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PubMed2001

Combined interleukin-12 and topical chemotherapy for established Leishmaniasis drastically reduces tissue parasitism and relapses in susceptible mice.

The efficacy of the association of paromomycin sulfate (PA) with recombinant (r) interleukin (IL)-12 was investigated by topical treatment of BALB/c mice infected with Leishmania major that displayed fully developed cutaneous lesions. Although healing was observed in PA-treated groups, lesions recurred in 100% of these animals 70 days after treatment. In contrast, lesions were absent in a high proportion of PA- and rIL-12-treated mice 120 days after treatment. The PA/rIL-12-treated mice had a switch in cytokine response, from high IL-4 and low interferon (IFN)-gamma levels to low IL-4 and high IFN-gamma levels, and reductions in parasite load, dissemination of parasites, and inflammation. Thus, the association of rIL-12 to topical chemotherapy for leishmaniasis may be an important strategy for increasing cure rates and decreasing the incidence of relapse.

Administration, Cutaneous↗
PubMed1998

Topical paromomycin/methylbenzethonium chloride plus parenteral meglumine antimonate as treatment for American cutaneous leishmaniasis: controlled study.

We determined the efficacy of the combination of the topical formulation 15% paromomycin sulfate/12% methylbenzethonium chloride (MBCL) and a short course (7 days) of parenteral meglumine antimonate (pentavalent antimony [Sb]) as treatment of American cutaneous leishmaniasis in Colombian patients. Patients were randomly assigned in unequal allocation (2:1:1:1) to group 1 (topical paromomycin/MBCL plus injectable Sb for 7 days), group 2 (topical placebo plus injectable Sb for 7 days), group 3 (topical paromomycin/MBCL plus injectable Sb for 3 days), and group 4 (injectable Sb for 20 days). Cure was defined as complete reepithelialization of all lesions without relapse. Cure rates among groups were as follows: 58% (34 of 59), group 1; 53% (16 of 30), group 2; 20% (6 of 30), group 3; and 84% (26 of 31), group 4. Seventy-one percent of the organisms identified to the species level were Leishmania braziliensis panamensis. We conclude that 10 days of therapy with paromomycin/MBCL does not augment the response of cutaneous leishmaniasis (predominately due to L. braziliensis panamensis) to a short course of treatment with meglumine antimonate.

Antiprotozoal Agents↗
PubMed1997

An in vitro model of infection of human biliary epithelial cells by Cryptosporidium parvum.

Cryptosporidium parvum infection in the immunosuppressed host is frequently complicated by biliary tract involvement. The recent production of human biliary epithelial cell lines was exploited to develop an in vitro model of biliary cryptosporidiosis. Infection with C. parvum oocysts was detected by IFA and ELISA and confirmed by transmission electron microscopy. Inoculation of monolayers with 10(4) to 5 X 10(5) oocysts/well resulted in a dose-dependent increase in infection. Time-course experiments showed that the number of parasitic stages was maximal at 18-24 h after inoculation. Infection was significantly enhanced by bile at concentrations of 50 and 100 microg/mL and inhibited by 400 microg/mL paromomycin. Infection of human biliary cells with C. parvum can be consistently achieved and monitored by use of IFA or ELISA. This system will be of use in evaluating mechanisms of C. parvum infection and response to therapeutic agents in biliary cryptosporidiosis.

Amebicides↗
PubMed2006

Amoebic hepatic abscesses in an HIV-positive patient.

Herein we report the case of hepatic amoebic abscesses in an HIV-positive Italian seaman with a history of promiscuous heterosexual intercourse. In October 2004, the patient was hospitalized because of fever and recurring abdominal pain. Abdominal ultrasonography revealed six hepatic hypoechoid oval lesions with hyperechoid margins. Stool samples were negative for parasites and bacteria, and serology for Entamoeba histolytica was also negative. Therapy with meropenem plus levofloxacin was initiated. After a partial resolution of clinical symptoms and reduction of three hepatic lesions, the patient was again hospitalized in December 2004, because of recurring intense pain at the right hypochondrium and fever. At this time, one hepatic lesion at the sixth segment was enlarged, two lesions were unchanged, and the remaining three smaller abscesses were resolved. Serum antibodies for E. histolytica and amoebic antigens on the largest abscess drainage were positive; moreover, E. histolytica was also identified on drainage fluid with polymerase chain reaction (PCR). Therapy with metronidazole followed by paromomycin improved both symptoms and radiographic images. This case report suggests that in HIV-infected patients, invasive amoebiasis should be considered and atypical aspects, such as multiple hepatic lesions, delayed positivity of serology for E. histolytica, and possible bacterial superinfection should be evaluated.

