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PubMed1993

History and future of antimicrobial diaminopyrimidines.

Numerous pyrimidine and purine analogs were synthesized in the late forties in G.H. Hitchings' group as potential nucleic acid antagonists. Several key observations finally led to the selection of pyrimethamine as an antimalarial and trimethoprim (TMP) as an antibacterial agent: i) 2,4-diamino-5-substituted pyrimidines interfered with folic acid utilization rather than being thymine antagonists as expected; ii) a large degree of selectivity could be obtained by suitable substitution and non-toxic diaminopyrimidines with preferential antimicrobial activity were found; iii) the identification of dihydrofolate reductase (DHFR) as the specific target for aminopterin and methotrexate in 1958 and for TMP in 1965, and the diversity of this enzyme in different species. Although several diaminopyrimidines were initially tested as monotherapies in clinical trials, the pronounced synergism between some of these new compounds and sulfonamides seen against Plasmodium was finally also applied in the development of TMP. Its combination with sulfamethoxazole later proved one of the most successful agents ever developed. Further milestones in the application of antimicrobial DHFR inhibitors were the introduction of TMP alone in 1972, the launch of a new combination of tetroxoprim, a close TMP-analog, with sulfadiazine, and the successful clinical trials with brodimoprim, which proved clinically efficacious and safe with once-daily low dose monotherapy. Efforts to discover new antimicrobial DHFR inhibitors have recently intensified. DHFRs from important gram-positive problem organisms such as S. aureus, S. epidermidis have been cloned and sequenced, as well as DHFRs from opportunistic pathogens such as P. carinii, T. gondii, and of mycobacteria. DHFR crystal structures from several of these organisms are available to aid rational inhibitor design.(ABSTRACT TRUNCATED AT 250 WORDS)

Anti-Infective Agents↗

PubMed1993

Basis of selectivity of antibacterial diaminopyrimidines.

The basis for the high affinity and selectivity of trimethoprim [2,4-diamino-5-(3',4',5'-trimethoxybenzyl)pyrimidine, TMP] and several close structural analogues is reviewed. Methoxy group substitution on the benzyl group of 2,4-diaminobenzylpyrimidine markedly affects both Escherichia coli dihydrofolate reductase (DHFR) Ki values and in vitro antibacterial activity. TMP is several hundred-fold more potent than the unsubstituted benzylpyrimidine, and the monomethoxy and dimethoxy analogues are of intermediate activity. However, equilibrium dissociation constants determined in the absence of cofactor (NADPH) show that the binding of these diaminobenzylpyrimidines in the enzyme-inhibitor binary complex is considerably weaker and does not vary among the compounds. Thus, the TMP binding affinity of E. coli DHFR is increased by NADPH in the ternary complex, and this increased affinity (cooperativity) varies with methoxy group substitution. In contrast, mouse DHFR has a weaker binding affinity for diaminobenzylpyrimidines, and none of the analogues show strong NADPH cooperative effects. The difference in the magnitude of NADPH/TMP cooperativity between bacterial and mammalian DHFR is an important factor in selectivity. The E. coli enzyme binds TMP more avidly in binary complex, and an additional selectivity factor of 30-fold arises from differences in cooperativity. Although the X-ray crystal structures of bacterial and vertebrate DHFR have been studied extensively, no single hypothesis convincingly explains the molecular basis of TMP selectivity. However, information on the three-dimensional structure of the enzyme has been used to rationally design novel, high-affinity inhibitors.

Animals↗

PubMed1996

Kinetic effects of trimethoprim-sulfamethoxazole in children with biliary atresia: a new dosing regimen.

