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PubMed1995

Case report: reversible hyperkalemia associated with trimethoprim- sulfamethoxazole.

Trimethoprim-sulfamethoxazole (TMP-SMX) is a fixed-dose antimicrobial agent used in a variety of infections. Adverse reactions are more common in patients with AIDS, but occasionally occur in immunocompetent patients. Renal toxicity is usually a hypersensitivity reaction to the sulfa component, and manifests as interstitial nephritis or sulfa crystallization in the renal tubules. Reversible hyperkalemia is a rarely reported side effect of TMP-SMX therapy attributed to TMP inhibition of potassium secretion in the distal renal tubule in a manner similar to the potassium sparing diuretic, amiloride. In this article, the author reports a case of hyperkalemia associated with TMP-SMK occurring in an elderly man with no other risk factors for hyperkalemia, which resolved upon discontinuation of the drug.

Aged↗
PubMed1997

Novel tetramethylpiperidine-substituted phenazines are potent inhibitors of P-glycoprotein activity in a multidrug resistant cancer cell line.

The multidrug resistance (MDR)-neutralizing and cytotoxic properties of 16 novel tetramethylpiperidine (TMP)-substituted phenazines were compared with those of clofazimine and B669 using a P-glycoprotein (P-gp)-expressing undifferentiated, human leukemia cell line (K562/MMB). Unchlorinated TMP-substituted phenazine molecules were more cytotoxic than their chlorinated counterparts, while the halogenated molecules, especially those with chlorine atoms at position 3 on the aniline and phenyl rings, were less cytotoxic but more effective as chemosensitizing, P-gp-neutralizing agents. One of the TMP-substituted phenazines, B4121, increased the sensitivity of K562/MMB cells to vinblastine by 100-fold. TMP-substituted phenazines are a novel class of pharmacologic anti-cancer agents with both direct cytotoxic, as well as MDR-neutralizing anti-tumor properties.

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

Theoretical comparison of filtration by the renal glomerulus and artificial membranes.

Improvement in filtration performance of artificial membranes will be possible if their structure mimics the renal glomerulus. Blood filtration with glomerular capillary and artificial membranes was, therefore, modeled to clarify the effects of their structure on filtration rates. Filtration rates were obtained by dividing membrane modules axially into a number of sections and using a calculus of finite differences. The modules were assumed to be composed of straight hollow fibers arranged in parallel, with a membrane surface area of 1.5 m2. The mean transmembrane pressure (TMP) was assumed to be too low for a protein gel layer to form on the membrane surface. A decrease in the inner diameter of membrane hollow fibers led to an increase in filtration rate because of an increased film mass transfer coefficient. A decrease in hollow fiber length also produced an increase in filtration rate because of decreased axial TMP drop. The glomerular capillary has a higher filtration rate than artificial membranes because of the low TMP drop and the low osmotic pressure at the membrane surface. Decreasing both the inner diameter and the length of the hollow fibers is effective in increasing the filtration rate at constant TMP.

Blood Flow Velocity↗
PubMed1991

Resolution of otitis media with effusion with the use of a stepped treatment regimen of trimethoprim-sulfamethoxazole and prednisone.

This double blind, placebo-controlled trial was designed to determine whether intervention with a stepped regimen of trimethoprim-sulfamethoxazole (TMP-SMX) and prednisone would prevent high risk children from developing chronic otitis media with effusion (OME) and recurrent acute otitis media. Forty-two children were enrolled, assigned to treatment with active drug or placebo and then examined at 2-week intervals. They received TMP-SMX (or placebo) during the first 2 weeks, TMP-SMX and prednisone (or placebo) during Weeks 3 and 4 for persistent OME and TMP-SMX (or placebo) for Weeks 5 and 6 if OME was still unresolved. After treatment 48% of active drug and 14% of placebo subjects resolved OME bilaterally (P less than 0.05). Active drug subjects also had fewer acute otitis media episodes than placebo subjects while receiving study treatment (P less than 0.01). Although this treatment regimen produced short term OME resolution, long term benefits were not demonstrated.

