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PubMed1974

In vitro susceptibility of Haemophilus influenzae to trimethoprim-sulfamethoxazole.

Thirty-four strains of Haemophilus influenzae (20 ampicillin sensitive and 14 ampicillin resistant), mostly type b isolates from cerebrospinal fluid or blood, were tested for susceptibility to a combination of trimethoprim-sulfamethoxazole (TMP-SMZ) in a ratio of 1 part TMP to 19 parts SMZ. All strains were very susceptible to the TMP-SMZ combination, with minimal inhibitory concentrations ranging from 0.007-0.14 to 0.06-1.18 mug of TMP-SMZ per ml. There was little difference in the susceptibility of the ampicillin-sensitive and ampicillin-resistant strains to TMP-SMZ.

Ampicillin↗
PubMed1981

Inactivation of transforming Bacillus subtilis deoxyribonucleic acid by monoadducts of 4,5',8-trimethylpsoralen.

4,5',8-Trimethylpsoralen (TMP) monoadducts inactive transforming deoxyribonucleic acid (DNA) in Bacillus subtilis. Contrary to TMP diadducts (TMP cross-links), which severely inhibit entry of donor DNA (G. Venema and U. Canosi, Mol. Gen. Genet. 179:1--11), TMP monoadducts have only a slight effect on entry. Since reextracted TMP-monoadduct-containing transforming DNA is a differentially repaired by Uvr- and Uvr+ recipients and cross-linkable to the recipient strand in the heteroduplex recombinant DNA molecules, the monoadducts can be integrated along with the donor DNA into the recipient chromosome.

Bacillus subtilis↗
PubMed1995

Trimethoprim-sulphamethoxazole in the treatment of persistent diarrhoea: a double blind placebo controlled clinical trial.

The efficacy of an absorbable antimicrobial agent trimethoprim-sulphamethoxazole (TMP-SMX) in the management of children with persistent diarrhoea was evaluated in a double blind, randomised, and placebo controlled trial. Of the 55 patients studied, 28 received TMP-SMX, and 27 received placebo. A trend in stool weight reduction was observed from the third day after the drug was started, and the reduction was statistically significant on day 6 and day 7. However, the difference in total stool output (g/kg) up to day 7 was not significantly different between the two groups. The proportion of children whose diarrhoea resolved by day 7 (therapeutic success) was significantly more in the treatment group compared with the placebo group (23 v 15). Additionally, mean duration of diarrhoea in the group that received TMP-SMX was less compared with the placebo group (6.0 v 8.3 days); this difference, however, was not significant. Hospital infection (probably nosocomial infection) was significantly less in the TMP-SMX treated group (1 v 10). The results of our study indicate that TMP-SMX has a clinical benefit in respect of reducing the stool output, and higher recovery rate within seven days of treatment. In addition, it prevented possible hospital acquired infection.

Child↗
PubMed1976

Activity and interaction of trimethoprim and sulphamethoxazole against Escherichia coli.

The activity of trimethoprim (TMP) and sulphamethoxazole (SMX), alone and in combination, against a sensitive strain of Escherichia coli was investigated in turbidimetric systems. In a static system in which the conditions of exposure of bacteria to drug resembled those of conventional minimum inhibitory concentration (MIC) titrations, both TMP and SMX exhibited antibacterial activity at concentrations well below the conventionally determined MIC, but regrowth occured at these concentrations during the overnight incubation period due to the emergence of adaptively resistant bacteria. Tests of combined drug action in the static turbidimetric system revealed even more synergic interaction than was apparent in conventional MIC tests. It is suggested that an important component of overall synergic interaction is the mutual suppression of adaptive "resistance" to the other agent. Studies in an in vitro model which simulates the hydrokinetic features of the urinary bladder showed that concentrations of TMP and SMX below the conventionally determined MIC inhibited the growth even of extremely dense bacterial populations so long as the concentration of drug was maintained. The response of cultures exposed to combinations of TMP and SMX in this system was so dominated by the effect of TMP that no synergic interaction with SMX was noted at concentrations of the drugs which are achievable in urine.

Drug Synergism↗
PubMed1991

Inhibitory effects of tetramethyl and tetraethyl derivatives of pyrazine on dog saphenous vein.