Pharmacokinetics for combination trimethoprim/ sulfamethoxazole (TMP/SMX) was studied in only four patients with biliary atresia (BA): three girls, 6.2,8.0 and 8.2 years of age and one boy 8.4 years of age, as this is an uncommon obstructive anomaly of the extrahepatic biliary system and has been described as having a poor prognosis. These four patients are the survivors of 27 initial children who were operated on previously. They have been receiving 2.3 +/- 0.5 mg/kg TMP, and 11.5 +/- 2.6 mg/kg SMX every 12 h since 2 weeks after surgical treatment for biliary atresia performed at 2-2.5 months of age. The patients have suffered some episodes of cholangitis during their short lives, most of them after interrupting temporally the chemotherapy. Nevertheless, they have achieved a favorable quality of life. TMP/SMX disposition was well characterized by a one compartment open pharmacokinetic model. Wide interpatient variability was observed for all pharmacokinetic parameters with coefficients of variation for t1/2 el, ClT, and Vd of 33.2, 49.6, and 26.3%, respectively, for SMX and 108.9, 52.1, and 71.0%, respectively, for TMP. A marked difference in the pharmacokinetics of TMP and SMX was observed, for example; (ClT: mean +/- SD; 90.3 +/- 47.0 ml/kg/g for TMP and 13.7 +/- 6.8 ml/kg/h for SMX), (t1/2 el with 7.93 +/- 8.64 h for TMP and 10.51 +/- 3.49 h for SMX). In order to develop dosage schedules that would reliably achieve peak serum concentrations of TMP/SMX in the therapeutic range, we found that established dose leads to high fluctuations at steady state between C(max), ss and C(min), ss, without maintaining therapeutic levels. Recommended maintenance dose varied from 8 to 30 mg/kg for SMX with a mean of 21.9 +/- 10.89 mg/kg/12 h, and from 0.8 to 4.5 mg/kg/12 h with a mean of 3.2 +/- 1.7 mg/kg/12 h. The present study illustrates the need for pharmacokinetic studies for the individualization of drug dosing in patients with BA.

Biliary Atresia↗

PubMedDate not supplied

Comparison of trimethoprim-sulfamethoxazole, dapsone, and pentamidine in the prophylaxis of Pneumocystis carinii pneumonia.

STUDY OBJECTIVE: To compare the incidence of Pneumocystis carinii pneumonia (PCP) in patients infected with the human immunodeficiency virus (HIV) receiving one of three prophylactic agents. DESIGN: Retrospective chart review. SETTING: A university-affiliated Department of Veterans' Affairs medical center HIV clinic. PATIENTS: All 200 HIV-infected patients enrolled in the clinic who were prescribed a PCP prophylactic drug during 18 months. INTERVENTIONS: Patients were administered oral trimethoprim-sulfamethoxazole (TMP-SMX) DS, oral dapsone, or aerosolized pentamidine in a heirarchic fashion. A subset of 110 patients received only one of the prophylaxis regimens for at least 6 months; they were examined separately for the purpose of statistical analysis. MEASUREMENTS AND MAIN RESULTS: One case of PCP was diagnosed in 1110 patient-months of oral TMP-SMX DS therapy, 6 in 418 patient-months of oral dapsone therapy, and 3 in 164 patient-months of aerosolized pentamidine therapy. In the subset population, the documented incidence of PCP was 0% among 71 TMP-SMX DS-treated patients, 16% among 25 dapsone-treated patients (p < 0.004), and 14% among 14 aerosolized pentamidine-treated patients (p < 0.03). For patients receiving primary prophylaxis, the incidence of PCP was 0% for 58 receiving TMP-SMX, 15% for 20 receiving dapsone (p = 0.015), and 17% for 6 receiving pentamidine (p = 0.094). CONCLUSION: We believe TMP-SMX DS was more effective than oral dapsone or aerosolized pentamidine in preventing PCP in these HIV-infected patients.

AIDS-Related Opportunistic Infections↗

PubMed1996

[Desensitization to trimethoprim-sulfamethoxazole in patients with HIV infection].

OBJECTIVE: To evaluate the safety and efficacy of an in-patient oral desensitization regimen in HIV- infected patients hypersensitive to trimethoprim-sulfamethoxazole (TMP-SMX). METHODS: TMP-SMX was given orally once a day using incremental doses every day, starting with 0.4 mg TMP/2 mg SMX at day 4 and achieving a full dosage of TMP-SMX (80 mg/400 mg) at day 5. Success was defined as clinical tolerance of the final dose for more than 10 days following completion of the procedure. RESULTS: Desensitization was successfully completed in 29 of 30 patients. A transient rash occurred in one patient during desensitization and resolved without need for discontinuation of the desensitization protocol. The procedure failed in one patient who experienced sustained moderate cutaneous reaction with fever on day 5. CONCLUSIONS: Our results suggest the safety and efficacy of an inpatient oral desensitization regimen in 30 HIV-infected patients who had experienced cutaneous reactions to trimethoprim-sulfamethoxazole (TMP-SMX). Specific desensitization to TMP-SMX allows to circumvent the limitations towards effective prophylaxis of PCP that are dependent on the occurrence of cutaneous reactions to the drug.

