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PubMed1988

Interstrand crosslinks due to 4,5',8-trimethylpsoralen and near ultraviolet light in specific sequences of animal DNA. Effect of constitutive chromatin structure and of induced transcription.

We have used low-level photocrosslinkage to study chromatin effects on psoralen intercalation at specific DNA sequences of various complexities in intact, cultured, Drosophila cells. Alkali-denatured DNA connected in both strands to a 4,5',8-trimethylpsoralen (TMP) interstrand crosslink is insensitive to digestion by the single strand-specific nuclease S1 and does not hybridize to complementary DNA. Crosslink number at any ultraviolet light exposure increases in proportion to the concentration [PS] of TMP dark binding sites that are occupied. The crosslinking constant, K, is the increase in crosslink number per length DNA per increment [PS]. Many factors influence K, including sequence composition and ionic strength. We show here that the ratio of K at any specific sequence (Kh, from hybridization measurements) to Kh at any other specific sequence or to K of total DNA (Kf, from fluorimetry measurements) can be calculated from measurements of crosslinkage, the mass fraction of the sequence in question or of total DNA that is connected in both strands to a crosslink. When crosslinked and uncrosslinked DNAs fragmented by mechanical shear were mixed in known proportions, Kf exceeded Kh of a single-copy gene by 15%. We treated cells with TMP plus near ultraviolet light, then tested for crosslinkage and for hybridization. A single-copy, larval gene at 70D, and a 250-copy type 1 ribosomal DNA intervening sequence, neither of which is transcribed in these cells, were as sensitive to crosslinkage as total, cell DNA. However, single-copy, heat shock gene sequences from loci 63BC and 95D, and the 180-copy ribosomal DNA coding sequence were more sensitive to crosslinkage than total DNA in the same preparations. The excess was largest in the shortest fragments, indicating a localized effect. The same sequences were crosslinked less readily than total DNA in vitro; we calculate a 3.4 to 3.8-fold excess crosslink number in these sequences due to chromatin microenvironment. We tested for effect of transcriptional induction on crosslink sensitivity in the heat shock genes. At low [TMP], heat shock stimulated crosslinkage at or very near heat shock genes in cells, but not in other sequences or in naked DNA. However, overall crosslink sensitivity was unaffected by heat shock. This suggests that transcription increased the affinity of some heat shock gene DNA binding sites for TMP without increasing the number of such sites.

Animals↗
PubMed1993

Pharmacokinetic profile of sulphamonomethoxine-trimethoprim in horses after intravenous, intramuscular and oral administration.

The pharmacokinetic profile of a sulphamonomethoxine-trimethoprim (SMM-TMP) combination was investigated in five horses. The combination was administered intravenously, intramuscularly and orally at a constant dose of 20 mg SMM plus 4 mg TMP kg-1 bodyweight. Following intravenous administration both drugs dispersed rapidly with distribution half-lives of about 12 minutes for SMM and about 18 minutes for TMP. Elimination half-lives for intravenous, intramuscular and oral administration were closely similar, indicating that elimination was independent of administration route. Bioavailability of the drugs in aqueous solution was good: about 72 per cent and 84 per cent for SMM and about 84 per cent and 98 per cent for TMP following intramuscular and oral administration, respectively. It is concluded that SMM-TMP administered orally once a day at 20 mg and 4 mg kg-1 bodyweight, respectively, maintains therapeutic concentrations, whereas twice daily intramuscular administration would be more effective for treating systemic infections in the horse than the once a day regimen usually adopted in veterinary practice.

Absorption↗
PubMed1987

In vitro susceptibility of Plasmodium falciparum malaria to pyrimethamine, sulfadoxine, trimethoprim and sulfamethoxazole, singly and in combination.