The effects of two structurally similar pyrazine derivatives, tetramethylpyrazine (TMP) and tetraethylpyrazine (TEP) on the contractile responses of dog saphenous vein to KCl (via membrane depolarization), phenylephrine (PHE, alpha 1-adrenergic agonist), and B-HT 920 (alpha 2-adrenergic agonist) were investigated. The relaxant or inhibitory effect of TMP and TEP was most potent on KCl-induced responses and least potent on PHE-induced responses. Their effect on KCl-induced responses was more prominent at 30 mM KCl than at 100 mM KCl. In Ca(2+)-free medium, PHE and B-HT 920 elicited transient responses, which were also markedly and reversibly inhibited by TMP and TEP. Similar results were also obtained when prostaglandin F2 alpha was used as an agonist. In all four types of contractile responses involving different receptors, the inhibitory effect of TEP was consistently more potent than that of TMP. We conclude that both TMP and TEP behave as a nonselective smooth muscle relaxant having similar and multiple actions including their general interference with the processes involving both Ca2+ entry and intracellular Ca2+ release.

Animals↗
PubMed2002

Effect of tetramethylpyrazine on lipid peroxidation in streptozotocin-induced diabetic mice.

Oxygen free radicals have been suggested to be a contributory factor in complications of diabetes mellitus. In the present study, we investigated the effect of tetramethylpyrazine (TMP) (10, 25 and 50 mg/kg), an active component of a Chinese medicinal plant Ligusticum wallich Franch (chuanxiang), on streptozotocin (STZ)-induced diabetic male ICR mice. STZ was injected as a single daily dose (4 mg/kg i.p. in buffered citrate solution, pH 4.0) for one week. A single daily dose of TMP (10, 25 or 50 mg/kg i.p.) was administered for 2 weeks to the STZ-induced diabetic mice immediately following 1 week STZ induction. Plasma glucose and serum blood urea nitrogen (BUN) concentrations were estimated at the time of sacrifice. Malonialdehyde (MDA) formation was measured from the liver and kidney tissues. TMP dose dependently inhibited glucose concentration and BUN elevation. TMP also remarkably reduced the degree of lipoperoxidation. Our results indicate that TMP may be an effective agent for treatment of diabetes mellitus complications with oxidative stress.

Animals↗
PubMed2002

Reduced folate carrier transports thiamine monophosphate: an alternative route for thiamine delivery into mammalian cells.

Although the reduced folate carrier RFC1 and the thiamine transporters THTR-1 and THTR-2 share approximately 40% of their identity in protein sequence, RFC1 does not transport thiamine and THTR-1 and THTR-2 do not transport folates. In the present study, we demonstrate that transport of thiamine monophosphate (TMP), an important thiamine metabolite present in plasma and cerebrospinal fluid, is mediated by RFC1 in L1210 murine leukemia cells. Transport of TMP was augmented by a factor of five in cells (R16) that overexpress RFC1 and was markedly inhibited by methotrexate, an RFC1 substrate, but not by thiamine. At a near-physiological concentration (50 nM), TMP influx mediated by RFC1 in wild-type L1210 cells was approximately 50% of thiamine influx mediated by thiamine transporter(s). Within 1 min, the majority of TMP transported into R16 cells was hydrolyzed to thiamine with a component metabolized to thiamine pyrophosphate, the active enzyme cofactor. These data suggest that RFC1 may be one of the alternative transport routes available for TMP in some tissues when THTR-1 is mutated in the autosomal recessive disorder thiamine-responsive megaloblastic anemia.

Animals↗
PubMed1979

A comparison of the in vitro activities of sulfamethoxazole and sulfadiazine combinations with trimethoprim.

The sensitivity of 125 strains of 13 species or genera of bacteria to sulfamethoxazole (SMZ), sulfadiazine (SDZ), trimethoprim (TMP), SMZ + TMP and SDZ + TMP was determined by means of trays. A comparison of all combinations of the different concentrations used shows that SMZ + TMP is in 1 case and SDZ + TMP in 4 cases more effective against the 13 species or genera tested than the other combinations. SMZ and SDZ were equally effective in synergistic action (as shown by the FIC indices) against the various kinds of bacteria.

Bacteria↗
PubMed1980

Bacterial growth kinetics of E. coli in the presence of various trimethoprim derivatives alone and in combination with sulfonamides.

Bacterial growth kinetic experiments have been performed to study the potentiating effect of trimethoprim (TMP) AND TMP derivatives on the antibacterial action of sulfonamides (SA). The TMP derivatives showed different inhibitory effects when used alone. Derivatives with decreased inhibitory activity excerted 'bactericidal' effects only at high concentrations. A rather fast development of bacteria with lower sensitivity against these derivatives has also been observed. In the combined action with SA, however, the same maximal 'kill' rate was observed for TMP derivatives as tetroxoprim or derivative IV (TABLE I) at low concentrations of these inhibitors. Under the experimental conditons there is no significant difference between the studied TMP derivatives and various SA in the combined action.

