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At least 703 records · Page 39Linked to original sources
PubMed1990

The growth rate of metastatic nonseminomatous germ cell testicular tumours measured by marker production doubling time--II. Prognostic significance in patients treated by chemotherapy.

Tumour growth rates have been measured in metastatic non-seminomatous germ cell testicular tumours (NSGCTT) by estimating the rate of rise of tumour marker production (TMP). TMP was calculated for the time between orchidectomy and the start of chemotherapy in a group of 58 patients with metastatic NSGCTT treated with BEP combination chemotherapy (bleomycin, etoposide and cisplatin). Calculation of TMP (iu/l/day) took account of the continuing clearance of marker from the serum. TMP increased with time in 51 patients and this rise generally appeared to be exponential. The rate of this increase was expressed as the marker production doubling time (MPDT) and is a measure of the tumour growth rate. MPDT varied from 0.5 to greater than 80 days (45 cases) for AFP + ve patients and from 1.8 to greater than 80 days (34 cases) for HCG + ve patients. Patients who failed BEP first line therapy had shorter MPDTs than those who responded (AFP P = 0.08, HCG P = 0.003). It was found that patients with a MPDT less than or equal to 4 days were more likely to fail treatment than those who had a MPDT greater than 4 days (AFP P = 0.009, HCG P = 0.005). MPDTs were independent of initial serum marker concentration. Patients with small volume disease had longer MPDTs than patients with large volume disease (AFP P = 0.02, HCG P = 0.04). Rapid tumour growth rate reflected by short MPDT carries a poor prognosis in patients with NSGCTT treated by BEP chemotherapy.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1985

Alterations of alveolar macrophage function and level of bronchopulmonary protease inhibitors in O,O,S-trimethyl phosphorothioate-induced lung injury.

O,O,S-Trimethyl phosphorothioate (OOS-TMP), an impurity present in widely used organophosphorus insecticides, has been shown to induce pneumotoxicity after oral administration. To date very little is known about the pathogenesis of the injury. Protease-anti-protease imbalance has been proposed as a mechanism of various lung injuries; thus, the effect of OOS-TMP on alpha 1-protease inhibitor capacity, pulmonary alveolar macrophage (PAM) esterases, cytotoxic activity and on specific esterase inhibitors in the bronchopulmonary lavage fluid and serum were measured. OOS-TMP (20 mg/kg) administered orally to rats produced a 27% increase in PAM esterase activity 6 h after treatment. The activity then declined to 63% of control value on day 3 and had not recovered to any significant extent on day 7. The cytotoxic activity of PAM was significantly increased at 6 h and 24 h following treatment. Chymotrypsin inhibitory capacity (CIC) of the lavage fluid was decreased by 45% at 6 h but recovered rapidly and reached control levels by 24 h. Trypsin inhibitory capacity (TIC) of serum was affected to a lesser extent such that no change was detected after 6, 12 or 24 h. These data, early elevation of PAM esterase levels with a concomitant increase in cytotoxic activity and decreased TIC and CIC in bronchopulmonary lavage fluid, support the view that pathogenesis of OOS-TMP produced lung injury could be due to increased protease levels.

Administration, Oral↗
PubMed1987

The metabolism of 2,3,4-trimethylpentane in male Fischer-344 rats.

The urinary metabolites of the potent nephrotoxic hydrocarbon 2,3,4-trimethylpentane (2,3,4-TMP) given Fischer-344 male rats by gavage included 1-hydroxy-2,3,4-trimethylpentane, 2,3,4-trimethyl-1-pentanoic acid and 2,3,4-trimethyl-5-hydroxy-1-pentanoic acid. Analyses were performed by gas-liquid chromatography (GC) and gas-liquid chromatography/mass spectrometry (GC/MS). A comparison of the urinary metabolites of 2,3,4-TMP with those of 2,2,4-trimethylpentane (2,2,4-TMP) showed that more monocarboxylic acid was produced with 2,3,4-TMP.

Animals↗
PubMed1992

A comparison of European High Test gasoline and PS-6 unleaded gasoline in their abilities to induce alpha 2u-globulin nephropathy and renal cell proliferation.

