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PubMed2000

Relationship of TIMI myocardial perfusion grade to mortality after administration of thrombolytic drugs.

BACKGROUND: Although improved epicardial blood flow (as assessed with either TIMI flow grades or TIMI frame count) has been related to reduced mortality after administration of thrombolytic drugs, the relationship of myocardial perfusion (as assessed on the coronary arteriogram) to mortality has not been examined. METHODS AND RESULTS: A new, simple angiographic method, the TIMI myocardial perfusion (TMP) grade, was used to assess the filling and clearance of contrast in the myocardium in 762 patients in the TIMI (Thrombolysis In Myocardial Infarction) 10B trial, and its relationship to mortality was examined. TMP grade 0 was defined as no apparent tissue-level perfusion (no ground-glass appearance of blush or opacification of the myocardium) in the distribution of the culprit artery; TMP grade 1 indicates presence of myocardial blush but no clearance from the microvasculature (blush or a stain was present on the next injection); TMP grade 2 blush clears slowly (blush is strongly persistent and diminishes minimally or not at all during 3 cardiac cycles of the washout phase); and TMP grade 3 indicates that blush begins to clear during washout (blush is minimally persistent after 3 cardiac cycles of washout). There was a mortality gradient across the TMP grades, with mortality lowest in those patients with TMP grade 3 (2.0%), intermediate in TMP grade 2 (4.4%), and highest in TMP grades 0 and 1 (6.0%; 3-way P=0.05). Even among patients with TIMI grade 3 flow in the epicardial artery, the TMP grades allowed further risk stratification of 30-day mortality: 0.73% for TMP grade 3; 2.9% for TMP grade 2; 5.0% for TMP grade 0 or 1 (P=0.03 for TMP grade 3 versus grades 0, 1, and 2; 3-way P=0.066). TMP grade 3 flow was a multivariate correlate of 30-day mortality (OR 0.35, 95% CI 0.12 to 1.02, P=0.054) in a multivariate model that adjusted for the presence of TIMI 3 flow (P=NS), the corrected TIMI frame count (OR 1.02, P=0.06), the presence of an anterior myocardial infarction (OR 2.3, P=0.03), pulse rate on admission (P=NS), female sex (P=NS), and age (OR 1.1, P<0.001). CONCLUSIONS: Impaired perfusion of the myocardium on coronary arteriography by use of the TMP grade is related to a higher risk of mortality after administration of thrombolytic drugs that is independent of flow in the epicardial artery. Patients with both normal epicardial flow (TIMI grade 3 flow) and normal tissue level perfusion (TMP grade 3) have an extremely low risk of mortality.

Aged↗
PubMed2000

Assessment of stereoselectivity of trimethylphenylalanine analogues of delta-opioid [D-Pen(2),D-Pen(5)]-enkephalin.

[D-Pen(2),D-Pen(5)]-Enkephalin (DPDPE) is an enzymatically stable delta-opioid receptor-selective peptide, which was modified by the trimethylation of the Phe(4) residue to give beta-methyl-2', 6'-dimethylphenylalanine (TMP), resulting in four conformations : (2R,3S)-beta-Phe-DPDPE, (2R,3R)-beta-Phe-DPDPE, (2R, 3S)-beta-Phe-DPDPE, and (2S,3R)-beta-Phe-DPDPE. Synthesis was by solid-phase techniques using enantiomerically pure amino acids to give the four optically pure diastereoisomer peptides. The potency and selectivity (delta- versus mu-opioid receptor) were evaluated by radioreceptor binding in rat brain, with a mu/delta ratio decrease for all TMP conformations, compared with the parent compound (DPDPE). Octanol/buffer distribution analysis showed enhanced lipophilicity of all TMP forms, with a sixfold enhancement associated with (2S,3S)-TMP. In situ vascular perfusion in anesthetized rats showed a 1.6-fold (p < 0.01) increase in the ratio of brain uptake for (2S,3S)-TMP and a 1.5-fold (p < 0.01) decrease in uptake for (2R,3R)-TMP. Saturability of (2S,3S)-TMP was shown (p < 0.01) against 100 microM unlabeled DPDPE, showing a shared nondiffusionary transport system. P-glycoprotein affinity was shown in situ for the parent and (2S,3S)-TMP (p < 0.01). Protein binding capacity of the TMP compounds in rat plasma and in situ mammalian bovine serum albumin-Ringer showed (2R,3S)-TMP and (2S,3R)-TMP with the lowest degree of protein binding (p < 0.01), and (2S,3S)-TMP and (2R,3R)-TMP with comparable affinities to DPDPE. Analgesia, via intravenous administration, showed significantly reduced (p < 0.01) end effect and time course for (2R,3R)-TMP, (2R,3S)-TMP, and (2S, 3R)-TMP as compared with DPDPE. These results demonstrate that topographical modification in a conformationally restricted peptide can significantly modulate potency and receptor selectivity, binding capacity, enzymatic stability, lipophilicity, P-glycoprotein affinity, and blood-brain barrier permeability, resulting in a change of bioavailability, and thereby provides insight for future peptide drug design.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMedDate not supplied

[Comparison of dialyzers in on-line hemodiafiltration].