Child↗
PubMed1990

High-performance liquid chromatographic assay for the simultaneous measurement of trimethoprim and sulfamethoxazole in plasma or urine.

Procedures for the simultaneous determination of trimethoprim (TMP) and sulfamethoxazole (SMX) in plasma or urine are reported. The drugs are extracted from plasma or urine by a single solid-phase extraction and quantitated by high-performance liquid chromatography. Both drugs are analyzed in the same chromatographic run. Intra- and interassay variability are less than 10% for both compounds, and the recovery and precision of TMP measurement are unaffected by concurrent SMX concentrations. Limits of quantitation for TMP and SMX in plasma were 0.02 and 0.21 microgram/ml, respectively. In urine, the limit of quantitation for both drugs was 1.0 microgram/ml. Metabolites of TMP and SMX did not interfere with the assay. Pharmacokinetic parameters from volunteers given two formulations of co-trimoxazole in a crossover comparison study are reported.

Biological Availability↗
PubMed1995

High-performance liquid chromatographic evaluation of the effect of heat treatment on trimethoprim and sulfamethoxazole stability in serum.

Heat treatment of patient samples is utilized as a method to decrease the risk of accidental transmission of human immunodeficiency virus (HIV). Heat treatment has been reported to affect the outcome of drug analysis. In this study, the effects of heat treatment (56 degrees C for 5 h) and storage for 2 months at -20 degrees C on the stability of trimethoprim (TMP) and sulfamethoxazole (SMX) at three different concentrations in serum (10/100, 1/20, and 0.1/5 microgram/mL) each were evaluated. Simultaneous determination of TMP, SMX, and sulfamethazine (SMeth), the internal standard, in serum was performed by a reversed-phase high-performance liquid chromatographic (HPLC) procedure with isocratic elution and ultraviolet detection. The peak/height ratios (PHRs) for each sample from untreated and heat-treated groups were compared. No statistically significant differences were found between untreated and heat-treated groups for TMP. Heat treatment decreased the PHR for SMX at 100 micrograms/ml concentration (p = 0.042) and increased the PHR for SMX at 20 micrograms/ml concentration (p = 0.049). These marginal differences are unlikely to be significant. Storage of samples for 2 months at -20 degrees C had no statistically significant effect on sample PHRs. Thus, heat treatment of serum does not alter clinical interpretation of TMP and SMX at clinically relevant concentrations and may protect laboratory workers from accidental HIV exposure.

Anti-Infective Agents↗
PubMed1979

Effect of trimethoprim-sulfamethoxazole on hematological recovery after total body irradiation and autologous marrow infusion in dogs.

To test the effect of the combination of trimethoprim-sulfamethoxazole (TMP-SMX) on hematological recovery after bone marrow transplantation, dogs were conditioned with 1,200 R total body irradiation and then infused with autologous marrow. Twenty dogs were given TMP-SMX at doses equivalent to 10, 20, or 40 mg TMP/kg/day beginning on the day of marrow infusion and continued until the granulocyte count reached 10(3)/mul; in addition, one-half of the dogs received methotrexate, 0.4 mg/kg on days 1, 3, 6, and 11 and then weekly until termination of the study. Granulocyte and platelet changes were compared to those of dogs given 1,200 R, autologous marrow infusion, and no TMP-SMX. Dogs given 10 and 20 mg TMP/kg/day had normal granulocyte and platelet recovery after irradiation. Dogs given 40 mg TMP/kg/day showed a significant delay in granulocyte recovery and mildly delayed platelet recovery. This suggests that TMP-SMX in prophylactic doses (5 mg TMP/kg/day) can be given safely to human patients immediately after allogeneic marrow transplantation and thus probably prevent even very early cases of Pneumocystis carinii pneumonia, and possibly bacterial infections as well.

