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Novel carrier-linked azo prodrugs of 4 and 5-aminosalicylic acids (4-ASA and 5-ASA respectively) using the same drugs as carriers in different permutations and combinations were designed for targeting colon affected with inflammatory bowel disease (IBD). Improved hydrophilic nature of the prodrugs assisted in minimizing their absorption in upper GIT and efficient delivery of the active drugs to colon as evidenced from their stability in aqueous buffers (pH 1.2 and 7.4) and upper GIT homogenates with 68-91% release on incubation with rat cecal matter. Amongst the series, 4A4AAZ (prodrug of 4-ASA with 4-ASA) at a dose of 53 mg/Kg was found to be the most promising candidate as it substantially alleviated the quantifying markers of colonic inflammation in TNBS-induced experimental colitis in Wistar rats. Moreover it displayed significantly lower GI toxicity (at ten times higher dose). 5-ASA- induced pancreatitis and sulfapyridine-induced adverse effects on liver that are characteristic of sulfasalazine were not observed with 4A4AAZ. It could be explored further as a potential candidate for IBD patients intolerant to pancreatitis induced by oral administration of 5-ASA.

Sterically hindered esters or esters of drugs with macromolecular carriers like dextran and cyclodextrin find wide applicability in colon-targeted delivery. We report here synthesis, in vitro release kinetics of macromolecular prodrug of 4-aminosalicylic acid (4-ASA) with β-cyclodextrin and its extensive pharmacological evaluation in 2, 4, 6- trinitrobenzenesulphonic acid - induced colitis in rats. Formyl 4-ASA was conjugated with β-cyclodextrin by CDI coupling followed by deprotection of the final product which was then characterized by IR, 1H-NMR and LC-MS. In vitro stability and release were studied in buffers (pH 1.2 and 7.4), stomach/small intestinal homogenates and rat cecal/fecal matters. The prodrug resisted pH-dependent hydrolysis. In stomach and small intestinal homogenates 20-23% release was observed (t1/2: 1278 and 1103 min respectively) while 68% and 92% release was furnished in rat cecal and fecal matters (t1/2: 341 and 245 min respectively). Mitigating effect of 4-AβCyd on colitis was moderate when compared with sulfasalazine or 4/5-ASA administered rectally, but it was comparable to that of aminosalicylates administered orally, suggesting incomplete delivery of 4-ASA to colon due to partial hydrolysis of 4-AβCyd in the upper GIT. The histological assessment of pancreas and liver of the prodrug-treated group showed no pathological changes indicating its better safety profile than that of sulfasalazine or oral 5-ASA. The prodrug brought about significant lowering in ulcer index compared to aminosalicylates suggesting significant improvement in gastro-protective effect than oral aminosalicylates.

Fifty-six serum posaconazole trough levels were measured in 17 cardiothoracic transplant recipients. Initial levels were ≤0.5, 0.51 to 0.99, and ≥1 μg/ml for 47, 29, and 24% of patients, respectively. Median trough levels associated with therapeutic success were higher than those associated with failure (1.55 versus 0.34 μg/ml; P = 0.006). Patients with levels consistently >0.5 μg/ml were more likely to have successful outcome ( P = 0.055). Age ≥65 years, oral administration, and absence of proton pump inhibitors were associated with higher levels of posaconazole ( P = 0.006, 0.006, and 0.001, respectively).

Even though sulfasalazine is drug of choice for treatment of ulcerative colitis (UC), 5-aminosalicylicacid (5-ASA)-induced pancreatitis and sulfapyridine-induced hepatitis are well documented in the literature. 4-aminosalicylic acid (4-ASA) is a promising but unexplored alternative, offering a lower risk of pancreatitis than 5-ASA. According to recent reports, a nutritional supplement of glucosamine could be useful in UC by suppressing activation of intestinal epithelial cells. Considering these findings, amide conjugates of aminosalicylates with D-glucosamine were synthesized by DCC coupling. In vitro release was studied in aqueous buffers, tissue homogenates of stomach/small intestine and rat cecal/fecal matter while therapeutic efficacy was evaluated in trinitrobenzenesulphonic acid (TNBS)-induced experimental colitis. The ameliorating effect of 5-ASA prodrug on the course of TNBS- induced colitis was comparable, while that for 4-ASA prodrug was moderate compared to sulfasalazine. Combination co-drug therapy of aminosalicylates with D-glucosamine offers an innovative and attractive platform that could be explored further for the safer management of UC.