UNLABELLED: At present we have a great variety of high-flux dialyzers whose characteristics in vitro seem similar. On-line HDF is a technique which combines diffusion with elevated convection and uses dialysate as replacement fluid. On-line HDF provides the highest clearances for small, medium-sized and large molecules and gives the best performance from the dialyzers. Conscious of this wide choice of dialyzers we evaluated the performance of different dialyzers in renowing small and medium-large molecules. Eleven patients were included in this study, 7 males and 4 females. Every patient received 11 on-line HDF sessions with Fresenius 4008B machine, Qi 100 ml/min or 6 L/h, QB 400 ml/min, QB 800 ml/min, UF 0.5 L/h and Td 60 min. Only the dialyzer was changed: 1.9 m2 cellulose triacetate (Tricea 190G), 2.1 m2 poly methyl methacrylate of PMMA (BK-2.1P), 1.8 m2 polyester-polymer Allol or PEPA (FLX-18GWS), 2.05 m2 acrylonitrile (Filtral 20), 2.1 m2 polyamide (Poliflux 2.1) and 1.8-2.4 m2 polysulfones (HF 80, BS-1.8S, APS-900, Arylane H9, Idemsa 2000, HdF 100). Arterial pressure, venous pressure and transmembrane pressure (TMP) were monitored. Plasma, urea, creatinine, phosphate, uric acid and beta 2m concentrations were measured at the beginning and at the end dialysis from arterial and venous blood lines, and arterial blood line with the slow flow method. Recirculation, dialyzer solutes clearance and solute reduction rates were calculated. No significant differences were found in arterial pressure, venous pressure and recirculation. Small molecule removal was similar except in BK-2.1P and HdF 100 dialyzers which were lower and higher respectively. There were differences in TMP and beta 2m removal among dialyzers employed. Mean TMP, beta 2m clearance and beta 2m reduction ratio were: Tricea 190G (TMP 336 mmHg, beta 2m K 79 ml/min and beta 2m reduction ratio 44.9%), BK-2.1P (TMP 485, beta 2m K 102 and beta 2mRR 48.3%), FLX-18 GWS (TMP 195, beta 2m K 140 and beta 2mRR 54.6%), Filtral 20 (TMP 245, beta 2m K 132 and beta 2mRR 54.1%), Poliflux 2.1 (TMP 209, beta 2m K 158 and beta 2mRR 56.0%), HF 80 (TMP 208, beta 2m K 160 and beta 2mRR 57.4%), BS-1.8S (TMP 186, beta 2m K 179 and beta 2mRR 59.6%), APS-900 (TMP 174, beta 2m K 176 and beta 2mRR 64.8%), Arylane H9 (TMP 206, beta 2m K 171 and beta 2mRR 59.9%), Idemsa 2000 (TMP 203, beta 2m K 169 and beta 2mRR 60.4%), HdF 100 (TMP 152, beta 2m K 186 and beta 2mRR 64.6%). CONCLUSIONS: Of the dialyzers evaluated in on-line HDF, cellulose triacetate and PMMA have a smaller beta 2m removal and their use is limited by an elevated TMP. The polysulfones provide greater beta 2m removal with lower TMP, particularly the APS-900 and HdF 100 dialyzers. The acrylonitrile, PEPA and polyamide are intermediate.

Equipment Design↗
PubMed1993

Efficacy and safety of rechallenge with low-dose trimethoprim-sulphamethoxazole in previously hypersensitive HIV-infected patients.

OBJECTIVE: This study was undertaken to determine whether patients infected with HIV and with prior hypersensitivity to trimethoprim-sulphamethoxazole (TMP-SMX) can be rechallenged successfully with TMP-SMX, what factors predict successful rechallenge, and whether hypersensitivity is due to TMP or to SMX. DESIGN: A prospective, open study. SETTING: A tertiary referral hospital. PATIENT: Thirty-one HIV-infected patients with a history of non-life-threatening hypersensitivity to TMP-SMX. INTERVENTIONS: Patients received TMP (300 mg twice a week) for 2 weeks and, where no major reaction occurred, subsequently with TMP-SMX (160 and 800 mg per tablet, one tablet two times a day, twice a week). Patients who developed significant and persistent hypersensitivity ceased SMX and were subsequently challenged with TMP-dapsone (300 and 100 mg, respectively, twice a week). MAIN OUTCOME MEASURES: That rechallenge is more likely to be successful in those with advanced HIV disease. RESULTS: Five out of 31 (16%) patients developed hypersensitivity to TMP, and two ceased TMP as a result. Fifteen of the 26 (58%) patients who received subsequent TMP-SMX developed hypersensitivity, 12 of whom ceased TMP-SMX because of this reaction. Hypersensitivity to TMP-SMX was significantly less common in those with a CD4+ cell count < 20 x 10(6)/l than in those with a CD4+ cell count > 20 x 10(6)/l (31 versus 85%; P = 0.03). Hypersensitivity to TMP-dapsone occurred in two out of nine patients with hypersensitivity to TMP-SMX on rechallenge. One patient developed transient dyspnoea following a dose of SMX, but no other serious adverse drug reaction occurred. CONCLUSIONS: Rechallenge with TMP-SMX appears safe in HIV-infected patients with a history of non-life-threatening hypersensitivity and is most likely to be successful in patients with a low CD4+ lymphocyte count. The data suggest a low rate cross-hypersensitivity between SMX and dapsone, at least at the doses used.

