PubMed Health⌕ Search

Biomedical subjects

M Mitten

Publications and source records attributed to M Mitten.

13 recordsLinked to original sources
PubMed2001

Novel erythromycin derivatives with aryl groups tethered to the C-6 position are potent protein synthesis inhibitors and active against multidrug-resistant respiratory pathogens.

A novel series of erythromycin derivatives has been discovered with potent activity against key respiratory pathogens, including those resistant to erythromycin. These compounds are characterized by having an aryl group tethered to the C-6 position of the erythronolide skeleton. Extensive structural modification of the C-6 moiety led to the discovery of several promising compounds with potent activity against both mef- and erm-mediated resistant Streptoccoccus pneumoniae. Preliminary mechanistic studies indicated that the new macrolides are potent protein synthesis inhibitors, which interact with methylated ribosomes isolated from resistant organisms. In experimental animal models, these compounds exhibited excellent in vivo efficacy and balanced pharmacokinetic profiles.

Animals↗
PubMed1999

Discovery of a series of cyclohexylethylamine-containing protein farnesyltransferase inhibitors exhibiting potent cellular activity.

Synthesis of a library of secondary benzylic amines based on the Sebti-Hamilton type peptidomimetic farnesyltransferase (FTase) inhibitor FTI-276 (1) led to the identification of 6 as a potent enzyme inhibitor (IC(50) of 8 nM) which lacked the problematic thiol residue which had been a common theme in many of the more important FTase inhibitors reported to date. It has previously been disclosed that addition of o-tolyl substitution to FTase inhibitors of the general description 2 had a salutary effect on both FTase inhibition and inhibition of Ras prenylation in whole cells. Combination of these two observations led us to synthesize 7, a potent FTase inhibitor which displayed an IC(50) of 0.16 nM for in vitro inhibition of FTase and an EC(50) of 190 nM for inhibition of whole cell Ras prenylation. Modification of 7 by classical medicinal chemistry led to the discovery of a series of potent FTase inhibitors, culminating in the identification of 25 which exhibited an IC(50) of 0.20 nM and an EC(50) of 4.4 nM. In vivo tests in a nude mouse xenograft model of human pancreatic cancer (MiaPaCa cells) showed that oral dosing of 25 gave rise to impressive attenuation of the growth of this aggressive tumor cell line.

Alkyl and Aryl Transferases↗
PubMed1999

Second-generation peptidomimetic inhibitors of protein farnesyltransferase demonstrating improved cellular potency and significant in vivo efficacy.

The synthesis and evaluation of analogues of previously reported farnesyltransferase inhibitors, pyridyl benzyl ether 3 and pyridylbenzylamine 4, are described. Substitution of 3 at the 5-position of the core aryl ring resulted in inhibitors of equal or less potency against the enzyme and decreased efficacy in a cellular assay against Ras processing by the enzyme. Substitution of 4 at the benzyl nitrogen yielded 26, which showed improved efficacy and potency and yet presented a poor pharmacokinetic profile. Further modification afforded 30, which demonstrated a dramatically improved pharmacokinetic profile. Compounds 26 and 29 demonstrated significant in vivo efficacy in nude mice inoculated with MiaPaCa-2, a human pancreatic tumor-derived cell line.

Alkyl and Aryl Transferases↗
PubMed1998

In vivo efficacy of ABT-255 against drug-sensitive and -resistant Mycobacterium tuberculosis strains.

Current therapy for pulmonary tuberculosis involves 6 months of treatment with isoniazid, pyrazinamide, rifampin, and ethambutol or streptomycin for reliable treatment efficacy. The long treatment period increases the probability of noncompliance, leading to the generation of multidrug-resistant isolates of Mycobacterium tuberculosis. A treatment option that significantly shortened the course of therapy, or a new class of antibacterial effective against drug-resistant M. tuberculosis would be of value. ABT-255 is a novel 2-pyridone antibacterial agent which demonstrates in vitro potency and in vivo efficacy against drug-susceptible and drug-resistant M. tuberculosis strains. By the Alamar blue reduction technique, the MIC of ABT-255 against susceptible strains of M. tuberculosis ranged from 0.016 to 0.031 microg/ml. The MIC of ABT-255 against rifampin- or ethambutol-resistant M. tuberculosis isolates was 0.031 microg/ml. In a murine model of pulmonary tuberculosis, 4 weeks of oral ABT-255 therapy produced a 2- to 5-log10 reduction in viable drug-susceptible M. tuberculosis counts from lung tissue. Against drug-resistant strains of M. tuberculosis, ABT-255 produced a 2- to 3-log10 reduction in viable bacterial counts from lung tissue. ABT-255 is a promising new antibacterial agent with activity against M. tuberculosis.

