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At least 145 records · Page 8Linked to original sources
PubMed2006

The 4'-O-benzylated doxorubicin analog WP744 overcomes resistance mediated by P-glycoprotein, multidrug resistance protein and breast cancer resistance protein in cell lines and acute myeloid leukemia cells.

BACKGROUND: The synthetic 4'-O-benzylated doxorubicin analog WP744 was designed to abrogate transport by the multidrug resistance (MDR)-associated ATP-binding cassette (ABC) proteins P-glycoprotein (Pgp) and multidrug resistance protein (MRP-1). We compared its uptake and cytotoxicity with those of doxorubicin and daunorubicin in cell lines overexpressing Pgp, MRP-1 or breast cancer resistance protein (BCRP) and in acute myeloid leukemia (AML) cells. METHODS: Cellular uptake was studied by flow cytometry and cytotoxicity in 96-h 96-well cultures in cell lines overexpressing Pgp, MRP-1 or wild type (BCRP(R482)) or mutant (BCRP(R482T), BCRP(R482G)) BCRP and in pre-treatment AML marrow cells. RESULTS: Uptake and cytotoxicity of WP744 were consistently greater than those of doxorubicin and daunorubicin at equimolar concentrations in all cell lines studied and in AML cells. CONCLUSION: WP744 overcomes transport by Pgp, MRP-1 and BCRP in cell lines and AML cells and is a promising agent for clinical development in AML and other malignancies with broad-spectrum multidrug resistance.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2004

Chloroquine resistance in Plasmodium chabaudi: are chloroquine-resistance transporter (crt) and multi-drug resistance (mdr1) orthologues involved?

We have identified in the rodent malaria parasite Plasmodium chabaudi orthologues of two Plasmodium falciparum genes, pfcrt and pfmdr1 which have been implicated as determinants of chloroquine resistance in the latter species. The sequences of the P. chabaudi genes, denoted, respectively, pccg10 and pcmdr1, were first determined in the chloroquine-sensitive clone AS, and found to be highly similar to those of P. falciparum. For pccg10, there was a nucleotide sequence identity of 68.6% and amino acid sequence identity of 75.1% within the predicted coding region. For pcmdr1, the sequence identities were 75.0% (nucleotide) and 78.1% (amino acid). The sequences of the genes were then determined in three P. chabaudi clones selected from clone AS which possessed three different levels of resistance to chloroquine. The sequences of both genes in all mutants were found to be identical to those of the sensitive AS from which they had been derived. Polymorphic sites were found in both genes between the AS clones and a genetically unrelated sensitive clone AJ. Analysis of genetic crosses between AJ and resistant AS clones showed no linkage between inherited parental alleles of pccrt and pcmdr1 and drug responses of the cloned progeny. This showed that neither of these genes, nor genes closely linked to them, were determinants of the chloroquine resistance in the P. chabaudi mutants.

Amino Acid Sequence↗
PubMed1998

Cytomegalovirus retinitis and viral resistance: ganciclovir resistance. CMV Retinitis and Viral Resistance Study Group.

Cytomegalovirus (CMV) retinitis is among the most common opportunistic infections in patients with AIDS and a substantial cause of visual loss. With long-term therapy, resistant CMV may develop. In a prospective study of 108 patients with CMV retinitis, 80.6% of patients were found to have either a positive blood culture or positive urine culture for CMV at the diagnosis of retinitis. At diagnosis of retinitis, 0.9% and 2.7% of patients had a ganciclovir-resistant blood culture isolate and urine culture isolate, respectively. Of 76 patients initially treated with ganciclovir, 11.4% had a resistant blood or urine culture isolate by 6 months of treatment and 27.5% by 9 months. The development of ganciclovir resistance during follow-up correlated with the occurrence of CMV retinitis in the contralateral eye (odds ratio = 9.06, P = .003).

AIDS-Related Opportunistic Infections↗
PubMed1981

Resistance to benzimidazole anthelmintics in equine strongyles. 2. Evidence of side-resistance, and susceptibility of benzimidazole-resistant strongyles to non-benzimidazole compounds.