Dose-Response Relationship, Drug↗
PubMed1984

Antimicrobial susceptibility, growth kinetic and pathogenicity of thymidine-requiring Streptococcus species.

18 strains of thymidine-requiring streptococcal mutants (thy-) were isolated from urines of patients with urinary tract infection treated with trimethoprim-sulfameth-oxazole (TMP-SMZ) or trimethoprim-sulfadiazine (TMP-SDZ). All thy- mutants were catalase- and beta-lactamase-negative, grew in the presence of bile and esculin, and required from 0.3 to greater than 1280 micrograms/ml of thymidine for normal growth. The antibiotic susceptibility of wild-type and thy- mutants to 21 antimicrobial agents tested were comparable except to trimethoprim (TMP), TMP-SMZ and TMP-SDZ. Ampicillin, penicillin G, erythromycin and rifampin were among the most active compounds tested. Growth kinetic studies with a Streptococcus faecalis thy- mutant in a synthetic basal medium without thymidine resulted in a decrease of 2-3 logarithmic units in viable cells after 24 h of incubation. The addition of thymidine to this thymidine-deprived culture prevented the thymineless death of the cells. In vivo, this thy- mutant was less virulent than the wild-type strain in producing kidney infection in mice.

Animals↗
PubMed1987

Trimethoprim and sulfadiazine penetration into bile and gallbladder in acute cholecystitis.

The concentrations of trimethoprim (TMP) and sulfadiazine (SDZ) in serum, bile and gallbladder wall of 9 patients with acute cholecystitis were measured after b.i.d. treatment with 160 mg of TMP + 500 mg of SDZ. The samples were collected 2-4 h after the last dose. Mean TMP concentrations were 1.71 +/- (SE) 0.51 micrograms/ml, 4.53 +/- 5.26 micrograms/ml and 2.31 +/- micrograms/g in serum, bile and gallbladder, respectively. Mean SDZ concentrations were 22.2 +/- 14.9 micrograms/ml in serum, 9.37 +/- 8.99 micrograms/ml in bile and 16.1 +/- 10.1 micrograms/g in gallbladder. The average ratios of bile-serum and gallbladder-serum concentrations were 2.64 and 1.35 for TMP and 0.42 and 0.73 for SDZ. There was a significant correlation between serum and gallbladder concentrations of both TMP and SDZ. No correlation existed between serum and bile levels.

Acute Disease↗
PubMed1991

Open randomized controlled parallel study of ofloxacin versus trimethoprim-sulfamethoxazole treatment of lower respiratory tract and urinary infections.

A total of 60 patients with lower respiratory tract or urinary tract infections were enrolled in an open, randomized, controlled, parallel study comparing 300 mg ofloxacin (OFX) b.i.d. with trimethoprim + sulfamethoxazole (TMP 800 mg + SMX 160 mg), 1 tablet, b.i.d. The signs and symptoms of low respiratory tract infection were cured in 12 patients (80%) of the OFX group and improved in 2 other patients (13%); at the end of therapy, the 2 germs that persisted were Streptococcus pneumoniae and Branhamella catarrhalis. Clinical cure was achieved in 13 patients (86%) in the TMP-SMX group, while 2 patients were considered as failures (14%); after therapy, the 3 organisms that persisted were 2 S. pneumoniae and 1 Pseudomonas aeruginosa. As far as urinary tract infections are concerned clinical cure and complete eradication of bacteria were achieved in 14 patients in the OFX group (93%); the germ that persisted was Escherichia coli (100,000 CFU), but the patient was asymptomatic. In patients of the TMP-SMX group the urinary infections were cured in 11 subjects (73%); the germs that persisted were 2 E. coli and 1 Proteus mirabilis. Adverse effects were reported for 3 patients (10%) in the OFX group and 4 patients (13%) in the TMP-SMX group. The measurement of serum and intracellular (polymorphonuclear cells and lymphocytes) levels of OFX and TMP-SMX and the assessment of the host's immunocompetence ruled out the possibility of any immunotoxicological side effect.

Acute Disease↗
PubMedDate not supplied

Cerebral blood flow responses to hypocapnia during hypotension.

