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PubMed2002

Pharmacokinetics and bioavailability of trimethoprim-sulfamethoxazole in alpacas.

The pharmacokinetics and bioavailability of trimethoprim-sulfamethoxazole (TMP-SMX) were studied in six healthy male-castrate alpacas (Lama pacos) after intravenous (i.v.) or oral (p.o.) drug administration of 15 mg/kg TMP-SMX using a crossover design with a 2-week washout period. After 90 days one group (n = 3) was given a p.o. dose of 30 mg/kg TMP-SMX and the other group (n = 3) was given a p.o. dose of 60 mg/kg TMP-SMX. After i.v. administration of 15 mg/kg of TMP-SMX the mean initial plasma concentration (C0) was 10.75 +/- 2.12 microg/mL for trimethoprim (TMP) and 158.3 +/- 189.3 microg/mL for sulfamethoxazole (SMX). Elimination half-lives were 0.74 +/- 0.1 h for TMP and 2.2 +/- 0.6 h for SMX. The mean residence times were 1.45 +/- 0.72 h for TMP and 2.8 +/- 0.6 h for SMX. The areas under the respective concentration vs. time curves (AUC) were 2.49 +/- 1.62 microg h/mL for TMP and 124 +/- 60 microg h/mL for SMX. Total clearance (Clt) for TMP was 21.63 +/- 9.85 and 1.90 +/- 0.77 mL/min kg for SMX. The volume of distribution at steady state was 2.32 +/- 1.15 L/kg for TMP and 0.35 +/- 0.09 L/kg for SMX. After intragastric administration of 15, 30 and 60 mg/kg the peak concentration (Cmax) of SMX were 1.9 +/- 0.8, 2.6 +/- 0.4 and 2.8 +/- 0.7 microg/mL, respectively. The AUC was 9.1 +/- 5, 25.9 +/- 3.3 and 39.1 +/- 4.1 microg h/mL, respectively. Based upon these AUC values and correcting for dose, the respective bioavailabilities were 7.7, 10.5 and 7.94%. Trimethoprim was not detected in plasma after intragastric administration. These data demonstrate that therapeutic concentrations of TMP-SMX are not achieved after p.o. administration to alpacas.

Administration, Oral↗
PubMedDate not supplied

Trimethoprim-sulfamethoxazole and trimethoprim alone for prophylaxis of infection in granulocytopenic patients.

Prophylactic trimethoprim-sulfamethoxazole (TMP-SMZ) has been shown to reduce the incidence of fever, parenteral antibiotic usage, and infections with gram-negative bacteria in hospitalized patients with neutropenia. Furthermore, TMP-SMZ was found to be equivalent to or better than oral, nonabsorbable antibiotics in direct comparisons and to have an additive effect when given together with other oral, nonabsorbable antibiotics. Adults given TMP-SMZ continuously had fewer readmissions for infection than did controls given TMP-SMZ only while hospitalized. TMP-SMZ used continuously in children with acute leukemia was effective in preventing bacterial and Pneumocystis carinii infections. For prophylaxis in granulocytopenic patients, TMP appeared equivalent to TMP-SMZ both in efficacy and incidence of side effects. However, TMP was less effective in suppressing gastrointestinal flora, including TMP-resistant gram-negative rods. Thus, TMP-SMZ has some role in preventing infections in high-risk patients, but further studies, especially comparisons with untreated patients may still be required. TMP used alone offers little advantage and has the theoretical disadvantage of not preventing infections caused by P. carinii or TMP-resistant gram-negative bacteria.

Adult↗
PubMed1990

Concentrations of trimethoprim and sulfamethoxazole in cerebrospinal fluid and serum in mares with and without a dimethyl sulfoxide pretreatment.