Two isolates of Plasmodium falciparum (F 32 and K 1) were tested against sulfadoxine (SDX), sulfamethoxazole (SMZ), pyrimethamine (PYR) and trimethoprim (TMP), using a 48 h microtest, with RPMI-1640 low in PABA and folic acid. The IC50 for F 32 was: PYR 6.1 X 10(-9) M (mol/litre), TMP 1.3 X 10(-7) M, Fansidar (SDX/PYR 80:1) less than 10(-8) to 1.3 X 10(-10) M and cotrimoxazole (SMZ/TMP 20:1) 2.6 X 10(-7) to 1.3 X 10(-8) M. The IC50 for K 1 was: PYR greater than 10(-6) M, TMP 8.2 X 10(-7) M, Fansidar 4.1 X 10(-7) to 1.1 X 10(-9) M and cotrimoxazole 1.8 X 10(-6) to 9.0 X 10(-8) M. The difference in IC50 between F 32 and K 1 against TMP and cotrimoxazole is much less than the difference between the IC50 values against PYR and Fansidar, indicating that cross-resistance between PYR and TMP exists, but is not complete. A method for calculating the IC50 by linear regression analysis is described.

Animals↗
PubMed1987

Investigations into the mechanism of immunosuppression caused by acute treatment with O,O,S-trimethyl phosphorothioate: generation of suppressive macrophages from treated animals.

At concentrations normally found in the spleen, macrophages from animals treated with O,O,S-trimethyl phosphorothioate (OOS-TMP) for 24 hr were previously shown to be immunosuppressive (Rodgers et al., 1985b). In addition, it was shown that macrophages from OOS-TMP-treated animals had a diminished capacity to present antigen (Rodgers et al., 1985c). In this report, it was shown that lowering the number of splenic adherent cells (95% macrophages by morphology) utilized in cell-mixing experiments to reconstitute the nonadherent splenic populations returned the humoral immune response to control levels. One day following acute administration of OOS-TMP, resident peritoneal cells were able to suppress the proliferation of P815 tumor cells. In addition, proliferative responses to concanavalin A and lipopolysaccharide were decreased at suboptimal concentrations of mitogen. Fresh supernatants from splenocytes cultured for 24 hr from OOS-TMP-treated animals blocked the generation of a humoral immune response. However, supernatants from splenocytes of control animals generated in the same manner did not block the generation of a humoral immune response. These data suggest that OOS-TMP induced the generation of suppressive macrophages which may potentially act through the release of labile factors which block proliferation or antigen- or mitogen-induced lymphocyte stimulation.

Animals↗
PubMed1992

Alpha 2u-globulin is the only member of the lipocalin protein superfamily that binds to hyaline droplet inducing agents.

The rate-limiting step in chemically induced, male rat-specific hyaline droplet nephropathy is the reversible binding of a xenobiotic to alpha 2u-globulin. In this study, equilibrium saturation binding experiments were conducted to evaluate the in vitro binding of d-limonene-1,2-oxide (dLO) and 2,4,4-trimethyl-2-pentanol (TMP-OH) to alpha 2u-globulin and members of the alpha 2u-globulin protein superfamily. Both dLO and TMP-OH bound to alpha 2u-globulin, with Scatchard analysis yielding dissociation constants of 5.6 and 6.4 x 10(-7) M, respectively. The Bmax for binding (nmol bound/mg protein) was 50.7 and 61.1 for dLO and TMP-OH, respectively, yielding a molar ratio of approximately 1 for both ligands. The ability of dLO and TMP-OH to bind to human-derived alpha 1-acid glycoprotein, rat-derived retinol-binding protein, human protein-1, and bovine beta-lactoglobulin was also studied. These superfamily proteins are generally abundant in plasma, are freely filtered across the glomerulus, and can bind a wide range of ligands. However, neither dLO nor TMP-OH bound to any of the superfamily proteins. In contrast, under identical experimental conditions, alpha 1-acid glycoprotein did bind progesterone (Kd = 10(-6) M), whereas both beta-lactoglobulin and retinol-binding protein bound retinol (Kd = 10(-8) M for both proteins). These results indicate that, under conditions where alpha 2u-globulin superfamily proteins bind to established ligands, the proteins do not interact with hyaline droplet inducing agents. Thus, the interaction between male rat-specific nephrotoxicants and alpha 2u-globulin is unique to this protein. More importantly, these results provide direct evidence that the presence of the alpha 2u-globulin superfamily proteins does not predispose humans to develop hyaline droplet nephropathy and renal cancer from this class of chemicals.

