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PubMed2006

Tetramethylpyrazine protects rat renal tubular cell apoptosis induced by gentamicin.

BACKGROUND: Gentamicin, a widely used antibiotic for the treatment of bacterial infection, can cause nephrotoxicity. Tetramethylpyrazine (TMP) is a compound purified from the rhizome of Ligusticum wallichi (Chuanxiong) and has been found to protect against ischaemia-reperfusion injury, nephritis and alcohol-induced toxicity in rat kidneys. METHODS: We used rat renal tubular cells (RTCs), NRK-52E, in this study. The cytotoxicity of gentamicin was checked with transferase-mediated deoxyuridine triphosphate nick end-labeling (TUNEL) staining, and the generation of reactive oxygen species was measured using the fluorescent probe 2,7-dichlorofluorescein. We evaluated several apoptotic parameters: cleaved caspase levels, tumour necrosis factor (TNF-alpha) excretion and nuclear factor Kappa B (NF-kappaB) activity. We also examined the TMP protective effect on gentamicin-induced apoptosis in rat kidneys. RESULTS: The results of this study showed that gentamicin was found to markedly induce apoptosis in NRK-52E cells in a dose-dependent manner; that TMP expressed a dose-dependent protective effect against gentamicin-induced apoptosis; that pre-treatment of the cells with 50 or 100 microM of TMP effectively decreased the reactive oxygen species formation induced by gentamicin; that TMP was found to inactivate the gentamicin-stimulated activities of caspase-3, caspase-8 and caspase-9, to inhibit gentamicin-induced release of cytochrome c, as well as to raise the expression of Bcl-x(L); that TMP inhibited the gentamicin-induced TNF-alpha excretion, and inactivated the transcription factor NF-kappaB; and that the TMP treatment significantly reduced apoptotic injury in rat RTCs. CONCLUSIONS: Based on the results of this study, we suggest that TMP can attenuate gentamicin-induced oxidative stress and apoptotic injury in rat RTCs, and that its character may have therapeutic potential for patients with renal diseases.

Animals↗
PubMed1993

Genetic variation of the SIVagm transmembrane glycoprotein in naturally and experimentally infected primates.

OBJECTIVE: An in-frame stop codon prematurely truncating the transmembrane glycoprotein (TMP) is a common feature of many simian immunodeficiency virus, African green monkey strain (SIVagm) molecular clones. The purpose of this study was to investigate the native form of the SIVagm TMP in a naturally infected African green monkey (AGM) and to study the fate of the stop codon following the passage of SIVagm in primates. DESIGN: Polymerase chain reaction was used to clone the entire intracellular portion of the TMP from: (1) peripheral blood mononuclear cells (PBMC) of the naturally infected AGM 155; (2) an isolate of SIVagm155 in rhesus PBMC and (3) PBMC from pig-tailed macaques and AGM experimentally infected with an SIVagm molecular clone encoding a truncated TMP. RESULTS: PBMC of the naturally infected AGM contained a 'swarm' of related virus genotypes that encoded a full-length TMP, whereas tissue-culture passage in rhesus PBMC resulted in a prematurely truncated form of the TMP. This premature stop codon persisted in PBMC of monkeys experimentally infected with an SIVagm molecular clone. Both macaques and AGM of same subspecies as AGM 155 (Cercopithecus pygerythrus) and other subspecies (C. aethiops and C. sabaeus) became infected with SIVagm155. Genetic drift of this region of env, as assessed by calculation of the nucleotide substitution/site/year rate, was similar to that of other retroviruses. CONCLUSIONS: The native form of the SIVagm TMP is a full-length gp40, similar to the SIV macaque (SIVmac) strain and HIV-1. However, passage of SIVagm in tissue culture can result in point mutations that introduce a premature stop codon. This stop codon persists during subsequent in vivo passage of SIVagm in primates. This contrasts with similar studies in macaques infected with SIVmac, in which reversion of the TMP stop codon was observed.

Amino Acid Sequence↗
PubMedDate not supplied

Control of water flux in a bioartificial kidney.