Each of seven mares was given an intravenous (IV) injection of 40% dimethyl sulfoxide (DMSO) at a dosage of 1 g/kg, over 35 min, immediately followed by a single IV injection of a trimethoprim (TMP) and sulfamethoxazole (SMZ) combination (SMZ 83%, TMP 17%) at a combined dosage of 44 mg/kg (7.48 mg/kg TMP; 36.52 mg/kg SMZ). Each horse served as its own control and was alternately treated with an identical dose of TMP-SMZ treatment alone at least seven days following or preceding the DMSO and TMP-SMZ treatment. Serum and cerebrospinal fluid (CSF) concentrations of TMP and SMZ were measured over a six hour period. Dimethyl sulfoxide treatment caused no significant difference in the mean serum concentration of SMZ or in the mean CSF concentrations of TMP or SMZ. The mean serum concentration of TMP was significantly (p less than 0.05) increased at the two, four and six hour sampling time in the mares receiving pretreatment with DMSO. The clearance of TMP was also significantly (p less than 0.05) decreased from 675 mL/h/kg to 327 mL/h/kg by DMSO administration. Concentrations of TMP and SMZ in the CSF in both treatment groups exceeded the minimum inhibitory concentrations for many common bacterial pathogens of equine origin. In addition, CSF concentration of TMP exceeded the serum concentrations required for 50% inhibition of dihydrofolate reductases of protozoan origin. Serum TMP and SMZ concentration were similar to those reported to be effective against Toxoplasma gondii in in vitro studies on the killing or inhibition of the organism.

Animals↗
PubMed1988

Serum and synovial fluid steady-state concentrations of trimethoprim and sulfadiazine in horses with experimentally induced infectious arthritis.

The tarsocrural joints of 11 horses were inoculated with 1.2 to 2.16 x 10(6) viable Staphylococcus aureus organisms susceptible to a trimethoprim-sulfadiazine (TMP-SDZ) combination with minimal inhibitory concentration (MIC) of 0.25 micrograms of TMP/ml and 4.75 micrograms of SDZ/ml. Antimicrobial treatment consisted of oral administration of a TMP-SDZ combination--30 mg/kg of body weight given once daily (group-1 horses) or 60 mg/kg given as 30 mg/kg every 12 hours (group-2 horses). Paired serum and synovial fluid samples were obtained before intra-articular inoculation with the S aureus, after inoculation with S aureus but before antimicrobial treatment, and after inoculation at various hourly intervals after oral administration of the TMP-SDZ combination. The TMP-SDZ combination was administered daily in the 2 dosages for 21 days. Samples were collected after day 3 of repetitive drug administration so that drug steady-state concentration would have been achieved. Serum and synovial fluid samples were analyzed for TMP and SDZ concentrations. Administration of the TMP-SDZ combination at a dosage of 30 mg/kg once daily was not effective in maintaining TMP or SDZ concentrations above the MIC of TMP-SDZ for the S aureus (0.25 and 4.75 micrograms/ml for TMP and SDZ, respectively) in the infected synovial fluid or in maintaining adequate TMP concentration in the serum. The alternative use of the TMP-SDZ combination at a dosage of 60 mg/kg given as 30 mg/kg every 12 hours was effective in maintaining serum and synovial fluid concentrations of TMP and SDZ that were greater than the MIC for the infective organism.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed1988

Inhibition of cytotoxic T lymphocyte and natural killer cell-mediated lysis by O,S,S,-trimethyl phosphorodithioate is at an early postrecognition step.

O,S,S,-Trimethyl phosphorodithioate (OSS-TMP), an organophosphate esterase inhibitor, has been shown to block the effector phase of the cytolytic reaction mediated by murine and human cytotoxic T lymphocytes (CTL) and human natural killer cells. The murine interleukin 2-dependent CTLL-1 (anti-Iad) clone was used to determine the phase of the cytolytic pathway inhibited by OSS-TMP. Pretreatment of the CTL or target cell with OSS-TMP was not effective at blocking lysis; however, inhibition of lysis was achieved if the reaction was carried out in the continuous presence of OSS-TMP (IC50 = 55 microM) or when CTL-target conjugates were performed and incubated with OSS-TMP (IC50 = 640 microM). Two structural analogues of OSS-TMP were unable to inhibit CTL-mediated lysis. In contrast to OSS-TMP, N-alpha-p-tosyl-L-lysine chloromethylketone required only a 5-min preincubation with the CTL to inhibit lysis. OSS-TMP did not block recognition-adhesion step(s) of the reaction since the ability to form conjugates was not impaired; however, the lytic efficiency of individual CTL-target pairs were blocked. OSS-TMP did not appear to be an inhibitor of the major granule-associated protease that cleaves the substrate, N-alpha-benzyloxycarbonyl-L-lysine thiobenzylester. Ca2+ pulse and kinetic experiments indicated that the OSS-TMP-sensitive site was at a pre-Ca2+-dependent phase but after recognition-adhesion. Human CTL and natural killer cell activity was also inhibited by OSS-TMP, suggesting the presence of a common site of action among these cytolytic systems. The results indicate that OSS-TMP may be a useful reagent in characterizing the early post-recognition events in the cytolytic pathway of CTL and natural killer effector cells.

