Pharmacological parameters of intravenously administered amphotericin B in rats: comparison of the conventional formulation with amphotericin B associated with a triglyceride-rich emulsion.
(25/1650)
The LD50 determined in rats for the potent antifungal amphotericin B (AB) increased from 4.2 to 12.0 when the conventional AB-deoxycholate (DOC) was compared with AB associated with a triglyceride-rich emulsion (AB-emulsion). The reduction in amphotericin B toxicity is not due to a modification in plasma clearance, as both formulations seem to be removed from plasma at the same rate. Major differences in amphotericin B tissue distribution were not seen for kidney and liver but were seen for the lung. After 24 h administration of a single amphotericin B dose (2.0 mg/kg body weight) 23.78 +/- 11.71 mg/kg tissue was recovered from the lung of animals treated with AB-DOC whereas for AB-emulsion only 5.19 +/- 2.50 mg/kg tissue was recovered. The higher lethality of AB-DOC may be related to the higher concentration of amphotericin B in the lung. The therapeutic efficacy of AB-emulsion was similar to that of AB-DOC as attested by survival curves obtained after treatment of mice infected by Candida albicans. This is highly relevant, as the same is not necessarily found for other less toxic proposed vehicles. The equivalent efficacy and the increment in the LD50 will result in an important improvement in the therapeutic activity of amphotericin B. Furthermore, some data related to storage and stability indicate the clinical utility of this type of drug delivery. (+info)
Acceleration of viral replication and up-regulation of cytokine levels by antimalarials: implications in malaria-endemic areas.
(26/1650)
Antimalarial drugs are widely used in malaria endemic areas, both for chemoprophylaxis and also empirically to treat patients presenting with fever. Previously, we have reported that chloroquine enhances the severity of Semliki forest virus (SFV) and encephalomyocarditis virus infection. The studies presented herein show that a broad spectrum of antimalarial drugs augmented the replication of SFV in mice, concomitant with greater tissue damage and up-regulation of mRNA levels of various inflammatory cytokine genes, including interleukin-1 receptor antagonist (IL-1Ra), II-1alpha, IL-1beta, IL-6, IL-12p40, and interferon-gamma inducing factor. Furthermore, chloroquine enhances IL-1Ra production in RAW cells in vitro. Since IL-1Ra is known to be up-regulated in a number of viral infections, we propose that a further enhancement of its expression by antimalarials may be responsible for the increased severity of viral infection in our studies. Thus, the widespread use of antimalarials in malaria-endemic areas may predispose the population to viral infections. Further studies are in progress to delineate mechanism(s) involved in cytokine up-regulation and acceleration of viral replication. (+info)
Sequence analysis of the small RNA segment of guinea pig-passaged Pichinde virus variants.
(27/1650)
The established animal model for Lassa fever is based on the new world arenavirus Pichinde (PIC). Natural isolates of PIC virus are attenuated in guinea pigs, but serial guinea pig passage renders them extremely virulent in that host. We have compared the nucleotide sequences of the small RNA segments of two attenuated, low-passage variants of the PIC virus Munchique strain (CoAn 4763) and two virulent, high-passage derivatives. Missense mutations in the glycoprotein precursor (GPC) gene at codons GPC-119, GPC-140, and GPC-164 and the nucleoprotein gene (NP) codons NP-35 and NP-374 were most closely associated with virulence. Codon GPC-140 is predicted to represent a region of peak hydrophilicity of the glycoprotein 1 (GP1); it is conceivable that mutations at this site could influence virulence by altering B cell epitopes or virus attachment protein conformation. (+info)
A new monospecific ovine Fab fragment antivenom for treatment of envenoming by the Sri Lankan Russell's viper (Daboia Russelii Russelii): a preliminary dose-finding and pharmacokinetic study.
(28/1650)
Russell's viper is the most important cause of life-threatening snake bite and acute renal failure in Sri Lanka. Only equine polyspecific antivenoms imported from India are available. They have not proved effective clinically or in clearing venom antigenemia and they frequently cause reactions. In an attempt to reduce mortality and morbidity, a new monospecific ovine Fab fragment antivenom (PolongaTab; Therapeutic Antibodies, Inc., London, United Kingdom) was raised against Sri Lankan Russell's viper venom. In a preliminary dose-finding study in 35 patients, an initial dose of 3-4 g restored blood coagulability permanently and stopped systemic bleeding, even in severely envenomed patients. Venom antigenemia disappeared within 1 hr of antivenom treatment but recurred, probably as a result of continued absorption of venom from the site of the bite, after the rapid clearance of therapeutic antibody. Twelve patients (34%) experienced early reactions that were usually mild and always responded to epinephrine. (+info)
Comparative study on the ability of IgG and F(ab')2 antivenoms to neutralize lethal and myotoxic effects induced by Micrurus nigrocinctus (coral snake) venom.