Alpha-Globulins↗
PubMedDate not supplied

Comparison of enoxacin versus trimethoprim-sulfamethoxazole in the treatment of patients with complicated urinary tract infection.

Given the prevalence of complicated urinary tract infection (UTI) and the resistance patterns of common uropathogens, antimicrobial therapy for complicated UTI must be carefully selected. For patients with complicated UTI who can be treated with oral medication, the quinolones or trimethoprim-sulfamethoxazole (TMP-SMX) are reasonable treatment choices. Enoxacin and TMP-SMX were compared for efficacy, safety, and bacteriologic response in this study. A total of 260 patients with complicated UTI were enrolled in a multicenter, open-label, randomized study and received enoxacin or TMP-SMX. Short-term assessments 5 to 9 days posttherapy and long-term assessments 4 to 6 weeks posttherapy included physical and clinical evaluations, laboratory testing, urine cultures, and susceptibility testing. Although enoxacin and TMP-SMX demonstrated comparable short-term efficacy rates, enoxacin exerted a potent, long-term bacteriologic response, particularly against Escherichia coli. Enoxacin therapy achieved a 94.7% long-term eradication rate against E coli compared with a 76.0% eradication rate against this pathogen with TMP-SMX. Most adverse events were mild, and a comparable incidence (approximately 17%) occurred in both treatment groups. These data indicate that enoxacin is an excellent addition to the armamentarium of agents commonly used in the treatment of patients with complicated UTI.

Adult↗
PubMed1985

Investigations into the mechanism of immunosuppression caused by acute treatment with O,O,S-trimethyl phosphorothioate. I. Characterization of the immune cell population affected.

Acute administration of O,O,S-trimethyl phosphorothioate (OOS-TMP), an impurity in technical formulations of malathion, to female C57B1/6 mice was previously shown to suppress the generation of both cytotoxic T lymphocyte to alloantigen and antibody-secreting cells to sheep red blood cells. In this report, macrophages were shown to be the immune cell population most affected by acute OOS-TMP pretreatment by cell separation and reconstitution experiments. Macrophages from OOS-TMP-treated animals had increased levels of nonspecific esterases. In addition, the size distribution of macrophages from treated animals was slightly larger and more heterogeneous than macrophages from control animals. However, macrophages from OOS-TMP-treated animals did not exhibit tumoricidal activity. These data suggest that macrophages from OOS-TMP-treated animals were similar to those located in nonimmune inflammatory sites.

Animals↗
PubMed1986

Organophosphorus pesticide immunotoxicity: effects of O,O,S-trimethyl phosphorothioate on cellular and humoral immune response systems.

The time course of immunosuppression induced by acute treatment with O,O,S-trimethyl phosphorothioate (OOS-TMP), an impurity in technical formulations of malathion, was examined in female C57B1/6 mice. Both cell-mediated and humoral immune responses were examined and included allospecific cytotoxic T cells, proliferative response to mitogens, interleukin-2 production and antibody production to sheep red blood cells. OOS-TMP pretreatment led to a reversible suppression of the generation of cytotoxic T lymphocytes and antibody-secreting cells to sheep erythrocytes. However, the mitogenic response of splenocytes from animals treated with nontoxic doses of OOS-TMP (as measured by body weight loss, serum cholinesterase levels and splenic lymphocyte number) to concanavalin A was not significantly suppressed, but the response to the B cell mitogen lipopolysaccharide was slightly decreased on day 1 following treatment. In contrast, interleukin-2 production was elevated by 24 h following treatment, but had returned to control levels by day 7. These data suggest that OOS-TMP was able to block the generation of cytotoxic T lymphocytes and antibody responses at doses of OOS-TMP that did not affect body weight or splenic lymphocyte number and this suppression was reversible.

Animals↗
PubMed1996

Lymphoblastoid transmembrane potential in bipolar patients, their siblings, and unrelated healthy comparison subjects.

