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PubMed2003

Effect of tetramethylpyrazine on exocrine pancreatic and bile secretion.

AIM: To investigate the effect of tetramethylpyrazine (ligustrazine, TMP) on the secretion of exocrine pancreas (and biliary). METHODS: In in vivo study, we investigated the effect of TMP on the secretion of pancreatic-bile juice (PBJ) in rats. Using human pancreatic duct cell line, CAPAN-1, combined with the short-circuit current (ISC) technique we further studied the effect of TMP on the pancreatic anion secretion. RESULTS: Administration of TMP (80 mg/kg, i.p.) significantly increased the secretion of PBJ (P<0.05), but the pH of PBJ and the secretion of pancreatic protein were not significantly affected. Basolateral addition of TMP produced a dose-dependent increase in ISC (EC50=1.56 mmol/L), which contained a fast transient ISC response followed by a slow decay. Apical application of Cl- channel blockers, DPC (1 mmol/L), decreased the response by about 67.1% (P<0.001), whereas amiloride (100 micromol/L), a epithelial sodium channel blockers, had no effect. Removal of extracellular HCO3- abolished TMP-induced increase in ISC by about 74.4% (P<0.001), but the removal of external Cl- did not. Pretreatment with phosphodiesterase inhibitor, IBMX(0.5 mmol/L), decreased the TMP-induced ISC by 91% (P<0.001). CONCLUSION: TMP could stimulate the secretion of PBJ, especially pancreatic ductal HCO3- secretion via cAMP or cGMP-dependent pathway. It need further study to investigate the roles of cAMP or cGMP in the effect of TMP on the secretion of exocrine pancreas.

Animals↗
PubMed1992

Trimethoprim-sulfamethoxazole compared with vancomycin for the treatment of Staphylococcus aureus infection.

OBJECTIVE: To compare trimethoprim-sulfamethoxazole (TMP-SMZ) and vancomycin regarding efficacy and safety in the therapy of serious Staphylococcus aureus infections. DESIGN: Randomized, double-blind comparative trial. SETTING: A tertiary-care hospital. PATIENTS: One hundred and one intravenous drug users hospitalized with S. aureus infection. MEASUREMENTS: Cure and failure rates; blood and wound cultures; minimum inhibitory and bactericidal concentrations; serum inhibitory and bactericidal titers; temperature; leukocyte count; durations of treatment and hospitalization; and toxicity. RESULTS: Of 228 intravenous drug users, 101 had S. aureus infection and were included in the efficacy analysis (43 received TMP-SMZ and 58 received vancomycin). Methicillin-resistant S. aureus (MRSA) accounted for 47% of S. aureus isolates, and 65% of patients were bacteremic. Infections were cured in 57 of 58 vancomycin recipients and in 37 of 43 TMP-SMZ recipients (P less than 0.02). Failure occurred mostly in patients with tricuspid valve endocarditis and only in those with infection caused by methicillin-sensitive S. aureus (MSSA). The mean duration of bacteremia was 6.7 days in TMP-SMZ recipients and 4.3 days in vancomycin recipients. Among 222 subjects hospitalized for at least 24 hours, toxicity rates were similar for TMP-SMZ (23%) and vancomycin (20%) recipients; nausea and vomiting were associated with TMP-SMZ and inflammation at the intravenous site was associated with vancomycin. Forty-four percent of TMP-SMZ recipients and 29% of vancomycin recipients experienced side effects in the efficacy cohort (P greater than 0.05). CONCLUSIONS: Vancomycin is superior to TMP-SMZ in efficacy and safety when treating intravenous drug users who have staphylococcal infections. However, all treatment failures occurred in patients with MSSA infection at any site. Therefore, TMP-SMZ may be considered as an alternative to vancomycin in selected cases of MRSA infection.

Adult↗
PubMed1975

[Comparison of pharmacokinetics of the combination trimethoprim and sulfamethoxazole in patients with liver diseases and healthy persons].