Animals↗
PubMed1999

Effect of trimethoprim-sulfamethoxazole as Pneumocystis carinii pneumonia prophylaxis on bacterial illness, Pneumocystis carinii pneumonia, and death in persons with AIDS.

To measure the effect of trimethoprim-sulfamethoxazole (TMP-SMX) in preventing bacterial illness, Pneumocystis carinii pneumonia (PCP), and death in people with AIDS, we conducted a retrospective medical record review of 1078 persons who were observed for 3 years on average who attended nine outpatient facilities in Seattle, Washington between January 1990 and April 1996. We calculated relative risk estimates to measure the protective effect of TMP-SMX on the development of major bacterial illnesses, PCP, and death. Use of TMP-SMX decreased the risk of PCP (relative risk [RR] = 0.23; 95% confidence interval [CI], 0.14-0.36) and deaths not attributable to PCP (RR = 0.59; 95% CI, 0.47-0.73). Prevention of major bacterial illnesses of known etiology was of borderline significance (RR = 0.77; 95% CI, 0.57-1.05) and became statistically significant with the addition of patients with infections of unknown etiology (RR = 0.77; 95% CI 0.61-0.97). Use of TMP-SMX PCP prophylaxis significantly reduced the risks of death and of PCP and was associated with a trend toward reduced risk of major bacterial infections.

AIDS-Related Opportunistic Infections↗
PubMed2005

Psychophysical investigation of ganglion cell loss in early glaucoma.

PURPOSE: To evaluate ganglion cell loss in early glaucoma using a variety of psychophysical tests and to identify optimal perimetric technique(s) for detection of early glaucomatous visual function loss. METHODS: Five perimetric tests, short wavelength automated perimetry (SWAP), temporal modulation perimetry (TMP), frequency doubling technology perimetry (FDT), detection acuity perimetry (DAP), and resolution acuity perimetry (RAP) were compared in their ability to discriminate between normal individuals and patients with early glaucoma or glaucoma suspects. Comparisons were also made by their ability to produce repeatable defects. The tests examined different visual functions that are likely to be mediated by different retinal ganglion cell subpopulations, thereby permitting examination of hypotheses of ganglion cell death in early glaucoma. RESULTS: All visual field tests demonstrated high performance in separating glaucoma patients from normal individuals. SWAP, TMP, FDT, and DAP provided the greatest discrimination between normal individuals and high- and low-risk glaucoma suspects. However, SWAP, TMP, and FDT obtained better consistency across the various analysis approaches (global indices and pointwise) than DAP and RAP. Of all the test types, FDT exhibited the highest proportion of repeatable abnormal test locations, with poor confirmation rates achieved by DAP and RAP. CONCLUSION: The performance of SWAP, FDT, and TMP suggests that these test types may all be suitable for detection of early loss of visual function in glaucoma. Ganglion cell subpopulations with lower levels of redundancy and/or those with larger cell sizes offer the most parsimonious explanation for earliest ganglion cell losses occurring in glaucoma.

Cell Death↗
PubMed1994

Analysis of the thymidine kinase of a herpes simplex virus type 1 isolate that exhibits resistance to (E)-5-(2-bromovinyl)-2'-deoxyuridine.

The mechanism responsible for the decreased sensitivity of a clinical herpes simplex virus type 1 (HSV-1) isolate, HSV-145, to (E)-5-(2-bromovinyl)-2'-deoxyuridine (BVDU) was examined. Measurements of 50% inhibitory doses of several drugs demonstrated that although HSV-145 was sensitive to phosphonoacetic acid, adenine arabinoside and acyclovir, its sensitivity to BVDU and 5-(2-chloroethyl)-2'-deoxyuridine was significantly less than that normally observed for HSV-1. Analysis of the thymidylate kinase (TMP-K) activity of HSV-145 thymidine kinase (TK) demonstrated a decreased level of TMP-K activity when compared to HSV-1 TK. The TMP-K activity of HSV-145 resembled that observed for HSV-2 and the TK-deficient strain HSV-1 TK-7. When the nucleotide sequence of the HSV-145 TK gene was compared to that of the HSV-1 strains C1(101) and SC16 a single nucleotide substitution (G changed to A at base position 502) was detected which would result in the substitution of threonine at amino acid position 168 for alanine. The substitution is the same as that for the laboratory-derived BVDU-resistant virus HSV-1 SC16B3. Collectively, these studies highlight the importance of amino acid conservation at position 168 of the HSV-1 TK in conferring efficient TMP-K activity and BVDU sensitivity.