Male Fischer-344 rats were administered European High Test gasoline (EHT) (50-500 mg/kg), PS-6 unleaded gasoline (UG) (16-500 mg/kg) or 2,2,4-trimethylpentane (TMP) (0.95-30 mg/kg) by gavage for ten consecutive days. To measure cell replication, rats were exposed to [3H]thymidine continuously over the last 7 days of the exposure period. Twenty-four hours after the final dose, protein droplet (PD) accumulation, alpha 2u-globulin (alpha 2u) concentration and the nuclear labeling index (LI), as a measure of cell replication, were measured in the kidneys of control and treated rats. Dose-related increases in PD, alpha 2u and cell replication were detected in the kidneys of rats treated with either gasoline mixture or TMP. The accumulation of PD and the increase in alpha 2u was greater in the kidneys of UG- and TMP-treated rats than in the kidneys of rats treated with EHT. These differences were attributed to the higher composition of branched hydrocarbons in UG, which have been shown to be the biologically active components for these endpoints. The extent of renal cell proliferation was similar in both EHT-, UG- and TMP-treated rats. This suggests that other components besides the branched hydrocarbons are responsible for the increased renal cell replication in EHT-treated rats.

Administration, Oral↗
PubMed2004

Comparison of reperfusion regimens with or without tirofiban in ST-elevation acute myocardial infarction.

There is continued debate as to whether a combined reperfusion regimen with platelet glycoprotein IIb/IIIa inhibitors provides additional benefit in optimal myocardial reperfusion of patients with a ST-elevation acute myocardial infarction (AMI). In addition, the best angiographic method to evaluate optimal myocardial reperfusion is still controversial. Patients (n = 144) with a first AMI presenting <6 hours from onset of symptoms were randomized to receive a conjunctive strategy (n = 72) with low-dose alteplase (50 mg) and tirofiban (0.4 microg/kg/min/30 minute bolus; infusion of 0.1 microg/kg/minute), or tirofiban plus stenting percutaneous coronary intervention (PCI). Control patients (n = 72) received standard strategy with either full-dose alteplase (100 mg) or stenting PCI [correction]. All patients were submitted to coronary angiographic study at 90 minutes. The primary end point was Thrombolysis In Myocardial Infarction (TIMI) grade 3 flow at 90 minutes. Secondary end points were TIMI myocardial perfusion (TMP) rates, a composite end point at 30 days (death, reinfarction, refractory ischemia, stroke, heart failure, revascularization procedures, or pulmonary edema), and bleeding or hematologic variables. The rate of TIMI 3 flow at 90 minutes for patients treated with alteplase alone was 42% compared with 64% for those who received low-dose alteplase and tirofiban. Standard stenting PCI achieved 81% of TIMI 3 flow compared with 92% when tirofiban was used. Significantly higher rates of TMP grade 3 were observed when tirofiban was used as the adjunctive treatment in both alteplase (66% vs 47%) and stenting PCI (73% vs 55%). Higher rates of the composite end point were observed in standard regimens compared with conjunctive regimens (hazard ratio 5.8, 95% confidence interval 1.27 to 26.6, p = 0.023). Regardless of reperfusion regimen, better outcomes were observed when a combination of TIMI 3 flow and TMP grade 3 was achieved. Beyond TIMI 3 flow rate, the TMP grade was an important determinant. The rates of major bleeding were similar (2.8%) for standard versus conjunctive regimens with tirofiban. Thus, tirofiban as a conjunctive therapy for lytic and stenting regimens not only improves TIMI 3 flow rates, but also the TMP3 rates, which are related to a better clinical outcome without an increase in the risk of major bleeding. This study supports the hypothesis that platelets play a key role not only in the atherothrombosis process, but also in the disturbances of microcirculation and tissue perfusion.

Aged↗
PubMed2005

Nocardiosis in Srinagarind Hospital, Thailand: review of 70 cases from 1996-2001.

