Clinical and economic effectiveness of an inpatient anticoagulation service

We conducted a prospective cohort study to evaluate clinical and economic end points achieved by a pharmacist-managed anticoagulation service compared with usual care (50 patients/group). The primary therapeutic end point was the time between starting heparin therapy and surpassing the activated partial thromboplastin time therapeutic threshold. The primary economic end point was the direct variable cost of hospitalization from admission to discharge. No significant differences between groups were noted for the primary therapeutic end point. Total hospital costs were significantly lower for patients receiving pharmacist-managed care than for those receiving usual care ($1594 and $2014, respectively, 1997 dollars, p=0.04). Earlier start of warfarin (p=0.05) and shorter hospital stay (5 and 7 days, p=0.05) were associated with the pharmacist-managed group.     

Seroprevalence of human herpesvirus-8 (HHV-8) in countries of Southeast Asia compared to the USA, the Caribbean and Africa.

Seroprevalence of HHV-8 has been studied in Malaysia, India, Sri Lanka, Thailand, Trinidad, Jamaica and the USA, in both healthy individuals and those infected with HIV. Seroprevalence was found to be low in these countries in both the healthy and the HIV-infected populations. This correlates with the fact that hardly any AIDS-related Kaposi's sarcoma has been reported in these countries. In contrast, the African countries of Ghana, Uganda and Zambia showed high seroprevalences in both healthy and HIV-infected populations. This suggests that human herpes virus-8 (HHV-8) may be either a recently introduced virus or one that has extremely low infectivity. Nasopharyngeal and oral carcinoma patients from Malaysia, Hong Kong and Sri Lanka who have very high EBV titres show that only 3/82 (3.7%) have antibody to HHV-8, demonstrating that there is little, if any, cross-reactivity between antibodies to these two gamma viruses.     

The role of fine-needle aspiration cytology in the evaluation of metastatic clear cell tumors

BACKGROUND: Clear cell tumors (CCTs) occur as primary neoplasms in a number of anatomic sites. Due to their overlapping morphologic features, these tumors can be challenging for the cytologist, particularly when they present as metastatic lesions. METHODS: Forty-nine fine-needle aspirations (FNA) of metastatic CCTs from 46 patients (age range, 29-87 years; mean, 64 years) were reviewed retrospectively. In addition to the routine smears and cell block preparations, ancillary studies were performed in selected cases. Clinical and/or histologic follow-up was obtained for all patients. RESULTS: The sites of the 49 FNAs were the lung (12 cases), lymph nodes (9 cases), liver (7 cases), bone (7 cases), soft tissue (4 cases), pelvis (2 cases), adrenal gland (2 cases), pancreas (1 case), thyroid (2 cases), peritoneum (2 cases), and vagina (1 case). Twenty-seven patients had a previous history of a CCT and the FNA material in these cases was consistent with a metastasis. The primary anatomic sites in these cases were the kidney (20 cases), ovary (2 cases), salivary gland (1 case), and cervix (1 case). On light microscopy, these tumors had a similar appearance and often were indistinguishable. Nineteen patients did not have a prior history of malignancy; 12 of these patients had a concurrent renal mass and the diagnosis of metastatic renal cell carcinoma was made. The anatomic site of origin of seven of the ten remaining tumors (kidney [2 cases], lung [2 cases], ovary [1 case], germ cell [1 case], and endometrium [1 case]) was established through immunocytochemical studies of cytologic material and clinical follow-up. CONCLUSIONS: FNA plays an important role in the diagnosis of metastatic CCT. Cytologic examination, ancillary studies, and clinical information can establish the anatomic site of origin in the majority (95%) of cases, precluding the necessity of obtaining additional tissue. Cancer (Cancer Cytopathol) Copyright 1999 American Cancer Society.     

Human small cell lung cancer NYH cells selected for resistance to the bisdioxopiperazine topoisomerase II catalytic inhibitor ICRF-187 demonstrate a functional R162Q mutation in the Walker A consensus ATP binding domain of the alpha isoform.