Pharmacokinetic characteristics of the antibacterial combination sulfamethoxazole (SMZ) plus trimethoprim (TMP) have been compared, following a single oral dose of 800 mg SMZ plus 160 mg TMP, between 3 groups of adult humans: A = 13 healthy persons, B = 4 patients with minor hepatic injury and C = 7 patients with severe, decompensated liver damage. The following data were determined: 1. the time tmax; 2. the maximum concentrations (cmax) of the two drugs reached in the plasma; 3. the half-life t1/2 of their elimination from the plasma; 4. their apparent distribution volume indicated in percent of body weight; 5. the share of metabolized SMZ in percent of total sulfonamide; 6. the concentration ratio of active SMZ to TMP, both total and unbound to plasma proteins; 7. the cumulative renal excretion of total sulfonamide and of non-metabolized TMP. Only the following differences between groups were observed: 1. The maximum plasma level of active SMZ as well as TMP was lower by an average factor of 1.5 to 2.0 in the two groups B and C as compared to group A. An analogous but diminishing difference lasted for the active SMZ up to the 24th, for TMP up to the 12th hour following medication. An influence of the liver disease on the absorption rate via alteration of the biliary conditions is envisaged as a possible explanation. 2. The elimination half-life of TMP, although lying in most of the liver patients within the range of healthy persons, was lengthened up to twice normal in some of the patients with severe liver damage. Such unusually long half-lives for TMP, however, are considered to be in the range of an individual peculiarity. 3. The renal excretion of TMP occurred in the liver-diseased patients on the average more slowly during the first 24 h and its cumulative value reached at the end of the 72 h observation time was somewhat lower than in the healthy persons. In group C at least this may be in connection with a concomitant reduction of the kidney function. None of the features indicated are considered to be of essential clinical importance, such as to discourage the use of the combination in cases of liver disease.

Adult↗
PubMedDate not supplied

Systematic review of the safety of trimethoprim-sulfamethoxazole for prophylaxis in HIV-infected pregnant women: implications for resource-limited settings.

Daily prophylaxis with trimethoprim-sulfamethoxazole (TMP-SMZ) significantly decreases morbidity and mortality among people living with HIV. Some clinicians are reluctant to use TMP-SMZ in pregnant and breastfeeding HIV-infected women because of concerns about the possible teratogenicity when used in the first trimester and about its potential to induce hyperbilirubinemia near term and during early breastfeeding. We systematically reviewed evidence regarding the toxicity of TMP-SMZ prophylaxis in pregnant and breastfeeding women to help guide practice in resource-limited settings. We identified relevant literature by searching PubMed and MEDLINE via OVID, Embase, and Science Citation Index for data on hyperbilirubinemia, kernicterus, and teratogenicity associated with administration of sulfonamides and TMP-SMZ through July 2005. We also reviewed the reference lists of identified articles. Most studies demonstrated that TMP-SMZ was not associated with hyperbilirubinemia when administered to mothers during pregnancy and breastfeeding. No cases of kernicterus were reported in neonates after maternal ingestion of sulfonamides. There is mixed evidence linking ingestion of TMP-SMZ and other sulfonamides in early pregnancy to elevated risks of oral clefts, neural tube defects, and cardiovascular and urinary tract abnormalities, although some sources found that supplementation with folic acid might ameliorate this potential risk. Existing guidelines recommend that HIV-infected pregnant women receive prophylaxis, but they differ with regards to stage of disease at which to initiate treatment, need for CD4+ T-lymphocyte testing, and prophylaxis during the first trimester. Existing data indicate that the risk of serious injury to neonates from maternal use of daily TMP-SMZ prophylaxis during pregnancy and breastfeeding is small. Given the substantial benefits of TMP-SMZ prophylaxis for HIV-infected women living in resource-limited settings, this review indicates that it is safe to abide by the WHO guidelines recommending daily TMP-SMZ prophylaxis for HIV-infected pregnant women.

Abnormalities, Drug-Induced↗
PubMed1989

Stability of concentrated trimethoprim-sulfamethoxazole admixtures.

The stability of trimethoprim-sulfamethoxazole (TMP-SMX) at various concentrations in 5% dextrose injection or 0.9% sodium chloride injection was studied. Appropriate volumes of TMP-SMX formulation (80 mg TMP and 400 mg SMX/5 mL) were mixed with 5% dextrose injection or 0.9% sodium chloride injection to provide dilutions of 1:25 v/v, 1:20 v/v, 1:15 v/v, and 1:10 v/v. Aliquots were removed at 0, 0.5, 1, 2, 4, 8, 14, 24, and 48 hours and filtered. The pH of the samples was determined, and the samples were assayed for trimethoprim and sulfamethoxazole content by high-performance liquid chromatography. Admixtures were visually inspected for precipitate before each sample was removed. The concentration of SMX in all admixtures did not change during the study period. The stability of TMP was dependent on concentration and vehicle. At a 1:25 v/v dilution, TMP was stable for 48 hours in 5% dextrose injection and 0.9% sodium chloride injection. At a 1:20 v/v dilution, TMP was stable for 24 hours in 5% dextrose injection and 14 hours in 0.9% sodium chloride injection. At a 1:15 v/v dilution, TMP was stable for four hours in 5% dextrose injection and two hours in 0.9% sodium chloride injection. At a 1:10 v/v dilution, TMP was stable for one hour in 5% dextrose injection and 0.9% sodium chloride injection. Concentrated solutions of TMP-SMX should be prepared in 5% dextrose injection, infused within one hour of preparation, and visually inspected for precipitation before and during infusion.