Acquired Immunodeficiency Syndrome↗

PubMed1998

First description of the effect of a non-sulfonylurea compound, tetramethylpyrazine, on coronary response to desoxyglucose-induced ischemia.

The compound 2,3,5,6-Tetramethylpyrazine (TMP; Ligustrazine), a flavouring component and sweetness enhancer for beverages constitutes a commonly used food additive. Now we studied the effect of TMP on coronary artery dilation during ischemia: In our experiments we used isolated, Langendorff-perfused guinea pig hearts, arrested with K(+)-rich Normal Tyrode solution (in mM: NaCl 129.5, KCl 15, MgCl2 0.8, CaCl2 1.0, glucose 10), buffered with 10 mM HEPES to pH 7.4 at 37 degrees C, equilibrated with 100% O2. Ischemia was simulated by equimolar replacement of glucose by 2-deoxyglucose (DOG), an inhibitor of oxydative phosphorylation. We found that coronary perfusion pressure (CPP) decreased by 20 +/- 1.2 cm H2O (from initially 90 cm H2O; n = 6, +/- SEM) within 15 min from the onset of DOG. In the presence of 1 mM TMP the decrease in CPP was largely attenuated and CPP declined by 1.4 +/- 1.0 cm H2O (n = 6, +/- SEM; p < 0.01). In 2 out of the 6 TMP experiments even as light increase in CPP (< 2 cm H2O) could be seen. We conclude that TMP, a blocker of ATP-dependent K(+)-channels in pancreatic beta-cells and possibly in arterial smooth muscle cells, prevents coronary dilation in response to ischemia. The possible suppression of this vital mobilization of coronary reserve during ischemia in patients with coronary artery disease certainly merits further attention and may question the use of this compound as a food additive.

Adenosine Triphosphate↗

PubMed1984

Post-sepsis prophylaxis in cancer patients.

One hundred children with cancer and bacterial sepsis were observed for one month after completion of antibiotic treatment for subsequent episodes of infection. After satisfactory clinical and bacteriological responses were achieved and antibiotic therapy terminated, 38 of the patients were maintained on trimethoprim--sulfamethoxazole (TMP-SMZ) and 62 did not receive the drug combination. Of the 26 neutropenic patients not receiving TMP-SMZ 23 (88%) had episodes of infection, whereas 4 (36%) of the 11 given the drug had recurrent or re-infection episodes (P = less than 0.001). A difference of similar significance was observed in the non-neutropenic patients. Infections in children in relapse of their malignancy were twice as frequent in those not receiving the drug as in those who received it (P = less than 0.02, greater than 0.01). Of the 19 patients who died during the month of observation, none had received TMP--SMZ. This study shows that the administration of TMP--SMZ after bacterial sepsis reduces the number of infectious episodes in neutropenic and non-neutropenic patients, with the exception of the non-neutropenic patient in remission.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1990

Pharmacokinetics of sulfamethoxazole and trimethoprim in Mexicans: bioequivalence of two oral formulations (URO-TS D and Bactrim F).

Two oral pharmaceutical formulations (URO-TS D and Bactrim F) containing 800 mg of sulfamethoxazole (SMZ) and 160 mg of trimethoprim (TMP) were given to 10 Mexican healthy volunteers, following a randomized cross-over design. Blood and urine samples were obtained, concentrations of TMP, SMZ, and its metabolite N4-acetyl SMZ were measured by HPLC and pharmacokinetic analyses were performed. The observed Cmax, tmax, half-life, AUC, and cumulative urinary excretion values for the three compounds studied were within the ranges that have been previously reported for European and North American subjects. Therefore, it appears that pharmacokinetics of SMZ and TMP in Mexicans are similar to those observed in Caucasian populations. When the two studied formulations were compared, no statistically significant differences were detected in any pharmacokinetic parameter. Therefore, it is concluded that both brands tested are bioequivalent. Moreover, these two formulations manufactured in Mexico yield SMZ and TMP plasma and urine levels similar to those obtained with equivalent formulations of European or North American origin.

Adult↗

PubMed1980

Stimulation of thymocyte mitogenic protein secretion and of cytostatic activity of mouse peritoneal macrophages by trehalose dimycolate and muramyldipeptide.