Amebicides↗
PubMed1995

Successful treatment of New World cutaneous leishmaniasis with a combination of topical paromomycin/methylbenzethonium chloride and injectable meglumine antimonate.

Colombian patients with New World cutaneous leishmaniasis were treated with a combination of a topical formulation (15% paromomycin sulfate/5% methylbenzethonium chloride, twice a day) and parenteral meglumine antimonate (20 mg of antimony [Sb]/kg.d]). Cohort 1 received topical therapy for 10 days and Sb for 7 days; 18 (90%) of the 20 patients were cured (follow-up, 12 months). Other clinical data suggested that neither the topical formulation alone nor the 7-day regimen of Sb alone would have cured many patients. In a subsequent cohort, which received topical therapy for 10 days and Sb for 3 days, the cure rate was 42% (eight of 19 patients). In Colombian cohorts (historical controls) treated with Sb alone for 10-15 days, the cure rate was 31%-36%. Side effects in cohort 1 patients consisted of local reactions to the topical formulation: burning and pruritus in 25% of patients and vesicle formation in 15% of patients. This is the first report that a regimen partially composed of topical antimicrobial agents can be highly effective for treatment of New World cutaneous leishmaniasis.

Administration, Topical↗
PubMedDate not supplied

Taeniasis unresponsive to a single dose of niclosamide: case report of persistent infection with Taenia saginata and a review of therapy.

A patient infected in Ethiopia with the beef tapeworm Taenia saginata was unsuccessfully treated with 2 g of niclosamide on four separate occasions over four months. clinical and parasitologic cures were effected by a regimen of 2 g of niclosamide given on three consecutive days. Niclosamide is the drug of choice for treatment of T. saginata and Taenia solium (pork tapeworm) infection; cure rates are approximately 90%. It is not absorbable and thus is nontoxic. Alternative treatments of taeniasis vary in the degree of safety; tin compounds and Aspidium extracts often are toxic. Paromomycin sulfate, which is also nonabsorbable, is effective, although adverse gastrointestinal effects are common with multiple-dose regimens. A relatively safe therapy is with mebendazole, a broad-spectrum anthelmintic agent, although efficacy has varied in different trials. A number of benzimidazoles, as well as nitazoxamide, have been effective against tapeworms. Praziquantel is the best alternative to niclosamide in terms of cost, efficacy, availability, and safety.

Adult↗
PubMed2000

Separate domains in GCN1 for binding protein kinase GCN2 and ribosomes are required for GCN2 activation in amino acid-starved cells.

GCN2 stimulates GCN4 translation in amino acid-starved cells by phosphorylating the alpha-subunit of translation initiation factor 2. GCN2 function in vivo requires the GCN1/GCN20 complex, which binds to the N-terminal domain of GCN2. A C-terminal segment of GCN1 (residues 2052-2428) was found to be necessary and sufficient for binding GCN2 in vivo and in vitro. Overexpression of this fragment in wild-type cells impaired association of GCN2 with native GCN1 and had a dominant Gcn(-) phenotype, dependent on Arg2259 in the GCN1 fragment. Substitution of Arg2259 with Ala in full-length GCN1 abolished complex formation with native GCN2 and destroyed GCN1 regulatory function. Consistently, the Gcn(-) phenotype of gcn1-R2259A, but not that of gcn1Delta, was suppressed by overexpressing GCN2. These findings prove that GCN2 binding to the C-terminal domain of GCN1, dependent on Arg2259, is required for high level GCN2 function in vivo. GCN1 expression conferred sensitivity to paromomycin in a manner dependent on its ribosome binding domain, supporting the idea that GCN1 binds near the ribosomal acceptor site to promote GCN2 activation by uncharged tRNA.