Bipolar illness appears to be characterized by alterations in ionic homeostasis that are related to mood state. This is reflected by reports of altered intracellular sodium and calcium concentrations, altered sodium pump (Na+,K+-adenosine triphosphatase), and calcium pump (Ca2+-adenosine triphosphatase) activity. Recent ex vivo studies with fresh lymphocytes and in vitro studies with cultured lymphoblasts suggest that there may be an enduring trait-related abnormality in Na+,K+-adenosine triphosphatase as well. We have previously found that the lymphocyte transmembrane potential (TMP) varies with mood state. To examine the question of trait-related changes in TMP, we studied TMP of immortalized lymphoblasts from 14 patients with bipolar illness, nine unaffected siblings, and eight normal subjects. TMP was the same in all three groups. These preliminary data suggest that TMP is a state-- rather than a trait-related marker.

Adult↗
PubMed1982

Comparison of the in vitro and in vivo anti-herpes activities of 1-beta-D-arabinofuranosylthymine and its 5'-monophosphate.

In vitro and in vivo anti-herpes activities of 1-beta-D-arabinofuranosylthymine 5'-monophosphate (ara-TMP) were compared with those of 1-beta-D-arabinofuranosylthymine (ara-T). On a molar basis ara-TMP was almost as active as ara-T against six strains of herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) as monitored by a cytopathogenicity-inhibition and a plaque reduction assay in human embryonic lung fibroblast cells. When tested against experimental encephalitis in mice inoculated intracerebrally with HSV-1, intraperitoneal or intravenous treatment with 150 mg/kg/day of ara-TMP or 100 mg/kg/day of ara-T, for 5 days was effective in increasing in the mean survival time of mice. For a single dose of ara-TMP, intravenous administration was more effective than intraperitoneal or oral administration. However, oral administration of ara-T was the most effective of the treatment regimens used. Substantial plasma levels of ara-T were detected for a longer time after oral administration of ara-T than after intravenous administration of ara-TMP or ara-T, suggesting that the efficacy of oral administration of ara-T may be correlated with the maintenance of the substantial blood drug levels.

Animals↗
PubMed1989

Effects of subacute administration of O,S,S-trimethyl phosphorodithioate on cellular and humoral immune response systems.

The effects of 14-day treatment with low doses of O,S,S-trimethyl phosphorodithioate (OSS-TMP), an impurity in technical malathion, on the generation of cell-mediated and humoral immune responses were examined in female C57BL/6 mice. At a dose of 2.0 mg/kg per day OSS-TMP, the generation of antibody-secreting cells to sheep red blood cells, the generation of cytotoxic T lymphocytes (CTL) to alloantigen and the production of Interleukin-2 were elevated approximately 2-3 fold, while no changes were observed in the proliferative responses to the polyclonal activators, Concanavalin A, lipopolysaccharide, or phytohemagglutinin. In contrast, at 5.0 mg/kg per day OSS-TMP, both the CTL and specific antibody responses were suppressed, while all other immune parameters examined were unchanged. Data from cell separation and reconstitution experiments indicated that both T and B lymphocytes were affected by these treatment regimes. These data suggest that long-term exposure to low doses of OSS-TMP may enhance the ability of an animal to generate an immune response while higher doses of OSS-TMP may suppress the generation of an immune response.

Animals↗
PubMed1986

Increased resorption of embryos in O,O,S-trimethyl phosphorothioate-treated rats.

Pregnant rats (N = 7) were dosed p.o. with O,O,S-trimethyl phosphorothioate (OOS-TMP) (LD50 = 85) at 20 mg/kg on days G8 and G10. Seven animals were treated with corn oil and pair-fed. Five control animals were treated with corn oil. The abdomen was palpated on day G15 and in 4 animals out of 7 treated with OOS-TMP, complete resorption was observed. All pair-fed and control animals maintained pregnancy until day G21. Total number of resorption/number of implants was 60/95 (63.2%) in OOS-TMP animals, 21/82 (25.6%) in pair-fed animals and 4/65 (6.5%) in control animals. Incidence of complete resorption and % resorption were significantly higher (P less than 0.03 and P less than 0.01) in comparison with those in pair-fed animals. Fetuses from OOS-TMP mothers showed slight growth retardation. By skeletal examination, a missing vertebra and delayed ossifications were found in animals treated with OOS-TMP (20 mg/kg).