OBJECTIVE: Nocardiosis is a common opportunistic infection found in both immunocompromised and immunocompetent patients. The clinical manifestations, underlying diseases, radiologic findings, antimicrobial susceptibility and treatment of nocardial infection are presented here. METHOD: A retrospective study at Srinagarind Hospital, Khon Kaen in Thailand was performed. Medical records from 1996-2001 were reviewed. RESULTS: There were 81 cases of nocardiosis during the study period but data of only 70 cases were available. 80% of cases were male. The mean age was 39.7+/-14.9 years. Underlying diseases were found in 80%, of which HIV infection was the most common (34.3%). The common clinical findings were fever, cough, and cutaneous abscess. The most common clinical syndrome was pleuropulmonary infection (44.3%), followed by skin and soft tissue infection (22.8%). Multiorgan dissemination was found in 11.4% of cases. The chest X-rays were abnormal in 46 cases (65.7%); alveolar and reticulonodular infiltration was common. Only 70% had positive cultures for Nocardia spp. The resistance rate of Nocardia isolates to trimethoprim-sulfamethoxazole (TMP-SMX) was very high (57.9%) in this study. Most of the patients (85.7%) were treated with antimicrobials, of which TMP-SMX was commonly used. In-hospital mortality was 20%. Most of the cases who died had dissemination, brain abscesses or infection with TMP-SMX-resistant strains. The long-term prognosis was good, with a treatment success rate of 93.75%. CONCLUSION: Nocardiosis is a common opportunistic infection in many immunocompromised conditions. It can present with various clinical syndromes, especially pleuropulmonary infection. Culture may not yield the organism but modified acid-fast staining is very helpful in diagnosis. Drug susceptibility testing should be performed due to increasing resistance to TMP-SMX.

Adult↗
PubMed2005

Trimethoprim-sulfamethoxazole induced rash and fatal hematologic disorders.

Trimethoprim-sulfamethoxazole (TMP-SMX) is a combination chemotherapeutic agent, a commonly used antibiotic. Adverse drug reactions occur in 6-8% of patients. Although, the most common adverse reactions include mild gastrointestinal distress and cutaneous events, also a wide range of hematological abnormalities have been ascribed to TMP-SMX. We report a 40-year-old male patient who developed an early onset neutropenia, thrombocytopenia, generalised rash and oral candidiasis after 5 days long TMP-SMX therapy. Although generalised rash may seen more and improves with discontinuation of the therapy; severe neutropenia, thrombocytopenia and oral candidiasis are seen very rare and rarely leads to fatality as it was in our case. Despite thrombocyte transfusions, whole blood transfusions, red cell concentrates and filgrastim therapy we lost our patient. We want to underline that although the TMP-SMX combination is usually well tolerated it can also lead to fatal complications.

Adult↗
PubMed2005

Inclusion complex of trimethoprim with beta-cyclodextrin.

The complexation of trimethoprim (TMP) with beta-cyclodextrin (beta-CD) was studied. UV-spectrophotometry and phase-solubility techniques were employed to investigate the complexation behaviour in liquid medium, and to demonstrate that the aqueous solubility of TMP increased 2.2-fold due to complexation with beta-CD. Solid samples prepared by co-evaporation (in 2 wt% acetic acid solution) have also been studied, using differential scanning calorimetry (DSC) and powder X-ray diffraction (XRD), to assess the formation of the inclusion complex. The water content of the complex and beta-CD was determined using thermo gravimetric analysis (TGA). In vitro dissolution analysis indicated that dissolution properties of TMP/beta-CD complex were superior compared to both pure TMP and the corresponding physical mixture of TMP and beta-CD.

Acetic Acid↗
PubMed2006

Rapid and simultaneous determination of sulfamethoxazole and trimethoprim in human plasma by high-performance liquid chromatography.

A simple and reproducible high-performance liquid chromatographic method was developed for simultaneous determination of sulfamethoxazole (SMX) and trimethoprim (TMP) in human plasma. The method entailed injection of the samples after deproteination with perchloric acid and subsequent neutralizing. Primidone was used as internal standard. Chromatography was performed on a C(18) column (250 mm x 4.6 mm, 5 microm) under isocratic elution with 50 mM aqueous sodium dihydrogen phosphate-acetonitrile-triethylamine (100:25:0.5, v/v), pH 5.9. Detection was made at 240 nm and analyses were run at a flow-rate of 1.5 ml/min at a temperature of 35 degrees C. The recovery was 83.4, 88.5 and 98.2% for TMP, SMX and internal standard, respectively. The precision of the method was 2.6-9.8% over the concentration range of 0.125-2 microg/ml for TMP and 0.39-50 microg/ml for SMX. The limit of quantification (LOQ) in plasma was 0.125 and 0.39 microg/ml for TMP and SMX, respectively. The method was used for a bioequivalence study.