The susceptibility of a known thiabendazole-resistant population of small strongyles to anthelmintics of both benzimidazole and non-benzimidazole groups, was determined. In the first study, 42 horses infected with thiabendazole-resistant small strongyles were allocated to 6 groups. Treatment groups received one of the following anthelmintics: mebendazole, febantel, febantel plus trichlorphon, morantel tartrate, or a combination of thiabendazole, piperazine and trichlorphon. Morantel tartrate and the thiabendazole/piperazine/trichlorphon combination produced highly significant (p less than 0.001) reductions in faecal strongyle egg counts 20 days post-treatment. Mebendazole, febantel and febantel plus trichlorphon failed to reduce strongyle egg counts significantly. Larval culture and differentiation indicated that in all cases of anthelmintic failure, small strongyles of the sub-family Cyathostominae were involved. Eighteen horses from groups in which treatment had failed were re-allocated to 3 groups. Treatment with either morantel tartrate or haloxon was highly efficient in reducing faecal strongyle egg counts. In the final study, fifty-four horses, infected with benzimidazole-resistant small strongyles were allocated to 10 groups. On day zero, each treatment group received one of the following anthelmintics: thiabendazole, cambendazole, mebendazole, oxibendazole, piperazine, thiabendazole/piperazine, cambendazole/piperazine, mebendazole/piperazine or oxibendazole/piperazine. Oxibendazole, piperazine and the benzimidazole/piperazine combinations produced highly significant reductions in faecal strongyle egg counts 20 days post-treatment (p less than 0.001). When administered alone, benzimidazole anthelmintics failed to reduce strongyle egg counts significantly, with the exception of oxibendazole. Larval culture and differentiation indicated that in all cases of anthelmintic failure, the species involved were small strongyles of subfamily Cyathostominae. There was no significant increase in benzimidazole resistance level (based on in vitro assay) as a result of drug treatment, over one generation.

Animals↗
PubMed2004

Linezolid and quinupristin/dalfopristin resistance in vancomycin-resistant enterococci and methicillin-resistant Staphylococcus aureus prior to clinical use in Turkey.

The aim of this study was to determine the in vitro antimicrobial activity of recently licensed quinupristin/dalfopristin and linezolid which have not yet been in clinical use in Turkey against methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE) strains isolated from various clinical specimens by using the Etest. The results showed that all MRSA strains were fully susceptible to both the new compounds. All strains were inhibited by 1 mg/l quinupristin/dalfopristin (mode MIC 0.38 mg/l) and by 3 mg/l linezolid (mode MIC 1.5 mg/l). Four strains of Enterococcus faecium showed an increase of resistance of 2-3 mg/l to quinupristin/dalfopristin (susceptible mode MIC 0.38 mg/l). With linezolid, all strains except two fell within the range 0.75-2.0 mg/l.

Acetamides↗
PubMed1991

Colony-stimulating factors increase resistance to atypical mycobacteria in resistant mice, whereas they decrease resistance in susceptible strains of mice.

Inbred strains of mice, notably the susceptible C57BL/6 and the resistant A/J strains of mice, were infected with a strain of Mycobacterium evium. The infection in the visceral organs of mice was then studied, and the effect of colony-stimulating factors, i.e., interleukin-3 (IL-3), granulocyte-macrophage colony-stimulating factor (GM-CSF), and macrophage colony-stimulating factor (CSF-1) on the infectious process was evaluated. Infusion of GM-CSF, CSF-1, and IL-3 led to a significant, albeit rather modest, increase in the mycobacterial resistance of A/J mice, as seen by a decrease in the number of colony-forming units (CFU) in the organs. Conversely, these CSFs dramatically increased the susceptibility of C57BL/6 mice, as seen by increased bacterial numbers in the spleens and livers. In vitro studies demonstrated that resident peritoneal macrophages from susceptible mice were more permissive than cells from resistant mice for mycobacterial growth. Application of CSFs on peritoneal macrophage monolayers led to an increased growth in both A/J and C57BL/6 monolayers for IL-3 and CSF-1 and a small microbiostatic effect for GM-CSF. Cytokine treatment did not, however, change the resistance/susceptibility phenotype of isolated macrophages. Our results indicate that CSFs may exert beneficial or detrimental effects on resistance to mycobacteria depending on the host genetic make up.