Drug Combinations↗
PubMed1983

[In vitro synergy between sulfamethoxazole and trimethoprim on strains of Staphylococcus aureus sensitive and resistant to methicillin].

The synergy between sulfamethoxazole (SMZ) and trimethoprim (TMP) is studied on 91 methicillin sensitive S. aureus strains (methi.S) and 95 methicillin resistant S. aureus strains (methi.R). In methi.S strains, the MIC 90% of SMZ, TMP and SMZ + TMP (19 SMZ/1 TMP) is respectively 64, 0.5 and 2 mg/l. 98% of methi.S strains have a FIC index less than or equal to 0.6 and only one strain has a FIC index greater than or equal to 0.6. In methi.R strains, the MIC 90% of SMZ, TMP and SMZ + TMP is respectively 256, 0.5 and 4 mg/l. 77% of methi.R strains have a FIC index less than or equal to 0.6. The relationship between FIC index and disc diffusion method is studied: bridging inhibition zone between SMZ 200 mcg disc, and TMP 2.5 micrograms disc and difference of the inhibition diameter between SMZ + TMP disc and TMP 1.25 micrograms disc. There is a good correlation only in methi.S strains in the first method and in methi.S and methi.R strains in the second method.

Drug Synergism↗
PubMed1984

[Pharmacokinetics, biological availability and residues of sulfadoxine and trimethoprim when used jointly on calves].

In calves (cross-breds--Bulgarian Brown Cattle breed and Black Spot Cattle bred) weighing about 189 kg pharmacokinetics of sulphadoxine (SD) and trimethoprim (TMP) was studied. The two substances were administered in combination (5 + 1) as a dosage form Tridoxin (Pharmachim, Bulgaria; 24% injectable solution) (TD) at a dose 15 mg/kg m. The results show that after intramuscular administration TD is absorbed relatively rapidly. SD and TMP have systemic availability 94.1 +/- 18.1% and 52.5 +/- 6.2% and produce blood levels, after a single dose of TD, higher than potentiated minimum inhibitory concentrations for 24-48 h and 5(4-8) h, respectively. Upon intravenous administration the two-compartmental model is applicable for the distribution and elimination of SD and TMP (for TMP in part of the animals one-compartmental model is applicable). The two substances are distributed relatively widely in organs and tissues. The biological half-life of TD--t1/2 beta for SD is 14.36 +/- 1.40 h and for TMP--2.40 +/- 0.31 (for one-compartmental model--1.92 +/- 0.26) h, Vd--429.9 +/- 16.9 ml/kg and for TMP in part of the animals one-compartmental model is applicable). The two substances are distributed relatively widely in organs and tissues. The biological half-life of TD--t1/2 beta for SD is 14.36 +/- 1.40 h and for TMP--2.40 +/- 0.31 (for one-compartmental model--1.92 +/- 0.26) h, Vd--429.9 +/- 16.9 ml/kg and for TMP in part of the animals one-compartmental model is applicable). The two substances are distributed relatively widely in organs and tissues. The biological half-life of TD--t1/2 beta for SD is 14.36 +/- 1.40 h and for TMP--2.40 +/- 0.31 (for one-compartmental model--1.92 +/- 0.26) h, Vd--429.9 +/- 16.9 ml/kg and 655.8 +/- 77.6 (for one-compartmental model--671.7 +/- 40.0) ml/kg, ClB--0.35 +/- 0.02 ml/kg/min and 2.87 +/- 0.35 (for one-compartmental model--4.15 +/- 0.80) ml/kg/min, respectively. After intramuscular injection at the dose used a suitable withdrawal time for meat and internal organs is 5 days and for milk--2 days.