Animals↗
PubMed2000

Dissolution kinetics of three-component compressed solid mixtures with largely different solubilities: flaking spheres.

The dissolution kinetics of three-component compressed solid spheres of various compositions of mannitol (MAN), sulfamethoxazole (SMX), and trimethoprim (TMP) were studied. Because the solubility of MAN was approximately 300 times that of SMX and TMP, the flaking phenomenon during dissolution process was observed. The critical flaking line was drawn between two critical flaking points in the triangular composition diagram of MAN-SMX-TMP mixtures (i.e., the compositions of 0.5022 MAN and 0.4978 SMX mass fractions, and 0.4906 MAN and 0.5094 TMP mass fractions), thus dividing the system into two distinct regions; namely, nonflaking and flaking regions. In the case of nonflaking region, only three dissolution behaviors for MAN-SMX-TMP three-component mixtures were proposed. The calculated dissolution rates of all components by using the multicomponent dissolution model previously proposed were found to satisfactorily approximate the observed values for both two- and three-component solid mixtures. In the case of flaking region, the observed dissolution rate of MAN was found to be the exponential function of the mass fraction ratio of either SMX or TMP to MAN for both two- and three-component mixtures. The slope of the semilogarithmic plot of the observed MAN dissolution rate versus the mass fraction ratio of either SMX or TMP to MAN was defined as retarding coefficients of SMX or TMP, r'(SMX) or r'(TMP), respectively. The erosion rate of either SMX or TMP was the product of mass fraction ratio of drug to MAN and the exponential function of such mass fraction ratio. The mathematical model was developed on the basis of simultaneous erosion followed by dissolution of eroded particles to predict the dissolution rate of each drug from MAN-SMX-TMP compressed solid spheres within the flaking region.

Chemistry, Pharmaceutical↗
PubMed1995

Development of a mechanism-based dosimetry model for 2,4,4-trimethyl-2-pentanol-induced alpha 2u-globulin nephropathy in male Fischer 344 rats.

A mechanism-based dosimetry model was developed to describe 2,4,4-trimethyl-2-pentanol (TMP-2-OH) dosimetry and renal alpha 2u-globulin (alpha 2u) nephropathy in the male Fischer 344 rat. Experimental data were collected to estimate the chemical-specific parameters (metabolic constants, tissue solubility, and oral absorption rate) necessary to describe TMP-2-OH dosimetry in male rats. The concentrations of alpha 2u and TMP-2-OH were measured in male rats up to 64 hr after a single oral dose of TMP-2-OH (6, 60, or 600 mg/kg). The model predicted the time course behavior of TMP-2-OH and alpha 2u in the kidney, but overestimated their renal concentrations by two or threefold. Simulations of renal alpha 2u concentration were sensitive to changes in TMP-2-OH-alpha 2u-binding affinity and degradation rate of the TMP-2-OH-protein complex. In contrast, simulation of the concentration of TMP-2-OH in the kidney was most sensitive to the amount of protein present. Oral absorption of TMP-2-OH was dose dependent. The model predicted that alpha 2u and TMP-2-OH concentration in the kidney is sensitive to changes in the rate of TMP-2-OH absorbed after oral administration. This model permitted a more rigorous evaluation than has previously been possible of the combination of protein characteristics and chemical dosimetry required for the accumulation of alpha 2u in the kidney of male rats. The behavior of the model is consistent with the qualitative aspects of the alpha 2u hypothesis. However, further characterization of alpha 2u distribution and renal hydrolysis will be required in order to fully characterize the hypothesis at the quantitative level.

