sepsis and one thrombotic event.
As compared with conventional therapy, the continuous intravenous infusion of epoprostenol produced symptomatic and hemodynamic improvement, as well as improved survival in patients with severe primary pulmonary hypertension.
Compound lipophilicity is of key importance to P450 binding affinity and enzyme selectivity. Here, lipophilicity is discussed with reference to the human drug-metabolizing P450 enzymes of families ...CYP1, CYP2 and CYP3. From an extensive compilation of log P values for P450 substrates, and by analysis of relationships between partitioning energy and substrate-binding free energy, the relevance of lipophilicity and other factors pertaining to P450 binding affinity is explained, leading to the formulation of lipophilicity relationships within substrates of each human P450 enzyme involved in drug metabolism. Furthermore, log P values for P450 substrates appear to represent markers for enzyme selectivity. Together with the important roles of hydrogen bonding and π–π stacking interaction energies, the desolvation of the P450 active site makes a major contribution to the overall substrate-binding energy and, consequently, a good agreement with experimental information is reported based on this analysis.
Lipophilicity appears to have a marked bearing on P450 substrate selectivity and metabolism. Substrate binding affinity is well correlated with log P data, and substrates of a given P450 exhibit well-defined ranges of log P values.
Objective
To prospectively compare the sensitivity and specificity of 16S rRNA PCR with culture for identifying the causative organism in synovial fluid obtained from dogs with suspected septic ...arthritis.
Methods
Synovial fluid cytology, PCR analysis and aerobic, anaerobic and Mycoplasma culture of samples from the affected joints of 18 dogs presenting with suspected septic arthritis were performed. Synovial fluid samples from the corresponding contralateral joints of 7 dogs were also analysed as negative controls.
Results
There was no significant difference between the sensitivity of bacterial detection via culture (63.2%) versus PCR (73.7%) of synovial fluid (P = 0.728) or between culture and combined PCR and culture (89.5%) of synovial fluid (P = 0.124). The specificity of PCR (42.9%) was significantly lower than culture specificity (100%) (P = 0.07).
Conclusion
Although 16S PCR may hold potential as an ancillary diagnostic test for identifying the causative organism in dogs with septic arthritis, our study failed to demonstrate improved accuracy compared with traditional synovial fluid culture.
The population pharmacokinetic/pharmacodynamic (PK/PD) approach was prospectively integrated in the clinical development of docetaxel to assess the PK profile in a large population of patients and ...investigate systemic exposure as a prognostic factor for clinical outcome.
PK analysis was performed at first course in 24 phase II studies of docetaxel monotherapy using four randomized limited-sampling schedules. Bayesian estimates of clearance (CL), area under the concentration-time curve (AUC), and peak and duration of plasma levels greater than threshold levels were used as measures of exposure. PD data included for efficacy, response rate, time to first response, and time to progression (TTP) in breast cancer and non-small-cell lung cancer (NSCLC), and for toxicity, grade 4 neutropenia, and febrile neutropenia at first course and time to onset of fluid retention. PK/PD analysis was conducted using logistic and Cox multivariate regression models.
PK protocol implementation was successful. Most of the patients registered (721 of 936, 77%) were sampled and 68% were assessable for PK (640 patients). First-course docetaxel AUC was a significant predictor (P = .0232) of TTP in NSCLC (n = 151). Docetaxel CL was a strong independent predictor (P < .0001) of both grade 4 neutropenia and febrile neutropenia (n = 582). Cumulative dose was the strongest predictor (P < .0001) of the time to onset of fluid retention (n = 631). However, the duration of exposure over 0.20 micromol/L (0.16 microg/mL) at first course was an independent predictor (P = .0029). Few patients (n = 25, 4%) received the recommended dexamethasone premedication.
First-course docetaxel PK is a predictor of first-course hematologic toxicity, but also of fluid retention, which is cumulative in nature. Patients with elevated hepatic enzymes have a 27% reduction in docetaxel CL and are at a higher risk of toxicity. A starting dose of 75 mg/m2 is currently being evaluated in this population. Prospective implementation of large-scale population PK/PD evaluation is feasible in early drug development and this approach generates clinically relevant findings.
Substrate SARs in human P450s Lewis, David F.V; Dickins, Maurice
Drug Discovery Today,
09/2002, Letnik:
7, Številka:
17
Book Review, Journal Article
Recenzirano
Drug metabolism is now an integral part of the drug discovery process, and the cytochromes P450 (CYPs) are the most important family of enzymes involved in human drug metabolism. An increased ...understanding of the properties of the substrates for the major human CYPs is thus highly desirable. This article shows how key characteristics of CYP substrates, such as lipophilicity, molecular mass and hydrogen-bonding potential, govern selectivity towards individual CYPs. Importantly, the variation in binding affinities of 60 human CYP substrates can be explained by understanding the key physicochemical, structural and electronic characteristics that govern substrate binding to each isozyme.
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