Animals↗
PubMed1980

Plasma levels of trimethoprim and sulfonamide after administration of trimethoprim-sulfamethoxazole and trimethoprim-sulfamoxole.

In a cross-over study with ten healthy volunteers, the plasma levels of trimethoprim (TMP) and sulfonamides were compared using orally given trimethoprim-sulfamethoxazole (TMP-SMX: Septra) and trimethoprim-sulfamoxole (TMP-SMO: Supristol) in recommended doses. The dosage schedule for TMP-SMX was 2 tablets every 12 h for nine doses, and for TMP-SMO it was 2 tablets as in the first dose, followed by 1 tablet every 12 h for eight more doses. Serial plasma levels of TMP and sulfonamides after the first dose of each of the two products showed no significant differences. However, after the ninth dose of each product, the paired t test revealed significantly higher levels of TMP and sulfonamides after TMP-SMX as compared with TMP-SMO.

Adult↗
PubMed1981

Stability of trimethoprim-sulfamethoxazole injection in two infusion fluids.

The concentrations over time of trimethoprim (TMP) and sulfamethoxazole (SMZ) in solution after preparations of admixtures of TMP-SMZ in 5% dextrose injection (D5W) and in 0.9% sodium chloride injection (NS) were measured. Admixtures (50 ml) containing three TMP concentrations (0.64 mg/ml, 1.6 mg/ml, and 3.2 mg/ml) and three SMZ concentrations (3.2 mg/ml, 8.0 mg/ml, and 16 mg/ml) were prepared in D5W or NS, representing 1:25 v/v, 1:10 v/v, and 1:5 v/v dilutions of TMP-SMZ injection, respectively. Aliquots of each admixture were obtained immediately upon dilution and after 0.5, 1, 2, 4, 8, and 24 hours. The aliquots were filtered and assayed for TMP and SMZ by high-pressure liquid chromatography. Each mixture was inspected visually for any changes in clarity or color, and the pH of each admixture was measured over time. The concentration of SMZ in all admixtures remained constant over 24-hour study period. The TMP concentration did not change significantly (less than 10% of initial concentration) after 1:25 v/v dilutions in either D5W or NS for up to four hours. With a dilution of 1:10 v/vv D5W TMP was stable at D5W for up to two hours. TMP precipitated rapidly in dilutions of 1:5 v/v in either D5W or NS. The pH of the admixtures ranged from 9.39 to 10.10. D5W is the preferred diluent for TMP-SMZ injection if a dilution ratio of 1:10 v/v is desired. Either D5W or NS may be used if a dilution ratio of 1:25 v/v is desired.

Drug Combinations↗
PubMed1995

Effect of gallium-porphyrin analogue ATX-70 on nitroxide formation from a cyclic secondary amine by ultrasound: on the mechanism of sonodynamic activation.

Sonodynamic therapy is a promising new modality for cancer treatment based on the synergistic effect on tumor cell killing by combination of a drug (typically a photosensitizer) and ultrasound. The mechanism of sonodynamic action was suggested to involve photoexcitation of the sensitizer by sonoluminescent light, with subsequent formation of singlet oxygen. In this work we studied the aqueous sonochemical reactions of the gallium-porphyrin derivative ATX-70, one of the most active sonodynamic agents found, using 50 kHz ultrasound. The experiments were carried out in the presence of 2,2,6,6-tetramethyl-4-piperidone hydrochloride (TMP), which reacts with singlet oxygen or .OH radicals to give the EPR-detectable nitroxide 2,2,6,6-tetramethyl-4-piperidone-N-oxyl (TMP-NO). Recently it has been suggested that the enhancement of TMP-NO yields in the presence of aqueous solutions of ATX-70 exposed to ultrasound was evidence for the formation of singlet oxygen in the system. Our results show that the surfactant cetyltrimethylammonium bromide (CTAB) can mimic the ATX-70-induced increase in the TMP-NO signal, but it fails to reproduce the behavior of ATX-70 in D2O: while the yields of TMP-NO in the presence of ATX-70 increase in D2O, the opposite effect was found with the surfactant CTAB. However, our data show that the increased TMP-NO yields in D2O are paralleled by an increased concentration of ATX-70 dimer, a form that is inactive in the photochemical generation of singlet oxygen. Our finding that the ATX-70-dependent enhancement of the TMP-NO signal was highest at approximately 20% O2, in both N2/O2 and argon/O2 mixtures, and decreased with increasing oxygen concentration is not compatible with the singlet oxygen mechanism. Finally, our results on the temperature dependence of the ATX-70-induced formation of TMP-NO are not consistent with the photochemical excitation of ATX-70 by sonoluminescent light: the ATX-70-dependent enhancement of TMP-NO signal increased with temperature in the range 10-25 degrees C, while the intensity of sonoluminescence of aqueous solutions both in multiple-bubble fields and in single-bubble experiments is known to decrease with increasing temperature.

