Anti-Inflammatory Therapy With Canakinumab for the Prevention and Management of Diabetes

Background

Subclinical inflammation mediated in part by interleukin (IL)-1β participates in peripheral insulin resistance and impaired pancreatic insulin secretion.

Onset of fulminant type 1 diabetes mellitus following hypophysitis after discontinuation of combined immunotherapy. A case report

Diabetes is a rare, but potentially life-threatening, adverse event of immune checkpoint inhibitors that requires prompt recognition and treatment. It usually occurs in the first 3 months of treatment and is typically related to programmed cell death-1 antibodies, alone or in combined therapy. It has rarely been described developing after immunotherapy cessation. We present a 51-year-old man with metastatic melanoma, who developed acute-onset diabetes 52 days after combined immunotherapy cessation with nivolumab and ipilimumab, and 25.6 months after receiving the first dose. He presented with acute hyperglycemic symptoms, ketosis, complete insulin depletion and negative autoimmunity, fulfilling the criteria of fulminant type 1 diabetes. The patient had previously developed hypophysitis with isolated adrenocorticotropic hormone deficiency during immunotherapy. We describe a case of late-onset fulminant type 1 diabetes developing after immunotherapy cessation. Patient education and active follow up after immunotherapy discontinuation are crucial to warrant a timely intervention.     

Bronchopulmonary pharmacokinetic and pharmacodynamic profiles of levofloxacin 750 mg once daily in adults undergoing treatment for acute exacerbation of chronic bronchitis

While previous reports have described the bronchopulmonary profile of the fluoroquinolones in healthy volunteers, limited data are available in infected patients. The purpose of this study was to determine the intrapulmonary profile of high-dose (750 mg) levofloxacin in patients during an acute exacerbation of chronic bronchitis (AECB). Twenty-four patients experiencing clinical signs and symptoms of AECB were enrolled. Once enrolled, patients received levofloxacin 750 mg once daily × 5 days. Bronchoalveolar lavage aspirates and simultaneous plasma samples were obtained at 4 h, 12 h or 24 h after the third dose. Concentrations in biologic matrixes were determined with a validated HPLC method. Epithelial lining fluid (ELF) concentrations were calculated using the urea dilution method. Five patients did not complete the trial, 19 patients underwent bronchoscopy, 18 (52 ± 13 yrs) had sufficient samples for analysis and confirmed medication compliance. Mean plasma concentrations at 4, 12, and 24 h were 8.0 ± 2.5, 5.8 ± 1.2, and 2.2 ± 1.2 μg/mL. Mean ELF values at 4, 12, and 24 h were 7.5 ± 3.0, 8.3 ± 6.0, and 1.2 ± 0.9 μg/mL. Mean alveolar macrophage (AM) concentrations at 4, 12, and 24 h were 38.5 ± 43.7, 13.4 ± 14.4, and 9.0 ± 7.5 μg/mL. The penetration (ELF/plasma ratio) into the infection site was 113%. In these subjects with AECB, levofloxacin 750 mg once daily reached adequate exposures in the plasma, ELF, and AMs for the most commonly associated pathogens.     

Hematocrit, urea and gender: the Hematocrit, Urea and GEnder formula for prognosing progressive renal failure in diabetic nephropathy

ObjectiveDiabetic nephropathy is a common cause of end stage renal disease. Notwithstanding, wide inter-individual variations in the speed of progression of diabetic nephropathy are frequent. We have used the score of the HUGE formula to predict progression of kidney disease in a group of diabetic nephropathy patients.Design and methodsThe sample consisted of 84 type 2 diabetic patients. At treatment entry, the mean age was 62.1 ± 12.5 years and 59.5% were male. Blood pressure was measured at office at each visit. Serum creatinine, urea, hematocrit and 24 h proteinuria were analyzed every 6 months. HUGE score was calculated from gender, urea and hematocrit.ResultsMean HUGE score was 0.99 ± 3.88. Using as cut off point 1.5, those patients who had a score equal or higher (n = 31) showed a bigger increase in serum creatinine after one year (41.8 ± 62.1%) than those subjects with score < 1.5 (n = 53) (18.7 ± 38.6%, p = 0.041). 5 patients with low HUGE score reached end stage renal failure (9.4%) and 10 patients in the high HUGE score group (32.3, p = 0.008). When logistic regression analysis was performed only a HUGE score higher than 1.5 (p = 0.003) and proteinuria higher than 2 g/day (p = 0.041) were independently associated to CRF progression (creatinine increment > 25%).ConclusionsIn diabetic nephropathy patients the HUGE equation may be useful to detect the subjects prone to progressive renal failure. Wider samples will be needed to confirm this finding and, most important, its applicability to other kinds of nephropathy.     

Use of medical resources and quality of life of patients with chronic heart failure: a prospective survey in a large Italian community hospital

AIMS: To assess the prevalence, clinical characteristics, use of medical resources and quality of life in consecutive patients with chronic heart failure (CHF) hospitalized in a large community hospital during 3 months. METHODS AND RESULTS: The study group included 354 patients with CHF, admitted in the Departments of Internal Medicine (97%) and Cardiology. Median age was 78 years [72;85], 45% were males. CHF was the main diagnosis in 72%; 28% were in NYHA class III and 49% in class IV; 42% had atrial fibrillation. The median hospital stay was 8 days [5;14], in-hospital mortality 9% in those admitted for CHF and 19% in those admitted primarily for other diseases. Patients with CHF occupied 15% of the beds; 1330 ECGs, 389 chest X-rays, 112 echocardiograms and 10 coronary angiograms were performed. A quality of life questionnaire revealed that 82% had problems with mobility, 54% with self-care and 88% with everyday activity. Thirty-nine percent of patients had at least one hospitalization during the previous year. CONCLUSIONS: Ninety-seven percent of hospitalized patients with CHF are admitted in the Internal Medicine wards and occupy 15% of beds. The majority of the patients are 72 years or older, with severe heart failure. The frequency of rehospitalization(s) and mortality rate in this population remains high. Echocardiography is performed only in 27% of patients.     

