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PubMed1980

The penetration of sulfadiazine, sulfamethoxazole and trimethoprim into the prostate gland, epididymis and testis in man.

Sulfadiazine (SD, 250 mg) or sulfamethoxazole (SM, 800 mg) in combination with trimethoprim (TMP, 160 mg) was given twice daily to male patients and the concentrations of these drugs were assayed simultaneously in plasma, urine and the male reproductive organs (prostate gland, epididymis and testis). The antibacterially active mean concentration of SD in the prostate was 0.33, in the epididymis 0.74 and testis 0.85 times that in the plasma. The respective values for SM were 0.21, 0.51 and 0.53 and for TMP 0.73--0.73, 179--2.00 and 1.90--2.23. This indicates that the penetration of TMP into these tissues is two-fourfold compared to that of these sulfonamides. The drug concentrations and the concentration ratios (SD/TMP, SM/TMP) obtained suggest that by standards proposed in the literature they are adequate for synergistic antibacterial action at the serum, urine and tissue levels. Although the amount of SD was only about 1/3 of that of SM it seems to be a comparable alternative with this small dosage in combination with TMP, when bacterial infections in the urinary tract or in the male reproductive organs are treated.

Cell Membrane Permeability↗
PubMedDate not supplied

[Changes in the transmembrane potential of developing loach embryos under the influence of insulin, inhibition of transcription and translation].

Results of continuous 7-8 hour registration of transmembrane potential (TMP) at the early stages of the loach (Misgurnus fossilis) development in normal conditions and in media with different insulin concentrations (the hormone with actinomycin D and cycloheximid and these antibiotics alone) are presented in this paper. The dependence of the absolute value and the mode of TMP changes in developing embryos upon insulin concentration has been established. It is shown that actinomycin D reduces the hormonal effect at the initial stages, while alone it does not cause any visible changes of TMP. Inhibition of translation with cycloheximid leads to sharp depolarizaton of the membrane and completely abolishes the periodicity of TMP oscillations, which in the norm corresponds to the time-course of the mitotic cycles during the synchronous cleavang of the blastomeres.

Animals↗
PubMed1980

Interaction of increased pressures of oxygen and sulfonamides on the in vitro and in vivo growth of pathogenic bacteria.

The objective of these experiments was to determine whether synergism will occur between increased oxygen tensions and PABA-folic acid inhibitors in vitro and in vivo. Initial in vitro experiments indicated that PO2 greater than or equal to 2.2 ATA alone exerts marked growth-inhibitory (static) effects. Oxygen at 2.2 ATA decreased the minimal inhibitory concentrations (MIC) of sodium sulfisoxazole (NaS) fivefold and trimethoprim (TMP), a sulfonamide potentiator, twofold. At 3.2 ATA O2, there was a twenty-fivefold decrease in MIC of NaS and a tenfold decrease for TMP: cidal effects were also obtained. There is a PO2 dependent increase in effectiveness of the combination of NaS + TMP, including cidal effects, in situations where static effects were noted in absence of increased oxygen levels. Similar effects were not obtained with air pressure controls. In goldfish infected with Vibrio anquillarum, 3.2 ATA O2 in combination with NaS increased survival from 20% to 75%. Similar results were not obtained with air pressure controls. Trimethoprim was toxic to goldfish. We conclude that increased oxygen tensions synergize with NaS or TMP, or both, in vitro to decrease their MIC and to produce bactericidal effects where bacteriostatic effects are normally found: oxygen also synergizes with NaS in vivo to markedly increase survival of goldfish.

Animals↗
PubMedDate not supplied

A large population-based follow-up study of trimethoprim-sulfamethoxazole, trimethoprim, and cephalexin for uncommon serious drug toxicity.