UC-PK1 cells were grown to confluence on microporous microcellulose membranes in order to test the feasibility of using transmembrane pressure (TMP) for controlling connective water transport in a bioartificial kidney. TMP was applied on either the apical or basal aspect of the polarized cell layer, while the fluid compartments on both sides of the membrane were perfused with tissue culture medium in a miniature flow chamber. The cell monolayer did not allow filtration in the apical to basal direction when positive TMP up to 30 mmHg was applied on the apical side. Application of positive TMP on the basal side led to measurable ultrafiltration. The hydraulic permeability, L(p), of the cell-seeded membranes was found to be increasing with time, reaching a steady state value after 60 min. There was a strong positive correlation between L(p) and applied TMP. For a constant TMP, L(p) was found to be independent of the shear rate between 2.6 and 10.5 sec-1. When positive pressure was changed abruptly back from the basal to apical site, the ultrafiltration rate decreased to zero within seconds. Morphologic studies suggest that the tight junctions between cells were broken by TMP applied on the basolateral aspect of the cell monolayer. It is concluded that, basolateral TMP may be used to control water flux in a bioartificial kidney.

Animals↗
PubMed1993

Effects of prostaglandin E1 or trimethaphan on local cerebral blood flow and carbon dioxide reactivity during cerebral aneurysm surgery.

Effects of prostaglandin E1 (PGE1) or trimethaphan (TMP) on local cerebral blood flow (LCBF) and carbon dioxide (CO2) reactivity were studied in 26 patient undergoing cerebral aneurysm surgery for subarachnoid hemorrhage (SAH) under isoflurane anesthesia. Measurement of LCBF was made using a thermal gradient blood-flow meter. Hypotension was induced with a continuous i.v. infusion of PGE1 or TMP. The dose of PGE1 or TMP was adjusted to maintain the MAP at about 70 mm Hg, and CO2 reactivity was studied during and after PGE1 or TMP administration. PaCO2 was changed by the controlled hyperventilation. CO2 reactivity was evaluated by the following formula: % delta LCBF/delta PaCO2% mm Hg. Hypotensive drugs were discontinued at the completion of aneurysm clipping. Mean arterial pressure (MAP) decreased immediately after the start of either PGE1 or TMP. Heart rate (HR) did not change significantly in either group. LCBF decrease at 30 min after start of TMP administration (p < 0.05 compared with preinfusion value), whereas LCBF was unchanged during PGE1 administration. Neither PGE1 nor TMP affected CO2 reactivity during cerebral aneurysm surgery, whereas CO2 reactivity showed a close correlation with presurgical neurological status: before, rs = -0.523, p < 0.01; during, rs = -0.794, p < 0.01; after, rs = -0.643, p < 0.01. Comparison of the outcomes after aneurysm surgery demonstrated no significant difference between groups; however, there was a close correlation between presurgical neurological status and outcome in both groups (rs = 0.829, p < 0.01). These results suggest that PGE1 is preferable to TMP in inducing hypotension for cerebral aneurysm surgery because this drug maintains both LCBF and CO2 reactivity.

Adult↗
PubMed1988

Some pharmacokinetic data of aditoprim and trimethoprim in healthy and tick-borne fever infected dwarf goats.

Aditoprim (AP) is a new dihydrofolate reductase inhibitor, which is structurally related to trimethoprim (TMP). The pharmacokinetics of AP (10 mg/kg) and TMP (20 mg/kg) were assessed in healthy dwarf goats. Therapeutic efficacy against rickettsial infections was tested in tick-borne fever (TBF) infected goats. The animals were given TMP (n = 5) or AP (n = 5) by i.v. injection, and subsequently the drugs were administered orally (same groups, similar doses). Finally, both groups were infected with TBF and the i.v. experiment was repeated. Plasma concentration-time curves for both drugs followed first-order two-compartment decay. For TMP, mean t1/2 beta +/- SEM (h) was 0.84 +/- 0.06 (i.v. control) and 0.90 +/- 0.06 (i.v. infected), respectively, whereas for AP values of 8.00 +/- 0.31 (i.v. control) and 10.28 +/- 0.67 (i.v. infected) were obtained (P less than 0.05). Mean Vd beta +/- SEM values (l/kg) were 3.84 +/- 0.27 (i.v. control) and 4.07 +/- 0.85 (i.v. infected) for TMP (NS) and 7.02 +/- 0.63 vs 9.29 +/- 0.21 (P less than 0.05) for AP. After i.v. injection, rumen fluid concentrations of AP were significantly (P less than 0.05) higher and more persistent than those of TMP. For AP, the plasma and rumen fluid concentrations at 3 h were 1.20 +/- 0.06 micrograms/ml and 0.85 +/- 0.17 microgram/ml, respectively. After oral administration of TMP, Cmax in plasma was 0.12 +/- 0.01 microgram/ml and the maximum was reached after 1.2 +/- 0.16 h; systemic bioavailability (F) was 10.3% (relative to AUC i.v.). Oral treatment with AP resulted in a Cmax value of 0.21 +/- 0.02 microgram/ml with Tmax of 22.5 +/- 1.65 h and a F value of 71%. Based on WBC, serum ALP and rectal temperature responses, it was concluded that both TMP and AP were inactive against Ehrlichia phagocytophila.