Anti-Infective Agents↗
PubMed2006

Crosslinked hydrogels for tympanic membrane repair.

PROBLEM: To provide a less expensive and more convenient protocol for the treatment of tympanic membrane perforations (TMPs). METHODS: Several materials were prepared and compared for TMP repair including Carbylan-SX, Gelatin-DTPH-PEGDA (GX), Carbylan-S/Gelatin-DTPH (Carbylan-GSX) (injectable and sponge), Gelfoam, Epifilm, and crosslinked thiolated chondroitin sulfate (CS-DTPH-PEGDA [CS-SX]). Hartley pigmented guinea pigs (Elm Hill) underwent bilateral myringotomy with 1 ear left as a control and the other treated with one of the previously mentioned materials. RESULTS: Carbylan-GSX (injectable and sponge), Gelfoam with saline, and CS-SX had the shortest time for TMP closure. Epifilm, Carbylan, and gelatin preparations resulted in closure rates similar to controls. CS-SX showed a marked inflammatory reaction compared with controls and other materials based on neutrophil, lymphocyte, epitheloid counts, and degree of fibrosis. CONCLUSIONS: This study shows the validity of Carbylan-GSX compared with Gelfoam as a material to promote TMP closure in an acute TMP guinea pig model.

Animals↗
PubMed2003

Mycobacterium tuberculosis thymidylate kinase: structural studies of intermediates along the reaction pathway.

Mycobacterium tuberculosis TMP kinase (TMPK(Mtub)) represents a promising target for developing drugs against tuberculosis because the configuration of its active site is unique in the TMPK family. To help elucidate the phosphorylation mechanism employed by this enzyme, structural changes occurring upon binding of substrates and subsequent catalysis were investigated by protein crystallography. Six new structures of TMPK(Mtub) were solved at a resolution better than 2.3A, including the first structure of an apo-TMPK, obtained by triggering catalysis in a crystal of a TMPK(Mtub)-TMP complex, which resulted in the release of the TDP product. A series of snapshots along the reaction pathway is obtained, revealing the closure of the active site in going from an empty to a fully occupied state, suggestive of an induced-fit mechanism typical of NMPKs. However, in TMPK(Mtub) the LID closure couples to the binding with an unusual location for a magnesium ion coordinating TMP in the active site. Our data suggest strongly that this ion is required for catalysis, acting as a clamp, possibly in concert with Arg95, to neutralise electrostatic repulsion between the anionic substrates, optimise their proper alignment and activate them through direct and water-mediated interactions. The 3'-hydroxyl moiety of TMP, critical to metal stabilisation, appears to be a target of choice for the design of potent inhibitors. On the other hand, the usual NTP-bound magnesium is not seen in our structures and Arg14, a P-loop residue unique to TMPK(Mtub), may take over its role. Therefore, TMPK(Mtub) seems to have swapped the use of a metal ion as compared with e.g. human TMPK. Finally, TTP was observed in crystals of TMPK(Mtub), locked by Arg14, thus providing a structural explanation for the observed inhibitory effect of TTP putatively involved in a mechanism of feedback regulation of the enzymatic activity.

Catalysis↗
PubMed1984

Dosing implications of rapid elimination of trimethoprim-sulfamethoxazole in patients with cystic fibrosis.

The first-dose and steady-state pharmacokinetics of trimethoprim and sulfamethoxazole were determined in 14 patients with cystic fibrosis. When pharmacokinetic data from the first dose were compared with those at steady state, both TMP and SMZ showed expected accumulations in serum concentrations and decreases in total body clearance. The area under the SMZ serum concentration-time curve was significantly greater at steady state, suggesting drug accumulation during long-term therapy. When pharmacokinetic characteristics for TMP and SMZ obtained in patients with cystic fibrosis were compared with those reported for normal adults, the patients were found to have shorter elimination half-lives and greater plasma clearances. In addition, the apparent volume of distribution for TMP was smaller for patients with cystic fibrosis than for normal adults, consistent with their reduced mass of adipose tissue. Our data support the need for increased dosing or decreased dosing intervals when administering TMP-SMZ to patients with cystic fibrosis.