Alanine↗
PubMed1990

Isolation and characterization of omnipotent suppressors in the yeast Saccharomyces cerevisiae.

Approximately 290 omnipotent suppressors, which enhance translational misreading, were isolated in strains of the yeast Saccharomyces cerevisiae containing the psi+ extrachromosomal determinant. The suppressors could be assigned to 8 classes by their pattern of suppression of five nutritional markers. The suppressors were further distinguished by differences in growth on paromomycin medium, hypertonic medium, low temperatures (10 degrees), nonfermentable carbon sources, alpha-aminoadipic acid medium, and by their dominance and recessiveness. Genetic analysis of 12 representative suppressors resulted in the assignment of these suppressors to 6 different loci, including the three previously described loci SUP35 (chromosome IV), SUP45 (chromosome II) and SUP46 (chromosome II), as well as three new loci SUP42 (chromosome IV), SUP43 (chromosome XV) and SUP44 (chromosome VII). Suppressors belonging to the same locus had a wide range of different phenotypes. Differences between alleles of the same locus and similarities between alleles of different loci suggest that the omnipotent suppressors encode proteins that effect different functions and that altered forms of each of the proteins can effect the same function.

Alleles↗
PubMed2001

eEF1A Controls ascospore differentiation through elevated accuracy, but controls longevity and fruiting body formation through another mechanism in Podospora anserina.

Antisuppressor mutations in the eEF1A gene of Podospora anserina were previously shown to impair ascospore formation, to drastically increase life span, and to permit the development of the Crippled Growth degenerative process. Here, we show that eEF1A controls ascospore formation through accuracy level maintenance. Examination of antisuppressor mutant perithecia reveals two main cytological defects, mislocalization of spindle and nuclei and nuclear death. Antisuppression levels are shown to be highly dependent upon both the mutation site and the suppressor used, precluding any correlation between antisuppression efficiency and severity of the sporulation impairment. Nevertheless, severity of ascospore differentiation defect is correlated with resistance to paromomycin. We also show that eEF1A controls fruiting body formation and longevity through a mechanism(s) different from accuracy control. In vivo, GFP tagging of the protein in a way that partly retains its function confirmed earlier cytological observation; i.e., this factor is mainly diffuse within the cytosol, but may transiently accumulate within nuclei or in defined regions of the cytoplasm. These data emphasize the fact that the translation apparatus exerts a global regulatory control over cell physiology and that eEF1A is one of the key factors involved in this monitoring.

Alleles↗
PubMed1973

Mitochondrial genetic analysis by zygote cell lineages in Saccharomyces cerevisiae.

Yeast strains were constructed carrying multiple mitochondrial markers conferring resistance to the inhibitors erythromycin, chloramphenicol, paromomycin and oligomycin. A pedigree analysis of two crosses was made by micromanipulating buds from zygotes. The first few daughter buds isolated from the zygotes sometimes gave rise to diploid clones which had a mixture of mitochondrial types. All possible classes of mitochondrial parental and recombinant types were found although they never appeared all together as the progeny from a single zygote. It was inferred that multiple recombination events took place in zygotes and in some of the buds derived from them. After removal of the first four or so daughter buds, subsequent buds from the zygote carried one mitochondrial type only. In cross I in which three markers were analyzed this was most frequently one of the parental types. In cross II (involving four mitochondrial markers) the later buds from the zygotes were frequently of recombinant mitochondrial type.

Chloramphenicol↗
PubMed1980

An antisuppressor that acts on omnipotent suppressors in yeast.

Six partially dominant antisuppressors were obtained that reduce the efficiency of two omnipotent yeast suppressors, sup45 and sup35, thought to be ribosomal ambiguity mutations. Each of these six antisuppressors was shown to fall within a single Mendelian locus, named asu9. The asu9 mutations are specific for omnipotent suppressors; they have no effect on several dominant tRNA-like suppressors. In the absence of suppressors, asu9 causes sensitivity to the aminoglycoside antibiotic, paromomycin. The properties of asu9 are consistent with the hypothesis that asu9 alters yeast ribosomal proteins.