Acyclovir↗
PubMed1988

A th-1 Mutant of Arabidopsis thaliana Is Defective for a Thiamin-Phosphate-Synthesizing Enzyme: Thiamin Phosphate Pyrophosphorylase.

We have examined the activity of the thiamin phosphate pyrophosphorylase in Arabidopsis thaliana wild type and in a mutant (th-1) which requires exogenous thiamin for growth. Mutant and wild-type plants grown in 1 x 10(-7) molar thiamin were used for the examination of the production of thiamin and thiamin monophosphate (TMP) using 4-methyl-5-hydroxyethylthiazole phosphate and 2-methyl-4-amino-5-hydroxymethylpyrimidine pyrophosphate as substrates. While the wild-type strain formed both thiamin and TMP, the th-1 mutant did not. When TMP was added to the extracts, the th-1 mutant, as well as wild type, produced thiamin. Accordingly, it was concluded that the th-1 mutant was defective in the activity of TMP pyrophosphorylase. Some of the characteristics of the enzyme from the wild-type plant were examined. The optimum temperature for the reaction is 45 degrees C, and the K(m) values for the substrates are 2.7 x 10(-6) molar for 4-methyl-5-hydroxyethylthiazole phosphate and 1.8 x 10(-6) molar for 2-methyl-4-amino-5-hydroxymethylpyrimidine pyrophosphate.

Journal Article↗
PubMed2002

A pseudo-quadruple hydrogen-bonding motif consisting of six N-H...O hydrogen bonds in trimethoprim formate.

The title compound, trimethoprim (TMP) formate [systematic name: 2,4-diamino-5-(3,4,5-trimethoxybenzyl)pyrimidin-1-ium formate], C(14)H(19)N(4)O(3)(+).CHO(2)(-), reveals a pseudo-quadruple hydrogen-bonding motif consisting of six N-H.O hydrogen bonds involving two unpaired TMP cations and two formate anions which are symmetrically disposed. The hydrogen-bonding motif is strikingly comparable with that observed in other TMP salts where the aminopyrimidine moieties of the TMP cations are centrosymmetrically paired. These conserved hydrogen-bonding motifs may serve as robust synthons in crystal engineering and design. The characteristic pseudo-quadruple hydrogen-bonding motif and other intermolecular hydrogen bonds operating in the crystal form a two-dimensional supramolecular sheet structure.

Crystallography, X-Ray↗
PubMed1998

Biological cells with gap junctions in low-frequency electric fields.

Biological effects have been observed from weak, low-frequency magnetic fields. It has been suggested that the observed effects are due to the induced currents and electric fields. The behavior of cells exposed to an electric field is investigated in this paper. The induced transmembrane potential (TMP) is examined in geometrically complex models of various cell configurations. The TMP is evaluated using the finite element method (FEM), a numerical technique that is well suited to complicated geometries. Because displacement currents can be neglected at very low frequencies, a FEM solver that considers only material conductivity is used. Therefore, our results apply only well below the relaxation frequency. Chains and clusters of gap-connected cells of various sizes are modeled. The conductivity and size of the gap junctions in the cell configurations are also varied. The results for small configurations are compared to models of ellipsoidal cells with shapes similar to those of the configurations. FEM estimates of TMP's in long, cylindrical cell chains are compared to the predictions of the leaky cable model. The FEM approach confirms that gap-junction-connected cells can be treated as a single similarly shaped cell. Gaps influence the potential in the interior of cell configurations, and these effects increase with gap size and conductivity. For configurations to which approximations such as the leaky cable model do not apply, the FEM approach can be used to estimate the TMP, if the model is adapted to fit within computational memory limits.