AIDS-Related Opportunistic Infections↗
PubMed1989

Significance of premature stop codons in env of simian immunodeficiency virus.

The location of the translational termination codon for the transmembrane protein (TMP) varies in three infectious molecular clones of simian immunodeficiency virus from macaques (SIVmac). The SIVmac251 and SIVmac142 infectious clones have premature stop signals that differ in location by one codon; transfection of these DNAs into human HUT-78 cells yielded virus with a truncated TMP (28 to 30 kilodaltons [kDa]). The SIVmac239 infectious clone does not have a premature stop codon in its TMP-coding region. Transfection of HUT-78 cells with this clone initially yielded virus with a full-length TMP (41 kDa). At 20 to 30 days posttransfection, SIVmac239 virus with a 41-kDa TMP gradually disappeared coincident with the emergence of a virus with a 28-kDa TMP. Virus production dramatically increased in parallel with the emergence of a virus with a 28-kDa TMP. Sequence analysis of viral DNAs from these cultures showed that premature stop codons arising by point mutation were responsible for the change in size of the TMP with time. A similar selective pressure for truncated forms of TMP was observed when the SIVmac239 clone was transfected into human peripheral blood lymphocytes (PBL). In contrast, no such selective pressure was observed in macaque PBL. When the SIVmac239 clone was transfected into macaque PBL and the resultant virus was serially passaged in macaque PBL, the virus replicated very well and maintained a 41-kDa TMP for 80 days in culture. Macaque monkeys were infected with SIVmac239 having a 28-kDa TMP; virus subsequently recovered from T4-enriched lymphocytes of peripheral blood showed only the 41-kDa form of TMP. These results indicate that the natural form of TMP in SIVmac is the full-length 41-kDa TMP, just as in human immunodeficiency virus type 1. Viruses with truncated forms of TMP appear to result from mutation and selection during propagation in unnatural human cells.

Amino Acid Sequence↗
PubMed1977

Treatment of gonorrhea with trimethoprim-sulfamethoxazole.

The following regimens were randomly administered to 271 men with gonococcal urethritis: 4.8 X 10(6) units of aqueous procaine penicillin G intramuscularly plus 1 g of probenecid orally (APPG); nine tablets of trimethoprim-sulfamethoxazole (TMP-SMZ; 720 mg of TMP and 3,600 mg of SMZ), orally as a single dose (TMP-SMZ-9); and 12 tablets of TMP-SMZ (960 mg of TMP and 4,800 mg of SMZ) orally as two doses of six tablets taken at a 6-hr interval (TMP-SMZ-12). The failure rates of the APPG, TMP-SMZ-9, and TMP-SMZ-12 regimens were 4%, 23%, and 19%, respectively. APPG was significantly more effective (P less than 0.05) than TMP-SMZ-9 or TMP-SMZ-12. Isolates of Neisseria gonorrhoeae from treatment failures as compared to those from treatment successes were significantly more resistant to SMZ (P less than 0.01) and to the TMP-SMZ combination in a ratio of 19 parts SMZ to one part TMP (P less than 0.05). Minimal inhibitory concentrations of SMZ, TMP, TMP-SMZ, and penicillin G showed positive correlation coefficients.

Administration, Oral↗
PubMed2005

Effect of microbial phytase addition with or without the trace mineral premix in nursery, growing, and finishing pig diets.

Two experiments were conducted to determine the interactive effects of phytase with and without a trace mineral premix (TMP) in diets for nursery, growing, and finishing pigs on growth performance, bone responses, and tissue mineral concentrations. Pigs (initial and final BW of 5.5 and 111.6 kg [Exp. 1] or 5.4 and 22.6 kg [Exp. 2]) were allotted to treatments on the basis of BW with eight (Exp. 1) or six (Exp. 2) replications of six or seven pigs per replicate pen. Pigs were started on the diets the day of weaning (average of 18 d). In both experiments, the treatments were with or without 500 phytase units/kg of diet and with or without the TMP in a 2 x 2 factorial arrangement. The Ca and available P concentrations were decreased by 0.10% in diets with phytase. The nursery phase consisted of Phase I (7 d), Phase II (14 d), and Phase III (13 d) periods. In Exp. 1, 26 of 52 pigs fed the diet without the TMP and without phytase had severe skin lesions and decreased growth performance; therefore, pigs fed this diet were switched to the positive control diet. In Exp. 2, the treatment without the TMP and without phytase had 12 replications instead of six. At the end of Phase III, half these replications were switched to the positive control diet and half were switched to the diet without the TMP but with phytase. In Exp. 1 during Phases II and III and in the overall data, pigs fed the diet without the TMP had decreased ADG and ADFI, but the addition of phytase prevented these responses (phytase x TMP; P < 0.02). Growth performance was not affected by diet during the growing-finishing period. Coccygeal bone Zn and Na concentrations were decreased (P < 0.09) in pigs fed the diet without the TMP, and adding phytase increased (P < 0.03) Zn and Fe concentrations. In Exp. 2 during Phases I and II, pigs fed the diet without the TMP had decreased ADG, but the addition of phytase prevented this response (phytase x TMP; P < 0.10). Pigs fed the diet without the TMP had decreased (P < 0.10) ADG (Phase II and overall), ADFI (Phases II and III and in the overall data), and G:F (Phase III). Coccygeal bone Zn and Cu concentrations were decreased (P < 0.09) in pigs fed the diet without the TMP, and adding phytase increased (P < 0.03) Zn concentration in the bones. These data indicate that removing the TMP in diets for nursery pigs decreases growth performance and bone mineral content, and that phytase addition to the diet without the TMP prevented the decreased growth performance.