Chromosome Mapping↗
PubMed1976

Amikacin, an aminoglycoside with marked activity against antibiotic-resistant clinical isolates.

A total of 319 clinical isolates known to be resistant to one or more aminoglycoside antibiotics were tested for their susceptibility to 10 aminoglycosides. The percentages of isolates found by an agar dilution method to be susceptible were: amikacin, 83.7%; tobramycin, 41.4%; butirosin A, 33.2%; dideoxykanamycin B, 32.6%; gentamicin C, 27.3%; lividomycin A, 17.6%; neomycin B, 10.7%; paromomycin, 10.3%; kanamycin A, 10.0%; and ribostamycin, 7.2%. The effectiveness of the antibiotics was related to their degree of resistance to bacterial enzymes; e.g., of the nine enzymes known to inactivate antibiotics containing 2-deoxystreptamine, amikacin was affected by one enzyme, tobramycin by five, and gentamicin and kanamycin by six. Examination of cell-free extracts from the 52 strains resistant to amikacin revealed that only four contained the amikacin-inactivating enzyme aminoglycoside-6'-acetyltransferase, a finding indicating that this mechanism of resistance is rare. Other experiments suggest that most amikacin-resistant strains, which are almost invariably resistant to all aminoglycosides, lack the ability to accumulate effectively either amikacin or presumably the other antibiotics intracellularly.

Acinetobacter↗
PubMed1976

Suceptibility of aminoglycoside-resistant gram-negative bacilli to amikacin: delineation of individual resistance patterns.

Gram-negative bacilli isolated from clinical specimens submitted for culture in two Paris hospitals during 1974 were studied for susceptibility to six currently used aminoglycosides: kanamycin, neomycin, paromomycin, lividomycin, gentamicin, and tobramycin. Resistance patterns of strains of various species including those of Enterobacteriaceae, Pseudomonas, and Moraxella were determined, and the strains were grouped into eight resistance "phenotypes." In comparative studies of 807 strains belonging to different phenotypes, amikacin was markedly more active than any of the six other antibiotics; at concentrations of less than or equal to 4 mug/ml, it inhibited about 88% of the strains, including those resistant to gentamicin and tobramycin. Some amikacin-resistant strains were found among different species. The mechanism of resistance to amikacin of strains of Serratia and Moraxella group II was related to an N-acetylating enzyme. Amikacin can be expected to be useful as an alternative treatment of infections due to gram-negative bacilli sensitive to aminoglycosides and also, more particularly, for the treatment of patients infected with multiresistant strains.

Amikacin↗
PubMed1993

Intensity of infection in AIDS-associated cryptosporidiosis.

A fluorescent monoclonal anti-Cryptosporidium antibody was used to count the oocysts in stools of 12 AIDS patients with chronic cryptosporidiosis. Oocyst excretion was present throughout the day in all 12 patients. Stool-to-stool variation in oocyst concentration was within one order of magnitude. Small variations were also found in daily mean oocyst concentration and total daily oocyst excretion in 3 patients who had multiple 24-h stool collections. However, there was a large patient-to-patient variation in mean oocyst concentration (from < 5.0 x 10(3) to 9.2 x 10(5) oocysts/mL) and 24-h total oocyst excretion (from < 6.0 x 10(6) to 1.2 x 10(9) oocysts/day). There was a significant correlation between oocyst excretion and numbers of Cryptosporidium organisms seen on small bowel biopsy. Oocyst excretion was reduced in 4 patients treated with paromomycin, but diarrhea improved only in the 2 patients with high initial oocyst excretion.

AIDS-Related Opportunistic Infections↗
PubMed2005

Functional characterization of the mitochondrial 12S rRNA C1494T mutation associated with aminoglycoside-induced and non-syndromic hearing loss.