Adolescent↗
PubMed2003

Characterization of trimethylpsoralen as a mutagen for mouse embryonic stem cells.

Given a large number of genes with unknown functions in model organisms, collections of mutants are valuable resources for studying gene function. For the mouse, embryonic stem cell technology offers the possibility to manipulate the genome and select for mutations in vitro. Mutant mice can then be generated from clones of interest to study the phenotype of these animals. We manipulate the genome of mouse embryonic stem (ES) cells chemically using the mutagen trimethylpsoralen (TMP). TMP predominantly causes deletions in the genome of Caenorhabditis elegans and Escherichia coli, but has not been established as a mutagen in mammalian systems yet. We have characterized TMP as a mutagen for mouse ES cells regarding death rates, mutation frequencies, and mutation spectrum. Allowing for 12.5% of cell survival, the mutation frequency at the mouse hypoxanthine-guanine phosphoribosyltransferase (Hprt) locus was 3.5 x 10(-5) on average. The characterization of a non-redundant set of 17 Hprt-deficient ES clones revealed that only 12% of clones contained genomic deletions and almost 50% were point mutations. Base substitutions were mostly transversions and all affected AT base pairs. We conclude that the mutation spectrum of TMP in mouse ES cells is different from that observed in C. elegans and E. coli.

Animals↗
PubMed1998

A retrospective study of treatment of cerebral toxoplasmosis in AIDS patients with trimethoprim-sulphamethoxazole.

AIMS OF THE STUDY: a retrospective study was designed to evaluate efficacy and tolerance of trimethoprim-sulphamethoxazole (TMP-SMZ) in AIDS patients with cerebral toxoplasmosis (TE). PATIENTS AND METHODS: we reviewed 471 patients with AIDS, and we analysed 71 AIDS patients with TE, who received intravenous therapy with TMP-SMZ (TMP: 10 mg/kg/day, SMZ: 50 mg/kg/day) for 4 weeks. RESULTS: 35 patients (49.2%) had a complete regression of clinical signs, and a complete resolution of radiological lesions was noted in 41 patients (57.7%). Improvement of clinical signs and radiological lesions were observed in 27 patients (38%), and in nine patients (12.6%), respectively. In contrast, nine patients (12.6%) did not show any clinical change, or worsened. Twenty-two patients (30.9%) suffered from adverse cutaneous reactions, whereas many patients had haematological toxicity. CONCLUSIONS: TMP-SMZ seems to be an efficient therapy for TE in AIDS patients, although further prospective, randomized therapeutic trials are required to confirm these results.

AIDS-Related Opportunistic Infections↗
PubMed1998

Efficient mutagenesis of zebrafish by a DNA cross-linking agent.

We developed a novel procedure for efficient mutagenesis of zebrafish using a DNA cross-linking agent 4,5',8-trimethylpsoralen (TMP), which is known to frequently induce small deletions in Escherichia coli and Caenorhabditis elegans. A specific-locus test and pilot screenings indicated that the TMP mutagenesis procedure was efficient. To confirm the successful mutagenesis by TMP, we characterized mutants with selective impairments in the nervous system. The no tectal neuron mutation hindered the development of the tectal neurons, while the edawakare mutation resulted in the enhancement of the extension and branching of the peripheral axons of trigeminal ganglion and Rohon-Beard sensory neurons. These results suggest that the TMP mutagenesis will provide an efficient method to isolate and characterize zebrafish mutants at molecular level.

Animals↗
PubMed2002

Simultaneous LC determination of trimethoprim and sulphamethoxazole in pharmaceutical formulations.

In the present study, a simple, sensitive, precise and rapid reversed-phase high performance liquid chromatographic (HPLC) method with ultraviolet detection for the simultaneous analysis of trimethoprim (TMP) and sulphamethoxazole (SPM) is developed and applied to the determination in commercial pharmaceutical preparations. These compounds are well separated on a Bondapak C(18) reverse phase column using a mobile phase consisted of a mixture of methanol:water (60:40; v/v) adjusted to pH 3 with 10% orthophosphoric acid at a flow rate of 1.8 ml min(-1). The proposed method was linear in the range 2.0-10.0 microgram ml(-1) for TMP and 10.0-50.0 microgram ml(-1) for SPM. The limit of detection were 0.45 and 1.21 microgram ml(-1) for TMP and SPM, respectively. The method which is rapid, simple and does not require any separation step, has been successfully applied to the assay of commercial tablet and oral suspension dosage forms containing TMP and SPM.