Cerebral vascular responses to hypocapnia during hypotension to a mean arterial blood pressure (MAP) = 50 mm Hg induced with sodium nitroprusside (SNP, n = 12) or trimethaphan (TMP, n = 12) were examined in dogs. Cerebral vascular resistance (CVR) and cerebral blood flow (CBF) at PaCO2 = 40 mm Hg, and PaCO2 = 20 mm Hg were examined first at normal MAP then at hypotension in six dogs in the SNP group and six dogs in the TMP group. In both the SNP group and the TMP group, CO2 responsiveness, as indicated by increased CVR and decreased CBF, was intact at normal MAP, but absent during hypotension. In the remaining 6 of 12 dogs in the SNP group and 6 of 12 dogs in the TMP group, CO2 responsiveness at MAP = 50 mm Hg was examined without prior determination of CO2 responsiveness at normal MAP. These additional studies were performed to rule out the possibility that absent CO2 responsiveness during hypotension in the initial groups resulted from (1) physiologic deterioration of the preparation with time, or (2) adaptation of brain extracellular fluid pH to a preceding period of hypocapnia. Again, during both SNP- or TMP-induced hypotension CO2 responsiveness was absent.

Animals↗
PubMed1995

Pentamidine aerosol versus trimethoprim-sulfamethoxazole for Pneumocystis carinii in acquired immune deficiency syndrome.

Pneumocystis carinii pneumonia remains one of the most common opportunistic infections in patients with acquired immune deficiency syndrome (AIDS). Treatment with either intravenous pentamidine or trimethoprim-sulfamethoxazole (TMP-SMX) is frequently complicated by serious adverse reactions. This study was a prospective, blinded comparison of 600 mg/d of pentamidine as an aerosol versus 15 mg/kg/d of trimethoprim plus 75 mg/kg/d of sulfamethoxazole for patients with mild or moderately severe P. carinii pneumonia (alveolar arterial oxygen difference of less than 55 mm Hg). Of 367 participants who were randomized to receive study therapies, 287 had proven and 16 had presumed Pneumocystis pneumonia. There were 29 deaths within 35 d of study initiation: 12 in the aerosolized pentamidine group and 17 in the TMP-SMX groups (log rank p = 0.28). The difference in mortality was 3.4% (95% CI = -3.5, 10.8%). Ninety-four patients treated with aerosolized pentamidine had to have their study therapy changed because of lack of efficacy, compared with 22 patients treated with TMP-SMX (p = 0.002). In addition PaO2 improved faster in patients treated with TMP-SMX. However, aerosolized pentamidine was discontinued less often than TMP-SMX because of toxicity (9.4 versus 40% p < 0.001). Rash (0.6 versus 14.9%), nausea and vomiting (1.7 versus 12.2%), and abnormalities of liver function tests (1.7 versus 12.2%) were the most common adverse effects necessitating treatment discontinuation. During 6-mo. follow-up there was no difference in mortality.(ABSTRACT TRUNCATED AT 250 WORDS)

AIDS-Related Opportunistic Infections↗
PubMed1983

Pharmacokinetics of two dosage levels of trimethoprim to 'steady-state' in normal volunteers.

Trimethoprim (TMP), previously available only with a sulphonamide, is now available alone. The kinetics of two dosage regimens (200 mg b.d. p o. and 300 mg o.d. p.o.) have been examined. The expected disposition of higher TMP concentrations following the initial dose of the 300 mg preparation is reversed when steady-state is reached, and is a function of dosage. The MIC of TMP for sensitive organisms in urine was greatly exceeded following both regimens and is the result of a favourable pH gradient. The serum concentrations at CSS (trough) following the 300 mg regimen did not consistently exceed the MIC for TMP, those for the 200 mg regimen were more satisfactory. The implications of these findings are that while both regimens would be satisfactory in the treatment of urinary tract infection the 200 mg regimen would be more appropriate for the treatment of infected sites where pH dependent accumulation of TMP does not occur.

Adult↗
PubMed1995

Tetramethylpyrazine improves spatial cognitive impairment induced by permanent occlusion of bilateral common carotid arteries or scopolamine in rats.

Effects of tetramethylpyrazine (TMP), a major constituent of Ligusticum chuanxiong, on spatial cognitive impairment induced by permanent occlusion of bilateral common carotid arteries (2VO) and scopolamine were investigated using 8-arm radial maze performance in rats. Permanent 2VO produced a severe learning deficit in non-pretrained rats. Daily administration of TMP (3-10 mg/kg, i.p.) from the 3rd day after permanent 2VO significantly improved the learning deficit. TMP did not influence the impairment of the retention task in the pretrained permanent 2VO rats, but it tended to reduce the number of errors elevated by 3-min delay interposition in these rats. In the scopolamine model, scopolamine (0.3 mg/kg, i.p.) significantly decreased the initial correct response and increased the number of errors. Single administration of TMP (1-3 mg/kg, i.p.) dose-dependently reversed the scopolamine-induced impairment of the maze performance. These results suggest that TMP has therapeutic potential for the treatment of dementia caused by cholinergic dysfunction and/or decrease of cerebral blood flow.