We conducted a population-based 45-day follow-up study of 232,390 people who were prescribed trimethoprim-sulfamethoxazole (TMP-SMZ), 266,951 prescribed trimethoprim alone, and 196,397 prescribed cephalexin, to estimate the risk of serious liver, blood, skin, and renal disorders resulting in referral or hospitalization associated with these drugs. The results were based on information recorded on office computers by selected general practitioners in the United Kingdom, together with a review of clinical records. The risk of clinically important idiopathic liver disease was similar for persons prescribed TMP-SMZ (5.2/100,000) and those prescribed trimethoprim alone (3.8/100,000). The risk for those prescribed cephalexin was somewhat lower (2.0/100,000). Only five patients experienced blood disorders, one of whom was exposed to TMP-SMZ; of seven with erythema multiforme and Stevens-Johnson syndrome, four were exposed to TMP-SMZ. The one case of toxic epidermal necrolysis occurred in a patient who took cephalexin. Finally, only five cases of acute parenchymal renal disease occurred, none likely to be caused by a study drug. We conclude that the risk of the serious diseases studied is small for the three agents, and compares reasonably with the risk for many other antibiotics.

Adult↗
PubMed1994

Reaction of cysteamine with individual DNA base radicals in gamma-irradiated nucleotides at low temperature.

An ESR investigation of the individual DNA base radicals produced by gamma-irradiation of frozen solutions of the nucleotides TMP, dCMP, dGMP and dAMP and their reactions with cysteamine upon annealing is reported. The results show that water radicals in bulk ice do not lead to the formation of DNA or cysteamine radicals. Radicals from the oxidation pathway which include the DNA base one electron oxidized radicals and their successors, G(C8)OH., A(C8)OH. and thymine dimers (.Tdi) and/or T(C6)OH; readily react with cysteamine to form RS. and ultimately RSSR-. Reactions of dGMP and dCMP radicals from the oxidation pathway with cysteamine occur at lower temperatures than those of dAMP and TMP, suggesting hole migration. Both T(C6)H. and C(N3)H. react with cysteamine to form RS. and diamagnetic products, but G(C8)H. and A(C8)H. do not. Subtraction of the anion radical T-. and its proton adduct T(C6)H. from the total radical yield of TMP (with or without cysteamine) suggests that somewhat less than half of the total TMP radicals found are a result of the oxidative pathway. Similar results are found in the other nucleotides. The total spectral intensity derived from the radicals from the oxidative pathway such as G(C8)OH., A(C8)OH. and .Tdi/T(C6)OH. are somewhat less than that for the protonated anion radicals. Only one non-base radical is identified, a sugar radical at the C(1)' site on the deoxyribose portion of dAMP. This species, S(A)., is also found to react with cysteamine or its disulfide radical anion. Analyses performed in the presence and absence of a thiol are found to allow for a clear separation of oxidative and reductive pathways.

Cysteamine↗
PubMed1994

[Effect of deliberate hypotension on renal functions during epidural block plus inhalation anesthesia: a comparison of prostaglandin E1 and trimethaphan].

To clarify the effect of prostaglandin E1 (PGE1) or trimethaphan (TMP) on the kidney during deliberate hypotension induced with epidural block plus inhalation anesthesia, we compared renal functions and renal tubular injury between the patient with PGE1-induced hypotension (n = 22) and those with TMP-induced hypotension (n = 18) undergoing spherical acetabular osteotomy. Hypotension was maintained at 75-80 mmHg of the systolic radial artery pressure for two hours. The urine volume, creatinine clearance, fractional sodium excretion and free water clearance were maintained within normal limits and they were not different between the two groups. The mean NAG index increased significantly to normal upper limits during hypotension in the PGE1 group but did not increase in the TMP group. However, there was no difference in the NAG index between the two groups. The changes in serum ADH level were not different between the two groups perioperatively. These results suggest that renal functions are not influenced by controlled hypotension induced with PGE1 or TMP during epidural plus general anesthesia.

Adult↗
PubMed1994

[Enhancement effect of tetramethylpyrazine on slow inward current in guinea pig papillary muscles].

Tetramethylpyrazine (TMP) could potentiate the force of contraction and increase the action potential duration (APD) of isolated guinea pig papillary muscles in a dose-dependent manner. Similar effects were also observable in BaCl2 or histamine-induced contraction and the accompanied slow action potential (SAP). In fact, contraction and SAP could also be induced by TMP itself at 3.0 mmol/L concentration and antagonized by verapamil (1 mumol/L) within 10 min. In the presence of propranolol or in experiments carried out in catecholamine-depleted (reserpine 2.5 mg/kg, i.p. 15 h prior to the experiment) muscles, TMP was unable to induce SAP and contraction. These results suggested that the effects of TMP on enhancing Isi were mediated by the release of catecholamine in myocardium.