Animals↗
PubMed2026

From resistance genes to resistance states and enzymatic context-dependence in antimicrobial resistance.

Antimicrobial resistance is often inferred from resistance genes and susceptibility phenotypes measured under standardized conditions. We argue that for many resistance genes, resistance is better viewed as a context-dependent functional state; the same gene can produce different phenotypes depending on the local microenvironment, enzyme kinetics, antibiotic exposure, and bacterial physiology.

Journal Article↗
PubMed1996

Testing the efficacy of a molecular surveillance network: methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus faecium (VREF) genotypes in six hospitals in the metropolitan New York City area. The BARG Initiative Pilot Study Group. Bacterial Antibiotic Resistance Group.

Molecular fingerprinting techniques are rapidly becoming indispensable tools for hospital epidemiology. On the other hand, the relative complexity and unfamiliarity of these techniques to most hospital diagnostic laboratories limit their usefulness. In an attempt to provide a solution for this dilemma, we tested the feasibility and efficacy of a cooperative venture in which molecular typing of isolates recovered from patients in six hospitals was performed at two microbiology research laboratories with expertise in these techniques. In a small preliminary study, 30 methicillin-resistant Staphylococcus aureus (MRSA) and 30 vancomycin-resistant Enterococcus faecium (VREF) isolates were collected over a 3-week period from six hospitals in the metropolitan New York area and transported to the Laboratory of Microbiology at The Rockefeller University during the summer months of 1994. Nineteen of the 27 confirmed MRSA isolates were closely related strains carrying the same mecA and the same Tn554 polymorphs in a pulsed-field gel electrophoresis (PFGE) background represented by closely related subtypes of a single pattern, indicating the wide distribution of this MRSA clone among the participating hospitals. Typing of the same 27 MRSA isolates was also performed at the Tuberculosis Center of the Public Health Research Institute and identical results were obtained. The 29 confirmed VREF isolates were highly heterogeneous and belonged to as many as 23 distinct clonal types as defined by PFGE patterns and probing with vanA. Characterization of the 60 isolates by these methods was completed in one month of full-time effort by a single experienced laboratory assistant guided by a doctoral-level expert in molecular fingerprinting techniques. The collection of samples for both MRSA and VREF was not intended to address epidemiological questions but to determine the feasibility of a multicenter study. On the basis of our preliminary findings we are encouraged that a larger cooperative effort is possible and with the correct sampling method we believe that epidemiological and surveillance studies could be accomplished that would provide a tracking system to assist hospitals, clinics, and chronic care facilities in controlling the spread of multidrug-resistant pathogens.

Anti-Bacterial Agents↗
PubMed2003

Rapid detection of rifampin resistance in Mycobacterium tuberculosis isolates by heteroduplex analysis and determination of rifamycin cross-resistance in rifampin-resistant isolates.

Direct heteroduplex analysis and a universal heteroduplex generator assay were performed to detect rifampin resistance rapidly in Turkish Mycobacterium tuberculosis isolates. Cross-resistance to rifapentine, rifabutin, and rifalazil was investigated. A relationship between specific mutations and resistance patterns, which can guide the choice of an appropriate therapeutic regimen for tuberculosis patients, was identified.

Antibiotics, Antitubercular↗
PubMed1994

[Resistance of Streptococcus pneumoniae to penicillin. "Bacteriological" resistance/"clinical" resistance].