Bisdioxopiperazine drugs such as ICRF-187 are catalytic inhibitors of DNA topoisomerase II, with at least two effects on the enzyme: namely, locking it in a closed-clamp form and inhibiting its ATPase activity. This is in contrast to topoisomerase II poisons as etoposide and amsacrine (m-AMSA), which act by stabilizing enzyme-DNA-drug complexes at a stage in which the DNA gate strand is cleaved and the protein is covalently attached to DNA. Human small cell lung cancer NYH cells selected for resistance to ICRF-187 (NYH/187) showed a 25% increase in topoisomerase IIalpha level and no change in expression of the beta isoform. Sequencing of the entire topoisomerase IIalpha cDNA from NYH/187 cells demonstrated a homozygous G-->A point mutation at nucleotide 485, leading to a R162Q conversion in the Walker A consensus ATP binding site (residues 161-165 in the alpha isoform), this being the first drug-selected mutation described at this site. Western blotting after incubation with ICRF-187 showed no depletion of the alpha isoform in NYH/187 cells in contrast to wild-type (wt) cells, whereas equal depletion of the beta isoform was observed in the two sublines. Alkaline elution assay demonstrated a lack of inhibition of etoposide-induced DNA single-stranded breaks in NYH/187 cells, whereas this inhibition was readily apparent in NYH cells. Site-directed mutagenesis in human topoisomerase IIalpha introduced into a yeast Saccharomyces cerevisiae strain with a temperature-conditional yeast TOP2 mutant demonstrated that R162Q conferred resistance to the bisdioxopiperazines ICRF-187 and -193 but not to etoposide or m-AMSA. Both etoposide and m-AMSA induced more DNA cleavage with purified R162Q enzyme than with the wt. The R162Q enzyme has a 20-25% decreased catalytic capacity compared to the wt and was almost inactive at <0.25 mM ATP compared to the wt. Kinetoplast DNA decatenation by the R162Q enzyme at 1 mM ATP was not resistant to ICRF-187 compared to wt, whereas it was clearly less sensitive than wt to ICRF-187 at low ATP concentrations. This suggests that it is a shift in the equilibrium to an open-clamp state in the enzyme's catalytic cycle caused by a decreased ATP binding by the mutated enzyme that is responsible for bisdioxopiperazine resistance.     

Nonsurgical internal biliary drainage by endoprosthesis

Insertion of an endoprostheses for internal biliary drainage was attempted upon 150 patients with obstructive jaundice. It was successful in 123 patients, and 99 patients had permanent drainage with the endoprosthesis. The plasma bilirubin level became normal in 64 of the patients. The effect upon jaundice was equal to that in 43 patients who underwent operation with palliative surgical bypass. The median survival time was not different from that for the patients with surgical anastomoses. Twenty-eight patients died in the first month after insertion, mostly of advanced malignant disease. Fifteen of the patients in the group with surgical anastomoses died within the first month. The insertion of an endoprosthesis for bile duct obstruction is relatively easy and seems to have little risk. Most complications are caused by the transhepatic cholangiography procedure. The method may be used for temporary drainage before operation, in transient benign obstructions or as permanent drainage in unresectable lesions. In patients with dislodgement or insufficient function, additional endoprosthesis may be inserted. Thus, sufficient palliation of jaundice is achieved with a low frequency of cholangitis. Internal biliary drainage by insertion of an endoprosthesis is a valuable alternative to surgical bypass in patients with unresectable lesions.     

Uptake and effects of nitrite in the marine teleost fish Platichthys flesus

The route of NO(2)(-) uptake and subsequent physiological effects were examined in the marine teleost, European flounder (Platichthys flesus), during exposure to 1 mM ambient NO(2)(-) for up to 11 days. Drinking of seawater resulted in a similar nitrite concentration in the anterior part of the intestine as in the ambient water. The NO(2)(-) concentration decreased along the gastro-intestinal tract, suggesting NO(2)(-) uptake across the intestinal epithelium. Comparison of NO(2)(-) uptake in fish that drank NO(2)(-)-contaminated seawater with fish that did not (i.e. had the intestine perfused with a NO(2)(-)-free saline during NO(2)(-) exposure) revealed that the intestinal route contributed some 66% of whole-body NO(2)(-) uptake. Plasma [NO(2)(-)] stayed below the ambient level. It reached a maximum of 0.35-0.4 mM on days 3-6 and then declined to 0.2 mM on day 11. The physiological effects of NO(2)(-) exposure were relatively minor compared with those reported in freshwater fish. Blood methemoglobin levels increased from approximately 4% in non-exposed fish to a maximum of 18% of total hemoglobin in exposed fish. An extracellular hyperkalemia was observed from day 3 of NO(2)(-) exposure, with a maximal increase in plasma K(+) concentrations of 38%. No mortality occurred during the 11 days of NO(2)(-) exposure. The lack of mortality can be related to the relatively low NO(2)(-) accumulation in the plasma and the relatively minor physiological disturbances.     

Glycosylation of the gastrin-releasing peptide receptor and its effect on expression, G protein coupling, and receptor modulatory processes