Animals↗
PubMed1985

Psoralens increase the concentration of cyclic AMP in human cells in vitro.

8-Methoxypsoralen (8-MOP) and 4,5',8-trimethylpsoralen (TMP) were assessed for their effects on cyclic AMP (cAMP) accumulation in normal human fibroblasts, epithelial cells, and mononuclear leukocytes in vitro. In the absence of ultraviolet A radiation, 8-MOP and TMP caused an increase in the concentration of cAMP, but not cyclic GMP, in all of these cells. The effect was seen within 1 min and was sustained over control levels for at least 6 h. At 15 min, the highest dose of 8-MOP or TMP increased the cAMP concentration of fibroblasts by 52% and 69%, respectively. In mononuclear leukocytes, 8-MOP led to a 142% increase in cAMP after 20 min. Several analogs of 8-MOP and TMP had no effect on the cyclic nucleotide system of the cells. The pattern of the time-dependent increase in cAMP indicated that the effect was probably due to an inhibition of phosphodiesterase, rather than an activation of adenylyl cyclase. These results demonstrate that clinically effective psoralens, in the absence of UV radiation, can alter the cAMP concentration of human fibroblasts, epithelial cells, and mononuclear leukocytes in vitro.

Cyclic AMP↗
PubMed1984

Effect of methotrexate on cells in a keratinized epithelium with an active thymidine salvage pathway assessed by autoradiography.

In the partially synchronized cell system of the hamster cheek pouch epithelium, the inhibitory effect of a bolus injection of methotrexate (Mtx) (2 g/m2, injected at 1200 hr) was analysed by means of both autoradiography and flow cytometry (FCM) in a 21-hr experiment. For autoradiography [3H]TdR and [3H]UdR were used as tracers for salvage and de novo pathways of thymidylate (TMP) synthesis, respectively. For FCM no tracers were injected. The autoradiographic studies demonstrated an active TdR salvage pathway for DNA synthesis, not affected by the impaired de novo TMP synthesis. The blocked de novo TMP synthesis was partially released 7 hr after Mtx injection, but it had not totally recovered at the end of the experiment. The decrease in the fraction of S-phase cells detected about 10 hr after Mtx injection by autoradiographic labelling with [3H]TdR and by FCM was found to be caused by a decrease in the number of cells entering S phase. However, Mtx did not influence the salvage TMP synthesis rate of cells entering S phase.

Animals↗
PubMed1993

In vitro cytotoxicity as a marker of hypersensitivity to sulphamethoxazole in patients with HIV.

Hypersensitivity to trimethoprim-sulphamethoxazole (TMP-SMX) in patients with HIV infection may be a result of either immune dysregulation, a direct cytotoxicity of the SMX-hydroxylamine metabolite (SMX-HA) (rather than SMX per se), or glutathione deficiency. We evaluated the in vitro cytotoxicity of SMX and SMX-HA to peripheral blood mononuclear cells (PBMC) of HIV-infected subjects to determine if the degree of in vitro cytotoxicity is associated with hypersensitivity, whether glutathione inhibits cytotoxicity, and whether in vitro cytotoxicity is predictive for the development of hypersensitivity. Given that fever is often a prominent feature of hypersensitivity, we also assessed whether SMX or SMX-HA could induce the in vitro production of IL-1 beta, IL-6 or tumour necrosis factor-alpha (TNF-alpha) by PBMC. The cytotoxicities of SMX and SMX-HA to PBMC were assessed in 45 HIV-infected patients with prior TMP-SMX therapy, and in eight HIV- controls. Twelve HIV-infected subjects were studied prospectively before primary Pneumocystis carinii pneumonia (PCP) therapy or rechallenge with TMP-SMX in previously hypersensitive subjects. Cytokine production was measured in four hypersensitive and two non-hypersensitive HIV-infected subjects, and three HIV-uninfected controls. The cytotoxicity of SMX-HA to PBMC was significantly greater in the 22 HIV-infected patients with prior hypersensitivity than both the 23 HIV-infected patients without hypersensitivity and the control group. Cytotoxicity was significantly reduced by glutathione only in the hypersensitive group. SMX did not induce cytotoxicity in any group. In 12 subjects studied prospectively, SMX-HA cytotoxicity was also significantly greater in those with subsequent hypersensitivity. Exposure of PBMC to SMX-HA resulted in a modest increase in the production of IL-6, IL-1 beta and TNF-alpha, although no major difference was detected between subjects with or without hypersensitivity. These data suggest that SMX-HA and glutathione deficiency are involved in the pathogenesis of hypersensitivity to TMP-SMX in HIV-infected patients, and that in vitro cytotoxicity could be useful in the diagnosis of hypersensitivity and predicting its likelihood.