Background Skin cancer, in particular squamous cell carcinoma (SCC), is the most common malignancy after solid-organ transplantation. SCC has been reported in immunosuppressed patients receiving voriconazole, but the agent has not been shown to be a risk factor. Universal voriconazole prophylaxis and alemtuzumab induction are standard in our lung transplant program. Methods We performed a retrospective, case–control study (matched 1:3) among lung transplant recipients at our center from 2003 to 2008. Results SCC was diagnosed in 3.1% (17 of 543) of patients at a median follow-up of 36 months. Median time to development of SCC was 19 months post-transplant. Risk factors for SCC by univariate analysis included older age ( p = 0.02), residence in locations with high levels of sun exposure ( p = 0.0001), single-lung transplant ( p = 0.02) and duration ( p = 0.03) and cumulative dose ( p = 0.03) of voriconazole. Duration of voriconazole (hazard ratio [HR] = 2.1; p = 0.04) and residence in locations with high sun exposure (HR = 3.8; p = 0.0004) were independent risk factors by multivariate analysis. SCC lesions were located on the head and neck in 94% of cases, and 53% had multiple lesions. All patients were treated with surgery. At least one independent lesion developed subsequently in 47% of patients. Local spread and distant metastases each occurred in 7% of cases. There were no deaths among the cases. Conclusions Voriconazole exposure is a risk factor for SCC after lung transplantation, particularly among older patients living in areas with high sun exposure. Voriconazole should be used cautiously in these patients.

Introduction. Little is known about the incidence or significance of mold infections in the explanted lungs of lung transplant recipients. Method. We reviewed the histopathology of the explanted lungs from 304 patients who underwent lung transplantation at our institution from 2005 to 2007 and received alemtuzumab induction therapy and posttransplant voriconazole prophylaxis. Results. Invasive mold infections were present in the explanted lungs of 5% (14 of 304) of patients, including chronic necrotizing pneumonias (n=7), mycetomas (n=4), and invasive fungal pneumonias (n=3). Only 21% (3 of 14) received immunosuppressive therapy within 1 year before lung transplantation, suggesting that lung damage itself predisposed patients to mold infections. The risk of mold infection was higher in patients with cystic fibrosis (11%, 4 of 35) than other underlying lung diseases (4%, 10 of 269). Pulmonary mold infections were not diagnosed or suspected in 57% (8 of 14) of patients. Despite secondary voriconazole prophylaxis, fungal infections developed in 43% (6 of 14) of patients with mold infections of the explanted lungs compared with 14% (42 of 290) of patients without mold infections (P=0.01). Three patients developed invasive fungal infections while on voriconazole prophylaxis and three developed fungal infections more than 8 months after the discontinuation of voriconazole. The mortality attributable to invasive fungal infections among patients with mold infections of the explanted lungs was 29% (4 of 14). Conclusion. Invasive mold infections in the explanted lungs are often not recognized before lung transplantation and are associated with poor outcomes.

Mesalazine is widely used systemically or topically to achieve and maintain remission in inflammatory bowel disease. Latentiated derivatives of mesalazine having L-histidine and L-tyrosine covalently linked via an amide linkage were designed, developed and screened in 2, 4, 6-trini-trobenzenesulphonic acid-induced experimental colitis in rats. Incubation of prodrugs with tissue homogenates of stomach and small intestine of rats furnished 4-8% and 9-12% release respectively over a 10-h period. Their colon-specific activation was confirmed from their release profile on incubation with rat fecal and cecal material at 37°C in anaerobic conditions (5% CO2). 79-98% release of mesalazine was observed in rat fecal matter while almost complete release of mesalazine (99%) was observed in rat cecal matter over a 10-h period. The half-lives of mesalazine prodrugs ranged between 236-295 min following zero order kinetics. The improving effect of latentiated derivatives on the symptoms of colitis induced by 2, 4, 6-trinitrobenzenesulphonic acid is comparable to sulfasalazine. Amongst the reported prodrugs, potential of SSDGV2 (latentiated derivative of mesalazine with L-histidine) can be explored further as a promising candidate for the safer management of inflammatory bowel disease.