Administration, Oral↗
PubMed2005

Tetramethylpyrazine downregulates angiotensin II-induced endothelin-1 gene expression in vascular endothelial cells.

1. Tetramethylpyrazine (TMP) is one of the active ingredients of the Chinese herb Ligusticum wallichii Franchat. It is well documented that TMP exerts a cardiovascular protective effect. The aims of the present study were to examine whether TMP alters angiotenisn (Ang) II-induced endothelin (ET)-1 gene expression and to identify the putative underlying signalling pathways in vascular endothelial cells. 2. Cultured vascular endothelial cells were pre-incubated with TMP, stimulated with AngII and ET-1 gene expression was then examined. The effects of TMP pretreatment on AngII-induced extracellular signal-regulated kinase (ERK) phosphorylation were investigated to elucidate the intracellular mechanism responsible for the effects of TMP on ET-1 gene expression. 3. Tetramethylpyrazine inhibited AngII-induced ET-1 gene expression, as revealed by nothern blotting and a promoter activity assay. Tetramethylpyrazine also inhibited the AngII-induced increase in intracellular reactive oxygen species (ROS), as measured by the redox sensitive fluorescent dye 2' 7'-dichlorofluorescin diacetate and ERK phosphorylation. 4. In summary, we have demonstrated, for the first time, that TMP inhibits AngII-induced ROS generation, ERK phosphorylation and ET-1 gene expression in vascular endothelial cells. Thus, the present study delivers important new insights into the molecular pathways that may contribute to the proposed beneficial effects of TMP in the cardiovascular system.

Angiotensin II↗
PubMed2001

Metabolic differences between attached and free-living marine bacteria: inadequacy of liquid cultures for describing in situ bacterial activity.

Marinobacter sp. strain CAB was cultivated with or without porous glass beads as solid support. Two substrates were used: the hydrophilic sodium lactate and a hydrophobic C(18)-isoprenoid ketone (6,10,14-trimethylpentadecan-2-one (TMP)). The substrate adsorption onto the beads was measured. Bacterial adhesion was determined by a direct count technique and amounted to 70% of total cells. In the immobilised cell cultures (ICC), generation times were 1.5 and 1.8 times shorter than in the planktonic cultures (FCC) with sodium lactate and with TMP, respectively. In ICC, the growth yields were lower (15.3(FCC) x 10(9) and 0.8(ICC) x 10(9) bacteria mg(-1) of sodium lactate; 50(FCC) x 10(9) and 35(ICC) x 10(9) bacteria mg(-1) of TMP). The mineralisation of substrates was estimated after mass spectrometric determination of the CO2 production rates of both free and immobilised cell cultures. The results indicated a higher specific CO2 production rate in the ICC with sodium lactate (3.1(FCC)+/-0.2 and 3.5(ICC)+/-0.3 nmol CO2 mg(-1) protein min(-1)) but not in the ICC with TMP (1.9(FCC)+/-0.7 and 0.5(ICC)+/-0.3 nmol CO2 mg(-1) protein min(-1)). The affinities for the two substrates were lower in the presence of the solid support (K(m,ICC)=18.2+/-0.2 microM and 37.1+/-2.0 microM, for sodium lactate and TMP, respectively) than without support (K(m,FCC)=8.5+/-1.5 microM and 8.4+/-1.2 microM, for sodium lactate and TMP, respectively). Moreover, the presence of a solid support showed a lower inhibition by the TMP (K(i,FCC)=3.8+/-1.0 microM and K(i,ICC)=12.2+/-2.5 microM) which may explain why the immobilised cell cultures degraded hydrophobic TMP more efficiently than the planktonic cultures.