Chemistry, Pharmaceutical↗
PubMed2003

Acute effects of cardiac resynchronization therapy on functional mitral regurgitation in advanced systolic heart failure.

OBJECTIVES: We studied the acute effects of cardiac resynchronization therapy (CRT) on functional mitral regurgitation in heart failure (HF) patients with left bundle branch block (LBBB). BACKGROUND: Both an decrease [corrected] in left ventricular (LV) closing force and mitral valve tethering have been implicated as mechanisms for functional mitral regurgitation (FMR) in dilated hearts. We hypothesized that an increase in LV closing force achieved by CRT could act to reduce FMR. METHODS: Twenty-four HF patients with LBBB and FMR were studied after implantation of a biventricular CRT system. Acute changes in FMR severity between intrinsic conduction (OFF) and CRT were quantified according to the proximal isovelocity surface area method by measuring the effective regurgitant orifice area (EROA). Results were compared with the changes in estimated maximal rate of left ventricular systolic pressure rise (LV+dP/dt(max)) and transmitral pressure gradients (TMP), both measured by Doppler echocardiography. RESULTS: Cardiac resynchronization therapy was associated with a significant reduction in FMR severity. Effective regurgitant orifice area decreased from 25 +/- 19 mm(2) (OFF) to 13 +/- 8 mm(2) (CRT). The change in EROA was directly related to the increase in LV+dP/dt(max) (r = -0.83, p < 0.0001). Compared with OFF, TMP increased more rapidly during CRT, and a higher maximal TMP was observed (OFF 73 +/- 24 mm Hg vs. CRT 85 +/- 26 mm Hg, p < 0.01). CONCLUSIONS: Functional mitral regurgitation is reduced by CRT in patients with HF and LBBB. This effect is directly related to the increased closing force (LV+dP/dt(max)). The results support the hypothesis that an increase in TMP, mediated by a rise in LV+dP/dt(max) due to more coordinated LV contraction, may facilitate effective mitral valve closure.

Aged↗
PubMed1997

Psoralens percutaneous permeation across the human whole skin and the epidermis in respect to their polarity (in vitro study).

8-methoxypsoralen (8-MOP), 5-methoxypsoralen (5-MOP) and 4,5',8-trimethylpsoralen (TMP) are commonly used in PUVA therapy [psoralen (P) + ultraviolet light A (UVA) irradiation] to treat skin diseases such as psoriasis and vitiligo. In order to predict the choice of the suitable drug(s) for topical applications, with appropriate dosage, percutaneous permeation of the psoralens, in connection with their solubilities and partition coefficients in an octanol/water system, were investigated. The percutaneous penetration experiments were accomplished by the deposit of ethanolic psoralen solution onto human skin and epidermis fragments mounted on Franz cells. Six cells were employed for each psoralen solution and for the whole skin layer as well as for the epidermis. The diffused psoralens in the receptor solution (1.4%, of human serum albumin) were quantified by using high performance liquid chromatography. The solubilities and the partition coefficients (PC) were carried out in an octanol/water system, in triplicate by using spectrofluorimetry. The results demonstrated that cumulated permeated quantities (ng/cm2) over 24 h, across the whole skin and the epidermis were in the following order for the three psoralens: 8-MOP > 5-MOP > TMP. The lipophilicity, expressed via the log PC, was as follows: 1.93 +/- 0.01 (8-MOP), 2.00 +/- 0.01 (5-MOP) and 3.14 +/- 0.01 (TMP). It was inversely correlated with cumulated penetrated amounts over 24 h in both whole skin and epidermis. From these results, TMP could be predicted as the most convenient psoralen for topical applications, because of its weak penetrability. Considering the relationship between psoralens lipophilicity and permeation, only 5-MOP and 8-MOP could be used, topically or orally, especially in the case of generalised skin disorders.

5-Methoxypsoralen↗