Animals↗
PubMed1998

Dynamics of clarithromycin and azithromycin efficacies against experimental Haemophilus influenzae pulmonary infection.

The dynamics of clarithromycin and azithromycin efficacy against pulmonary Haemophilus influenzae infection in rats were evaluated. Efficacy was measured by reduction in pulmonary H. influenzae burden on days 3 and 7 postinoculation. Clarithromycin therapy was effective on day 3 or 7 of therapy, while azithromycin was effective on day 7 but not on day 3 of therapy. Both macrolides produced marked efficacy against all six strains of H. influenzae tested, including four strains for which MICs were above the susceptible breakpoint (8 microgram/ml) concentration of clarithromycin. The two macrolides demonstrated markedly different pharmacokinetic characteristics, with clarithromycin present in both blood and tissue, while azithromycin was concentrated primarily in tissue. During pulmonary infection in rats, H. influenzae was found in both intracellular locations and an extracellular location in the lung. Blood concentrations of clarithromycin and azithromycin approximated human pharmacokinetics, and the blood concentrations for either macrolide rarely exceeded MICs for H. influenzae. At dosages producing blood concentrations similar to values achieved clinically, clarithromycin produced efficacy on day 3 of therapy, while both clarithromycin and azithromycin were equally effective on day 7. The different dynamics of clarithromycin and azithromycin suggest that length of therapy should be considered as a key parameter in evaluations of drug efficacy.

Animals↗
PubMed1995

Efficacies of ABT-719 and related 2-pyridones, members of a new class of antibacterial agents, against experimental bacterial infections.

The 2-pyridones are a new class of broad-spectrum orally bioavailable antibacterial agents. These compounds are potent bacterial DNA gyrase inhibitors which differ from fluoroquinolones by placement of the nitrogen atom in the ring juncture. ABT-719 is an S isomer and a representative 2-pyridone. ABT-719 administered orally or subcutaneously was 4- to 10-fold more effective than ciprofloxacin against Staphylococcus aureus, Streptococcus pneumoniae, and Streptococcus pyogenes infections in normal mice. ABT-719 was equivalent in efficacy to ciprofloxacin for treatment of gram-negative bacterial infections caused by Pseudomonas aeruginosa or Escherichia coli. The racemate and R forms of ABT-719 produced similar results against gram-positive and gram-negative bacterial infections. The 50% effective doses of ABT-719 were at least threefold lower than those of ciprofloxacin for therapy of intracellular infections caused by Salmonella typhimurium or Listeria monocytogenes. In immunosuppressed mice, ABT-719 was more effective than ciprofloxacin against quinolone-sensitive S. aureus, Enterococcus faecalis, and Enterococcus faecium. The pharmacokinetic properties of ABT-719 were consistent with its relative efficacy. The 2-pyridones are potent, orally available antibacterial agents with efficacy against gram-positive and gram-negative bacterial infections in mice.

Animals↗
PubMed1994

Efficacy of A-73209, a potent orally active agent against VZV and HSV infections.

A-73209 is a novel oxetanocin derivative with potent in vitro and in vivo activity against VZV, HSV-1, and HSV-2. A-73209 was two logs more potent than acyclovir against five thymidine kinase positive (TK+) strains of VZV in vitro (mean EC50 0.01 vs. 1.22 micrograms/ml). The activity of A-73209 was one log more potent than acyclovir against TK+ HSV-1 strains in vitro (EC50 = 0.03 vs. 0.32 micrograms/ml). A-73209 yielded a mean EC50 of 2.2 micrograms/ml compared to a mean EC50 of 0.37 micrograms/ml for acyclovir against a panel of TK+ HSV-2 strains in vitro. The in vitro activity of A-73209 against thymidine kinase negative or deficient strains of VZV, HSV-1 and HSV-2 was much lower than for the corresponding TK+ strains. A-73209 produced efficacy superior to acyclovir against lethal systemic or intracerebral HSV-1 infections in mice. The greater efficacy of A-73209 relative to acyclovir was especially apparent with oral dosing. Against HSV-2 infections in mice, the efficacy of A-73209 ranged from equal to 1.7 times less active relative to acyclovir with oral dosing. A-73209 was orally bioavailable in mice, with maximal serum concentrations well in excess of in vitro inhibitory concentrations. A-73209 appears to be a potent and selective agent against varicella-zoster virus and herpes simplex virus infections.