Antineoplastic Agents↗
PubMed1994

[Influence of combined Salvia miltiorrhiza and Ligusticum wallichii on pharmacokinetics of tetramethylpyrazine in rats].

Influence of Salvia miltiorrhiza (SM) and/or Ligusticum wallichii (LW) on pharmacokinetics of tetramethylpyrazine (TMP) was observed in rats. The content of TMP in LW and LW-SM decoctions were 375.8 and 236.2 micrograms/ml respectively. The rat serum components after oral administration of LW were analyzed by modified HPLC. One of 3 compounds was detected, which was identified as TMP by the comparison of the parameters of 4 spectrums (UV, IR, MS and NMR) with those of TMP in literature. Pharmacokinetics of TMP in rats after the oral administration of LW and LW-SM decoction respectively showed that: (1) both of the data fitted adequately to two-compartment open model; (2) Ka, AUC and serum concentration were higher (P < 0.05-0.01) for LW decoction than that for LW-SM decoction, indicating a higher bioavailability. It demonstrated that the absorption of TMP of LW-SM decoction was slower and the bioavailability of TMP of LW-SM decoction reduced. Contents of TMP in LW and LW-SM decoction and serum concentration of TMP were determined by HPLC method.

Animals↗
PubMed1994

In vitro susceptibility of equine Salmonella strains to trimethoprim and sulfonamide alone or in combination.

The in vitro activity of trimethoprim (TMP) and 9 sulfonamides and their combinations in 6 concentration ratios was tested against 62 Salmonella strains isolated from horses over a 3-year period in the Netherlands, using the agar-dilution method. Most of the isolates were S typhimurium strains (n = 52); the others were S heidelberg (n = 3), S hadar (n = 2), S thompson (n = 2), S enteritidis (n = 1), S infantis (n = 1), and S derby (n = 1). The minimal TMP concentration at which 50% of the Salmonella strains were inhibited (MIC50) was 0.12 micrograms/ml. Sulfachlorpyridazine (SCP; MIC50, 16 micrograms/ml), sulfamethoxazole (SMX; MIC50, 32 micrograms/ml), and sulfadiazine (SDZ; MIC50; 32 micrograms/ml) were the most potent of the sulfonamides tested. The antimicrobial effect of the sulfonamides, in combination with TMP (additive, synergistic, or antagonistic), was expressed by the fractional inhibitory concentration (FIC) index. Concentrations of SDZ and SCP with TMP had marked synergism at all tested TMP-to-sulfonamide concentration ratios (1:1 to 1:160; FIC index, 0.10 to 0.50); SMX had synergy with TMP at all ratios, except 1:1 (FIC index, 0.10 to 0.27). Sulfamethazine, sulfamerazine, sulfadoxine (SDX), sulfatroxazole, sulfadimethoxine, and sulfacetamide had MIC50 greater than their breakpoint MIC value and are, therefore, less potent drugs. However, synergy with TMP was found for these less potent sulfonamides at certain concentration ratios, depending on the sulfonamide used. Sixteen Salmonella strains were resistant to TMP, all sulfonamides, and TMP-sulfonamide combinations; 14 of these strains were S typhimurium phage type 200, 1 was S typhimurium phage type 61, and 1 was S typhimurium phage type 10.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

[Evidence of elevated soluble plasma thrombomodulin in atherosclerosis].