Many gastrointestinal G protein-coupled receptors are glycosylated; however, which potential glycosylation sites are actually glycosylated and their role in receptor transduction or receptor modulation (internalization, down-regulation, desensitization) is largely unknown. We used site-directed mutagenesis to address these issues with the gastrin-releasing peptide receptor (GRP-R). Each of the four potential glycosylation sites was mutated by converting the Asn (N) to Gln (Q). Transient expression in CHOP cells demonstrated that changing Asn(24) or Asn(191) inhibited GRP-R cell surface expression, whereas elimination of Asn(5) and Asn(20) had no effect. Using ligand cross-linking studies in stable mutants expressed in Balb 3T3 cells, all four potential extracellular sites were glycosylated with carbohydrate residues of approximately 13 kDa on Asn(5), 10 kDa on Asn(20), 5 kDa on Asn(24), and 9 kDa on Asn(191). Removal of three glycosylation sites (N5,20,24,Q mutant) did not alter receptor affinity or G protein coupling; therefore, it could be speculated that deglycosylation at Asn(191) might be responsible for the altered G protein coupling seen with complete enzymatic deglycosylation of the native receptor previously reported. Removal of any single glycosylation site did not interfere with GRP-R induced chronic desensitization or down-regulation. However, elimination of all three NH(2)-terminal sites (N5,20,24) markedly attenuated both processes, with no effect on acute homologous desensitization and with only a minimal alteration of GRP-R internalization, supporting the findings of other studies that suggest that chronic desensitization and down-regulation are functionally coupled, distinct from acute desensitization and distinct from internalization. These data show that separate and specific glycosylation sites are important for GRP-R trafficking to the cell surface, ligand binding, G protein coupling, chronic desensitization, and down-regulation.     

Pharmacokinetics, pharmacodynamics, and safety of inhaled cyclosporin A (ADI628) after single and repeated administration in healthy male and female subjects and asthmatic patients

Severe asthmatics treated with oral/inhaled corticosteroids are at risk of side effects (adrenal suppression). Oral cyclosporin A has been effective in asthma treatment, and nebulized cyclosporin A has been administered for approximately 6 months with no nephrotoxicity or hepatotoxicity, suggesting a wider therapeutic margin for an inhaled cyclosporin A for treatment of asthma. Single- and repeated-dose studies in healthy and asthmatic male and female subjects were conducted to determine the pharmacokinetics, pharmacodynamics, and safety of a new formulation of inhaled cyclosporin A (ADI628) metered-dose inhaler (MDI). ADI628 had roughly dose-linear increases in blood concentrations with moderate variability after single and multiple administration in healthy subjects. Steady-state ADI628 concentrations reflected an effective half-life of 7.0 to 12.5 hours. No overt gender-related differences were observed after single inhaled 10 mg ADI628 dose. However, asthmatics and females (20 mg dose group) had lower ADI628 concentrations as compared to healthy males, probably due to lower inspiratory flow rates and probably not due to disease- or gender-related differences in metabolism/elimination of ADI628. Renal excretion was a minor route of elimination for ADI628 with no dose- or gender-related differences. The blood ADI628 exposure in humans was 1/3- to 1/6-fold lower than the no-effect dose in dogs. Also, the blood ADI628 exposure after the highest inhaled dose was much lower than after the administration of the efficacious oral cyclosporin A dose (3 mg/kg) for treating asthma. The highest steady-state dose (10 mg bid) resulted in ADI628 concentrations that are not typically associated with systemic nephrotoxicity or immunosuppression. Furthermore, repeated inhaled doses of ADI628 were safe and generally well tolerated with no apparent systemic immunosuppressive activity in healthy and asthmatic subjects.     

Pharmacokinetics, pharmacodynamics, and safety of a platelet GPIIb/IIIa antagonist, RGD891, following intravenous administration in healthy male volunteers

The pharmacokinetics (PK), pharmacodynamics (PD), and safety of a platelet GPIIb/IIIa receptor antagonist, RGD891, and its active metabolite, RGD039, were evaluated after administration of various intravenous regimens of RGD891 to healthy male volunteers in two Phase I studies. Plasma and urine concentrations of RGD891 and RGD039 were measured by validated LC/MS/MS methods with minimum quantifiable limit (MQL) of 1 ng/mL and 10 ng/mL, respectively. PD activity was assessed by percent inhibition of ADP (20 microM)-induced platelet aggregation. Following intravenous dosing, the RGD891 was the predominant compound in plasma. The PK of RGD891 was dose independent associated with modest between-subject variability. RGD891 was rapidly cleared (Cl, 11.2-15.5 L/h), exhibited a restricted distribution (Vss, 23.0-25.9 L) and a short terminal t1/2 lambda z (1.2-2.1 h). Plasma concentrations of the metabolite (RGD039) increased with dose but were variable. RGD039 had longer t1/2 lambda z of 4.5 to 6.6 hours. Renal excretion of unchanged drug played an important role in the elimination of the parent compound. Both RGD891 and RGD039 exhibited renal clearance values that were comparable to the glomerular filtration rate. Intravenous administration of RGD891 effectively inhibited platelet aggregation in a dose-dependent and reversible manner. At the highest dose (60 micrograms/kg bolus dose + 336 micrograms/kg 8-h infusion) > 90% inhibition of platelet aggregation was achieved. PD activity was primarily attributed to the parent compound. Inhibition of platelet aggregation was dependent on the anticoagulant present, with samples containing PPACK showing 20% to 30% lower activity as compared to citrate. RGD891 was safe and well tolerated across the various regimens studies.