Pembrolizumab-Induced Hypophysitis With Isolated Adrenocorticotropic Hormone (ACTH) Deficiency: A Rare Immune-Mediated Adverse Event.

Pembrolizumab is an immune checkpoint inhibitor that targets the programmed cell death protein 1 antigen to stimulate an immune response against tumor cells. It has successfully induced remission in patients with severe metastatic disease, including those refractory to other chemotherapeutic regimens. Immune checkpoint inhibitors may result in immune-related adverse events affecting multiple organs, including endocrine organs, leading to thyroiditis and hypophysitis, among others. Isolated adrenocorticotropic hormone deficiency and hypophysitis have been reported in patients treated with nivolumab, another programmed cell death protein 1 inhibitor. However, clinical characteristics of these side effects associated with pembrolizumab have yet to be described in detail. We describe a case of an 85-year-old Caucasian male undergoing treatment of metastatic urothelial carcinoma with pembrolizumab, who abruptly developed hypophysitis requiring emergent intervention.

Allometric scaling of marbofloxacin pharmacokinetics: a retrospective analysis.

The association between physiologically dependent pharmacokinetic parameters (CL(B), T1/2beta, Vd(ss)) of marbofloxacin and body weight was studied in eight animal species based on allometric equation Y = aWb, where 'Y' is the pharmacokinetic parameter, 'W' is body weight, 'a' is allometric coefficient (intercept) and 'b' is the exponent that describes relation between pharmacokinetic parameter and body weight. The body clearance of marbofloxacin has shown significant (P < 0.0001) relation with size (Bwt) in various animal species. However, half-life and volume of distribution were not in association with body weight. Although half-life and volume of distribution were not in a good correlation with body weight, statistically significant association between the body clearance and body weight suggests validity of allometric scaling for predicting pharmacokinetic parameters of marbofloxacin in animal species that have not been studied yet. However further study considering large sample size and other parameters influencing pharmacokinetics of marbofloxacin is recommended.

Evolving practices in the management of acute kidney injury in the ICU (Intensive Care Unit).

Acute kidney injury (AKI) is a life-threatening illness whose mortality has remained high since the introduction of hemodialysis three decades ago. Current therapeutic options have been limited to dialytic support because there are no approved pharmacologics for the treatment of AKI. Previous clinical trials have focused on drugs and interventions that increase renal perfusion. These approaches have not been fruitful to date. However, early goal-directed therapy (EGDT) appears to improve renal and overall outcomes. The mechanism whereby EGDT improves outcomes appears to be related to decreased levels of proinflammatory cytokines and apoptosis. Inflammation and AKI are intimately related in preclinical studies. This relationship has been recently confirmed in clinical studies as well. Elevated concentrations of plasma IL-6 predict AKI in patients with sepsis, acute respiratory distress syndrome (ARDS), and hospital-acquired pneumonia. We postulate that inflammation causes AKI. This hypothesis could explain why clinical interventions focused on improving renal perfusion alone have not been effective. If inflammation causes AKI, than therapeutic interventions that decrease inflammation should improve renal outcome. Lung-protective strategies in patients with ARDS increase survival and decrease levels of proinflammatory cytokines. As expected, these decreased levels of proinflammatory cytokines as a result of implementing a lung-protective strategy are associated with improved renal outcome. Mounting evidence supports the hypothesis that inflammation is an important causal component of AKI. Interventions that safely decrease inflammation should be integrated in good clinical practice in order to maximize benefit. In the future, interventions and drugs targeted at inflammation may prove to be robust agents for the treatment of AKI.

Evaluation of the World Health Organization staging system for HIV infection and disease in Ethiopia: association between clinical stages and laboratory markers.

OBJECTIVE: To study the association between the clinical axis of the World Health Organization (WHO) staging system of HIV infection and disease and laboratory markers in HIV-infected Ethiopians. DESIGN: Cross-sectional study. METHODS: Clinical manifestations and stage of HIV-positive individuals participating in a cohort study of HIV infection progression, and of HIV-positive patients hospitalized with suspicion of AIDS, were compared to CD4+ T-cell count and viral load. RESULTS: Of the 86 HIV-positive participants of the cohort study, 53 (62%), 16 (19%), 16 (19%), and one (1.2%) were in stage 1, 2, 3 and 4, respectively. Minor weight loss (n = 15) and pulmonary tuberculosis (n = 9) were the most commonly diagnosed conditions among the 38 (44%) symptomatic HIV-positive individuals. Although 23 (27%) HIV-positive participants had CD4+ T-cell counts less than 200 x 10(6)/l, only one was in clinical stage 4. Among 79 hospitalized HIV-positive patients, 15 (19%) and 64 (81%) were in stage 3 and 4, respectively. The majority (83.5%) had CD4+ T-cell counts < 200 x 10(6)/l. Individuals at stage 3 had lower CD4+ T-cell counts and higher viral loads when seen in hospital as compared to cohort participants (P = 0.06 and 0.008, respectively). When grouping the two study populations, the median CD4+ T-cell count decreased (337, 262, 225, 126, and 78 x 10(6)/l, P< 0.01), and the median viral load increased (4.08, 3.89, 4.47, 5.65, and 5.65 log10 copies/ml, P < 0.01), with increasing clinical stage of HIV infection (1, 2, 3 cohort, 3 hospital, and 4, respectively). Median CD4+ T-cell counts were remarkably low in HIV-negative participants (749 x 10(6)/l), and in HIV-positive participants at stage 1 and 2 (337 and 262 x 10(6)/l, respectively). CONCLUSIONS: There was a good correlation between WHO clinical stages and biological markers. CD4+ T-cell counts were low in Ethiopians, particularly during early stages of HIV-1 infection, and preliminary reference values at different stages of HIV-1 infection were determined. In HIV-infected Ethiopians, lymphocyte counts less than 1,000 x 10(6)/l in non-hospitalized individuals, and less than 2,000 x 10(6)/l in hospitalized patients, had high positive predictive value, but low sensitivity, in identifying subjects with low CD4+ T-cell counts (< 200 x 10(6)/l) who would benefit from chemoprophylaxis of opportunistic infections. The on-going longitudinal study will be useful to confirm the prognostic value of the WHO staging system.