Immunomodulators of bacterial origin, such as muramyl-dipeptide (MDP) and trehalose dimycolate, are able to stimulate some important biological functions of macrophages, such as their capacity to secrete a monokine, the thymocyte mitogenic protein (TMP), and to limit the growth of mastocytoma cells in vitro. Adherent cells from the peritoneal cavity of untreated mice do not secrete significant amounts of TMP and are not cytostatic. In contrast, adherent peritoneal cells from mice injected with trehalose dimycolate (emulsified in water) secrete TMP and are strongly cytostatic for P815 cells. Trehalose dimycolate is also active when added in vitro: (a) it enhances the cytostatic action of thioglycollate-elicited macrophages; (b) alone or in sequence with MDP, it induces an appreciable cytostatic activity in resident macrophages; (c) it limits the decline of the strong cytostatic action of trehalose-dimycolate-elicited macrophages occurring during in vitro cultivation. MDP also stimulates the cytostatic activity of the macrophages in vitro. The most interesting effect of MDP is its capacity to induce a strong secretion of TMP after a short contact (1 h) with elicited macrophages.

Acetylmuramyl-Alanyl-Isoglutamine↗

PubMed2005

Simultaneous determination of thymidylate and thymidine diphosphate by capillary electrophoresis as a rapid monitoring tool for thymidine kinase and thymidylate kinase activities.

A simple and rapid capillary electrophoretic method was developed for the simultaneous determination of thymidylate (TMP) and thymidine 5'-diphosphate (TDP) in enzyme assays without using radioactive-labeled substrates. Prior to electrophoretic separation, addition of acetonitrile and sodium chloride to the assay solution and brief centrifugation are recommended for the purpose of sample cleanup and sample stacking. The separation of micromolar TMP and TDP from millimolar adenosine 5'-triphosphate (ATP) was performed at 25 degrees C using sodium tetraborate as the background electrolyte. Under the optimal condition, a good separation with high efficiency was achieved in 6 min. Several parameters affecting the separation were studied, including the pH of electrolyte, the applied voltage, and acetonitrile-salt sample stacking. The fronting of the ATP peak resulting from the interference of magnesium ion in the enzyme assay buffer was suppressed by the addition of sodium ethylenediaminetetraacetate to the sample solution. Using deoxyadenylate as an internal standard, the linear range of the method was 5-200 microM, and the concentration limits of detection of TMP and TDP were 2.6 and 3.8 microM, respectively. Application of the proposed method for simultaneous determination of TMP and TDP in enzyme assays was demonstrated by the activity assays of thymidine kinase and thymidylate kinase from white spot syndrome virus. This is a sensitive, nonradioactive method for thymidine kinase and thymidylate kinase assays.

Electrophoresis, Capillary↗

PubMed1992

Backwashing procedure for on-line reuse of a plasma fractionator in cryofiltration.

During membrane plasma fractionation therapy there are reported incidences of membrane plugging requiring the corrective actions of either filter replacement or backwashing (BW) in order to continue the treatment. In this preliminary study, a simple BW procedure to allow for on-line reuse of the filter (Asahi AP06M) during the treatment was evaluated to assess its efficacy and safety in cryofiltration (CF). Evaluations were carried out on two patients treated for rheumatoid arthritis. Seven tests, each using 1 L or 2 L warmed saline as a BW solution were performed to evaluate the decrease of the transmembrane pressure (TMP) between just before and after backwashing and TMP change during cryofiltration procedures between before and after backwashing. Sieving coefficients of total protein, albumin, immunoglobulins (G, M, A), fibrinogen, and rheumatoid factor were also calculated at 1,000 ml plasma volume processed. Results showed statistically significant decreases of TMP from 300 mm Hg to 70 mm Hg between just before and after both backwashing procedures, and that there were no significant changes in the TMP increase during the cryofiltration procedure between pre- and post-BW. The protein sievings were not significantly affected by BW. The use of a second liter for rinsing did not reduce the inlet pressure further suggesting that 1 L BW was adequate. The accumulated solutes did not affect significantly the effective mean pore size. The BW procedure did not affect the overall patient safety during therapy.(ABSTRACT TRUNCATED AT 250 WORDS)

Arthritis, Rheumatoid↗

PubMed2004

Predictors of receipt of a fluoroquinolone versus trimethoprim-sulfamethoxazole for treatment of acute pyelonephritis in women in Manitoba, Canada.