Administration, Oral↗
PubMed1978

Pharmacokinetics of sulfadiazine and trimethoprim in man.

Sulfadiazine (SDZ) 800 mg and trimethoprim (TMP) 160 mg were given orally to 10 normal subjects and the concentration of SDZ and TMP in serum and urine was followed for 24 h. Both drugs showed a significant negative correlation between individual "peak" concentrations in serum and the body weight of the subject. Twelve hours after dosing the serum concentration was 12 to 25 microgram/ml for SDZ and 0.3 to 1.1 microgram/ml for TMP. Individual concentration ratios between SDZ and TMP in serum were 4.8 (1 h)--145 (24 h), and in the urine the ratio was close to 6 throughout the 24 h collection period. The range of urinary concentrations was from 65 to 400 microgram/ml for SDZ and from 13.8 to 93.4 microgram/ml for TMP. The fraction (formula: see text) was 21% during the 0--8 h period, 33% during the 8--15 h period and 41% during the 15--24 period. The average "t1/2" was 15.2 +/- 7.4 h for SDZ and 7.4 +/- 1.9 h for TMP. Individual subjects showed a significant correlation between the serum clearance of TMP and SDZ (p less than 0.01) and also between the renal clearance of the two drugs (p less than 0.05). The serum clearance was significantly correlated with the renal clearance for TMP but not for SDZ. For SDZ Vd was significantly negatively correlated with the elimination constant; for TMP no such correlation was found. The serum clearance of SDZ was significantly correlated with the percentage of SDZ which was excreted as the (presumably) acetylated compound. The renal clearance of SDZ was independent of the serum concentration of SDZ. There was a highly significant negative correlation between the renal clearance and serum concentration of TMP, as well as for "acetylated SDZ". The renal clearance of "acetylated SDZ" averaged more than six times that of unconjugated SDZ. With increased urine flow the renal clearances of TMP and SDZ were significantly increased.

Absorption↗
PubMed2003

Thrombolysis in myocardial infarction myocardial perfusion grade in angiography correlates with myocardial salvage in patients with acute myocardial infarction treated with stenting or thrombolysis.

OBJECTIVES: We sought to assess the relationship between the Thrombolysis In Myocardial Infarction (TIMI) myocardial perfusion (TMP) grade and myocardial salvage as well as the usefulness of TMP grade in comparing two different reperfusion strategies. BACKGROUND: The angiographic index of TMP grade correlates with infarct size and mortality after thrombolysis for acute myocardial infarction (AMI). Its relationship to myocardial salvage and its usefulness in comparing different reperfusion strategies are not known. METHODS: We analyzed the TMP grade on angiograms obtained at one to two weeks after treatment in 267 patients enrolled in two randomized trials that compared stenting with thrombolysis in AMI. Patients were classified into two groups: 159 patients with TMP grade 2/3 and 108 patients with TMP grade 0/1. Two scintigraphic studies were performed: before and one to two weeks after reperfusion. The salvage index was calculated as the proportion of the area at risk salvaged by reperfusion. RESULTS: Patients with TMP grade 2/3 had a higher salvage index (0.49 +/- 0.42 vs. 0.34 +/- 0.49, p = 0.01), a smaller final infarct size (15.4 +/- 15.5% vs. 22.1 +/- 16.2% of the left ventricle, p = 0.001), and a trend toward lower one-year mortality (3.8% vs. 8.3%, p = 0.11) than patients with TMP grade 0/1. The relationship between TMP and salvage index was independent of the form of reperfusion therapy. The proportion of patients with TMP grade 2/3 was significantly higher after stenting than after thrombolysis (70.9% vs. 48.1%, p = 0.001). CONCLUSIONS: These findings show that the TMP grade is a useful marker of the degree of myocardial salvage achieved with reperfusion and a sensitive indicator of the efficacy of reperfusion strategies in patients with AMI.

Abciximab↗
PubMed2000

Determination and quantification of sulfadiazine and trimethoprim in swine tissues using liquid chromatography with ultraviolet and mass spectrometric detection.