Thrombomodulin (TM) is a very efficient natural anti-thrombin glycoprotein expressed on the endothelial cell surface. Circulating soluble thrombomodulin is also detected by enzyme immunoassay in plasma and represents some fragments of membrane TM with various molecular weight. Plasma TM (TMp) levels are elevated in diseases associated with endothelium damage. We have explored TMp in patients with atheromatous disease and compared its level with others endothelial cell markers, particularly those who indicate cell activation, as tissue-type plasminogen activator (t-PA), inhibitor of plasminogen activator (PAI-1) and prostacyclin (PG12). Thirty seven patients with documented atheromatous artery disease were included in this study. They were not diabetics and their hepatic and renal functions were normal. Mean age was 71 +/- years. Routine serum parameters were checked out as well as others more specific for endothelium activation (TMp, PG12, PAI-1, t-PA) measured by enzyme immunoassay. Patients were classified according to three localizations of atheromatous involvement: - 15 patients with peripheral occlusive arteriopathy disease (POAD) - 6 with coronary artery disease (CAD); and 16 with polyvascular involvement (POLY). They were compared with 21 controls without any vascular lesions (mean age: 43 +/- 13 years). In controls TMp was 36 +/- 8 ng/ml without significant change according with age and sex. In patients whatever the localization of atheroma, TMp was found significantly higher: POAD = 51.3 +/- 19.7 ng/ml (p = 0.003); CAD = 49.2 +/- 15.4 ng/ml (p = 0.008); POLY = 49.6 +/- 17.2 ng/ml (p = 0.003). A positive correlation was pointed out in all patients between TMp and t-PA (p = 0.047), TMp and PG12 (p = 0.008). A positive correlation between TMp and t-PA (p = 0.034) was found only in the subgroup with POAD. In this study, there was no correlation between TMp and the following parameters: leucocytes, haemoglobin, cholesterol, HDL, LDL-cholesterol, Lp(a), fibrinogen.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1996

Determination of trimethoprim and sulphadoxine residues in porcine tissues and plasma.

Healthy gilts and market-ready hogs were administered a single intramuscular (IM) injection of Borgal, a commercial formulation of trimethoprim-sulfadoxine (TMP-SDX), once or twice daily. The objectives were to determine if a newly-developed high-performance liquid chromatographic (HPLC) method would be suitable for measuring the residual concentrations of TMP in the plasma of these live animals, and to determine if the administration of this veterinary drug would leave measurable residues in their plasma and tissues at slaughter. Plasma and tissue concentrations of SDX and TMP from these animals were determined over a period of 14 d using thin-layer chromatography/densitometry (TLCD), and the newly-developed HPLC method, respectively. The lowest detectable limit (LDL) for SDX in plasma and tissue was 20 ppb by TLCD. The HPLC method had a LDL of 5 ppb for TMP in plasma and tissue. Both methods were then used to provide baseline data on the absorption and depletion of TMP and SDX from these healthy animals. It was observed that both TMP and SDX were readily absorbed into the blood and tissues, but TMP was eliminated much faster than SDX. No TMP residues were detected in the plasma of any of the gilts at and beyond 21 h after drug administration. Also, no TMP residues were detected in the plasma of any of the market-ready hogs 24 h after drug administration at either the label dose or twice the label dose. Sulfadoxine residues at concentrations above the maximum residue limit (MRL) of 100 ppb were, however, detected in the plasma, muscle, kidney, liver, and injection sites of hogs slaughtered 1 and 3 d after a single IM administration at the label dose. Although SDX residues were still detectable in the lungs, kidney, liver and plasma of some hogs 10 d after administration of the label dose and twice the label dose, these were below the MRL. Postmortem examination revealed necrosis and inflammation at the injection sites, but no visible deposits of the injected drug.

Animals↗
PubMed1998

Trimethylpsoralen bath PUVA is a remittive treatment for psoriasis vulgaris. Evidence that epidermal immunocytes are direct therapeutic targets.

BACKGROUND: Psoriasis vulgaris can be effectively treated with trimethylpsoralen (TMP) bath PUVA therapy (psoralen plus UVA), but no data exist on the extent to which psoriatic pathology is affected by this treatment, or on its cellular mechanism of action. OBSERVATIONS: Eleven patients with recalcitrant psoriasis vulgaris were treated with TMP bath PUVA therapy and observed through clinical and histological measures. Clinical resolution of psoriasis was achieved in 10 of 11 patients. Histopathological resolution of epidermal hyperplasia (marked by keratin 16 expression) was achieved in 90% of individuals treated with TMP bath PUVA. Epidermal acanthosis was reduced by 40% at 2 weeks and 66% by the end of treatment. Epidermal improvement correlated best with reduction in intraepidermal T lymphocytes, which were reduced by 76% at 2 weeks of treatment and 93% at the end of treatment. Furthermore following TMP bath PUVA therapy, the numbers of epidermal CD1a+ Langerhans cells were markedly reduced, and CD86+ cells were eliminated. Through in vitro assays, TMP was found to be about 10,000-fold more active as a lymphotoxic agent compared with 8-methoxypsoralen (8-MOP). Additionally, at physiologic concentrations, lymphocytes were killed more readily by TMP PUVA (TMP plus UVA) than were keratinocytes. CONCLUSIONS: Treatment with TMP bath PUVA was effective in treating moderate to severe psoriasis, even in darker pigmented individuals. It is likely that this treatment ameliorates psoriasis through direct effects on activated leukocytes in lesional skin.