PURPOSE: The increasing and comparatively high proportion of uropathogens in Canada resistant to trimethoprim-sulfamethoxazole (TMP-SMX) may be partially responsible for the increasing use of fluoroquinolones. A number of patient-specific variables have been identified as risk factors for infections caused by antibiotic-resistant pathogens. However, variables unrelated to need, have also been associated with receipt of broad-spectrum antibiotics. We identified patient variables associated with receipt of a fluoroquinolone versus TMP-SMX for treatment of acute pyelonephritis. METHODS: Healthcare claims from the province of Manitoba, Canada for the period February 1996 to March 1999 were examined to identify episodes of pyelonephritis in non-pregnant females between 18 and 65 years of age treated with TMP-SMX or a fluoroquinolone. Patient variables were identified based on healthcare claims review and data from Statistics Canada. Logistic regression was used to model the probability of receipt of a fluoroquinolone. RESULTS: A total of 1084 women met inclusion criteria; 653 treated with TMP-SMX and 431 treated with a fluoroquinolone. Age, income, rural residence, recent antibiotic use, recent hospitalization and presentation to an emergency room (ER) were positively associated with receipt of a fluoroquinolone. CONCLUSIONS: Patient variables reportedly associated with an increased probability of resistant organisms (e.g., age, recent antibiotic use and recent hospitalization) were significantly associated with an increased probability of receipt of fluoroquinolones. However, variables unrelated to antibiotic resistance (e.g., income, rural residence and presentation to an ER) were also significantly associated with receipt of a fluoroquinolone.

Acute Disease↗

PubMed1993

Assessment of binding of 2,4,4-trimethyl-2-pentanol to low-molecular-weight proteins isolated from kidneys of male rats and humans.

A number of chemicals cause a nephrotoxic syndrome in male rats, referred to as protein droplet or alpha 2u-globulin (alpha 2u) nephropathy. To evaluate the potential human risk for developing a similar chemically-induced protein-mediated nephrotoxic response, the low-molecular-weight protein fraction (LMWPF) was isolated from the kidneys of male rats and humans to compare protein concentrations and chemical binding capabilities. Kidney cytosol, prepared from control male rats, was applied to a G-75 gel filtration column and LMWPF (containing proteins from 10,000 to 30,000 Da) were collected and concentrated. 2,4,4-Tri[3H]methyl-2-pentanol ([3H]TMP-2-OH), a chemical known to bind alpha 2u and cause it to accumulate in the kidneys of treated male rats, was incubated with the LMWPF for 1 hr at 25 degrees C. This mixture was applied to a PD-10 column to separate total protein (free and chemically bound) from free [3H]TMP-2-OH. The total protein fraction was injected onto a DEAE anion exchange column and proteins were eluted with a NaCl gradient. [3H]TMP-2-OH was found to coelute with alpha 2u. The alpha 2u protein peaks were identified using SDS-PAGE and Western blot analysis. The LMWPF from human kidneys was then prepared and analyzed identically to that from the male rat kidneys. Human kidney had a concentration of proteins lower than that of the male rat kidney, with a smaller percentage of low-molecular-weight (LMW) proteins. Unlike the results obtained using rat kidney LMWPF, [3H]TMP-2-OH was not found to coelute with the human kidney LMWPF. Taken together, these findings indicate that humans do not possess a protein similar to alpha 2u in relative abundance or binding characteristics and that humans may not be at risk of developing a chemically induced protein-mediated nephrotoxic response.

Adult↗

PubMed1989

A pneumotoxin, O,O,S-trimethyl phosphorothioate, induces hemorheological alteration in rats.

O,O,S-trimethyl phosphorothioate (OOS-TMP), an impurity present in widely used organophosphorus insecticides, has been shown to induce lung injury after oral administration. To date, very little is known about the hemorheological changes which may occur during the inflammation of lung caused by OOS-TMP. The present study has demonstrated that oral administration of OOS-TMP (10 mg/kg, 20 mg/kg) to rats produced an increase in whole blood apparent viscosity at 24, 48 and 72 h following the treatment in rats. Concomitantly, the plasma fibrinogen level and red blood cell (RBC) aggregation were increased at 24 and 48 h. There was no change in RBC filterability. Thus, OOS-TMP, a pneumotoxin, was capable of causing a systemic hemorheological alteration, probably via increase in fibrinogen content, an acute-phase protein, in rats.