High-performance liquid chromatographic procedures with ultraviolet detection were developed for the quantitative determination of sulfadiazine (SDA) and trimethoprim (TMP) in swine tissues (kidney, liver, muscle, fat and fat + skin). In addition, high-performance liquid chromatography with atmospheric pressure chemical ionization mass spectrometry was used for the confirmation of the identity of the analytes of interest. Chromatographic separation was achieved on a Spherisorb ODS-2 column (250 x 4.6 mm id, dp 5 microns). The mobile phase for SDA analysis consisted of 1% acetic acid in water-acetonitrile (85 + 15, v/v). For TMP analysis a 80 + 15 + 5 (v/v/v) mixture of 0.25% triethylammonium acetate in water, acetonitrile and methanol was used as the eluent. Sulfamerazine and ormethoprim were used as the internal standards for SDA and TMP analysis, respectively. For the isolation of the compounds of interest from biological samples, a liquid-liquid extraction with acetone and ethyl acetate, followed by a clean-up using a solid-phase extraction column (aminopropyl and benzenesulfonic acid for SDA, benzenesulfonic acid for TMP) was performed. Calibration graphs were prepared for all tissues and linearity was achieved over the concentration ranges tested (50-1000 ng g-1 for SDA, r > or = 0.9979; 25-500 ng g-1 for TMP, r > or = 0.9994). The method was validated at the maximum residue level (MRL, 100 ng g-1 for SDA and 50 ng g-1 for TMP), at half the MRL and at double the MRL for both SDA and TMP. The accuracy and precision (expressed as the within-day repeatability) were found to be within the required ranges for each specific concentration. The quantification limits were 50 ng g-1 for SDA and 25 ng g-1 for TMP. The limits of detection were below one half the MRLs. Both methods were selective for the determination of SDA and TMP. Biological samples (kidney, liver, muscle, fat and fat + skin) from pigs that received a commercial SDA-TMP preparation with the feed for five consecutive days (dose rate: 25 mg SDA and 5 mg TMP kg body weight-1 day-1) were analyzed using the described methods. The quantitative results were used to calculate a withdrawal time (12 days) to reach residue levels below the respective MRLs. This calculation was performed according to the recommendations of the European Agency for the Evaluation of Medicinal Products (EMEA/CVMP/036/95).

Animals↗
PubMed2006

Impact of myocardial perfusion on left atrial remodeling following primary angioplasty for acute myocardial infarction.

OBJECTIVES: To investigate the impact of myocardial perfusion on left atrial remodeling and its determinants after primary percutaneous coronary intervention for acute myocardial infarction. BACKGROUND: Left atrial volume is an important predictor of morbidity and mortality in acute myocardial infarction, while thrombolysis in myocardial infarction (TIMI) myocardial perfusion (TMP) grade is an angiographic index associated with infarct size and mortality. As yet, however, the relationship between TMP grade and left atrial remodeling has not been investigated. METHODS: Conventional transthoracic echocardiography was performed in 105 patients (55+/-13 years old, 92 men) with acute myocardial infarction within 24 h and after 6 months (mean 9+/-4, range 6-29 months) following successful primary percutaneous coronary intervention. Absolute left atrial volume was calculated using an elliptical model. Myocardial perfusion was evaluated, using TMP grade, by visual assessment on the coronary angiogram. Patients were divided into three groups on the basis of myocardial perfusion status, as TMP 0/1 (n=36), TMP 2 (n=36) and TMP 3 (n=33). RESULTS: No difference was observed between baseline and follow-up left atrial volumes in the overall study population (42.5+/-16.1 vs. 43.5+/-17.4 ml, P=0.519). As regards TMP grade, follow-up left atrial volume significantly increased in the TMP 0/1 group (43+/-17 vs. 54.6+/-1.1 ml, P<0.001) and significantly decreased in the TMP 3 group (42.9+/-15.7 vs. 35.5+/-12.2 ml, P=0.001) compared with initial values. No change was observed in left atrial volume in the TMP 2 group. Multivariate analysis showed that TMP grade (P<0.001) and anterior location of myocardial infarction (P<0.001) were independent determinants of left atrial remodeling. CONCLUSIONS: These results suggest that poor myocardial perfusion and anterior location of myocardial infarction can affect left atrial remodeling in patients with acute myocardial infarction undergoing primary percutaneous coronary intervention. It appears that adequate myocardial perfusion is crucial to prevent left atrial remodeling, a poor prognostic factor in acute myocardial infarction.