Bacterial Adhesion↗
PubMed1977

Pharmacokinetics and tolerance of a single twelve-tablet dose of trimethoprim (960 mg)-sulfamethoxazole (4,800 mg).

To evaluate the potential usefulness of a single large oral dose of trimethoprim-sulfamethoxazole (TMP-SMZ) for the treatment of uncomplicated genitourinary gonorrhea, the pharmacokinetics of a 12-tablet dose containing 960 mg of TMP and 4,800 mg of SMZ were studied in 15 male volunteers, and the tolerance of this regimen was compared to that of a placebo in a double-blind crossover study. Both TMP and SMZ were rapidly absorbed. Peak mean serum concentrations (+/- standard deviation) of TMP, total SMZ, and free SMZ were 9.2 +/- 2.2, 259.4 +/- 40.9, and 233.7 +/- 33.6 mug/ml, respectively. Elimination half-lives were 16.7, 14.6, and 12.9 h, respectively. When results were compared to data from similar studies after smaller doses, peak mean serum concentrations were proportional to dose, but elimination half-lives were longer after larger doses. Urinary concentrations of TMP, total SMZ, and free SMZ were many-fold higher than serum concentrations. Percents recovery (+/- standard deviation) in urine were 60.6 +/- 10.6, 80.2 +/- 7.8, and 37.4 +/- 6.5%, respectively, during the 48 h after administration. The incidence of severe headache and of objective transient oliguria was significantly higher after TMP-SMZ than after placebo. Although the observed serum concentrations of TMP and SMZ surpassed concentrations necessary to inhibit clinical isolates of Neisseria gonorrhoeae in vitro for longer than 24 h, the adverse reactions associated with a 12-tablet dose of TMP-SMZ would preclude the clinical usefulness of such a therapeutic regimen.

Adolescent↗
PubMed1980

Effect of trimethoprim and trimethoprim-sulfamethoxazole on development of drug-resistant vaginal and fecal floras.

Trimethoprim-sulfamethoxazole (TMP-SMX) or trimethoprim (TMP) alone was given on a random double-blind basis to 26 young women to treat urinary tract infections. Fecal and introital aerobic bacterial floras were identified at 1, 7, 14, and 42 days to analyze changes in these floras or development of resistance to TMP or TM-SMX. Neither TMP alone nor the TMP-SMX combination administered for 2 weeks selected a resistant fecal or introital flora. In the few individuals who had strains resistant to TMP or TMP-SMX before initiation of therapy, these organisms did not persist once therapy began. Both programs effectively cleared the introitus and rectal areas of Enterobacteriaceae. Concentrations of TMP adequate to inhibit the majority of Escherichia coli strains causing urinary tract infections were found in the vaginal secretions.

Adult↗
PubMed1981

Trimethoprim-sulfamethoxazole therapy of experimental Escherichia coli meningitis in rabbits.

We used two strains of ampicillin-susceptible Escherichia coli to produce meningitis in rabbits and utilized these models (i) to compare the killing effects of parenteral trimethoprim-sulfamethoxazole (TMP-SMZ) and ampicillin on E. coli in cerebrospinal fluid after 8 h of treatment and (ii) to measure the penetration of TMP-SMZ and ampicillin into cerebrospinal fluid and the brain. At 16 h after intracisternal inoculation with a test strain, rabbits were treated with TMP (6 mg/kg per h) and SMZ (30 mg/kg per h), ampicillin (40 mg/kg per h), or saline intravenously for 8 h. TMP-SMZ levels were measured by high-pressure liquid chromatography, and ampicillin levels were measured by microbiological assay. Mean +/- standard deviation concentrations of TMP, SMZ, and ampicillin in cerebrospinal fluid (mean percent penetration) at the completion of 8 h of therapy were 0.80 +/- 0.41 (18%), 15.7 +/- 21.1 (27.2%), and 2.6 +/- 1.7 (8.9%) microgram/ml, respectively. TMP, SMZ, and ampicillin levels in brain homogenate after 8 h of therapy were 0.23 +/- 0.07 (6.6%), 3.31 +/- 3.3 (5.5%), and 0.6 +/- 4.53 (1.9%) microgram/g, respectively. TMP-SMZ infusion for 8 h produced a significant reduction in mean bacterial counts in cerebrospinal fluid in both models of meningitis compared with saline controls. The decrease in mean bacterial counts with TMP-SMZ therapy was equivalent to that produced by ampicillin.