Alkaline Phosphatase↗

PubMed1980

Non-specific incorporation of nucleic acid precursors in Blastomyces dermatitidis and Histoplasma capsulatum.

Incorporation of thymidine, thymidine monophosphate (TMP), thymidine triphosphate (TTP), uridine and orotic acid into DNA, RNA and protein in Blastomyces dermatitidis and Histoplasma capsulatum was studied utilizing a specific acid hydrolysis technique developed for these fungi. Thymidine was incorporated to the greatest extent (approximately 0.5% of added label) followed by uridine, orotic acid, TMP and TTP. In Blastomyces, uridine and orotic acid labeled primarily RNA. TMP and TTP labeled RNA, DNA and protein at nearly the same level. In Histoplasma RNA was labeled poorly by any of these precursors. TMP and TTP labeled DNA predominately and protein to a slightly lower level. Deoxyadenosine or uridine media supplements of 250 micrograms/ml did not enhance incorporation. All precursors tested were found to be nonspecific in that RNA, DNA and protein were labeled. All data indicate that neither RNA nor DNA synthesis can be specifically measured in whole cells or acid precipitates by any of these precursors. Specific radiometric monitoring with these isotopes therefore requires the separation of these macromolecules.

Animals↗

PubMed1991

The influence of chlorpromazine on the potential-induced shape change of human erythrocyte.

The effect of chlorpromazine (CPZ) on the shape of human erythrocytes with different values of transmembrane potential (TMP) was investigated. The shape of red blood cells with negative values of the TMP remained unchanged after the formation of stomatocytes by chlorpromazine, while cells with positive TMP showed a characteristic time course of shape change during the incubation with CPZ. Experiments with vanadate show that this might be due to a difference in the activity of the phospholipid-translocase at different values of TMP.

Chlorpromazine↗

PubMed1994

Pharmacokinetics of sulphadoxine and trimethoprim in sows: influence of lactation.

A potentiated sulpha drug was administered intravenously to 12 sows on the 17th day of lactation and to 4 sows in early pregnancy to study the influence of lactation on its disposition kinetics. The dose-rate of sulphadoxine (SDX) used was 12 mg/kg b.w. while that of trimethoprim (TMP) was 2.4 mg/kg b.w. The pharmacokinetic parameters of SDX showed no significant difference between lactating and pregnant sows (Vss, 0.24 +/- 0.04 L/kg; Cls, 0.25 +/- 0.05 ml/min per kg: MRT, 17.08 +/- 4.48 h). SDX did not accumulate in milk, the concentrations in milk being less than the concentrations in serum at the same time. Of the pharmacokinetic parameters for TMP, only the mean residence time was significantly different between the two groups (Vss, 1.60 +/- 0.31 L/kg; Cls, 4.62 +/- 1.07 ml/min per kg: MRTlactating, 5.43 +/- 1.26 h; MRTpregnant, 7.74 +/- 1.72 h). TMP was excreted in milk to a considerable extent, the ratio of its concentration in milk to that in serum at the same time being over 2.2. These two substances show a completely different pharmacokinetic behaviour. Even though TMP is excreted more quickly in lactating sows, adjusting the dose of this potentiated sulpha drug does not seem to be appropriate.

Animals↗

PubMedDate not supplied

Tetramethylpyrazine protects mice against thioacetamide-induced acute hepatotoxicity.

In this study, the intraperitoneal administration of 1 mg/kg thioacetamide (TAA) produced hepatotoxicity in mice. The increase in serum SGOT and SGPT produced at 24 h by this regimen was decreased in a dose-dependent manner by coadministration of tetramethylpyrazine (TMP; 10, 25 and 50 mg/kg). A rise in serum interleukin-2 was similarly prevented. Increased concentrations of malondialdehyde (MDA) generated in vitro in liver homogenates prepared from TAA-treated mice were decreased by TMP treatments. The increase in MDA produced by TAA was also prevented by in vitro addition of TMP to liver homogenates. These results suggest that part of the hepatocellular injury induced by TAA is mediated by oxidative stress caused by the action of cytokines through lipid peroxidation. TMP appears to act by preventing lipid peroxidation.

Alanine Transaminase↗