Adult↗
PubMed1996

In vitro and in vivo binding of trimethoprim and sulphachlorpyridazine to equine food and digesta and their stability in caecal contents.

Binding of antibiotics to food has received little attention in equine medicine, although such binding could potentially reduce the bioavailability and clinical efficacy. In the present study, binding of trimethoprim (TMP) and sulphachlorpyridazine (SCP) to hay, grass silage and concentrate was investigated in vitro in buffer at pH 6.8 at different concentrations. The binding of TMP and SCP to caecal contents was also studied. In addition, the degradation of TMP and SCP by the caecal microflora was investigated by incubating sterilized and non-sterilized caecal contents for 3 h at 37 degrees C under anaerobic conditions and comparing the TMP and SCP contents. Further, a TMP/SCP powder formulation was adminstered orally with concentrate at a dose rate of 5 mg/kg TMP and 25 mg/kg SCP to three ponies with a caecum fistula; the animals were deprived of food for 8 h before administration. Blood samples, caecal contents samples and faecal samples were collected and analysed for TMP and SCP concentrations by means of high performance liquid chromatography (HPLC). Three non-fistulated ponies, acting as control animals, were fed the same dose of TMP/SCP with concentrate after 8 h of food deprivation and blood samples were taken. The percentage of in vitro binding of TMP as well as SCP to hay, grass silage and concentrate at concentrations of 4 micrograms/mL to 10 micrograms/mL was high (60-90%). TMP and SCP were also extensively bound to caecal contents (50-70%). At spiking concentrations above 10 micrograms/mL the percentage of binding decreased. There was no evidence of biodegradation of TMP or SCP in caecal contents. In vivo, both drugs could be detected in the caecal contents and in the faeces of three fistulated ponies. However, the fistulated ponies differed from the control ponies in that their TMP and SCP plasma concentrations were higher, and two fistulated ponies did not show double peaks in their plasma concentration-time curves. Therefore, the fistulated ponies did not provide an optimal model for in vivo binding studies. Despite this limitation, it can be concluded that binding of TMP and SCP to food is a major cause of the limited bioavailability of these drugs in the horse. It is hypothesized that the binding is reversible, and that a second absorption phase occurs in the large intestine, but part of the administered dose remains bound as both drugs were found in the faeces.

Administration, Oral↗
PubMed1996

A study of the pharmacokinetics and tissue residues of an oral trimethoprim/sulphadiazine formulation in healthy pigs.

Twenty-six healthy female pigs weighing 19.5-33 kg were used in three separate experiments. The animals were fed individually twice a day. Trimethoprim/sulphadiazine (TMP/SDZ) formulation was added to feed in the amount of 6 mg/kg bw (TMP) and 30 mg/kg bw (SDZ). TMP and SDZ concentrations in blood plasma, muscles, liver and kidneys were measured. Pharmacokinetic parameters show that the absorption of TMP from the alimentary tract in pigs is faster than the absorption of SDZ, and the elimination of TMP is slower than that of SDZ. The absorption half-lives were 0.96 (TMP) and 2.24 h (SDZ), whereas elimination half-lives were 5.49 (TMP) and 4.19 h (SDZ). The observed TMP:SDZ ratios in blood plasma after multiple dose administration ranged from 1:11.4 to 1:23.2. One day after administration of the last dose of TMP/SDZ the plasma concentration ratio was 1:15.5, but in muscles, liver and kidneys it was much lower: 1:0.79, 1:0.14 and 1:1.53 respectively. The absolute TMP and SDZ tissue concentrations 1 day after the last multiple dose administration were very low (maximum TMP: 0.29 micrograms/g in liver; maximum SDZ: 0.23 micrograms/g in kidneys). Neither drug was detected in any tissue 8 days after the last administration of TMP/SDZ. Based on our results, it was concluded that there is no support for the TMP:SDZ pharmaceutical ratio 1:5 in oral formulations of these compounds for pigs. The administration oral TMP/SDZ formulations once a day may result in the absolute tissue concentrations of these drugs being too low for antibacterial activity. The withdrawal period for such an oral TMP/SDZ formulation for pigs (according to accepted guidelines in Europe for MRL of TMP < 0.05 mg/kg of tissue) should not be less than 5 days.