6-Phytase↗
PubMed2026

Genome-wide identification of conditionally essential genes for growth in the presence of sulfamethoxazole and trimethoprim in sulfamethoxazole- and trimethoprim-resistant Escherichia coli.

UNLABELLED: Resistance to sulfonamides (SULs) and trimethoprim (TMP) in Escherichia coli threatens their clinical relevance. Beyond known resistance mechanisms, little is understood about the cellular responses that enable resistant E. coli to grow under these antibiotic stresses. This study aimed to identify genes that support bacterial growth under SUL and TMP stress. Two saturated transposon mutant libraries were constructed in resistant E. coli MG1655 harboring either dfrA1 or sul2. They were grown with and without 1/2 and 1/4 minimum inhibitory concentration (MIC) of sulfamethoxazole (SMX) or TMP, and mutant depletion was assessed via transposon-directed insertion-site sequencing. At 1/2 MIC, 36 and 89 genes were identified as conditionally essential during SMX and TMP exposure, while 5 and 2 genes were classified as conditionally essential at 1/4 MIC. Genes identified as conditionally essential at 1/4 MIC were also important at 1/2 MIC. Conditionally essential genes belonged to lipopolysaccharide biosynthesis, peptidoglycan metabolism, energy production, membrane integrity, phosphate metabolism, and stress responses, highlighting the role of these factors in maintaining cell stability under SMX and TMP stress. Validation with 10 conditionally essential genes (apaH, mtn, surA, waaO, nlpI, prc, wzxE, fadR, degP, and tpiA) showed that deletion mutants indeed exhibited growth defects and two- to eightfold reductions in MIC under antibiotic stresses compared to their parent strains. This study highlights cellular responses to SMX and TMP under antibiotic stress, and it has identified a list of genes whose products may serve as potential helper drug targets to resensitize resistant E. coli to SMX and TMP treatments. IMPORTANCE: Sulfonamides (SULs) and trimethoprim (TMP) are broad-spectrum antimicrobials. They are commonly used to treat infections in both humans and animals. Resistance against SUL and TMP is widespread in pathogenic bacteria, and there is a need to overcome this problem. One possibility is to target the cellular mechanism by which the resistant bacteria adapt to growth in the presence of the antimicrobials. In this study, we identify the genes, besides the resistance genes, which enable resistant Escherichia coli to grow in the presence of SUL and TMP. We further show that knocking out many of these genes attenuates the resistant E. coli for growth during SUL and/or TMP stress, irrespective of which SUL- or TMP-resistant gene the bacteria carry. The gene products of these genes may serve as potential helper drug targets to resensitize resistant E. coli to sulfamethoxazole and TMP treatments.

Escherichia coli↗
PubMedDate not supplied

Protection from O,O,S-trimethyl phosphorothioate-induced immune suppression.

Acute administration of nontoxic doses of an impurity in technical malathion, O,O,S-trimethyl phosphorothioate (OOS-TMP), was able to block the in vitro generation of cytotoxic T lymphocytes (CTL) to alloantigen and antibody-secreting cells (Ab) to sheep red blood cells (SRBC). The effects of an antagonist of the delayed toxicity and lung damage of OOS-TMP, O,O,O-trimethyl phosphorothionate (OOO-TMP), and pretreatment of tolerance-inducing doses of OOS-TMP on OOS-TMP-induced immune suppression were examined. Treatment groups included (A) acute administration of OOO-TMP, (B) coadministration of OOO-TMP with OOS-TMP (at concentrations which have been shown previously to block lung toxicity). (C) repeated (4 x on consecutive days) administration of OOS-TMP (which was shown previously to block a lung toxicity which occurs following a challenge with OOS-TMP) and (D) repeated administration of OOS-TMP followed by a challenge dose of OOS-TMP 24 h before death. There was no change in lymphoid organ size following any of these treatments. However, splenocytes from animals that were exposed to treatment regimes A, B and D had significantly elevated proliferative responses to mitogens concanavalin A (ConA) and lipopolysaccharide (LPS). The ability of splenocytes to generate an Ab response to SRBC was significantly elevated following treatment regime A and at the lower dose in treatment regime D. All other treatment protocols did not alter this immune parameter. There was no difference in the ability of splenocytes to generate a CTL response following these treatment regimes. In conclusion, the degree of protection from immune suppression by these treatments which have been shown to protect against lung toxicity varied with the sensitivity of the immune parameters to suppression by acute administration of OOS-TMP.

