12 research outputs found
A phase I, open-label, randomized crossover study to assess the effect of dosing of the MEK 1/2 inhibitor Selumetinib (AZD6244; ARRY-142866) in the presence and absence of food in patients with advanced solid tumors
<p><b>Purpose:</b> This Phase I study assessed whether food influences the rate and extent of selumetinib absorption in patients with advanced solid malignancies and determined the safety, tolerability, and pharmacokinetic (PK) profile of selumetinib and its active metabolite N-desmethyl-selumetinib in fed and fasted states.</p>
<p><b>Methods:</b> A single dose of 75 mg selumetinib was to be taken with food on Day 1 followed by a single dose of 75 mg after fasting for at least 10 h on Day 8, or vice versa, followed by twice daily dosing of 75 mg selumetinib from Day 10. Plasma concentrations and PK parameters were determined on Days 1 and 8. Patients could continue to receive selumetinib for as long as they benefitted from treatment.</p>
<p><b>Results:</b> In total, 31 patients were randomized to receive selumetinib; 15 to fed/fasted sequence and 16 to fasted/fed sequence. Comprehensive PK sampling was performed on 11 and 10 patients, respectively. The geometric least-squares means of C<sub>max</sub> and AUC for selumetinib were reduced by 62% (ratio 0.38 90% CI 0.29, 0.50) and 19% (ratio 0.81 90% CI 0.74, 0.88), respectively, under fed compared with fasting conditions. The rate of absorption (t<sub>max</sub>) of selumetinib (fed) was delayed by approximately 2.5 h (median). The food effect was also observed for the active metabolite N-desmethyl-selumetinib. Selumetinib was well tolerated.</p>
<p><b>Conclusions:</b> The presence of food decreased the extent of absorption of selumetinib. It is recommended that for further clinical studies, selumetinib be taken on an empty stomach. Selumetinib demonstrated an acceptable safety profile in the advanced cancer population.</p>
A narrative review on the similarities and dissimilarities between myalgic encephalomyelitis/chronic fatigue syndrome (me/cfs) and sickness behavior
It is of importance whether myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a variant of sickness behavior. The latter is induced by acute infections/injury being principally mediated through proinflammatory cytokines. Sickness is a beneficial behavioral response that serves to enhance recovery, conserves energy and plays a role in the resolution of inflammation. There are behavioral/symptomatic similarities (for example, fatigue, malaise, hyperalgesia) and dissimilarities (gastrointestinal symptoms, anorexia and weight loss) between sickness and ME/CFS. While sickness is an adaptive response induced by proinflammatory cytokines, ME/CFS is a chronic, disabling disorder, where the pathophysiology is related to activation of immunoinflammatory and oxidative pathways and autoimmune responses. While sickness behavior is a state of energy conservation, which plays a role in combating pathogens, ME/CFS is a chronic disease underpinned by a state of energy depletion. While sickness is an acute response to infection/injury, the trigger factors in ME/CFS are less well defined and encompass acute and chronic infections, as well as inflammatory or autoimmune diseases. It is concluded that sickness behavior and ME/CFS are two different conditions
Gender differences in the use of cardiovascular interventions in HIV-positive persons; the D:A:D Study
Peer reviewe
Cerebrovascular and cardiovascular responses associated with orthostatic intolerance and tachycardia
Safety and efficacy of sequential chemotherapy with carboplatin plus gemcitabine followed by weekly paclitaxel in advanced non-small cell lung cancer