Antigens, CD↗
PubMed1979

Double-blind comparison of sulphonamide-trimethoprim combinations in acute uncomplicated urinary tract infections.

The effects of a twice daily dosage of a combination of 410 mg sulphadiazine + 90 mg trimethoprim (SD + TMP) and 800 mg sulphamethoxazole + 160 mg trimethoprim (SMZ + TMP) were compared in uncomplicated urinary tract infections. All but one patient in each treatment group, i.e. 36 SD + TMP treated and 42 SMZ + TMP treated patients respectively, were cured. The percentage of side-effects related to therapy in the patients receiving the combination with sulphadiazine was 15.1% and in those with sulphamethoxazole 23.7%. Due to the small number tested, however, differences were not statistically different. It is noteworthy that only one of the SD + TMP patients had to stop therapy because of a rash, whereas therapy was stopped for this reason in three of the SMZ + TMP patients. SD + TMP represents a good alternative to SMZ + TMP in the treatment of urinary tract infections.

Adolescent↗
PubMed1990

Modulation of macrophage protease activity by acute administration of O,O,S trimethyl phosphorothioate.

Previous studies showed that acute administration of O,O,S trimethyl phosphorothioate (OOS-TMP), a contaminant in malathion, acephate and fenitrothion, led to increases in metabolic activities, such as, secretion of interleukin 1 and nonspecific esterase, of splenic and peritoneal macrophages. In this report, the effect of OOS-TMP administration on the levels of the neutral proteases, elastase, collagenase and plasminogen activator, in cultures supernatants of peritoneal and splenic macrophages is presented. Acute administration of OOS-TMP elevated collagenase levels only at day 3 following treatment with 10 or 20 mg/kg OOS-TMP. Levels of elastase in culture supernatant of peritoneal and splenic macrophages, on the other hand, was elevated at days 1, 3, 5 and 7 following administration of OOS-TMP. The effect on elastase secretion was dose-dependent at days 5 and 7 after treatment. Levels of plasminogen activator activity in the culture supernatants of splenic macrophages was elevated at day 5 following treatment with both doses of OOS-TMP. At days 1 and 3, the level of plasminogen activator inhibitor was suppressed. However, at days 5 and 7 plasminogen activator inhibitory activity was close to control values. These data show that OOS-TMP administration led to an elevation in the levels of neutral proteases in culture supernatants of peritoneal and splenic macrophages. This elevation indicates that acute OOS-TMP administration alters another parameter of macrophage function, which is elevated following exposure to acute inflammatory stimuli.

Animals↗
PubMed1988

Effects of acute administration of O,O,S-trimethyl phosphorothioate on the respiratory burst and phagocytic activity of splenic and peritoneal leukocytes.

An impurity in malathion, O,O,S-trimethyl phosphorothioate (OOS-TMP), was previously shown to be immunosuppressive. The immune cell type which induced immune suppression caused by OOS-TMP at 24 hrs after administration was found to be splenic macrophages. Further characterization of macrophages from OOS-TMP treated mice indicated that OOS-TMP led to macrophage differentiation. In this study, these initial studies were continued and extended to examine the effects of OOS-TMP on splenic and peritoneal macrophages at various times following exposure. Administration of OOS-TMP increased the size heterogeneity of cell volume, phagocytic capability and respiratory burst activity of splenic and peritoneal macrophages. However, by day 7 splenic and peritoneal macrophages from treated animals had size frequency histograms, phagocytic capability and respiratory burst activity similar to control. These data would suggest that macrophages not previously exposed to OOS-TMP migrated to the spleen and peritoneum of treated animals. This migration may allow the restoration of the ability of splenocytes from treated animals to generate an immune response. Alternatively, these data may indicate that 7 days following exposure to OOS-TMP, the differentiative state of the splenic and peritoneal macrophages of treated mice had decayed and hence these cells had regained resident characteristics.

Animals↗