Action Potentials↗
PubMed1994

[Pharmacokinetic characteristics of tetramethylpyrazine and study on hemorheology in rat model of spleen deficiency syndrome].

UNLABELLED: In this experiment, the essence of Spleen Deficiency Syndrome (SDS) was explored with the rat model of SDS using tetramethylpyrazine (TMP). 120 Wistar rats were divided into two groups, 60 each for control and test group, they were treated with normal saline and reserpine respectively. The hemorheological parameters were also studied in 6 each of both groups. The pharmacokinetic properties were investigated in the remaining control group and test group. RESULTS: (1) Two-compartment open model of the control group was turned into that of one-compartment in test group; (2) The SDS model significantly affected the absorption and distribution of TMP in rats. AUC was much higher and serum concentration of TMP increased significantly than that of control. Hemorheological parameters (viscosity of whole blood, fibrinogen, etc.) increased significantly (P < 0.05-0.01), it demonstrated that the SDS model was in a state of Blood Stasis. It might be one of the pharmacokinetic mechanisms of TMP in the SDS model of rats.

Animals↗
PubMed1994

[Antibiotic treatment of brucellosis].

Forty years after active drug therapy was defined, the treatment of brucellosis still raises the problem of selecting the correct antibiotic and the duration of treatment. Indeed, requirements may be complex since one must select antibiotics which are active in vitro and which diffuse readily into the tissues and into the cells without developing bacterial resistance. Prescriptions must also be long enough, not only to achieve cure, but also to eliminate the Brucella strain. Antibiotics must be found which meet this last criteria yet do not lead to toxic effects or impair the patient's own immune response. Acute septicemic brucellosis in adult men and non-pregnant women has been effectively treated with the following three regimens: 1) doxycycline 200 mg/d and rifampin 900 mg/d orally for 45 days; 2) doxycycline 200 mg/d orally for 45 days and streptomycin 1 g/d IM for three weeks; 3) TMP-SMZ 320-1600 mg/d and rifampin 900 mg/d orally for 45 days. All regimens require a combination of two antibiotics and a prolonged course for total recovery, although casual relapses may occur. The doxycycline-rifampin combination shows the most favorable efficacy/safety ratio, and either antibiotic alone was used successfully in pregnant women by some investigators. The TMP-SMZ-rifampin combination is recommended in children below 8 years of age. Osteoarticular infections can be treated with doxycycline plus rifampin for 3 to 6 months, and streptomycin during the first 2 or 3 weeks. In nervous system complications, the preferred treatment is TMP-SMZ plus rifampin for 3 to 6 months. Brucellar endocarditis should be treated parenterally with streptomycin or gentamycin combined with TMP-SMZ, rifampin and doxycycline, and often requires valvular replacement. Many other antibiotics have been used with good clinical responses in the treatment of brucellosis, e.g., chloramphenicol, erythromycin, ampicillin, and more recently cephalosporins, thienamycin and fluoroquinolones; however, more cases have to be studied before any of these agents is definitely chosen for the treatment of brucellosis.

Adult↗
PubMed1994

Isolation and characterization of the THI6 gene encoding a bifunctional thiamin-phosphate pyrophosphorylase/hydroxyethylthiazole kinase from Saccharomyces cerevisiae.