Item does not contain fulltextBACKGROUND: Improving survival in non-small cell lung cancer (NSCLC) will require new strategies or new drugs. Sequential administration of conventional non-cross-resistant cytotoxic drugs offers an opportunity to increase drug diversity while maintaining dose intensity. This Phase II trial was designed to assess the efficacy and feasibility of such a regimen in advanced NSCLC. METHODS: Patients with NSCLC stage IIIB or IV received as first-line treatment four cycles of carboplatin (AUC 5) (day 1) plus gemcitabine 1000 mg/m(2) (days 1 and 8) every 3 weeks. Thereafter, treatment continued with 12 weekly cycles of paclitaxel 80 mg/m(2). RESULTS: In total, 46 patients were included. Median age was 59.6 years (range 41.3-74.3 years) and 93.5 % (n = 43) had Eastern Cooperative Oncology Group performance score of 0 or 1. All but 6 had stage IV disease, and 13 (28.3 %) had squamous cell carcinomas. Thirty-six (78 %) patients completed 4 cycles of carboplatin-gemcitabine and 35 patients received at least 1 cycle of paclitaxel, of whom 16 (46 % of total) patients completed 12 cycles of paclitaxel. The overall objective response rate was 49 %. Sixteen (37 %) patients had a response to carboplatin-gemcitabine, increasing to 21 (49 %) patients after administration of paclitaxel. Of the 13 assessable patients who showed a partial response (PR) on carboplatin-gemcitabine, 12 (92 %) patients showed also a PR on paclitaxel. Of 19 assessable patients with stable disease (SD) on carboplatin-gemcitabine, 4 (21 %) had a PR and 13 (68 %) SD on paclitaxel. Toxicity was moderate: 24 % stopped because of toxicity. CONCLUSION: Sequential chemotherapy with carboplatin-gemcitabine and weekly paclitaxel is active and feasible in advanced NSCLC patients
Development of a definition for Rapid Progression (RP) of renal function in HIV-positive persons: The D:A:D study
Background: No consensus exists on how to define abnormally rapid deterioration in renal function (Rapid Progression, RP). We developed an operational definition of RP in HIV-positive persons with baseline estimated glomerular filtration rate (eGFR) >90 ml/min/1.73 m2 (using Cockcroft Gault) in the Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) study from 2004 to 2011. Methods. Two definitions were evaluated; RP definition A: An average eGFR decline (slope) ≥5 ml/min/1.73 m 2/year over four years of follow-up with ≥3 eGFR measurements/year, last eGFR <90 ml/min/1.73 m2 and an absolute decline ≥5 ml/min/1.73 m2/year in two consecutive years. RP definition B: An absolute annual decline ≥5 ml/min/1.73 m2/year in each year and last eGFR <90 ml/min/1.73 m2. Sensitivity analyses were performed considering two and three years' follow-up. The percentage with and without RP who went on to subsequently develop incident chronic kidney disease (CKD; 2 consecutive eGFRs <60 ml/min/1.73 m2 and 3 months apart) was calculated. Results: 22,603 individuals had baseline eGFR ≥90 ml/min/1.73 m2. 108/3655 (3.0%) individuals with ≥4 years' follow-up and ≥3 measurements/year experienced RP under definition A; similar proportions were observed when considering follow-up periods of three (n=195/6375; 3.1%) and two years (n=355/10756; 3.3%). In contrast under RP definition B, greater proportions experienced RP when considering two years (n=476/10756; 4.4%) instead of three (n=48/6375; 0.8%) or four (n=15/3655; 0.4%) years' follow-up. For RP definition A, 13 (12%) individuals who experienced RP progressed to CKD, and only (21) 0.6% of those without RP progressed to CKD (sensitivity 38.2% and specificity 97.4%); whereas for RP definition B, fewer RP individuals progressed to CKD. Conclusions: Our results suggest using three years' follow-up and at least two eGFR measurements per year is most appropriate for a RP definition, as it allows inclusion of a reasonable number of individuals and is associated with the known risk factors. The definition does not necessarily identify all those that progress to incident CKD, however, it can be used alongside other renal measurements to early identify and assess those at risk of developing CKD. Future analyses will use this definition to identify other risk factors for RP, including the role of antiretrovirals. © 2014 Kamara et al.; licensee BioMed Central Ltd
Variable impact on mortality of AIDS-defining events diagnosed during combination antiretroviral therapy: not all AIDS-defining conditions are created equal.
Abstract
Background—The extent to which mortality differs following individual acquired
immunodeficiency syndrome (AIDS)–defining events (ADEs) has not been assessed among
patients initiating combination antiretroviral therapy.