Animals↗
PubMed2005

Tetramethylpyrazine inhibits ATP-activated currents in rat dorsal root ganglion neurons.

Tetramethylpyrazine (TMP) is one of the alkaloids contained in Ligustrazine which has been used in traditional Chinese medicine as an analgesic for injury and dysmenorrhea. ATP can elicit the sensation of pain. This study observed the effects of TMP on ATP-activated current (IATP) in rat DRG neurons. TMP (0.1-1 mM) concentration-dependently inhibited ATP (100 microM)-activated current in rat DRG neurons. The inhibitory time of ATP (100 microM)-activated current appeared at 15 s after preapplication of TMP and reached its peak at about 45 s. The dose-response curves for IATP in the absence and presence of 1 mM TMP showed that TMP (1 mM) shifted the concentration-response curve of IATP downward markedly and the two EC50 values were very close (75 vs. 82 microM), while the threshold value remained unchanged. Therefore, the inhibitory effect of TMP on IATP may be noncompetitive. TMP did not alter the reversal potential (0 mV) of ATP-activated current, indicating that the site of TMP action is on or near the exterior surface of channel protein and not within the channel pore. Externally applied TMP (1 mM) increases the inhibitory effect of chelerythrine (PKC inhibitor) contained in pipette solution on IATP. The site of TMP action may be the binding of TMP to an allosteric site on the large extracellular region of ATP receptor-ion channel complex (P2X receptors) or PKC site of the N-terminus of P2X receptors. The mechanism of TMP action may be the allosteric regulation via acting on the large extracellular region of ATP receptor-ion channel complex (P2X receptors) and promoting the phosphorylation of PKC site of the N-terminus of P2X receptors.

Action Potentials↗
PubMed1999

Trimethoprim-sulfamethoxazole resistance among urinary coliform isolates.

OBJECTIVE: A large majority of urinary tract infections are caused by coliform organisms. Trimethoprim-sulfamethoxazole (TMP-SMX) resistance among uropathogens is increasing in many areas. The objective of this study was to determine risk factors for TMP-SMX-resistant coliforms in patients with urinary tract infections. DESIGN: Retrospective case-control study. SETTING: Emergency department of a tertiary care university hospital. PATIENTS: We studied 448 emergency department patients aged 14 years or older with a urinary tract infection caused by a coliform organism. Cases consisted of all patients with a culture-documented urinary tract infection caused by a TMP-SMX-resistant coliform, while control patients were those with a TMP-SMX-sensitive organism. MEASUREMENTS AND MAIN RESULTS: A univariate analysis of clinical variables associated with TMP-SMX resistance was performed. Multiple logistic regression was performed to determine independent predictors of TMP-SMX resistance. Resistance to TMP-SMX was seen in 15% of isolates. Numerous variables were associated with TMP-SMX resistance on the univariate screen. Independent predictors of resistance were diabetes (odds ratio [OR] 3.1; 95% confidence interval [CI] 1.2, 8.4), recent hospitalization (OR 2.5; 95% CI 1.1, 5.7), current use of antibiotics (OR 4.5; 95% CI 2.0, 10.2), and recent use of TMP-SMX (OR 5.1; 95% CI 2.2, 11.5). When those with recent hospitalization were excluded from analysis, independent predictors were current use of any antibiotic (OR 3.5; 95% CI 1.4, 8. 4) and recent use of TMP-SMX (OR 5.9; 95% CI 2.4, 14.3). CONCLUSIONS: Coliforms resistant to TMP-SMX are common in our emergency department. Diabetes, recent hospitalization, and the use of antibiotics, particularly the use of TMP-SMX, are independent risk factors for TMP-SMX resistance. Clinicians should consider these findings when deciding on antimicrobial therapy for patients with urinary tract infections.

Adult↗
PubMed1997

Effects of triclosan and triclosan monophosphate on maximum specific growth rates, biomass and hydrolytic enzyme production of Streptococcus sanguis and Capnocytophaga gingivalis in continuous culture.

