The economic impact of cytomegalovirus infection after liver transplantation

BACKGROUND: We studied the economic impact of cytomegalovirus (CMV) disease and its effective reduction with antiviral prophylaxis in liver transplant recipients. METHOD: Analysis of institutional charge data accumulated during a prospective, randomized, controlled trial comparing oral acyclovir 800 mg four times daily for 120 days (ACV) and intravenous ganciclovir 5 mg/kg every 12 h for 14 days followed by ACV for 106 days (GCV) was performed. RESULTS: Liver transplant recipients who developed CMV disease had significantly higher charges (median: $148,300) than those who developed asymptomatic CMV infection ($119,600) or experienced no CMV infection ($114,100) (P<0.01). A multiple linear regression analysis indicated that CMV disease is associated with a 49% increase in charges, independent of other factors influencing increased hospitalization charges. In CMV-seronegative patients who received a CMV-seropositive donor organ, GCV prophylaxis was associated with a significant reduction in charges, as compared to ACV prophylaxis ($113,900 vs. $153,300, respectively; P=0.02). CONCLUSIONS: CMV disease is an independent risk factor for increased resource utilization associated with liver transplantation. The use of an effective prophylactic antiviral regimen provides savings in health care resources, particularly in patients at high risk for developing CMV disease.     

Hypersensitivity reactions associated with exposure to naproxen and ibuprofen: A cohort study

The aim of the study was to evaluate the risks of hospitalisation and death due to hypersensitivity reactions associated with the NSAIDs naproxen and ibuprofen, using a record-linkage database for Tayside, Scotland (population 400,000). Cohorts of patients exposed to naproxen (n=54,038) and ibuprofen (n=79,513) were assembled. There were no deaths due to hypersensitivity. There was an increased risk of unvalidated hypersensitivity reactions during periods on-drug versus off-drug in patients exposed to naproxen and ibuprofen. However, after checking medical records, none of the three valid cases of hypersensitivity in the naproxen cohort and neither of the two in the ibuprofen cohort were judged to be due to NSAID exposure. A ‘worst-case’ scenario gave an adjusted rate-ratio of on-drug with naproxen versus on-drug with ibuprofen of 1.63 (0.50, 5.29). The study shows that hypersensitivity reactions associated with NSAID use are rare, and provides no evidence that the risks of hypersensitivity reactions differ between naproxen and ibuprofen.     

Synthesis and biological activity of analogues of the antidiabetic/antiobesity agent 3-guanidinopropionic acid: discovery of a novel aminoguanidinoacetic acid antidiabetic agent

3-Guanidinopropionic acid (1, PNU-10483) has been demonstrated to both improve insulin sensitivity and to promote weight loss selectively from adipose tissue in animal models of non-insulin-dependent diabetes mellitus (NIDDM). However, 1 has also been shown to be a substrate for both the creatine transporter and creatine kinase, leading to marked accumulation in muscle tissue as the corresponding N-phosphate 4. In an effort to identify novel entities that maintain antidiabetic potency without susceptibility to creatine-like metabolism, an analogue program was undertaken to explore the effects of various structural modifications, including homologation, simple substitution, single atom mutations, and bioisosteric replacements for the guanidine and carboxylic acid. Overall, the scope of activity encompassed by the set of new analogues proved to be exceedingly narrow. Notable exceptions demonstrating equivalent or improved antidiabetic activity included the alpha-amino derivative 29, aminopyridine 47, isothiourea 67, and aminoguanidine 69. On the basis of its superior therapeutic ratio, aminoguanidine 69 was selected for preclinical development and became the foundation for a second phase of analogue work. Furthermore, in vitro studies demonstrated that 69 is markedly less susceptible to phosphorylation by creatine kinase than the lead 1, suggesting that it should have less potential for accumulation in muscle tissue than 1.     

Interactive roles of superoxide and inducible nitric oxide synthase in rat intestinal injury provoked by non-steroidal anti-inflammatory drugs.

The role of nitric oxide (NO) formed by inducible NO synthase (iNOS), superoxide and the lipopolysaccharide from luminal bacteria in non-steroidal anti-inflammatory drug-induced intestinal injury was investigated in the rat. Administration (s.c. or p.o.) of indomethacin (10 mg kg(-1)), flurbiprofen (40 mg kg(-1)) or diclofenac (40 mg kg(-1)) increased the vascular leakage of radiolabelled albumin in the jejunum, determined after 24 h, associated with the induction of iNOS, assessed by the conversion of radiolabelled L-arginine. Pre-treatment with ampicillin (200 mg kg(-1) day(-1), p.o.), metronidazole (200 mg kg(-1) day(-1), p.o.), or polymixin B (15 mg kg(-1) day(-1), s.c.), inhibited indomethacin-induced lesion formation, reduced microvascular leakage and prevented the expression of iNOS activity. Administration of the highly selective iNOS inhibitor, GW273629 ((R)-2-amino-4,4-dioxo-6(1-iminioethylamino)-4-thiahexanoic acid; 5 mg kg(-1), s.c.), 18 h after indomethacin, likewise prevented the intestinal lesions and attenuated the microvascular leakage. Superoxide dismutase conjugated with polyethylene glycol (3000 U kg(-1), i.v.), inhibited the indomethacin-induced lesions and microvascular leakage, but not the expression of iNOS activity. These findings suggest that non-steroidal anti-inflammatory drugs compromise mucosal integrity, leading to luminal bacterial translocation. This provokes iNOS induction, leading to microvascular injury involving both NO and superoxide.     