From January 1988 to December 1992, 143 Streptococcus pneumoniae strains have been isolated at a significant level from 136 patients hospitalized in the pulmonary care unit of CHI Créteil. The clinical presentations were: 83 pneumonia (P), 48 acute bronchitis (B) and 12 colonizations (C). Fourteen strains were found to be penicillin resistant (MIC > 0.125 mg. l-1): 11 P, 2 B, 1 C. Two patients were lost of view after the beginning of the treatment: a pneumonia (Serotype 23F, MIC = 2 mg. l-1) and a bronchitis (Serotype 23F, MIC = 2 mg. l-1). Treatment was pristinamycine for one and amoxicilline alone or associated to clavulanic acid for the other 13. We observed the failure of the treatment in two. A pneumonia (Serotype 23, MIC = 2 mg. l-1) was treated before hospitalization by josamycine (3 days), then cefpodoxime (4 days) and amoxicillin-clavulanic acid (1.5 gr/d during 7 days). Healing was obtained with the increase to 3 gr/d. The other failure was a pneumonia without improvement after 11 days with 3 gr/d of amoxicilline. The treatment was stopped during 5 days and a protected brushing was performed. A Streptococcus Pneumoniae (Serotype 23F, MIC = 8 mg. l-1) was isolated. The clinical status rapidly improved with erythromycine (3 gr/d) to which the strain was susceptible. "Bacteriological" Resistance to penicillin is demonstrated (10 percent in our sample, 17 percent in France during 1991). However amoxicillin to a sufficient dosage is still enough ("Clinical" Resistance < 1 percent in our sample) for the treatment of respiratory infections except when the MIC is at a high level.

Adult↗
PubMed2007

Multidrug resistance gene-1 polymorphisms and resistance to cyclosporine A in patients with steroid resistant ulcerative colitis.

BACKGROUND: Cyclosporine A (CsA) is inconstantly effective in inducing remission in acute attacks of ulcerative colitis (UC) not responding to steroids. This study aimed to establish whether multidrug resistance gene (MDR)1 polymorphisms would be associated with CsA failure. PATIENTS AND METHODS: The distribution of the different genotypes of single nucleotide polymorphisms (SNP) G2677T/A and C3435T of MDR1 exons 21 and 26, respectively, was studied in 154 patients (mean age, 44 yr) who had received CsA to treat severe attacks of steroid resistant UC in 11 centers in France and Belgium. Patients were classified as CsA failure (n = 50) when they needed colectomy within 30 days after CsA initiation. The SNPs were detected by use of a 5' nuclease allelic discrimination assay. RESULTS: There was a significant association between the G2677T/A polymorphism distribution (exon 21) and the risk for CsA failure (P = 0.0001). The TT genotype of exon 21 was significantly associated with the risk compared with the two other genotypes (odds ratio, 3.77; 95% confidence interval, 1.42-9.97, P = 0.007). There was no significant association between the genotype C3435T distribution (exon 26) and the risk of CsA failure (P = 0.23). CONCLUSION: The TT genotype of exon 21 MDR1 polymorphisms is associated with a higher risk of CsA failure in patients with steroid resistant UC. Further studies should be performed to establish whether other treatments could be more efficient to avoid surgery in this subset of patients.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2002

Antibiotic resistance - is resistance detected by surveillance relevant to predicting resistance in the clinical setting?

Local, regional, national and global surveillance initiatives have several important functions, which include identifying shifts in antibiotic resistance, detecting the emergence of new resistance mechanisms and monitoring the impact of changes made to empiric prescribing, infection control and public health guidelines. Although the need for surveillance is indubitable and its use in the treatment of individual patients important, it cannot unequivocally predict outcomes in patients with infections. Treatment regimens for individual patients with suspected or demonstrated infections should be developed following consideration of symptoms, laboratory findings and relevant medical history, and in the context of appropriate local and widespread antibiotic resistance trends.

Anti-Bacterial Agents↗
PubMed2005

Identification of the hepatic efflux transporters of organic anions using double-transfected Madin-Darby canine kidney II cells expressing human organic anion-transporting polypeptide 1B1 (OATP1B1)/multidrug resistance-associated protein 2, OATP1B1/multidrug resistance 1, and OATP1B1/breast cancer resistance protein.