Methods—We analyzed data from 31,620 patients with no prior ADEs who started combination
antiretroviral therapy. Cox proportional hazards models were used to estimate mortality hazard
ratios for each ADE that occurred in >50 patients, after stratification by cohort and adjustment for
sex, HIV transmission group, number of anti-retroviral drugs initiated, regimen, age, date of
starting combination antiretroviral therapy, and CD4+ cell count and HIV RNA load at initiation
of combination antiretroviral therapy. ADEs that occurred in <50 patients were grouped together
to form a “rare ADEs” category.
Results—During a median follow-up period of 43 months (interquartile range, 19–70 months),
2880 ADEs were diagnosed in 2262 patients; 1146 patients died. The most common ADEs were
esophageal candidiasis (in 360 patients), Pneumocystis jiroveci pneumonia (320 patients), and
Kaposi sarcoma (308 patients). The greatest mortality hazard ratio was associated with non-
Hodgkin’s lymphoma (hazard ratio, 17.59; 95% confidence interval, 13.84–22.35) and progressive
multifocal leukoencephalopathy (hazard ratio, 10.0; 95% confidence interval, 6.70–14.92). Three
groups of ADEs were identified on the basis of the ranked hazard ratios with bootstrapped
confidence intervals: severe (non-Hodgkin’s lymphoma and progressive multifocal
leukoencephalopathy [hazard ratio, 7.26; 95% confidence interval, 5.55–9.48]), moderate
(cryptococcosis, cerebral toxoplasmosis, AIDS dementia complex, disseminated Mycobacterium
avium complex, and rare ADEs [hazard ratio, 2.35; 95% confidence interval, 1.76–3.13]), and
mild (all other ADEs [hazard ratio, 1.47; 95% confidence interval, 1.08–2.00]).
Conclusions—In the combination antiretroviral therapy era, mortality rates subsequent to an
ADE depend on the specific diagnosis. The proposed classification of ADEs may be useful in
clinical end point trials, prognostic studies, and patient management
Variable impact on mortality of AIDS-defining events diagnosed during combination antiretroviral therapy: not all AIDS-defining conditions are created equal
Abstract
Background—The extent to which mortality differs following individual acquired
immunodeficiency syndrome (AIDS)–defining events (ADEs) has not been assessed among
patients initiating combination antiretroviral therapy.
Methods—We analyzed data from 31,620 patients with no prior ADEs who started combination
antiretroviral therapy. Cox proportional hazards models were used to estimate mortality hazard
ratios for each ADE that occurred in >50 patients, after stratification by cohort and adjustment for
sex, HIV transmission group, number of anti-retroviral drugs initiated, regimen, age, date of
starting combination antiretroviral therapy, and CD4+ cell count and HIV RNA load at initiation
of combination antiretroviral therapy. ADEs that occurred in <50 patients were grouped together
to form a “rare ADEs” category.
Results—During a median follow-up period of 43 months (interquartile range, 19–70 months),
2880 ADEs were diagnosed in 2262 patients; 1146 patients died. The most common ADEs were
esophageal candidiasis (in 360 patients), Pneumocystis jiroveci pneumonia (320 patients), and
Kaposi sarcoma (308 patients). The greatest mortality hazard ratio was associated with non-
Hodgkin’s lymphoma (hazard ratio, 17.59; 95% confidence interval, 13.84–22.35) and progressive
multifocal leukoencephalopathy (hazard ratio, 10.0; 95% confidence interval, 6.70–14.92). Three
groups of ADEs were identified on the basis of the ranked hazard ratios with bootstrapped
confidence intervals: severe (non-Hodgkin’s lymphoma and progressive multifocal
leukoencephalopathy [hazard ratio, 7.26; 95% confidence interval, 5.55–9.48]), moderate
(cryptococcosis, cerebral toxoplasmosis, AIDS dementia complex, disseminated Mycobacterium
avium complex, and rare ADEs [hazard ratio, 2.35; 95% confidence interval, 1.76–3.13]), and
mild (all other ADEs [hazard ratio, 1.47; 95% confidence interval, 1.08–2.00]).
Conclusions—In the combination antiretroviral therapy era, mortality rates subsequent to an
ADE depend on the specific diagnosis. The proposed classification of ADEs may be useful in
clinical end point trials, prognostic studies, and patient management