Thiamin-phosphate pyrophosphorylase (TMP-PPase; EC 2.5.1.3) involved in de novo synthesis of thiamin in Saccharomyces cerevisiae is a bifunctional enzyme with 4-methyl-5-beta-hydroxyethylthiazole kinase (Th-kinase; EC 2.7.1.50) activity, which is an octamer of identical 60-kDa subunits (Kawasaki, Y. (1993) J. Bacteriol. 175, 5153-5158). Previous study demonstrated that the activities of both TMP-PPase and Th-kinase are reduced by the mutation of a single nuclear gene, designated THI6. We have cloned the THI6 gene from a yeast genomic library by functional complementation of the thi6 mutant and determined by DNA blot analysis that THI6 is located on chromosome XVI. The nucleotide sequence of the THI6 gene contained an open reading frame of 1,620 base pairs encoding a 540-amino acid polypeptide with a calculated molecular weight of 58,058, which is similar to the determined molecular mass of the purified bifunctional enzyme. Gene disruption demonstrated that the thi6 null strain is auxotrophic for thiamin, indicating that the THI6 protein is essential for thiamin synthesis in yeast. A recently isolated thi6 mutant, thi6-3, bearing a replacement of Glu370 by Lys370, showed a decrease in only Th-kinase activity, proving that the THI6 gene of S. cerevisiae encodes a structural gene of the thiamin biosynthetic bifunctional enzyme. Furthermore, complementation analysis of the thi6 null strain with the modified THI6 DNAs by a 12-nucleotide linker insertion suggested that a region from amino acids 138 to 187 and that from amino acids 370 to 453 are involved in functional domains of TMP-PPase and Th-kinase, respectively, whereas the COOH-terminal region is necessary for both enzyme activities. Strains conferring no Th-kinase but slight TMP-PPase activity could grow in medium without thiamin, suggesting that 4-methyl-5-beta-hydroxyethylthiazole is not involved in the pathway of de novo synthesis of thiamin via 4-methyl-5-beta-hydroxyethylthiazole monophosphate. Northern blot analysis demonstrated that THI6 gene expression is regulated at the mRNA level by intracellular thiamin pyrophosphate, a coenzyme form of thiamin, and that it requires the positive regulatory factors encoded by the THI2 and THI3 genes.

Alkyl and Aryl Transferases↗
PubMed1993

[Therapeutic effects and mechanisms of tetramethylpyrazine on lung injury in acute haemorrhagic necrotizing pancreatitis in rats].

To evaluate the therapeutic effects and mechanisms of tetramethylpyrazine (TMP), a Chinese herbal medicine, on the lung injury in bile-induced acute haemorrhagic necrotizing pancreatitis (AHNP) in the SD rats, the rats were randomly divided into three groups: sham-operative, untreated and TMP treated. AHNP model were induced by ligation with 5% taurocholate. The changes of lung index, serum lipid peroxide (LPO), TXB2, 6-keto-PGF1 alpha, and lung pathology at light and electron microscope were all investigated at 1, 6, 12 hours after induction of AHNP model. Survival rate of AHNP in rats were recorded also. Results of the study showed that in untreated group, the time-related progressive pancreatic haemorrhage and necrosis, accompanied by pancreatitis-associated lung injury, such as pronounced pulmonary congestion, alveolar and interstitial edema, polymorphonuclear granulocytes infiltration, transparent membrane formation, the density of layer body in type II endothelial cells decreasing, with some vacuole formation, mitochondria, endoplasmic reticulum swollen, basal membrane of endothelial cells rupture were observed. The level of LPO elevated at 1 hour after induction of AHNP and peaked at 12 hours. TXB2 and 6-keto-PGF1 alpha was increased. Using TMP treatment, survival rate increased, and lung at light and electron microscope were much improved and lung index, value of LPO, TXB2 decreased significantly, 6-keto-PGF1 alpha increased slightly, the ratio of TXB2/6-keto-PGF1 alpha was stabilized. It was suggested that TMP has definite therapeutic effects on AHNP-related lung injury in rats, and exerted by scavenging oxygen free radical, inhibiting synthesis of TXA2, augmenting production of PGI2 and maintaining balance between TXA2 and PGI2.

6-Ketoprostaglandin F1 alpha↗
PubMed1993

Identification of octopaminergic agonists with selectivity for octopamine receptor subtypes.

Previous studies utilizing relatively nonselective octopamine (OA) agonists have suggested that differences may exist between the pharmacological responses of Gs-linked OA receptors found in various insect tissues and species. The present experiments identify and characterize two structurally related phenyl(imino)imidazolidine (PII) derivatives that demonstrate a significant degree of OA receptor subtype selectivity and, when used in concert, are able to distinguish tissue- and/or species-related differences in OA receptor response. In membrane preparations, 2,4,6-triethyl-PII (TEP) showed > 60-fold selectivity for activating adenylate cyclase in the firefly light organ vs. that in Manduca sexta nerve cord, whereas 2,4,6-trimethyl-PII (TMP) showed > 2-fold selectivity for activating adenylate cyclase in Manduca nerve cord vs. that in the light organ. Within the same tissue, the potency ratio for TEP/TMP was 29 in the light organ and 0.2 in the nerve cord, a degree of selectivity much greater than that of other PII analogs examined. Corresponding physiological measurements of octopaminergic response correlated well with biochemical measurements. TEP was 24-fold more potent than TMP for OA-mediated light emission in intact firefly light organs, whereas TMP was more than 3-fold more potent than TEP as an antifeeding agent in Manduca. These results indicate that the PII analogs, TEP and TMP, should prove quite useful for characterizing and differentiating OA receptor subtypes in various tissues and species. In addition, these findings provide further evidence that light emission in fireflies and disruption of feeding in Manduca involve Gs-linked OA receptors, subtypes of which are distributed differently in the end organs of these two species.