Until recently, it was generally believed that the transport of various organic anions across the bile canalicular membrane was mainly mediated by multidrug resistance-associated protein 2 (MRP2/ABCC2). However, a number of new reports have shown that some organic anions are also substrates of multidrug resistance 1 (MDR1/ABCB1) and/or breast cancer resistance protein (BCRP/ABCG2), implying MDR1 and BCRP could also be involved in the biliary excretion of organic anions in humans. In the present study, we constructed new double-transfected Madin-Darby canine kidney II (MDCKII) cells expressing organic anion-transporting polypeptide 1B1 (OATP1B1)/MDR1 and OATP1B1/BCRP, and we investigated the transcellular transport of four kinds of organic anions, estradiol-17beta-d-glucuronide (EG), estrone-3-sulfate (ES), pravastatin (PRA), and cerivastatin (CER), to identify which efflux transporters mediate the biliary excretion of compounds using double-transfected cells. We observed the vectorial transport of EG and ES in all the double transfectants. MRP2 showed the highest efflux clearance of EG among these efflux transporters, whereas BCRP-mediated clearance of ES was the highest in these double transfectants. In addition, two kinds of 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors, CER and PRA, were also substrates of all these efflux transporters. The rank order of the efflux clearance of PRA mediated by each transporter was the same as that of EG, whereas the contribution of MDR1 to the efflux of CER was relatively greater than for PRA. This experimental system is very useful for identifying which transporters are involved in the biliary excretion of organic anions that cannot easily penetrate the plasma membrane.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2004

VX-710 (biricodar) increases drug retention and enhances chemosensitivity in resistant cells overexpressing P-glycoprotein, multidrug resistance protein, and breast cancer resistance protein.

PURPOSE: The pipecolinate derivative VX-710 (biricodar; Incel) is a clinically applicable modulator of P-glycoprotein (Pgp) and multidrug resistance protein (MRP-1); we studied its activity against the third multidrug resistance (MDR)-associated drug efflux protein, breast cancer resistance protein (BCRP). EXPERIMENTAL DESIGN: VX-710 modulation of uptake, retention, and cytotoxicity of mitoxantrone, daunorubicin, doxorubicin, topotecan, and SN38 was studied in cell lines overexpressing Pgp, MRP-1 and wild-type (BCRP(R482)) and mutant (BCRP(R482T)) BCRP. RESULTS: In 8226/Dox6 cells (Pgp), VX-710 increased mitoxantrone and daunorubicin uptake by 55 and 100%, respectively, increased their retention by 100 and 60%, respectively, and increased their cytotoxicity 3.1- and 6.9-fold, respectively. In HL60/Adr cells (MRP-1), VX-710 increased mitoxantrone and daunorubicin uptake by 43 and 130%, increased their retention by 90 and 60%, and increased their cytotoxicity 2.4- and 3.3-fold. In 8226/MR20 cells (BCRP(R482)), VX-710 increased mitoxantrone uptake and retention by 60 and 40%, respectively, and increased cytotoxicity 2.4-fold. VX-710 increased daunorubicin uptake and retention by only 10% in 8226/MR20 cells, consistent with the fact that daunorubicin is not a substrate for BCRP(R482), but, nevertheless, it increased daunorubicin cytotoxicity 3.6-fold, and this increase was not associated with intracellular drug redistribution. VX-710 had little effect on uptake, retention, or cytotoxicity of mitoxantrone, daunorubicin, doxorubicin, topotecan, or SN38 in MCF7 AdVP3000 cells (BCRP(R482T)). CONCLUSIONS: VX-710 modulates Pgp, MRP-1, and BCRP(R482), and has potential as a clinical broad-spectrum MDR modulator in malignancies such as the acute leukemias in which these proteins are expressed.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1995

[Effects of nitroglycerin, prostaglandin E1, trimetaphan and nicardipine on systemic vascular resistance, pulmonary vascular resistance and pulmonary-systemic vascular resistance ratio in dogs].

Effects of the experimentally induced hypotension with 4 vasodilators; nitroglycerin (TNG), prostaglandin E1 (PGE1), trimetaphan (TMP) and nicardipine (NCP) on systemic vascular resistance (SVR), pulmonary vascular resistance (PVR) and pulmonary-systemic vascular resistance ratio (PVR/SVR ratio) were studied in dogs. The SVR values were significantly reduced by TNG, PGE1 and NCP, and not affected by TMP. The PVR values were significantly reduced by TNG and PGE1, and not affected by TMP and NCP. The PVR/SVR ratio values were significantly reduced by TNG, and significantly increased by NCP, and not affected by PGE1 and TMP. We concluded that TNG reduced PVR and SVR but it affected PVR more; PGE1 reduced PVR and SVR equivalently; TMP did not affect PVR and SVR remarkably; NCP reduced SVR but did not affect PVR.

Alprostadil↗