Mahidol University

About: Mahidol University is a education organization based out in Bangkok, Nakhon Pathom, Thailand. It is known for research contribution in the topics: Population & Malaria. The organization has 23758 authors who have published 39761 publications receiving 878781 citations.

Brivanib Versus Sorafenib As First-Line Therapy in Patients With Unresectable, Advanced Hepatocellular Carcinoma: Results From the Randomized Phase III BRISK-FL Study

Abstract: Purpose Brivanib is a dual inhibitor of vascular-endothelial growth factor and fibroblast growth factor receptors that are implicated in the pathogenesis of hepatocellular carcinoma (HCC). Our multinational, randomized, double-blind, phase III trial compared brivanib with sorafenib as first-line treatment for HCC. Patients and Methods Advanced HCC patients who had no prior systemic therapy were randomly assigned (ratio, 1:1) to receive sorafenib 400 mg twice daily orally (n = 578) or brivanib 800 mg once daily orally (n = 577). Primary end point was overall survival (OS). Secondary end points included time to progression (TTP), objective response rate (ORR), disease control rate (DCR) based on modified Response Evaluation Criteria in Solid Tumors (mRECIST), and safety. Results The primary end point of OS noninferiority for brivanib versus sorafenib in the per-protocol population (n = 1,150) was not met (hazard ratio [HR], 1.06; 95.8% CI, 0.93 to 1.22), based on the prespecified margin (upper CI limit for ...

Population Pharmacokinetics of Colistin Methanesulfonate and Formed Colistin in Critically Ill Patients from a Multicenter Study Provide Dosing Suggestions for Various Categories of Patients

Abstract: With increasing clinical emergence of multidrug-resistant Gram-negative pathogens and the paucity of new agents to combat these infections, colistin (administered as its inactive prodrug colistin methanesulfonate [CMS]) has reemerged as a treatment option, especially for critically ill patients. There has been a dearth of pharmacokinetic (PK) data available to guide dosing in critically ill patients, including those on renal replacement therapy. In an ongoing study to develop a population PK model for CMS and colistin, 105 patients have been studied to date; these included 12 patients on hemodialysis and 4 on continuous renal replacement therapy. For patients not on renal replacement, there was a wide variance in creatinine clearance, ranging from 3 to 169 ml/min/1.73 m 2 . Each patient was treated with a physician-selected CMS dosage regimen, and 8 blood samples for PK analysis were collected across a dosage interval on day 3 or 4 of therapy. A linear PK model with two compartments for CMS and one compartment for formed colistin best described the data. Covariates included creatinine clearance on the total clearance of CMS and colistin, as well as body weight on the central volume of CMS. Model-fitted parameter estimates were used to derive suggested loading and maintenance dosing regimens for various categories of patients, including those on hemodialysis and continuous renal replacement. Based on our current understanding of colistin PK and pharmacodynamic relationships, colistin may best be used as part of a highly active combination, especially for patients with moderate to good renal function and/or for organisms with MICs of ≥1.0 mg/liter.

Assessment of the pharmacodynamic properties of antimalarial drugs in vivo.

Abstract: Malaria is unusual among the systemic infections of humans in that the number of organisms causing the disease may be quantitated with reasonable precision. This applies particularly to those causing benign human malarias, i.e., Plasmodium vivax, P. malariae, and P. ovale, as these parasites are not sequestered in the microcirculation (13). The assessment of parasite burden for the sequestering, potentially lethal parasite P. falciparum is more difficult, but there are some clues which allow a rough estimation of the proportion of parasites circulating in the bloodstream (65). If the number of organisms causing an infection is known, then the pharmacodynamic properties required of an anti-infective drug to produce a cure can be defined. The assessment of the treatment response in malaria rests on the clinical outcome (mortality, speed of recovery from coma, fever clearance, etc.) and the parasitological outcome—the subject of this discussion. Although a great deal remains to be learned about the pharmacodynamic properties of antimalarial drugs in vivo, sufficient information is already available to construct simple models which predict for how long antimalarial treatment should be given and the chances of treatment failure (i.e., recrudescence of the infection). In the management of individual patients, the ratio of the parasitemia at the time of treatment to the count 48 h later (the parasite reduction ratio [PRR]), representing the fractional reduction per asexual life cycle, may be a simple but useful predictive index. General principles. Parasitological recovery from malaria is assessed conventionally by the clearance of parasites from peripheral blood smears (68). In highly drug-resistant infections, parasites do not disappear from the peripheral blood or may increase following the administration of antimalarial drugs. Parasites with lower grades of resistance disappear from the peripheral blood (in fact, the concentration falls below the level of microscopic detection) but recur at a later time, usually in association with a return of symptoms. The efficacy of antimalarial drug treatment is assessed in terms of the speed at which symptoms and signs resolve and parasitemia declines (usually recorded as the parasite clearance time [PCT]) and the proportion of patients in whom infections recur within a defined period (71). Relationship between parasitemia and disease. Assessment of the therapeutic response in falciparum malaria is complicated by the loose relationship between parasitemia (number of parasites per unit volume of blood) and disease severity (10). A patient may be admitted in a deep coma with evidence of liver and renal dysfunction and severe metabolic acidosis, yet parasites are visible only on the thick blood film (,0.02%), whereas in areas where the disease is endemic a child may be able to walk and continues to eat when nearly half of the erythrocytes are parasitized. Several factors explain this discrepancy. As immunity to malaria develops with repeated infections in areas where the disease is endemic, the parasitemia threshold at which symptoms develop rises. This is often termed antitoxic immunity or premunition (2). It reflects a change in the relationship between parasite burden and both the release of and the response to illness-inducing cytokines (25). Interestingly, this relationship differs among the parasites causing human malarias; for example, P. vivax has a lower pyrogenic threshold (ca. 200/ml) than P. falciparum (ca. 10,000/ ml) (23). As a consequence, adults living in areas where malaria is endemic who have been exposed repeatedly to malaria during their lives tolerate detectable parasitemias (total parasite burden, .10) without symptoms, whereas nonimmune persons with such burdens are ill. The second important factor explaining the discrepancy between parasitemia and disease severity relates to the stage and synchronicity of infection (53, 65). In P. falciparum malaria, only the first half of the 48-h life cycle is visible to the microscopist. At approximately 16 to 24 h of asexual development, intraerythrocytic parasites start to induce the expression of adhesins on the infected erythrocyte surface (20). Parasitized erythrocytes aggregate with uninfected erythrocytes (rosetting) and also begin to adhere to vascular endothelium, particularly in the venules. This process is termed cytoadherence, and it leads to sequestration of the mature parasites in the deep vasculature (67). Thus, in P. falciparum malaria, depending on stage and synchronicity, the bulk of the infecting asexual stage parasites may be either circulating (when the mean age of development is in the first half of the cycle) and measurable or sequestered (when the mean age of development is in the second half of the cycle) and not measurable (53). In the expanding phase of the infection, there are usually more circulating than sequestered parasites and there can be considerable differences in synchronous infections (65). As pathophysiological processes in falciparum malaria are thought to relate to the sequestered forms of the parasite and subsequent merogony (67), and not to the younger circulating asexual stages, patients tend to be more ill when the majority of their parasites are sequestered (i.e., not visible to the microscopist) or just after schizont rupture (merogony). In benign human malarias, which synchronize more readily than falciparum malaria, fever and rigors are associated with synchronous merogony (22, 23, 28). These symptoms result from the simultaneous release of malaria-related pyrogens * Mailing address: Faculty of Tropical Medicine, Mahidol University, 420/6 Rajvithi Road, Bangkok 10400, Thailand. Phone: 66 2 246 0832. Fax: 66 2 246 7795.