Abnormalities, Drug-Induced↗
PubMed1986

Similarity of isozyme pattern of serum lactate dehydrogenase following treatments with O,O,S-trimethyl phosphorothioate and paraquat.

Oral administration of O,O,S-trimethyl phosphorothioate (OOS-TMP) causes delayed mortality and lung injury in rats. The present study was carried out to determine whether serum lactate dehydrogenase (LDH) activity and its isozyme pattern were capable of detecting lung injury and possible other organ damages caused by OOS-TMP. Carbon tetrachloride (CCl4, 1 ml/kg, i.p., 24 h) and paraquat (25 mg/kg, i.p., 48 h) were selected as standard chemicals for liver injury, and lung and kidney injuries, respectively. The activity of serum LDH increased to 4 times above control following treatment of rats with OOS-TMP (20 mg/kg, p.o., 72 h). Treatment with CCl4 increased the activity to 8 times while paraquat only slightly increased the activity. Isoelectrophoresis of serum samples showed that OOS-TMP increased the activities of isozymes LDH 1 and LDH 2. This isozyme pattern was similar to the pattern of paraquat but quite different from the pattern in animals treated with CCl4, where LDH 5 was most predominant, or in control animals. Thus, the isozyme pattern strongly suggests that OOS-TMP causes the similar organ damage evoked by paraquat, lung and kidney.

Administration, Oral↗
PubMed1990

Lack of detectable metabolism for solubilized 2,3,4-trimethylpentane by rat kidney proximal tubules.

Primary proximal tubule suspension cultures exposed to solubilized 2,3,4-trimethylpentane (2,3,4-TMP) resulted in a linear dose response, as determined by cellular lactate dehydrogenase leakage. The EC50 for 2,3,4-TMP was 16.3 mM. Metabolite analysis by gas chromatography/mass spectrometry of supernate and cell extracts from cultures exposed to 2,3,4-TMP (12.0 mM) failed to detect the presence of metabolites. Electron-microscopic examination of proximal tubules exposed to 2,3,4-TMP indicated ultrastructural changes that included increased mitochondrial swelling, increased vesiculation, decreased microvilli and pyknotic nuclei. This study indicates that kidney proximal tubules do not appear to metabolize 2,3,4-TMP.

Animals↗
PubMed2004

Effect of chronic systemic use of trimethoprim-sulfamethoxazole in the conjunctival bacterial flora of patients with HIV infection.

PURPOSE: To investigate the effect of orally administered trimethoprim-sulfamethoxazole (TMP-SMZ) on the prevalence, species distribution, and resistance of the conjunctival bacterial flora in adults with human immunodeficiency virus (HIV) infection. DESIGN: Cross-sectional study, with clinical and experimental laboratory investigation. METHODS: Samples from the inferior conjunctival fornix were collected and submitted for culture to evaluate aerobic flora. RESULTS: Sixty samples were collected. Negative cultures were found in 17 (56.7%) eyes of the TMP-SMZ group and in 10 (33%) of the control group (P = .036). All Staphylococcus species isolates in the TMP-SMZ group were resistant to the drug, whereas 50% of the control group presented this finding (P = .025). In the study group, all bacteria were resistant to TMP-SMZ, compared with only 47% of the microorganisms in the control group. CONCLUSION: Orally administered TMP-SMZ in patients with HIV infection seems to exert a selection pressure in the microorganisms present on the conjunctiva.

Administration, Oral↗
PubMed2006

Microfiltration for separation of green algae from water.