Administration, Oral↗
PubMed1984

Pharmacokinetics of trimethoprim and sulfamethoxazole in serum and cerebrospinal fluid of adult patients with normal meninges.

The pharmacokinetics of trimethoprim (TMP) and sulfamethoxazole (SMX) in cerebrospinal fluid (CSF) and serum after a single intravenous infusion of 5 mg of TMP and 25 mg of SMX per kg of body weight over approximately 120 min were studied i nine patients who had uninflamed meninges and were undergoing elective myelography. Peak concentrations of TMP and SMX in CSF were 1 microgram/ml and 13.8 micrograms/ml, respectively. The peak TMP concentration in CSF occurred significantly earlier than the peak SMX concentration (60 versus 480 min postinfusion). At 15 h, there was no detectable TMP in the CSF, and there was 4.7 micrograms of SMX per ml of CSF. In the postdistribution phase (in CSF), simultaneous CSF-to-serum concentration ratios ranged from 0.23 to 0.53 for TMP and from 0.20 to 0.36 for SMX. CSF penetration (measured by comparison of the area under the curve of the composite CSF and serum concentration-time curves) was 18% for TMP and 12% for SMX. A loading dose of TMP-SMX (bases on TMP) of 10 to 12 mg/kg and a maintenance dose of 6 mg/kg every 8 h or 8 mg/kg every 12 h (with a 2-h infusion) should yield steady-state peak concentrations of at least 5 micrograms of TMP per ml of serum and 160 micrograms of SMX per ml of serum. Further studies of TMP-SMX administered in these doses in the treatment of serious bacterial infection, including meningitis, are warranted.

Adult↗
PubMedDate not supplied

Typus melancholicus personality type and the five-factor model of personality.

Personality traits are significant factors in the development and course of depression. Apart from the classical five-factor model of personality, other personality constellations, such as Tellenbach's Typus melancholicus, have been described in association with depressive disorder. Several instruments have been developed to assess the Typus melancholicus personality (TMP). A systematic comparison of these instruments has not been done to date. The goal of this study was the comparison of four questionnaires used in assessing TMP. Four TMP questionnaires were compared and their relationship to the five-factor model of personality was examined among 264 psychiatric patients and normal controls. It was found that the TMP type represents a trait distinct from those of the five-factor model. TMP inventories had only moderate concurrent validity. The single TMP scales focus on different aspects of the TMP, despite their common core. Both the five-factor personality traits and the TMP scales were able to differentiate a group of depressed patients from control groups. The results show that TMP is not one trait but a personality trait constellation. This leads to the conclusion that a number of dimensions must be taken into consideration in the construction of a TMP inventory. This multidimensionality contributes to the refinement of the TMP concept and differentiates its therapeutic implications.

Adolescent↗
PubMed2002

Trimethoprim-sulfamethoxazole activity and pharmacodynamics against glycopeptide-intermediate Staphylococcus aureus.

STUDY OBJECTIVE: To determine the activity of trimethoprim-sulfamethoxazole (TMP-SMX) against glycopeptide-intermediate Staphylococcus aureus (GISA). DESIGN: In vitro study. SETTING: University laboratory. MEASUREMENTS AND MAIN RESULTS: Minimum inhibitory concentrations (MICs) of TMP-SMX were determined for three GISA strains. Time-kill assays were conducted at 1 x MIC and at simulated peak serum concentrations (Cmax). Two dosing regimens of TMP-SMX were investigated: TMP-SMX 8 mg (TMP)/kg/day and TMP-SMX 15 mg/kg/day, each divided into two doses/day Both dosages were studied against each strain in a two-compartment in vitro model to determine concentration-related activity. All isolates were susceptible to TMP-SMX. In time-kill studies at 1 x MIC, TMP-SMX was bacteriostatic against all isolates and bactericidal against two of three strains at simulated Cmax. The 15 mg/kg/day (divided-dose) regimen provided the best overall reduction in colony-forming units/ml. CONCLUSION: All GISA strains were susceptible to TMP-SMX. In addition, it appears that TMP-SMX may have concentration-dependent antibacterial activity against these organisms. As an option in the management of GISA infection, TMP-SMX merits further study.