Ampicillin↗
PubMed1996

Antibacterial activities of epiroprim, a new dihydrofolate reductase inhibitor, alone and in combination with dapsone.

Epiroprim (EPM; Ro 11-8958) is a new selective inhibitor of microbial dihydrofolate reductase. EPM displayed excellent activity against staphylococci, enterococci, pneumococci, and streptococci which was considerably better than that of trimethoprim (TMP). EPM was also active against TMP-resistant strains, although the MICs were still relatively high. Its combination with dapsone (DDS) was synergistic and showed as in vitro activity superior to that of the TMP combination with sulfamethoxazole (SMZ). The EPM-DDS (ratio, 1:19) combination inhibited more than 90% of all important gram-positive pathogens at a concentration of 2 + 38 micrograms/ml. Only a few highly TMP-resistant staphylococci and enterococci were not inhibited. EPM was also more active than TMP against Moraxella catarrhalis, Neisseria meningitidis, and Bacteroides spp., but it was less active than TMP against all other gram-negative bacteria tested. Atypical mycobacteria were poorly susceptible to EPM, but the combination with DDS was synergistic and active at concentrations most probably achievable in biological fluids (MICs from 0.25 +/- 4.75 to 4 + 76 micrograms/ml). EPM and the EPM-DDS combination were also highly active against experimental staphylococcal infections in a mouse septicemia model. The combination EPM-DDS has previously been shown to exhibit activity in Pneumocystis carinii and Toxoplasma models and, as shown in the present study, also shows good activity against a broad range of bacteria including many strains resistant to TMP and TMP-SMZ.

Animals↗
PubMed2006

High prevalence of antimicrobial resistance among Shigella isolates in the United States tested by the National Antimicrobial Resistance Monitoring System from 1999 to 2002.

Shigella spp. infect approximately 450,000 persons annually in the United States, resulting in over 6,000 hospitalizations. Since 1999, the National Antimicrobial Resistance Monitoring System (NARMS) for Enteric Bacteria has tested every 10th Shigella isolate from 16 state or local public health laboratories for susceptibility to 15 antimicrobial agents. From 1999 to 2002, NARMS tested 1,604 isolates. Among 1,598 isolates identified to species level, 1,278 (80%) were Shigella sonnei, 295 (18%) were Shigella flexneri, 18 (1%) were Shigella boydii, and 7 (0.4%) were Shigella dysenteriae. Overall, 1,251 (78%) were resistant to ampicillin and 744 (46%) were resistant to trimethoprim-sulfamethoxazole (TMP-SMX). Prevalence of TMP-SMX- or ampicillin- and TMP-SMX-resistant Shigella sonnei isolates varied by geographic region, with lower rates in the South and Midwest regions (TMP-SMX resistance, 27% and 30%, respectively; ampicillin and TMP-SMX resistance, 25% and 22%, respectively) and higher rates in the East and West regions (TMP-SMX resistance, 66% and 80%, respectively; ampicillin and TMP-SMX resistance, 54% and 65%, respectively). Nineteen isolates (1%) were resistant to nalidixic acid (1% of S. sonnei and 2% of S. flexneri isolates); 12 (63%) of these isolates had decreased susceptibility to ciprofloxacin. One S. flexneri isolate was resistant to ciprofloxacin. All isolates were susceptible to ceftriaxone. Since 1986, resistance to ampicillin and TMP-SMX has dramatically increased. Shigella isolates in the United States remain susceptible to ciprofloxacin and ceftriaxone.

Ampicillin↗
PubMed1997

Interpretive criteria and quality control parameters for testing of susceptibilities of Haemophilus influenzae and Streptococcus pneumoniae to trimethoprim and trimethoprim-sulfamethoxazole. The Antimicrobial Susceptibility Testing OC Group.