Factors modulating the epithelial response to toxicants in tracheobronchial airways

As one of the principal interfaces between the organism and the environment, the respiratory system is a target for a wide variety of toxicants and carcinogens. The cellular and architectural complexity of the respiratory system appears to play a major role in defining the focal nature of the pulmonary response to environmental stressors. This review will address the biological factors that modulate the response of one of the major target compartments within the respiratory system, the tracheobronchial airway tree. Individual airway segments respond uniquely to toxic stress and this response involves not only the target cell population, e.g. epithelium, but also other components of the airway wall suggesting a trophic interaction within all components of the airway wall in maintaining steady state and responding to injury. A number of biological factors modulate the nature of the response, including: (1) metabolic potential at specific sites for activation and detoxification; (2) the nature of the local inflammatory response; (3) age of the organism at the time of exposure; (4) gender of the exposed organism; (5) history of previous exposure; and (6) species and strain of the organism exposed.     

Metabolic activation of fluoropyrrolidine dipeptidyl peptidase-IV inhibitors by rat liver microsomes.

The current study evaluated the potential for two dipeptidyl peptidase-IV (DPP-IV) inhibitor analogs (1S)-1-(trans-4-([(4-trifluoromethoxyphenyl)sulfonyl]amino)cyclohexyl)-2-[(3S)-3-fluoropyrrolidin-1-yl]-2-oxoethanaminium chloride and (1S)-1-(trans-4-([(2,4-difluorophenyl)sulfonyl]amino)cyclohexyl)-2-[(3S)-3-fluoropyrrolidin-1-yl]-2-oxoethanaminium chloride (MRL-A and MRL-B), containing a fluoropyrrolidine moiety in the structure, to undergo metabolic activation. The irreversible binding of these tritium-labeled compounds to rat liver microsomal protein was time- and NADPH-dependent and was attenuated by the addition of reduced glutathione (GSH) or N-acetylcysteine (NAC) to the incubation, indicating that chemically reactive intermediates were formed and trapped by these nucleophiles. Mass spectrometric analyses and further trapping experiments with semicarbazide indicated that the fluoropyrrolidine ring had undergone sequential oxidation and defluorination events resulting in the formation of GSH or NAC conjugates of the pyrrolidine moiety. The bioactivation of MRL-A was catalyzed primarily by rat recombinant CYP3A1 and CYP3A2. Pretreatment of rats with prototypic CYP3A1 and 3A2 inducers (pregnenolone-16alpha-carbonitrile and dexamethasone) enhanced the extent of bioactivation which, in turn, led to a higher degree of in vitro irreversible binding to microsomal proteins (5- and 9-fold increase, respectively). Herein, we describe studies that demonstrate that the fluoropyrrolidine ring is prone to metabolic activation and that GSH or NAC can trap the reactive intermediates to form adducts that provide insight into the mechanisms of bioactivation.     

Mechanisms of the synergistic interaction between the bisphosphonate zoledronic acid and the chemotherapy agent paclitaxel in breast cancer cells in vitro.

Breast cancer patients often receive both paclitaxel and zoledronic acid as part of their treatment, and these drugs are reported to have synergistic effects on the induction of apoptosis of breast cancer cells in vitro. We have found that the synergistic interaction is drug sequence dependent, with maximal levels of apoptosis achieved when cells are treated with paclitaxel followed by zoledronic acid, as opposed to the reverse sequence or simultaneous treatment. The synergistic interaction persists at clinically relevant concentrations and incubation periods. We report that the sequential treatment is associated with cell cycle changes and depends on breast cancer cell characteristics, with hormone independence, mutated p53 status and presence of BRCA1 gene being associated with higher levels of apoptosis. Finally, we have found that the synergistic induction of apoptosis is via zoledronic acid-mediated inhibition of the mevalonate pathway.     

Factors associated with enrollment in cancer genetics research.

Previous studies have identified low patient accrual in large-scale cancer clinical trials, particularly for underrepresented groups, such as ethnic minorities, females, and patients >65 years. As there have been few studies examining participation in cancer genetics epidemiologic research, our objective was to identify clinical and demographic factors predicting enrollment in these studies. A total of 1,111 patients diagnosed with colorectal cancer presenting to a gastrointestinal oncology clinic were approached to enroll in a study investigating the role of the MSH6 gene in familial colorectal cancer. Patient consent was sought for providing a blood specimen for DNA analysis and review of medical records/tumor specimens and contacting family members to confirm the family history of cancer. Seven predictor variables for enrollment (age, sex, ethnicity, family history of colorectal cancer in a first-degree relative, presence of children, insurance type, and type of visit) were analyzed using logistic regression analysis to determine the effect on decision to enroll. Of 1,111 patients approached, 696 (62.6%) enrolled in the study. Of these approached individuals, 4.2% were of nonwhite ethnicity and 33.5% were age > or =65 years. Patients of white ethnicity [odds ratio (OR), 2.10; P = 0.018], males (OR, 1.47; P = 0.002), those ages < or =65 years (OR, 1.42; P = 0.009), and those with a first-degree relative with colorectal cancer (OR, 1.57; P = 0.005) were significantly more likely to enroll. Fewer than 4% of all participants denied permission for the study researchers to access information from medical records or to be recontacted by researchers to discuss the enrollment of additional family members. Our data suggest that, once subjects decided to enroll, the majority (88%) was comfortable with consenting to all study components, including the creation of cell lines and future recontact. Low participation rates for ethnic minorities, females, and elderly patients are similar for both cancer genetics and clinical trial studies.