Adenylyl Cyclases↗
PubMed1996

Trimethoprim-sulfamethoxazole and hypouricemia.

BACKGROUND: Hypouricemia has been reported in a substantial fraction of patients with AIDS and attributed to an HIV-related renal urate transport defect. We tested the alternative hypothesis that hypouricemia was associated with the administration of high-dose trimethoprim-sulfamethoxazole (TMP-SMX). METHODS: Sociodemographic, clinical, and repeated laboratory data on 45 hospitalized patients with Pneumocystis carinii pneumonia (PCP) with and without HIV infection, were abstracted by a blinded reviewer. The primary outcome of interest was the percent change in serum uric acid concentration from baseline to hospital day 5 +/- 1. RESULTS: Subjects who received TMP-SMX were older (mean age 44.8 vs. 37.0, p = 0.02), less likely to be HIV-seropositive (61% vs. 94%, p = 0.01), and more likely to have received glucocorticoid therapy (75% vs. 35%, p = 0.01) than those who received pentamidine, dapsone-trimethoprim, clindamycin-primaquine, sulfadiazine-pyramethamine, or a combination of these agents. The administration of TMP-SMX was associated with a 37% +/- 12% reduction in serum uric acid concentration, adjusting for the effects of age, sex, race, HIV antibody status, renal function, serum sodium, and the use of diuretics and glucocorticoids (p = 0.005). CONCLUSION: Among a diverse cohort of hospitalized patients with PCP, treatment with high-dose TMP-SMX was strongly associated with a reduction in serum uric acid concentration over time.

AIDS-Related Opportunistic Infections↗
PubMedDate not supplied

Stenotrophomonas (Xanthomonas) maltophilia: a multidrug-resistant nosocomial pathogen.

Stenotrophomonas (Xanthomonas) maltophilia is emerging as a multidrug-resistant nosocomial pathogen. In general, the organism is opportunistic, colonizing or infecting patients with predisposing risk factors such intensive care unit residence, malignancy, mechanical ventilation, and previous antibiotic exposure. It can cause a variety of infections depending on underlying patient-specific medical conditions. It is often part of multimicrobial infections, and determining its role as a pathogen is difficult. Trimethoprim-sulfamethoxazole (TMP-SMX) has traditionally been the most active agent against S. maltophilia. Other classes of antibiotics, with few exceptions, have not been effective. Synergistic antimicrobial combinations are now being investigated due to the bacteriostatic nature of TMP-SMX, and increasing reports of resistance to TMP-SMX. The combination of ticarcillin-clavulanate plus TMP-SMX appears to be the most promising regimen studied thus far.

Anti-Bacterial Agents↗
PubMed1998

PUVA-induced cell mortality in NCTC 2544 keratinocytes: is it related to the microenvironmental properties of the excited states of psoralens?

The phototoxic effect of psoralen (PSO), 5-methoxypsoralen (5MOP), 8-methoxypsoralen (8MOP) and 4,5',8-trimetylpsoralen (TMP) has been compared on the NCTC 2544 keratinocyte cell line in terms of cell mortality and lipid peroxidation. The order of effectiveness for cell photokilling is TMP, 5MOP >> 8MOP, PSO, whereas a little lipid peroxidation is observed for the four psoralens under study. Oxygen-independent membrane damage seem to play a key role in the lethal photodamage because the biological effectiveness of the most hydrophobic lipid-soluble psoralens, TMP and 5MOP, is about an order of magnitude higher than that of the more water-soluble 8MOP and PSO. In relation to this hypothesis, and in contrast to 8MOP, TMP is readily extracted from cells by ethyl acetate, a good membrane solvent, as shown by GC/MS analysis on cell extracts. The results are discussed in terms of the highly microenvironment-dependent photophysical properties of psoralens. By the measure of the intracellular psoralen concentration, the neutral red uptake and the lipid peroxidation products, this work provides evidence that PUVA therapy-mediated cell mortality is a lipid peroxidation-independent phenomenon.