Effect of Hydrocortisone on Mortality and Organ Support in Patients With Severe COVID-19: The REMAP-CAP COVID-19 Corticosteroid Domain Randomized Clinical Trial.

Abstract: Importance Evidence regarding corticosteroid use for severe coronavirus disease 2019 (COVID-19) is limited. Objective To determine whether hydrocortisone improves outcome for patients with severe COVID-19. Design, Setting, and Participants An ongoing adaptive platform trial testing multiple interventions within multiple therapeutic domains, for example, antiviral agents, corticosteroids, or immunoglobulin. Between March 9 and June 17, 2020, 614 adult patients with suspected or confirmed COVID-19 were enrolled and randomized within at least 1 domain following admission to an intensive care unit (ICU) for respiratory or cardiovascular organ support at 121 sites in 8 countries. Of these, 403 were randomized to open-label interventions within the corticosteroid domain. The domain was halted after results from another trial were released. Follow-up ended August 12, 2020. Interventions The corticosteroid domain randomized participants to a fixed 7-day course of intravenous hydrocortisone (50 mg or 100 mg every 6 hours) (n = 143), a shock-dependent course (50 mg every 6 hours when shock was clinically evident) (n = 152), or no hydrocortisone (n = 108). Main Outcomes and Measures The primary end point was organ support–free days (days alive and free of ICU-based respiratory or cardiovascular support) within 21 days, where patients who died were assigned –1 day. The primary analysis was a bayesian cumulative logistic model that included all patients enrolled with severe COVID-19, adjusting for age, sex, site, region, time, assignment to interventions within other domains, and domain and intervention eligibility. Superiority was defined as the posterior probability of an odds ratio greater than 1 (threshold for trial conclusion of superiority >99%). Results After excluding 19 participants who withdrew consent, there were 384 patients (mean age, 60 years; 29% female) randomized to the fixed-dose (n = 137), shock-dependent (n = 146), and no (n = 101) hydrocortisone groups; 379 (99%) completed the study and were included in the analysis. The mean age for the 3 groups ranged between 59.5 and 60.4 years; most patients were male (range, 70.6%-71.5%); mean body mass index ranged between 29.7 and 30.9; and patients receiving mechanical ventilation ranged between 50.0% and 63.5%. For the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively, the median organ support–free days were 0 (IQR, –1 to 15), 0 (IQR, –1 to 13), and 0 (–1 to 11) days (composed of 30%, 26%, and 33% mortality rates and 11.5, 9.5, and 6 median organ support–free days among survivors). The median adjusted odds ratio and bayesian probability of superiority were 1.43 (95% credible interval, 0.91-2.27) and 93% for fixed-dose hydrocortisone, respectively, and were 1.22 (95% credible interval, 0.76-1.94) and 80% for shock-dependent hydrocortisone compared with no hydrocortisone. Serious adverse events were reported in 4 (3%), 5 (3%), and 1 (1%) patients in the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively. Conclusions and Relevance Among patients with severe COVID-19, treatment with a 7-day fixed-dose course of hydrocortisone or shock-dependent dosing of hydrocortisone, compared with no hydrocortisone, resulted in 93% and 80% probabilities of superiority with regard to the odds of improvement in organ support–free days within 21 days. However, the trial was stopped early and no treatment strategy met prespecified criteria for statistical superiority, precluding definitive conclusions. Trial Registration ClinicalTrials.gov Identifier:NCT02735707