Dental plaque species, Streptococcus sanguis and Capnocytophaga gingivalis, were grown in continuous culture with progressively increasing concentrations of triclosan or its phosphorylated derivative, triclosan monophosphate (TMP). For both organisms, the maximum specific growth rates decreased with increasing concentrations of triclosan or TMP until complete inhibition of growth occurred, which for S. sanguis was at 20 mg/L and 50 mg/L, and for C. gingivalis was at 10 mg/L and 5 mg/L for triclosan and TMP respectively. For both species, biomass levels remained approximately constant or, in some cases, increased slightly at low levels of triclosan or TMP. However, biomass levels then decreased significantly as the triclosan or TMP concentrations approached lethal levels. For S. sanguis, levels of hydrolytic enzymes (acid phosphatase, leucine aminopeptidase and esterase) generally remained approximately constant or increased with increasing concentrations of triclosan or TMP until close to inhibitory levels where enzyme levels were reduced. The ratio of extracellular soluble enzymes to cell-bound enzymes remained constant or increased slightly with increasing levels of triclosan or TMP. For C. gingivalis, production of hydrolytic enzymes (neutral phosphatase, leucine aminopeptidase and trypsin-like protease) remained constant or were reduced when grown with low levels of triclosan and TMP but in some cases increased with higher levels of agents. The proportion of extracellular soluble activity increased significantly when concentrations of agent neared inhibitory levels. The results taken together show that the physiology of cells is significantly altered and that hydrolytic enzymes are released from the cells when these are grown in the presence of increasing concentrations of triclosan or TMP. Enzyme release is more pronounced in the Gram-negative C. gingivalis and indicates that triclosan or TMP can cause membrane perturbation with subsequent release of membrane-located (S. sanguis) or periplasmic (C. gingivalis) hydrolytic enzymes. S. sanguis was more sensitive to triclosan than TMP while C. gingivalis was more sensitive to TMP. This suggests that, in C. gingivalis, TMP may diffuse into the cell wall more easily than triclosan and then be converted to triclosan by phosphatase activity within the cell wall complex, where it may give rise to high localized concentrations and subsequent cell damage.

Acid Phosphatase↗
PubMed1996

Ligustrazine-induced endothelium-dependent relaxation in pulmonary arteries via an NO-mediated and exogenous L-arginine-dependent mechanism.

1. Ligustrazine (tetramethylpyrazine, TMP) is a vasodilator that has been reported to have pulmonary selective properties in vivo, but not in vitro. Although TMP is generally described as being endothelium-independent, we provide evidence here that TMP may have an endothelium-dependent and nitric oxide (NO)-mediated mechanism in pulmonary arteries that could predominate at concentrations used therapeutically in China. 2. The study was performed on isolated pulmonary (1-2 mm i.d.), intrapulmonary (200-850 microns) and mesenteric (200-400 microns) arteries of the rat using a Mulvaney-Halpen small vessel myograph, following preconstriction with phenylephrine (PE, 10 microM), prostaglandin F2 alpha (PGF2 alpha, 100 microM), or 75 mM K+ (KPSS, equimolar substitution for Na+). Values are shown as mean +/- s.e.mean, or for EC50S as mean [+/-95% confidence limits]. 3. TMP caused a concentration-dependent relaxation against all three agonists in both large (1.56 +/- 0.04 mm) and small (399 +/- 20 microM) pulmonary arteries; it was more potent in small compared to large arteries constricted with PE or PGF2 alpha (P < 0.05), but not those constricted with KPSS. The NO synthase (NOS) inhibitor, NG-monomethyl-L-arginine (L-NMMA, 100 microM) caused a significant shift to the right of these relationships, such that the EC50 for TMP in large pulmonary arteries constricted with PE increased from 522 [+130, -104] microM (n = 12) to 1828 [+395, -325] microM (n = 6, P < 0.01). Both removal of the endothelium and methylene blue (10 microM) had similar effects. 4. L-Arginine substantially reduced the EC50 for TMP in pulmonary arteries; in the presence of 400 microM L-arginine the EC50 for TMP in large arteries constricted with PE was 14.7 [+21.0, -8.6] microM, (n = 6, P < 0.001), and with 10 microM L-arginine 96.7 [+45.1, -30.7] microM, (n = 6, P < 0.001). Similar effects were seen in small arteries. L-Arginine had no effect in the absence of an endothelium. D-Arginine was ineffective, and inhibition of L-arginine uptake with L-lysine blocked the action of L-arginine. L-Arginine (400 microM) had no significant effect on TMP-induced relaxation in mesenteric arteries (n = 5). 5. L-Arginine itself caused a concentration-dependent relaxation in intrapulmonary arteries (639 +/- 34 microM) constricted with PE, reaching a maximum relaxation around 100-400 microM (42.4 +/- 3.0%, n = 16), but this was independent of the endothelium. TMP (10 and 100 microM) significantly enhanced the relaxation to L-arginine, with a maximum relaxation in the presence of 100 microM TMP of 81.7 +/- 6.2% (n = 5, P < 0.01), but the effect of TMP was entirely dependent on the endothelium. A similar effect was observed in PGF2 alpha-constricted pulmonary arteries. 6. These results show that TMP stimulates NO production at low concentrations in pulmonary arteries, via an apparently novel endothelium-resident mechanism that is dependent on exogenous L-arginine. Normal plasma L-arginine levels of around 150 microM would allow this mechanism to be maximally activated. As mesenteric arteries do not seem to express the mechanism to any significant extent, at low concentrations TMP would be effectively selective to the pulmonary vasculature, and may thus have potential as a therapeutic agent in pulmonary vascular disease.