Cell Line↗
PubMed1997

Is the ultrastructural damage caused by subinhibitory concentrations of trimethoprim and sulphadiazine part of their normal mechanism of action?

The test organism was Escherichia coli 1810 which was highly resistant to trimethoprim (TMP). Electron microscopy (EM) of cells grown in the presence of subinhibitory concentrations of 300 micrograms/ml sulphadiazine (SD) and/or 300 micrograms/ml TMP indicated marked structural damage. No effect on the outer membrane (OM) or ultrastructure of E. coli 1810 was observed with 7.68 micrograms/ml TMP and/or 16.9 micrograms/ml SD. Concentrations of antibacterials affecting the ultrastructure of the bacterial cells of resistant and sensitive E. coli as determined by EM, were shown by a permeability probe (Triton X-100) to alter the OM permeability and to partially inhibit growth of E. coli 1810 cultures. It was concluded that, since the action of SD and TMP, singly and in combination, on the cell structure of E. coli 1810 took place only at concentrations approaching the respective MICs, then this was a part of their normal mechanisms of antibacterial action.

Anti-Bacterial Agents↗
PubMed1998

[Experiences with the rectal use of chemotherapeutic agents. 2. Pharmacokinetic examinations with animals].

The aim of the investigations was to optimise vehicle for trimethoprim (TMP) suppositories ready for clinical trials. The rectal absorption of TMP was studied in anaesthetized rats. The drug liberation properties of the five mixed vehicles with promising in vitro results (Part 1.) were studied. The course of the blood level curves was monitored with serial sampling. The TMP concentration of blood was determined by bioassay. Individual bases were compared with the use of the pharmacokinetic parameters derived from the analysis of the obtained blood level curves, with special respect to biological availability (BA). The extent of bioavailability is influenced considerably by the hydro-, lipo- or lipohydrophilic property of the vehicle. TMP, if incorporated in the proper vehicle, is absorbed well. With three vehicles the extent of absorption exceeded the absorption seen with oral administration on the same model (BA = 38.8%). The best results were achieved with the lipophilic base Witepsol W 35 containing 10% of Polysorbate 20 and 10% of Polysorbate 61 (BA = 63.8%) and with Witepsol W 35 containing 10% of Polysorbate 60 (BA = 64.9%). The hydrophilic Macrogol 1540 vehicle containing 5% of Macrogol 400 had only slightly worse results (BA = 52.9%). In the case of the lipohydrophilic Witepsol W 35 vehicle with 10% of Polysorbate 20 and 10% of Polysorbate 61 content a significant negative exponential relation was found between the administered doses and their respective bioavailability values, this tendency had been observed during the in vitro examinations, too. No such relation was found in the case of the lipophilic Witepsol W 35 vehicle containing 10% of Miglyol 812.

Administration, Oral↗
PubMed1999

Membrane polarization induced in the myocardium by defibrillation fields: an idealized 3-D finite element bidomain/monodomain torso model.

This study develops a three-dimensional finite element torso model with bidomain myocardium to simulate the transmembrane potential (TMP) of the heart induced by defibrillation fields. The inhomogeneities of the torso are modeled as eccentric spherical volumes with both the curvature and the rotation features of cardiac fibers incorporated in the myocardial region. The numerical computation of the finite element bidomain myocardial model is validated by a semianalytic solution. The simulations show that rotation of fiber orientation through the depth of the myocardial wall changes the pattern of polarization and decreases the amount of cardiac tissue polarized compared to the idealized analytic model with no fiber rotation incorporated. The TMP induced by transthoracic and transvenous defibrillation fields are calculated and visualized. The TMP is quantified by a continuous measure of the percentage of myocardial mass above a potential gradient threshold. Using this measure, the root mean square differences in TMP distribution produced by reversing the electrode polarity for anterior-posterior and transvenous electrode configurations are 13.6 and 28.6%, respectively. These results support the claim that a bidomain model of the heart predicts a change of defibrillation threshold with reversed electrode polarity.

Computer Simulation↗