Toxicologic effects of ribavirin in cats

Ribavirin, a broad-spectrum antiviral agent active in vitro against a number of RNA and DNA viruses, has been associated with moderate toxicity in laboratory animals and humans. Clinically, ribavirin has been used effectively in persons primarily to treat life-threatening viral diseases such as acute haemorrhagic fever or viral pneumonia of infants. In order to evaluate the feasibility of using this antiviral agent in cats, the effects of oral (p.o.), intramuscular (i.m.) and intravenous (i.v.) doses of ribavirin in 27 9-month-old specific-pathogen-free cats were evaluated by haematology, clinical chemistries, bone marrow biopsies and histopathology. Ribavirin was administered once daily for 10 consecutive days at a dose of either 11, 22, or 44 mg/kg after which all cats were euthanatized and necropsied. Most cats receiving 22 or 44 mg of ribavirin/kg became anorectic and suffered some degree of weight loss (0.2 to 0.6 kg), and about one-third of the cats developed diarrhoea and/or mucous membrane pallor. Icterus or haemorrhage was not observed. The most profound and consistent haematologic change, particularly among the moderate and high dosage groups regardless of route of administration, was a significant and severe thrombocytopenia (range, 33-78% reduction in mean platelet counts vs. baseline). Other changes, particularly reductions in total WBC and neutrophils and reductions in RBC and PCV, tended to occur at lower ribavirin dosages, but generally they were not statistically significant. Cats given 44 mg of ribavirin/kg i.v. showed significant decreases in leukocyte variables, including total WBC (P = 0.016), neutrophils (P = 0.026) and lymphocytes (P = 0.047). Mild-to-moderate increases in serum alanine aminotransferase and alkaline phosphatase activities occurred at doses of 22 and 44 mg/kg. Evaluation of bone marrow biopsies before and after treatment revealed that cats given 11 mg of ribavirin/kg had mild megakaryocytic (MK) hypoplasia, whereas cats receiving 22 or 44 mg/kg had progressively severe degrees of MK hypoplasia and dysplasia, asynchronous MK maturation, and increased myeloid:erythroid ratio. Pathologic changes in ribavirin-treated cats generally were mild and included primarily enteritis (seven cats) and hepatocellular vacuolation and/or centrilobular necrosis (seven cats). Results of this study in cats indicated that daily administration of ribavirin at a dose range of 11 to 44 mg/kg induced a dose-related toxic effect on bone marrow, primarily on megakaryocytes and erythroid precursors, and at the higher dosages is suppressed numbers of circulating leukocytes.     

Novel recombinant analogues of bovine placental lactogen. G133K and G133R provide a tool to understand the difference between the action of prolactin and growth hormone receptors

Two new analogues of bovine placental lactogen (bPL), bPL(G133K) and bPL(G133R), were expressed in Escherichia coli, refolded, and purified to a native form. Binding experiments, which are likely to represent the binding to site 1 only, to intact FDC-P1 cells transfected with rabbit (rb) growth hormone receptor (GHR) or with human (h) GHR, to Nb2 rat lymphoma cells, or to rabbit mammary gland membranes prolactin receptor (PRLR), revealed only small or no reduction in binding capacity. The complex formation between these analogues and receptor extracellular domains (R-ECD) of various hormones was determined by gel filtration. Wild type bPL yielded 1:2 complex with hGHR-ECD, rat PRLR-ECD, and rbPRLR-ECD, whereas both analogues formed only 1:1 complexes with all R-ECDs tested. Real time kinetics experiments demonstrated that the ability of the analogues to form homodimeric complexes was compromised in both PRLR- and GHR-ECDs. The biological activity transduced through lactogenic receptors in in vitro bioassays in rabbit mammary gland acini culture and in Nb2 cells was almost fully retained, whereas the activity transduced through somatogenic receptors in FDC-P1 cells transfected with rbGHRs or with hGHRs was abolished. Both analogues exhibited antagonistic activity in the latter cells. To explain the discrepancy between the effect of the mutation on the signal transduced by PLR versus GHRs we suggest that: 1) the mutation impairs the ability of site 2 of bPL to form a stable homodimeric complex with both lactogenic and somatogenic receptors by a drastic shortening of the half-life of 2:1 complex; 2) the transient existence of the homodimeric complex is still sufficient to initiate the signal transduced through lactogenic receptors but not through somatogenic receptors; and 3) one possible reason for this difference is that JAK2, which serves as a mediator of both receptors, is already associated with lactogenic receptors prior to hormone binding-induced receptor dimerization, whereas in somatogenic receptors the JAK2 receptor association occurs subsequently to receptor dimerization.     