Anti-Bacterial Agents↗
PubMed2003

Hyponatremia and/or hyperkalemia in patients treated with the standard dose of trimethoprim-sulfamethoxazole.

OBJECTIVE: High-dose trimethoprim-sulfamethoxazole (TMP-SMX) is known to cause hyperkalemia by blocking amiloride-sensitive sodium (Na) channels in distal nephrons. The purpose of this study was to establish whether the standard dose of TMP-SMX could cause electrolyte disorders. METHODS AND PATIENTS: Serum Na, potassium (K) and creatinine (Cr) levels were examined retrospectively in 53 of 77 patients prescribed TMP-SMX, before and after taking the antibiotic combination. RESULTS: Electrolyte disorders (Na < 135 mEq/l and/or K > 5.0 mEq/l) were found in 14 of the 53 patients (26.4%) during TMP-SMX treatment. The average dose was 145.7 +/- 24.9 mg/day. The dose of TMP was significantly larger in patients with electrolyte disorders (267.7 +/- 84.2 mg vs. 101.9 +/- 9.38 mg, p = 0.0024). Electrolyte disorders were also seen in 9.1% and 22.2% of patients given the low dose (TMP < 80 mg) or standard dose (TMP 80-120 mg) of TMP-SMX, respectively. Electrolyte disorders were seen in 85.7% of patients with renal dysfunction (Cr > 1.2 mg/dl), compared with 17.5% of patients with normal renal function (p = 0.0008). Logistic regression analysis showed that the dose of TMP and the presence of renal dysfunction increased the incidence of electrolyte disorders with an odds ratio of 2.35 and 80.29, respectively. CONCLUSION: Electrolyte disorders, particularly hyperkalemia and hyponatremia can be detected in patients given TMP-SMX. These disorders are more frequent in patients given high doses, but can also be detected after low-dose administration. Renal dysfunction accelerates the incidence of electrolyte disorders induced by TMP-SMX.

Anti-Infective Agents↗
PubMed1986

The antimicrobial activities of trimethoprim and sulfonamides.

The folate inhibitor trimethoprim (TMP) is active against and potentially cidal to a few higher microorganisms and a wide spectrum of pathogenic bacteria except for Bacteroides, Branhamella, Brucella, Chlamydia, Clostridium, Mycobacterium, Mycoplasma, Nocardia, Neisseria, Pseudomonas and Treponema. These organisms tend to be more sensitive to sulfonamides (SUL) than to TMP, whereas TMP is 10- to 100-fold more active than SUL against most other bacteria. Synergy between TMP and SUL occurs at drug concentrations equal to or less than their respective MICs and is often seen in vitro with isolates that are sensitive or moderately resistant to one or both of the components. Synergy occurs over a wide range of ratios between TMP and SUL, the optimal being that between their respective MICs when acting singly. In vitro synergy is more impaired by bacterial resistance than by suboptimal TMP:SUL ratios. The vast majority of clinical isolates of Haemophilus, staphylococci, streptococci and enteric bacteria are inhibited in vitro by the minimum concentrations of drug attained in plasma during therapy. Exceptions are found among Enterobacter, Citrobacter, Serratia, Proteus and in particular Klebsiella where SUL resistance is common and isolates with TMP MICs of 5 mg/l or more may occur and lead to failure of TMP-SUL therapy in systemic infections. In the urinary tract drug concentrations that are synergistic and therefore inhibitory in vitro against isolates moderately resistant to SUL (MIC less than or equal to 1 g/l) and/or TMP (MIC less than or equal to 0.1 g/l) are present during TMP-SUL therapy. However, whether the synergy and the bactericidal effect of TMP-SUL observed in vitro play a role in vivo is controversial.

Bacteria↗