In this study, we report the biochemical characterization of the deafness-associated mitochondrial 12S rRNA C1494T mutation using 27 cybrid cell lines constructed by transferring mitochondria from 9 lymphoblastoid cell lines derived from a Chinese family into human mitochondrial DNA (mtDNA)-less (rho degrees) cells. Six cybrids derived from two asymptomatic members, and nine cybrids derived from three symptomatic members of the Chinese family carrying the C1494T mutation exhibited approximately 38 and 43% decrease in the rate of mitochondrial protein labeling, respectively, compared with twelve cybrids derived from four Chinese control individuals. These defects are apparently a primary contributor to significant reductions in the rate of overall respiratory capacity or the rate of malate/glutamate promoted respiration, or succinate/G3P-promoted respiration, or TMPD/ascorbate-promoted respiration in mutant cybrid cell lines derived from either symptomatic or asymptomatic individuals. Furthermore, the very significant/nearly identical increase in the ratio of doubling times in DMDM medium in the presence/absence of high concentration of paromomycin was observed in symptomatic or asymptomatic cybrid cell lines carrying the C1494T mutation as compared with the average rate in control cell lines. These observations provide the direct biochemical evidences that the C1494T mutation is a pathogenic mtDNA mutation associated with aminoglycoside-induced and non-syndromic hearing loss. In addition, these data provide the first biochemical evidence that nuclear background plays a critical role in the phenotypic manifestation of non-syndromic hearing loss and aminoglycoside toxicity associated with the C1494T mutation.

Cell Growth Processes↗
PubMed2005

Interplay between GCN2 and GCN4 expression, translation elongation factor 1 mutations and translational fidelity in yeast.

Genetic screens in Saccharomyces cerevisiae have identified the roles of ribosome components, tRNAs and translation factors in translational fidelity. These screens rely on the suppression of altered start codons, nonsense codons or frameshift mutations in genes involved in amino acid or nucleotide metabolism. Many of these genes are regulated by the General Amino Acid Control (GAAC) pathway. Upon amino acid starvation, the kinase GCN2 induces the GAAC cascade via increased translation of the transcriptional activator GCN4 controlled by upstream open reading frames (uORFs). Overexpression of the GCN2 or GCN4 genes enhances the sensitivity of translation fidelity assays that utilize genes regulated by GCN4, such as the suppression of a +1 insertion by S.cerevisiae translation elongation factor 1A (eEF1A) mutants. Paromomycin and the prion [PSI+], which reduce translational fidelity, do not increase GCN4 expression to induce the suppression phenotype and in fact reduce derepression. eEF1A mutations that reduce translation, however, reduce expression of GCN4 under non-starvation conditions. These eEF1A mutants also reduce HIS4 mRNA expression. Taken together, this system improves in vivo strategies for the analysis of translational fidelity and further provides new information on the interplay among translation fidelity, altered elongation and translational control via uORFs.

Alcohol Oxidoreductases↗
PubMed2005

Crystallographic studies of Homo sapiens ribosomal decoding A site complexed with aminoglycosides.

Aminoglycosides are highly effective antibacterial drugs that decrease translation accuracy by binding to the aminoacyl-tRNA decoding site (A site) of 16S ribosomal RNA. On the other hand, they are highly toxic to mammals through kidney and ear-associated illnesses by binding to ribosomal A sites. To understand the mechanism of toxicity of aminoglycosides to mammals at atomic level, crystallographic studies have been carried out with a number of Homo sapiens mitochondrial and cytoplasmic A sites complexed with aminoglycosides. Several X-ray diffraction data sets were successfully collected. Initial phases of mitochondrial A site with tobramycin and cytoplasmic A site with paromomycin were derived by the molecular replacement method. Refinements of atomic parameters are now under progress.

Aminoglycosides↗
PubMed1996

Pneumatosis cystoides intestinalis in AIDS-associated cryptosporidiosis. More than an incidental finding?

A 34-year-old man with acquired immunodeficiency syndrome (AIDS) developed pneumatosis cystoides intestinalis associated with an intestinal infection with Cryptosporidium organisms. The pneumatosis resolved upon treatment of the cryptosporidiosis with paromomycin and clofazimine. Four other cases of benign pneumatosis cystoides intestinalis in adults with AIDS and associated cryptosporidiosis have been reported, which suggests that cryptosporidial infection may be pathogenetically involved in the pneumatosis and not merely incidental.

AIDS-Related Opportunistic Infections↗