Animals↗
PubMed1993

Longitudinal comparison of temporal-modulation perimetry with white-on-white and blue-on-yellow perimetry in ocular hypertension and early glaucoma.

We obtained data over 3 years on temporal-modulation perimetry (TMP), standard automated [white-on-white (W/W)] perimetry, and short-wavelength-sensitive [blue-on-yellow (B/Y)] perimetry in ocular hypertensive (OH) patients and patients with early glaucomatous visual-field loss (EG). Evidence of visual-field defects was obtained with the use of both B/Y perimetry and TMP in the majority of OH and EG eyes that demonstrated progression on W/W perimetry as well as in all stable EG eyes. Using the nerve-fiber-bundle pattern to compare testing procedures, we determined that these defects were generally as extensive or more extensive than the concurrent W/W abnormalities. In terms of location over the 3 years of testing, TMP and B/Y defects were reasonably consistent in the EG eyes, somewhat less consistent in the OH eyes demonstrating progression, and both inconsistent and infrequent in the stable OH eyes. The greatest degree of overlap occurred between the location of defects obtained by use of the higher TMP frequencies (8 and 16 Hz) and that of defects obtained by use of B/Y perimetry. Since these two methods are thought to isolate different visual mechanisms subserved by different visual pathways, these results suggest that early glaucomatous visual-field damage as revealed by TMP and B/Y perimetry may not be specific to a single visual pathway.

Color Perception Tests↗
PubMed1993

Mechanical ventilation for Pneumocystis carinii pneumonia in patients with the acquired immunodeficiency syndrome. Is the prognosis really improved?

The mortality rate among patients with human immunodeficiency virus (HIV) requiring mechanical ventilation (MV) for acute respiratory failure (ARF) secondary to Pneumocystis carinii pneumonia (PCP) is still a matter of discussion. For some authors, it is in the 50 percent range, while for others the prognosis is grim, with virtually no survivors. The aim of this retrospective study conducted between January 1987 and January 1992 was to analyze the outcome of such patients. We studied 33 patients, 29 men and 4 women (38.6 +/- 9.9 years, 21 homosexuals, 8 intravenous drug users, 3 transfusion related, 1 heterosexual) infected by HIV for at least 19.7 +/- 21.6 months. It was the first PCP episode in all but 2 patients and the diagnosis was made by bronchoalveolar lavage (n = 32) or lung biopsy specimen (n = 1). Only three patients were receiving primary prophylaxis for PCP (trimethoprim-sulfamethoxazole [TMP-SMZ], n = 2; pentamidine, n = 1). Pneumocystis carinii pneumonia was the first manifestation of AIDS in nine patients. The duration of symptoms prior to treatment was 19.6 +/- 11.3 days. At the time of hospital admission, laboratory findings were as follows: PaO2 = 40.7 +/- 7.8 mm Hg on room air; serum LDH = 1,172 +/- 792 IU/L; T4 cell count = 60.2 +/- 67/mm3. Mechanical ventilation was always required for ARF, which was never induced by bronchoscopy. The interval between treatment and MV was 8.1 +/- 6.5 days and the duration of MV was 11.4 +/- 9.9 days. The patients were classified into 3 groups on the basis of the duration and type of treatment before MV, as follows: group 1, n = 10: TMP-SMZ (20-100 mg/kg) IV and methylprednisolone (MP) < 5 days before MV; group 2, n = 4: TMP-SMZ > or = 5 days and MP < 5 days; group 3, n = 19: TMP-SMZ and MP > or = 5 days before MV. (The MP dose was as follows: 240 mg/d once a day from day 1 to day 3; 120 mg/d from day 4 to day 6; and 60 mg/d from day 7 to day 9.) Despite MV, TMP-SMZ, and MP, death secondary to PCP-related ARF occurred in 81.9 percent of patients, 20 +/- 4.8 days after the beginning of treatment and 11.4 +/- 9.9 days after the beginning of MV. Six patients survived, five in group 1 and one in group 3.(ABSTRACT TRUNCATED AT 400 WORDS)

AIDS-Related Opportunistic Infections↗