Estimating the proportion of post-myocardial infarction patients who may benefit from prophylactic implantable defibrillator placement from analysis of the CAST registry. Cardiac Arrhythmia Suppression Trial

We defined the proportion of post-myocardial infarction patients who would have been eligible for the Multicenter Automatic Defibrillator Implantation Trial (MADIT) from a population of 94,797 patients with myocardial infarction entered into the Cardiac Arrhythmia Suppression Trial Registry. From this large population, only between 0.3% to 1.7% would have met strict eligibility criteria for MADIT.     

Unusual complication of nasal CPAP: subcutaneous emphysema following facial trauma

Subcutaneous emphysema is an unusual complication of nasal continuous positive airway pressure (CPAP). We report a case of a 58-year-old man who fell and sustained mild facial trauma to the left side of his head. After using CPAP the following night, he developed diffuse subcutaneous emphysema of his face and left neck. He discontinued CPAP, and his symptoms improved. The potential mechanisms of this patient's subcutaneous emphysema and the prior reports of this complication following facial trauma or dental procedure without use of CPAP are reviewed. Although there are case reports of bacterial meningitis and pneumocephalus following use of nasal CPAP, we are not aware of any prior reports of subcutaneous emphysema following use of CPAP. In light of our experience and the above related case reports, we would suggest nasal CPAP be withheld temporarily in the setting of acute facial trauma.     

Novel cytotoxic acylated oligorhamnosides from Mezzettia leptopoda

Activity-guided fractionation of a stem extract of Mezzettia leptopoda using human oral epidermoid carcinoma (KB) cells led to the isolation of seven highly acylated oligorhamnosides. Four of these constituents are novel, namely, n-octyl 2-O-acetyl-alpha-L-rhamnopyranosyl-(1-->3)-2, 4-di-O-acetyl-alpha-L-rhamnopyranosyl-(1-->3)-4-O-hexanoyl-alpha-L-rh amnopyranoside (mezzettiaside 8) (1); n-octyl 2, 3-di-O-acetyl-alpha-L-rhamnopyranosyl-(1-->3)-4-O-hexanoyl-alpha-L-rh amnopyranoside (mezzettiaside 9) (2); n-octyl 2, 4-di-O-acetyl-alpha-L-rhamnopyranosyl-(1-->3)-4-O-hexanoyl-alpha-L-rh amnopyranoside (mezzettiaside 10) (3); and n-octyl 2,3, 4-tri-O-acetyl-alpha-L-rhamnopyranosyl-(1-->3)-4-O-hexanoyl-alpha-L-r hamnopyranoside (mezzettiaside 11) (4). Three known compounds were identified as mezzettiasides 2 (5), 3 (6), and 4 (7), respectively, previously isolated from this same plant. The structures of novel compounds 1-4 were determined by spectroscopic methods. All the isolates were evaluated against a panel of human cancer cell lines in this study, and compounds 1-2 and 4-7 were found to be weakly cytotoxic toward KB and/or human colon and lung cancer cell lines.     

Viral lesions of the eye in human immunodeficiency virus infection]

HIV infection destroying cellular immunity system creates prerequisites for herpesvirus involvement of the anterior and posterior segments of the eye. A total of 370 HIV-infected patients were examined. Ocular diseases were detected in 53 (14.35%). The most prevalent conditions were retinal angiopathy (most often with cotton-like foci--in 7.3% and cytomegalovirus (CMV) retinitis in 4.1%). Cotton-like foci in the presence of CMV activation (evidenced by high level of CMV DNA in peripheral blood) are a sign of probable CMV infection manifesting by retinitis or involvement of other organs. Intravenous gancyclovir in a dose of 7.5 mg/kg twice a day and its combination with interferon inductor poludan are effective methods for therapy of CMV infection, preventing blindness or poor vision. Moreover, combination of chemotherapy with interferon inductors cured involvement of the anterior segment of the eye--herpetic keratitis and iridocyclitis, which sometimes develop in the presence of HIV infection.     

Extremely low birth weight infants have lower Fc gamma RIII (CD 16) plasma levels and their PMN produce less Fc gamma RIII compared to adults

The authors developed a new apparatus for extracting nitrogen or other inert gases from blood by flushing (sparging) the specimen with another gas. To investigate the utility of the new methodology, the apparatus was used in conjunction with a mass spectrometer to measure the blood N2 content of healthy normobaric, non-smoking, adult volunteers; the mean was found to be 11.7 microliters/ml +/- 0.9 microliter. This compares closely with values cited in the literature. The within-subject variation for repeat samples taken several weeks apart was significantly (P < 0.003) less than the variation between different subjects, suggesting that there may be true differences in N2 content between different individuals. These data must be considered preliminary, a larger study is needed to investigate population differences in detail. The advantages of the new method are discussed.