Pharmacodynamic assessment of ertapenem (MK-0826) against Streptococcus pneumoniae in a murine neutropenic thigh infection model

The objective of this study was to determine the susceptibility breakpoint of a new carbapenem, ertapenem (MK-0826), against Streptococcus pneumoniae strains based on bacterial density and survival studies in a murine thigh infection model. Sixteen S. pneumoniae isolates for which MICs ranged from 0.015 to 4.0 mg/liter were tested with neutropenic ICR mice. Animals were infected with bacteria at 10(5) to 10(6) CFU per thigh and were treated with ertapenem starting at 2 h postinfection for 4 days. Ertapenem was given subcutaneously at 50 mg/kg of body weight every 6 h, which simulates the human pharmacodynamic profile (in particular, the duration of time that the concentration of free drug remains above the MIC of 2 mg/liter). At 0 and 24 h postinfection, thighs were harvested for bacterial density determination. Survival was assessed during 4 days of therapy and 3 days after the therapy. A protein binding study was conducted with mice by use of the ultrafiltration method. Protein binding in mice was approximately 95%, which is comparable to that in humans. The average change in bacterial density ranged from -0.22 to -4.4 log CFU per thigh over 24 h compared to 0-h controls. The extent of microbial eradication was dependent on the MIC for the S. pneumoniae isolate. Substantial bactericidal activities (i.e., killing of approximately 2 log CFU per thigh) were consistently observed against isolates for which MICs were 相似文献   

Accuracy of sonography with a hydration test in differentiating between excretory renal obstruction and renal sinus cysts

PURPOSE: The aim of this prospective study was to determine whether sonography with a hydration test to induce diuresis can be used to reliably differentiate between excretory renal obstruction and renal sinus cysts. METHODS: We performed sonographic examination of all patients diagnosed with minimal or moderate obstruction of the intrarenal collecting system or renal sinus cysts on the basis of excretory urography, CT, or both between September 1, 1998, and October 31, 1999. The largest fluid-filled structures in the renal sinus were sonographically measured before and after each patient ingested 1.5 l of water. Cases in which the maximum diameters of the largest anechoic structures increased by at least 10% after hydration were diagnosed with excretory renal obstruction. The sonographic diagnoses were compared with the final diagnoses on excretory urography, CT, or both. RESULTS: Both kidneys were affected in 16 of the 36 patients examined, for a total of 52 kidneys. The sonographic diagnosis was consistent with the results of urography or CT in 48 (92%) of the 52 kidneys. The sonographic approach had a specificity of 92% and a sensitivity of 93% for the diagnosis of excretory renal obstruction, with only 1 false-negative and 3 false-positive results. CONCLUSIONS: When used with the stimulated diuresis test, sonography can reliably distinguish between excretory renal obstruction and renal sinus cysts and can be used as an alternative to other imaging techniques such as urography.     

Pharmacodynamic assessment of clarithromycin in a murine model of pneumococcal pneumonia

The pharmacodynamic profile of clarithromycin (CLR) was evaluated with a murine model of pneumonia. Eight Streptococcus pneumoniae isolates, including three macrolide-sensitive and five macrolide-resistant strains, were inoculated intratracheally into immunocompromised ICR mice as 10(8)-CFU bacterial suspensions. Orally administered CLR daily doses ranging from 5 to 600 mg/kg of body weight were given over 5 days, during which animal survival was monitored. The bacterial density in lung tissues was examined after 24 h of CLR treatment and in control groups. Pharmacokinetic analysis of CLR in mice demonstrated that the regimen of 150 mg/kg twice a day was representative of human pharmacokinetics and was used to compare the efficacy of CLR against sensitive and resistant S. pneumoniae strains. Immunocompetent CBA/J mice were also infected and treated as described above and evaluated for bacterial density and survival to assess the effect of the presence of leukocytes. All three pharmacodynamic parameters, the duration (percent) of the time that serum CLR concentrations remain above the MIC (%T>MIC), the ratio of the area under the concentration-time curve from 0 to 24 h (AUC(0-24)) to the MIC, and the ratio of the maximum concentration of drug in serum to the MIC, were found to be closely correlated to CLR bacterial efficacy (P < 0.001). Furthermore, all parameters had close correlation to bacterial density (r(2) = 0.72 to 0.82), median survival (r(2) = 0.93 to 0.94), and total percent survival (r(2) = 0.91 to 0.92). These in vivo data suggest that the bacterial activity of CLR is closely correlated with all three parameters over a wide range of exposures and, as a consequence of parameter interdependency, AUC(0-24)/MIC is the most reasonable predictor of antibiotic efficacy. In this neutropenic pneumonia model, CLR was less efficacious against S. pneumoniae strains for which MICs were >or=4 microg/ml. However, the presence of leukocytes in the immunocompetent mice resulted in improved bactericidal activity, relative to that in the neutropenic animals, despite an MIC of 4 microg/ml.