Acyclovir↗
PubMed1994

Treatment of experimental Pneumocystis carinii infection by combination of clarithromycin and sulphamethoxazole.

The efficacy of clarithomycin and sulphamethoxazole for treatment of experimental Pneumocystis carinii infection was investigated. Rats were immunosuppressed with dexamethasone and inoculated intratracheally with 5 x 10(6) P. carinii cysts. After 2 weeks, the lung tissues were assayed for P. carinii cyst burden. The combination of clarithromycin and sulphamethoxazole caused a significantly greater reduction in cyst burden than either drug alone. Up to 50% of the rats treated with the combination of clarithromycin and sulphamethoxazole were negative for P. carinii cysts. Equivalent doses of the individual drugs given alone did not produce cures. The combination of clarithromycin and sulphamethoxazole was more than twice as effective as either drug alone. Clarithromycin combined with sulphamethoxazole in treatment of P. carinii infection could be especially useful since clarithromycin monotherapy provides safe and effective treatment against many other pathogens, including several that are associated with AIDS.

Animals↗
PubMed1994

Enteral formula composition does not affect response to lethal infectious challenge in mice.

The effects of enteral formulations on the response of mice to infectious challenge with Listeria monocytogenes, influenza A or Candida albicans were studied to test the efficacy of specialized ingredients. CF-1 outbred female mice (12-15 g) were fed nonpurified diet (Purina No. 5002) or commercially available liquid formulas: Osmolite HN, Perative or Impact. There were no differences between the groups fed the liquid formulas with regards to mean survival time or percentage of survivors in any of these models of infection. Examination of spleens from the groups challenged with L. monocytogenes, lungs from mice infected with Influenza A and kidneys from the groups challenged with C. albicans revealed no differences in cure rate of survivors. Pre-feeding periods of up to 8 d before infection produced similar results for mice fed enteral formulations compared to nonpurified diet. Contrary to previous reports, the use of Impact did not improve resistance to disease in mice challenged with lethal doses of L. monocytogenes, as compared with mice fed Osmolite HN. Additionally, mice fed Impact, Perative, or nonpurified diet responded similarly to challenge with L. monocytogenes, C. albicans or influenza A. The results indicate that these acute lethal animal models of infectious challenge may be of limited use to distinguish effects of modified nutrient composition of enteral formulas.

Animals↗
PubMed1993

Clarithromycin therapy of experimental Treponema pallidum infections in hamsters.

Clarithromycin was shown to be effective therapy for Treponema pallidum infections in hamsters. Clarithromycin therapy was effective when initiated either 1 or 8 days after infection. The delay in initiation of therapy allowed an active infection to develop. The treponemal burden in lymph tissue of treated hamsters was eradicated, as determined by dark-field microscopy and by inoculation of lymph material into susceptible hamsters. Treatments with clarithromycin and the 14-hydroxy metabolite of clarithromycin were equally effective. Therapy with clarithromycin and penicillin was not antagonistic and did not appear to be synergistic when the two drugs were given concurrently. Pharmacokinetic evaluation of clarithromycin in hamsters showed that the doses which produced effective therapy yielded concentrations in serum similar to those routinely achieved in human sera. These findings demonstrate that clarithromycin is effective in treating active or incubating syphilis in the hamster model and could be useful in treating humans.

Animals↗
PubMed1993

Efficacy of clarithromycin for treatment of experimental Lyme disease in vivo.

Clarithromycin provided effective therapy against arthritis induced by Borrelia burgdorferi infection in the hamster. In vitro, clarithromycin was at least 1 log more potent than tetracycline against two isolates of B. burgdorferi from human sources, as measured by MICs and 50% inhibitory concentrations. Clarithromycin was effective in preventing the onset of B. burgdorferi-induced arthritis, as determined by several parameters of paw swelling. When administered after the onset of arthritis, clarithromycin therapy reduced the degree of swelling and decreased recovery time. These results suggest that clarithromycin has potential as an effective therapy for Lyme disease.

Animals↗