Animals↗
PubMed1985

Susceptibility of enterococci to trimethoprim and trimethoprim-sulfamethoxazole.

The in vitro activities of trimethoprim (TMP), alone and in combination with sulfamethoxazole (SMX), against 131 clinical isolates of enterococci, 126 Streptococcus faecalis isolates, and 5 Streptococcus faecium isolates were determined by a broth microdilution method with Mueller-Hinton broth that was substantially free of inhibitory substances. The geometric mean MIC of TMP for strains of S. faecalis was 0.164 micrograms/ml (range, 0.03 to 8 micrograms/ml), with a geometric mean MBC of 0.298 micrograms/ml (range, 0.063 to 8 micrograms/ml). Although all strains were resistant to the sulfonamide alone, the inhibitory and bactericidal activities of TMP against strains of S. faecalis were markedly potentiated when TMP was combined in a fixed ratio of 1:19 with SMX; the geometric mean MIC of TMP was reduced to 0.016 micrograms/ml (range, 0.002 to 0.25 micrograms/ml), with a geometric mean MBC of 0.031 micrograms/ml (range, 0.004 to 0.25 micrograms/ml). The combination had no synergistic effect against strains of S. faecium; the geometric mean MICs and MBCs of both agents were ca. 0.06 micrograms/ml. The MBC/MIC ratios for TMP and TMP-SMX were less than or equal to 16 for all 131 strains. MICs and MBCs for TMP-SMX were unchanged, and for TMP they decreased when performed in broth supplemented with 50% heat-inactivated pooled human serum. For TMP and TMP-SMX, the susceptibilities of isolates with high-level resistance to gentamicin or streptomycin were the same as those of isolates susceptible to less than or equal to 2,000 micrograms of aminoglycoside per ml. These results suggest that TMP-SMX and TMP alone could prove useful in the treatment of serious enterococcal infections, including infections by strains with high-level resistance to aminoglycosides.

Aminoglycosides↗
PubMed1996

Genetic characterization of trimethoprim resistance in Haemophilus influenzae.

We previously demonstrated that trimethoprim (Tmp) resistance in Haemophilus influenzae is mediated by chromosomally encoded dihydrofolate reductase (DHFR) with a modified primary structure and distinct kinetic properties. To gain insight into the relationship of the DHFR structure and the level of Tmp resistance that it confers on the host bacterium, we cloned and characterized the folH genes of one Tmp-susceptible and two Tmp-resistant H. influenzae strains. Differences were observed between Tmp-susceptible and Tmp-resistant isolates both in the promoter region and in the coding sequences. The effect of differences between H. influenzae folH genes on Tmp susceptibility was investigated in Escherichia coli. Various folH gene hybrids were constructed, and their influence on Tmp susceptibility was determined. Resistance in E. coli mediated by folH from H. influenzae strain R1047 was associated with alterations in the promoter and the central part of folH. In contrast, the E. coli Tmp resistance phenotype associated with the folH gene of H. influenzae R1042 was characterized by alterations in one or more of three amino acid residues at the C-terminal part of the protein. These data indicate that Tmp resistance is not only related to alterations in the promoter region of the folH gene and the Tmp binding domains at the N-terminal and central part of DHFR. Alterations in the C-terminal part may also cause Tmp resistance, probably as a result of a change in secondary structure and the subsequent loss of Tmp binding affinity.

Amino Acid Sequence↗
PubMed2006

Oral trimethoprim-sulphamethoxazole levels in stable HIV-infected children.

BACKGROUND: Effective treatment of Pneumocystis jiroveci pneumonia (PCP) requires therapeutic serum concentrations of 5-10 microg/ml trimethoprim (TMP); consequently intravenous trimethoprim-sulphamethoxazole (TMP-SMZ) is recommended therapy. However, oral therapy is desirable as the intravenous route is costly, time-consuming, more difficult to administer and carries a risk of needlestick injury. OBJECTIVE: To investigate whether therapeutic TMP levels for treatment of PCP can be attained with oral therapy in HIV-infected children. METHODS: A prospective dose-escalation study was undertaken of serum TMP levels attained following oral doses of TMP of 5 mg/kg, 10 mg/kg or 20 mg/kg in stable HIV-infected children. Children who received a 20 mg/kg dose were randomised to get a second dose (5 or 10 mg/kg TMP) at 6 hours. TMP levels were measured at baseline, peak (3 hours), and trough (6 hours) using liquid chromatography. An additional TMP level was taken at 9 hours in those who received a second TMP dose. RESULTS: Median (25th-75th percentile) peak serum TMP levels following a 5 mg/kg, 10 mg/kg or 20 mg/kg oral loading dose were 0.93 (0.5-1.5) microg/ml, 1.94 (1.4-2.2) microg/ml and 7.68 (6.1-7.8) microg/ml respectively. Peak TMP levels at 9 hours after a second TMP dose of 5 or 10 mg/kg were 6.98 (3.4-8.8) microg/ml and 9.25 (8.2-10.3) microg/ml respectively. CONCLUSION: Therapeutic concentrations of TMP for treatment of P. jiroveci can be attained with an oral loading dose of 20 mg/kg and sustained with a second dose at 6 hours of either 5 mg or 10 mg/kg in stable HIV-infected children.