Two hundred twenty-eight strains of Haemophilus influenzae and 234 strains of Streptococcus pneumoniae were tested by broth microdilution and disk diffusion methods for susceptibility to trimethoprim (TMP) and TMP-sulfamethoxazole (SMX) to evaluate proposed criteria. Data are presented to support the proposed TMP MIC breakpoints of < or = 2.0 micrograms/ml for susceptibility and > or = 4.0 micrograms/ml for resistance for both species and TMP-SMX MIC breakpoints of < or = 2.0-38 micrograms/ml for susceptibility and > or = 4.0-76 micrograms/ml for resistance. Corresponding zone diameter breakpoints for H. influenzae for both drugs are proposed: < or = 10 mm = resistant; > or = 16 mm = susceptible. A 10-laboratory study documented reproducibility of such tests with standard control strains. The following control limits are proposed for tests of H. influenzae ATCC 49247 against TMP; MIC, 0.12 to 0.5 microgram/ml; zone diameter, 27 to 33 mm. The current limits for TMP-SMX were confirmed. For tests of S. pneumoniae ATCC 49619, MICs of TMP were 1.0 to 4.0 micrograms/ml and the current TMP-SMX MIC range was confirmed. Disk susceptibility tests of either drug against pneumococci were not reproducible, and consequently neither quality control limits nor interpretive criteria could be established. Endpoint interpretation and lot-to-lot variability in Mueller-Hinton agars were significant factors leading to interlaboratory variability.

Anti-Bacterial Agents↗
PubMedDate not supplied

Trioxsalen in the presence of UVA is able to induce nuclear factor kappa B binding activity in HaCaT keratinocytes.

It has been described that treatment of cells with high dose psoralen and UVA induce the production of reactive oxygen species (ROS) leading to DNA damage. Transcription factor nuclear factor kappa B (NFkappaB) plays a crucial role in regulating not only cell growth but also cell differentiation, and ROS seem to be partly involved in these mechanisms. The aim of this research was to find out the effect of a combined treatment with trioxsalen (TMP)/UVA on NFkappaB binding activity in HaCaT keratinocytes. HaCaT keratinocytes were treated with 27 microg/l TMP. This concentration did not affect the proliferation rates, nor was it toxic, as shown by cytotoxicity assays. After treatment with TMP with or without UVA (1 J/cm(2)), NFkappaB binding activity in nuclear protein extracts was measured by electrophoretic mobility shift assays. The effect on cytokines and cytokine receptor genes was investigated using cDNA expression arrays. An inhibitory effect on NFkappaB binding activity was found between 30 and 60 min after TMP supplementation of the culture media. UVA irradiation induced a 2-fold increase in NFkappaB binding activity in TMP supplemented HaCaT keratinocytes compared with the non-irradiated control. In addition, NFkappaB binding activity was higher after UVA irradiation with TMP than in UVA irradiated cells in the absence of TMP. TGF-alpha, IL-1R, IL-2Ralpha, IL-12beta and PDGF expression was induced by UVA. However, all of them except PDGF were inhibited by combined TMP/UVA treatment. Using an inhibitor of NFkappaB activation, we found out that under these conditions, these cytokines or cytokine receptor genes are apparently not regulated by NFkappaB. Our results indicate that a combined TMP/UVA treatment of HaCaT keratinocytes induces NFkappaB binding activity, and that this is a synergistic effect. The investigated cytokines, and cytokine receptor genes do not seem to be NFkappaB regulated; however, TMP shows anti-inflammatory capacities in vitro.

Cell Division↗
PubMed1989

Renal effects of trimethoprim in ciclosporin- and azathioprine-treated kidney-allografted patients.

Sixteen stable renal transplant patients on chronic ciclosporin (CS, n = 8) or azathioprine (AZA, n = 8) treatment were given trimethoprim (TMP) 160 mg twice a day for 7 days. This TMP dose did not affect glomerular filtration, as 99mTc-DTPA clearance was unchanged in both groups. TMP did, however, increase serum creatinine and reduce creatinine clearance in all patients. This effect was most pronounced in CS-treated patients. We conclude that even at the moderate dosage, as employed presently, TMP blocks tubular secretion of creatinine. This route for creatinine excretion is quite important as the clearance ratio between creatinine and DTPA averaged 1.21 in CS-treated patients and 1.05 in AZA-treated patients before TMP treatment. During TMP the ratio was reduced to 0.95 and 0.99, respectively, suggesting a complete cessation of tubular creatinine secretion by TMP. TMP did not, however, significantly affect other markers of renal tubular function.