(29/1650)
A comparative study was performed on the ability of IgG and F(ab')2 antivenoms to neutralize lethal and myotoxic activities of Micrurus nigrocinctus venom. Both antivenoms were adjusted to a similar neutralizing potency in experiments where venom and antivenoms were preincubated prior to injection. No significant differences were observed between IgG and F(ab')2 antivenoms concerning neutralization of lethal effect in rescue experiments, i.e., when antivenom was administered intravenously after envenomation. However, F(ab')2 antivenom was more effective in prolonging the time of death when subneutralizing doses were administered immediately after venom injection. Both products partially reversed the binding of M. nigrocinctus alpha-neurotoxins to acetylcholine receptor in vitro. The IgG and F(ab')2 antivenoms effectively neutralized venom-induced myotoxicity when administered intravenously immediately after envenomation, although neutralization was poor if antivenom injections were delayed. Intramuscular injection of venom promoted diffusion of antivenom antibodies throughout muscle tissue, and F(ab')2 diffused to a higher extent than IgG molecules. Thus, despite the observation that F(ab')2 antivenom was more effective than IgG antivenom in prolonging the time of death when subneutralizing doses were administered immediately after envenomation, no major differences were observed in antivenom neutralization of lethal and myotoxic effects or in their capacity to reverse neurotoxin binding to the acetylcholine receptor. (+info)
Letter re: "Cyclosiloxanes produce fatal liver and lung damage in mice".
(30/1650)
Comments on Lieberman's article: Cyclosiloxanes Produce Fatal Liver and Lung Damage in Mice. Environ Health Perspect 107:161-165 (+info)
Exogenous cytokine modulation or neutralization of interleukin-10 enhance survival in lipopolysaccharide-hyporesponsive C3H/HeJ mice with Klebsiella infection.
(31/1650)
Klebsiella pneumoniae has been isolated from liver abscesses in patients with leukaemia or diabetes. The resistance of Klebsiella infection in lipopolysaccharide (LPS)-hyporesponsive mice is unclear. Female C3H/HeJ and C3H/HeN mice, 6-8 weeks old, were intraperitoneally (i.p.) injected with K. pneumoniae. The results showed that C3H/HeJ mice were 24 times more susceptible [lethal dose 50% (LD50) 250 colony-forming units] than C3H/HeN mice to K. pneumoniae infection. C3H/HeJ mice, uninfected or infected with K. pneumoniae, had higher liver interleukin (IL)-10 levels and IL-10 mRNA levels than C3H/HeN mice. Previously, pretreatment with IL-1beta and tumour necrosis factor-alpha (TNF-alpha) protected C3H/HeJ mice from lethal bacterial infection. Therefore the effects of pretreatment with IL-1beta and TNF-alpha or antimurine IL-10 antibody i.p. 1 hr before this infection in both strains of C3H mice were examined. Pretreatment with TNF-alpha or anti-IL-10 antibody enhanced the survival of both strains of mice. TNF-alpha, in combination with IL-1beta, enhanced the survival and bacterial clearance better than single pretreatment in C3H/HeJ mice. Anti-IL-10 antibody increased bacterial clearance and significantly reduced liver cytokine mRNA levels in C3H/HeJ mice more than it did in the controls during infection. These results indicate that exogenous cytokine modulation or neutralization of IL-10 enhance the resistance of LD50 infection in C3H/HeJ mice. (+info)
Mapping of an epitope recognized by a neutralizing monoclonal antibody specific to toxin Cn2 from the scorpion Centruroides noxius, using discontinuous synthetic peptides.
(32/1650)
The Na+-channel-affecting toxin Cn2 represents the major and one of the most toxic components of the venom of the Mexican scorpion Centruroides noxius Hoffmann. A monoclonal antibody BCF2 raised against Cn2 has been shown previously to be able to neutralize the toxic effect of Cn2 and of the whole venom of C. noxius. In the present study the epitope was mapped to a surface region comprising the N- and C-terminal segments of Cn2, using continuous and discontinuous synthetic peptides, designed on the basis of the sequence and a three-dimensional model of Cn2. The study of peptides of varying length resulted in the identification of segments 5-14 and 56-65 containing residues essential for recognition by BCF2. The peptide (abbreviated SP7) with the highest affinity to BCF2 (IC50 = 5.1 microM) was a synthetic heterodimer comprising the amino acid sequence from position 3-15 (amidated) of Cn2, bridged by disulfide to peptide from position 54-66, acetylated and amidated. Similar affinity was found with peptide SP1 [heterodimer comprising residues 1-14 (amidated) of Cn2, bridged with synthetic peptide 52-66 (acetylated)]. SP1 and SP7 were used to induce anti-peptide antibodies in mouse and rabbit. Both peptides were highly immunogenic. The sera obtained were able to recognize Cn2 and to neutralize Cn2 in vitro. The most efficient protection (8.3 microgram Cn2 neutralized per mL of serum) was induced by rabbit anti-SP1 serum. (+info)