Summary Simvastatin is a selective HMG-CoA reductase inhibitor and ezetimibe has lipid-lowering activity. Both are potential anti-lipidemic agents used in combination to reduce the amount of cholesterol and triglycerides in systemic circulation. This paper describes a simple, precise, and accurate HPTLC method for simultaneous estimation of the compounds as the bulk drugs and in the tablet dosage form. Chromatographic separation was performed on aluminium-backed silica gel 60 F254 plates with 8:2 (v/v) toluene-2-propanol as mobile phase. The separated spots were densitometrically evaluated at 240 nm. The drugs were satisfactorily resolved with RF values 0.48 ± 0.01 and 0.53 ± 0.01 for simvastatin and ezetimibe, respectively. The accuracy and reliability of the method were assessed by determination of validation data for linearity (0.4–2.0 μg per spot for both simvastatin and ezetimibe), precision (intra-day RSD 0.51–1.04%, inter-day RSD 0.34–1.11% for simvastatin; intra-day RSD 0.47–0.61%, inter-day RSD 0...

BACKGROUND Early diagnosis and treatment of invasive pulmonary aspergillosis (IPA) improves outcome. METHODS We compared the performance of publicly available pan-Aspergillus, Aspergillus fumigatus-, and Aspergillus terreus-specific real-time polymerase chain reaction (PCR) assays with the Platelia galactomannan (GM) assay in 150 bronchoalveolar lavage (BAL) samples from lung transplant recipients (16 proven/probable IPA, 26 Aspergillus colonization, 11 non-Aspergillus mold colonization, and 97 negative controls). RESULTS The sensitivity and specificity of pan-Aspergillus PCR (optimal quantification cycle [Cq], ≤35.0 by receiver operating characteristic analysis) and GM (≥.5) for diagnosing IPA were 100% (95% confidence interval, 79%-100%) and 88% (79%-92%), and 93% (68%-100%) and 89% (82%-93%), respectively. The sensitivity and specificity of A. fumigatus-specific PCR were 85% (55%-89%) and 96% (91%-98%), respectively. A. terreus-specific PCR was positive for the 1 patient with IPA due to this species; specificity was 99% (148 of 149 samples). Aspergillus PCR identified 1 patient with IPA not diagnosed by GM. For BAL samples associated with Aspergillus colonization, the specificity of GM (92%) was higher than that of pan-Aspergillus PCR (50%; P = .003). Among negative control samples, the specificity of pan-Aspergillus PCR (97%) was higher than that of BAL GM (88%; P = .03). Positive results for both BAL PCR and GM testing improved the specificity to 97% with minimal detriment to sensitivity (93%). CONCLUSIONS A recently developed pan-Aspergillus PCR assay and GM testing of BAL fluid may facilitate the diagnosis of IPA after lung transplantation. A. fumigatus- and A. terreus-specific real-time PCR assays may be useful in rapidly identifying the most common cause of IPA and a species that is intrinsically resistant to amphotericin B, respectively.