Cross-flow microfiltration was used for separation of green algae, Chlorella sp., from freshwater. The transmembrane pressure (TMP) was adjusted at 40, 50 and 60 kPa, respectively. The cross-flow velocity was set at 0.43 m/s for laminar flow and 0.84 m/s for turbulent flow, respectively. The results showed that flux increased as TMP increased from 40 to 50 kPa. But drastic flux decline was observed when operating at TMP of 60 kPa. Raising cross-flow velocity increased the initial flux of MF under TMP of 60 kPa. Nevertheless, implementing turbulent cross-flow did not improve the drastic flux decline under the highest TMP. Preozonation increased the dissolved organic carbon, decreased algal viability and made the size of algal cells smaller. It also increased dissolved polysaccharide that derived from extracellular organic matter (EOM). Different effects of preozonation on flux behavior of MF were observed when utilizing hydrophobic and hydrophilic membrane. Generally speaking, preozonation improved performance of microfiltration by reducing cake compressibility and the biomass loading when both membranes were used. However, dissolved polysaccharide released during preozonation was adsorbed onto the hydrophobic membrane. Consequently, fouling resistance of the hydrophobic membrane became higher. These arguments were verified by classification of hydrodynamic resistances.

Chlorella↗
PubMed2004

Chemometric and derivative methods as flexible spectrophotometric approaches for dissolution and assaying tests in multicomponent tablets.

Two derivative spectrophotometric (ratio derivative spectra and algorithm bivariate calibration) and a chemometric methods (partial least squares, PLS) are proposed for the simultaneous determination of binary mixtures in tablet analysis and dissolutions tests, without prior separation. These approaches are successfully applied to quantify trimethoprim (TMP) combined with sulfamethoxazole (SMX) or sulfamethazine (SMZ) or sulfafurazole (SFZ) using the information in the absorption spectra of appropriate solutions. Beer's law was obeyed in the concentration range of 0.98-17.5 microg/ml for TMP, 0.95-17.2 microg/ml for SMX, 1.16-17.5 microg/ml for SMZ and 0.97-17.4 microg/ml for SFZ. The first derivative (1D) bivariate algorithm method involves the use of four calibration curves: two for each compound at two different wavelengths, selected by Kaiser's method. Similarly, the first derivative ratio spectrophotometry employs the linear relationship between the ratio spectra of the analytes and the concentration range. The results were compared with those obtained by PLS multivariate calibration. The calibration models from PLS were pre-treated by orthogonal signal correction and evaluated by cross-validation using the 'SIMCA-P 9' software. Synthetic mixtures of TMP and sulfonamides were used in five different sets for the validity of the calibrations. Mean recoveries for derivative ratio, derivative bivariate and PLS methods were found to be between 99.7% and 102.0% for TMP, 99.4% and 100.2% for SMX, 99.3% and 101.0% for SMZ and 98.1% and 102.3% for SFZ. The calibrations of the three methods were successfully applied to the assaying and dissolution of placebo and commercial tablets without any prior separation. More than 85% of TMP, SMX and SMZ were dissolved within 15 min. For SFZ, only 85% of the compound was dissolved after 60 min. In this study, the three spectrophotometric methods can be satisfactorily used for the quantitative analysis and for dissolution tests of multicomponent dosage forms.

Algorithms↗
PubMed2005

High-performance liquid chromatography method for the simultaneous determination of sulfamethoxazole and trimethoprim in bovine milk using an on-line clean-up column.

A bidimensional HPLC method for the simultaneous determination of sulfamethoxazole (SMX) and trimethoprim (TMP) in bovine milk has been developed and validated. After centrifugation, aliquots (150 microl) of milk samples were directly injected to a column-switching HPLC system. At the first step a RAM octyl-BSA column was employed to automatically remove proteins that otherwise would interfere with milk analysis. The mobile phase 0.01 M phosphate buffer pH 6.0:acetonitrile (95:5, v/v) was used in the first 5 min for the elution of milk proteins and then 0.01 M phosphate buffer pH 6.0:acetonitrile (83:17, v/v) for transfer SMX and TMP to the analytical column. The separation of SMX and TMP from one another and from other remaining milk components was performed on an octyl column using the mobile phase 0.01 M phosphate buffer pH 5.0:acetonitrile (82:18, v/v), which were detected by UV at 265 nm. The calibration graphs were linear in the concentration ranges of 25-800 ng/ml and 50-400 ng/ml for SMX and TMP, respectively. The intra- and inter-assay coefficients of variation were less than 15% for both drugs. The validated method was applied to the analysis of milk samples of twelve (two groups of six) cows after administration (intramuscular or subcutaneous) of a single recommended therapeutic dose of the SMX-TMP combination.

Animals↗