Adult↗
PubMed1981

Mechanisms of trimethoprim resistance in enterobacteria isolated in Finland.

Dihydrofolate reductases (DHFR) were studied in two groups of trimethoprim (TMP)-resistant Enterobacteria, isolated in Turku, Finland. The first group consisted of six strains with a high level of TMP resistance (MIC greater than 1,000 mg/l) and all of them were found to harbour an additional TMP-insensitive DHFR thought to be responsible for the high degree of resistance. Three Proteus mirabilis strains in this group synthesized chromosomal reductases with reduced TMP sensitivity as well. A second group of six strains, exhibiting MIC values for TMP between 16 and 512 mg/l was seen to be resistant by the production of a chromosomally altered TMP-insensitive DHFR, produced either in normal or slightly elevated amounts. With one exception these strains were all fully susceptible to sulfadiazine and strong synergism with TMP was present. Resistance to nalidixic acid was also frequently observed in this group. In conclusion, three different basic mechanisms were found to be responsible for TMP resistance in Enterobacteria from Finland and these were seen to occur not only independently but also simultaneously in the same strain.

Aminopterin↗
PubMed2006

Anti-apoptotic and neuroprotective effects of Tetramethylpyrazine following spinal cord ischemia in rabbits.

BACKGROUND: Tetramethylpyrazine (TMP) is one of the most important active ingredients of a Chinese herb Ligusticum wallichii Franchat, which is widely used in many ischemia disorders treatments. However, the exact mechanism by which TMP protects the spinal cord ischemia/reperfusion (I/R) injury is still unknown. For this purpose, rabbits were randomly divided into sham group, control group and TMP group. After the evaluation of neurologic function, the spinal cords were immediately removed for biochemical and histopathological analysis. Apoptosis was measured quantitatively by the terminal transferase UTP nick end-labeling (TUNEL) method and confirmed by electron microscopic examination, the expression of Bax and Bcl-2 was immunohistochemically evaluated and quantified by Western blot analysis. RESULTS: Neurologic outcomes in the TMP-group were significantly better than those in the control group (P < 0.05). TMP decreased spinal cord malondialdehyde (MDA) levels and ameliorated the down regulation of spinal cord superoxide dismutase (SOD) activity. TMP significantly reduced the loss of motoneurons and TUNEL-positive rate. Greater Bcl-2 and attenuated Bax expression was found in the TMP treating rabbits. CONCLUSION: These findings suggest that TMP has protective effects against spinal cord I/R injury by reducing apoptosis through regulating Bcl-2 and Bax expression.

Animals↗
PubMed2005

Anti-fungal activity of sulfamethoxazole toward Aspergillus species.

Invasive mycosis has significantly increased in frequency among immunocompromised hosts leading to excessive morbidity and mortality. The combination of sulfamethoxazole (SMX) and trimethoprim (TMP) has been used extensively for the treatment and prophylaxis of infections by various microbes. The purpose of this study is to estimate the anti-fungal activity of SMX-TMP and examine the mechanism of activity. To investigate the antimicrobial activity of SMX-TMP in vitro, a mixture of SMX and TMP at 5:1 was serially diluted and added to potato dextrose agar medium or C-limiting agar medium. Aspergillus species were inoculated on the medium plate with SMX-TMP. The growth of A. fumigatus and A. oryzae was inhibited by addition of SMX-TMP. The anti-Aspergillus effect depended on not TMP but SMX and that was inhibited by p-aminobenzoic acid (PABA). A. niger was not sensitive against SMX-TMP in PDA medium, but sensitive in C-limiting medium. Those results showed that the activity depends on culture medium. Furthermore, addition of human serum did not influence the activity of SMX. The finding in this study suggested that SMX might be effective against Aspergillus species in clinical practice and prophylaxis treatment.

Antifungal Agents↗