Valganciclovir prophylaxis is advocated for lung transplant recipients, but its efficacy is unknown.Retrospective review was done of 109 donor-positive/recipient-negative lung transplant patients who received alemtuzumab induction and valganciclovir for cytomegalovirus prophylaxis.Median duration of follow-up after transplant was 27 months. Valganciclovir dose reductions (900 mg/day or renal-equivalent) were required for 18 patients (17%) due to toxicity, most commonly for neutropenia (n = 15) or gastrointestinal symptoms (n = 2). Of the 109 patients, 34 (31%) had no CMV infections, 45 (41%) had asymptomatic viremia, and 30 (27%) had CMV disease. CMV disease developed off prophylaxis in 10 patients (18%) at a median of 8.7 months after transplant and 2 months after valganciclovir discontinuation. Breakthrough disease occurred during prophylaxis in 10 patients (9%) at a median of 6.7 months. Patients with asymptomatic viremia or no CMV infection received prophylaxis for median 8.6 and 8.7 months, respectively. Risk factors for CMV disease by univariate analysis were increased age (p = 0.01), single-lung transplant (p = 0.03), chronic obstructive pulmonary disease (p = 0.05), reduced-dose valganciclovir (p = 0.001), and less than 6 months of prophylaxis (p = 0.005). By multivariate analysis, advanced age (p = 0.01) and reduced-dose valganciclovir (p = 0.0006) were independent risk factors for CMV disease. CMV disease developed in 4 patients (4%) due to ganciclovir-resistant viruses. CMV-attributable mortality was 5% (5 of 109), including 100% (4 of 4) with ganciclovir-resistant disease.Valganciclovir prophylaxis among donor-positive/recipient-negative lung transplant recipients delayed but did not eliminate CMV disease or CMV-related deaths and was limited by toxicity and ganciclovir-resistance. Our experience suggests that valganciclovir at reduced-doses or for less than 6 months is sub-optimal in preventing CMV disease.

We investigated in 51 consecutive outpatients with symptomatic congestive heart failure caused by abnormal left ventricular (LV) ejection fraction treated with furosemide or torsemide (10% also with metolazone), beta blockers, and angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, 55% with spironolactone, and 18% with digoxin, the effects of doubling the dose of furosemide, torsemide, and metolazone on symptoms, weight, 6-minute walk distance, and echocardiographic measurements of LV systolic and diastolic function at 24 ± 6 days follow-up. At follow-up, the weight decreased from 70 ± 6 kg to 65 ± 6 kg (P < 0.001), the New York Heart Association functional class decreased from 2.9 ± 0.4 to 2.1 ± 0.2 (P < 0.001), the Minnesota With Heart Failure Questionnaire score decreased from 43 ± 7 to 28 ± 8 (P < 0.001), the 6-minute walk distance increased from 270 ± 46 m to 318 ± 44 m (P < 0.001), and there was no significant change in LV ejection fraction, LV end-diastolic dimension, LV end-systolic dimension, left atrial dimension, pulmonary artery systolic pressure, peak mitral early/ atrial ratio, mitral deceleration time, and velocity time interval. In conclusion, doubling the dose of diuretics in outpatients with symptomatic congestive heart failure caused a significant loss of weight and a significant improvement in symptoms and 6-minute walk distance but did not change LV systolic and diastolic function.

Colon-specific mutual azo prodrugs of 5-aminosalicylic acid with essential amino acids were synthesized for the management of inflammatory bowel disease. The structures were confirmed by elemental and spectral analyses. 85-88% release of 5-aminosalicylic acid was achieved in rat fecal matter with half-lives ranging from 140 to 160 min, following first order kinetics. The prodrugs exhibited comparable ameliorating effect as that of sulfasalazine on trinitrobenzenesulfonic acid-induced experimental colitis in rats with a better safety profile.

Mutual amide prodrugs of 4-aminosalicylic acid with d -phenylalanine and l -tryptophan were synthesized for targeted drug delivery to the inflamed gut tissue in inflammatory bowel disease. Stability studies in aqueous buffers (pH 1.2 and 7.4) showed that the synthesized prodrugs were stable in both the buffers over a period of 10 h. In rat fecal matter the release of 4-aminosalicylic acid from the prodrugs was in the range of 86–91% over a period of 20 h, with half-lives ranging between 343 and 412 min following first order kinetics. Targeting potential of the carrier system and the ameliorating effect of the amide conjugates were evaluated in trinitrobenzenesulfonic acid-induced experimental colitis model in rats. The prodrugs were assessed for their probable damaging effects on pancreas and liver with the help of histopathological analysis and for their ulcerogenic potential by Rainsford's cold stress method. They were found to have improved safety profile than sulfasalazine, oral 4- and 5-aminosalicylic acid with similar pharmacological spectrum and advantages of sulfasalazine.