AIDS-Related Opportunistic Infections↗
PubMed1999

Tetramethylpyradizine prevents inducible NO synthase expression and improves survival in rodent models of endotoxic shock.

This study is to investigate the possible mechanism of beneficial effects of tetramethylpyrazine (TMP) on endotoxic shock which we showed in our preliminary study (Liao et al. 1998; Proc Natl Sci Counc Repub China B 22:46-54). Here, we have confirmed the beneficial effects of TMP on the hypotension, vascular hyporeactivity to noradrenaline (NA), release of tumour necrosis factor-alpha (TNF-alpha) and nitric oxide (NO) in a rat model of circulatory shock induced by bacterial endotoxin (E. coli lipopolysaccharide, LPS). In addition, we further examined the expression of inducible NO synthase in the lung and in the aorta from these rats and evaluated the effect of TMP on the 36-h survival rate in a murine model of endotoxaemia. Male Wistar-Kyoto rats were anaesthetised and instrumented for the measurement of mean arterial pressure (MAP) and heart rate (HR). Injection of LPS (10 mg kg(-1), i.v.) resulted in an acute fall followed by a substantial fall in MAP within 4 h and an increase in HR. In contrast, animals pretreated with TMP (10 mg kg(-1), i.p.; at 30 min prior to LPS) maintained a significantly higher MAP but the tachycardia was further enhanced at 1-2 h when compared to rats given only LPS (LPS rats). The pressor effect of NA (1 microg kg(-1), i.v.) was also significantly reduced after the treatment of rats with LPS. Similarly, the thoracic aorta obtained from rats at 4 h after LPS showed a significant reduction in the contractile responses elicited by NA (1 microM). Pretreatment of LPS rats with TMP partially, but significantly, prevented this LPS-induced hyporeactivity to NA in vivo and ex vivo. The injection of LPS resulted in a bell-shaped change in plasma TNF-alpha level which reached a maximum at 1 h, whereas the effect of LPS on the plasma level of nitrate (an indicator of NO formation) was increased in a time-dependent manner. This increment of both TNF-alpha and nitrate levels was significantly reduced in LPS rats pretreated with TMP. Endotoxaemia for 4 h caused a significantly increased protein expression of iNOS in the lung and the aorta. In LPS rats pretreated with TMP, iNOS protein expression in lung and aorta homogenates was attenuated by 75+/-3% and 57+/-6%, respectively. In addition, the lack of evidence of pressor effect of TMP on rats with endotoxaemia for 4 h suggested that TMP inhibits the induction of iNOS rather than directly inhibiting NOS activity. Treatment of conscious ICR mice with a high dose of endotoxin (60 mg kg(-1), i.p.) resulted in a survival rate of only 15% at 36 h (n=20). However, therapeutic application of TMP (10 mg kg(-1), i.p.; at 0, 6, 15 and 24 h after LPS) increased the 36 h survival rate to 55% (n=20). Thus, TMP inhibits the expression of iNOS and mitigates the delayed circulatory failure caused by endotoxic shock in the rat. In addition, TMP also improves survival in a murine model of severe endotoxaemia.

Animals↗
PubMed1996

Dynamics of trimethoprim bound to dihydrofolate reductase--a deuterium NMR study.

We have employed deuterium NMR techniques to determine the dynamics of trimethoprim (TMP) in a binary complex with dihydrofolate reductase (DHFR) or in a ternary complex with DHFR and cofactor NADP+ in the fully hydrated state. TMP was deuterated at the following positions: (2',6'-D2)TMP, (3'-Ome-D3)TMP and (3',4'-Ome-D6)TMP. Dynamics of TMP were deduced from lineshape simulation and relaxation measurements of the deuterium NMR powder spectra of the three samples obtained at various temperatures. The results showed that in the polycrystalline state the TMP molecule is very rigid. The only detectable motion is the methyl group rotation at a rate of 10(10) s-1 at 25 degrees C, as determined from simulation of the partially relaxed powder patterns. When bound to DHFR a residual deuterium quadrupole splitting of 140 kHz was observed for (2',6'-D2)TMP at temperatures up to 30 degrees C, suggesting that the benzyl ring in the bound state is also very rigid. In contrast, in the binary complex with DHFR the methoxyl groups of TMP undergo librational motion of 10(7) s-1 about the C3-O bond at an amplitude of 54 degrees for the meta methoxyl group and about the C4-O bond at an amplitude of 70 degrees and similar rate for the para methoxyl group at 30 degrees C. The presence of the cofactor, NADP+, appears to tighten up the binding pocket such that the motion freedom of TMP is more restricted. The rigidity of TMP in a protein complex as revealed by our deuterium NMR results is in accord with the tight binding of TMP to DHFR.

Deuterium↗