Adult↗
PubMed2006

A peptidoglycan hydrolase motif within the mycobacteriophage TM4 tape measure protein promotes efficient infection of stationary phase cells.

The predominant morphotype of mycobacteriophage virions has a DNA-containing capsid attached to a long flexible non-contractile tail, features characteristic of the Siphoviridae. Within these phage genomes the tape measure protein (tmp) gene can be readily identified due to the well-established relationship between the length of the gene and the length of the phage tail--because these phages typically have long tails, the tmp gene is usually the largest gene in the genome. Many of these mycobacteriophage Tmp's contain small motifs with sequence similarity to host proteins. One of these motifs (motif 1) corresponds to the Rpf proteins that have lysozyme activity and function to stimulate growth of dormant bacteria, while the others (motifs 2 and 3) are related to proteins of unknown function, although some of the related proteins of the host are predicted to be involved in cell wall catabolism. We show here that motif 3-containing proteins have peptidoglycan-hydrolysing activity and that while this activity is not required for phage viability, it facilitates efficient infection and DNA injection into stationary phase cells. Tmp's of mycobacteriophages may thus have acquired these motifs in order to avoid a selective disadvantage that results from changes in peptidoglycan in non-growing cells.

Amino Acid Motifs↗
PubMed2006

Aetiological factors related to a positive direct antiglobulin test result in human immunodeficiency virus-infected patients.

BACKGROUND AND OBJECTIVES: The aim of this study was to examine the clinical importance and causes of a positive result in the direct antiglobulin test (DAT) in human immunodeficiency virus-infected (HIV(+)) patients. We therefore studied haematological parameters in outpatient samples, and also analysed the impact of highly active anti-retroviral therapy (HAART) on the DAT results. STUDY DESIGN AND METHODS: Haematological parameters, clinical stages, chemo-antibiotic treatments and HAART treatment were studied to determine any relationships with DAT results in 115 consecutive HIV(+) patients. RESULTS: Significantly lower haemoglobin (Hb) levels were detected in patients with HIV who had a positive DAT result. Hepatitis C virus (HCV) co-infection (odds ratio 2.529) and trimethoprim-suphamethoxazfole (TMP-SMX) prophylaxis (odds ratio 3.751) had a significant association with DAT positivity. Patients receiving HAART were less likely to have a positive DAT [odds ratio (OR) 0.383; P = 0.035]. Among the patients treated with TMP-SMX, those with a positive DAT had lower Hb levels (11.9 g/dl) than those with a negative DAT (14.2 g/dl; P = 0.04). HCV antibody positivity and TMP-SMX prophylaxis showed a cumulative effect on positive DATs (OR 4.533). The surface exploratory analysis indicated the distribution of the positive DATs in relationship with the CD4(+) count and Hb levels. CONCLUSIONS: Significantly lower Hb levels were detected in DAT-positive HIV(+) patients. HCV co-infection and TMP-SMX prophylaxis appear to confer an increased risk of DAT positivity. The presence of red blood cell autoantibodies may be associated with anaemia in HIV disease in the absence of overt haemolysis.

Anemia↗