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PubMed1991

NCI-Black-Reiter (NBR) male rats fail to develop renal disease following exposure to agents that induce alpha-2u-globulin (alpha 2u) nephropathy.

The NCI-Black-Reiter (NBR) rat is the only strain of male rat known not to synthesize the hepatic form of the low molecular weight protein, alpha 2u-globulin. In previous studies, NBR rats were shown not to develop renal disease when exposed to decalin, a compound known to induce alpha 2u-globulin nephropathy in other rat strains. The objective of this study was to show that the presence of alpha 2u-globulin (alpha 2u) is essential for the development of this syndrome in rats exposed to 2,2,4-trimethylpentane (TMP), 1,4-dichlorobenzene (DCB), isophorone (IP), PS-6 unleaded gasoline (UG), and d-limonene (d-L). The induction of alpha 2u-nephropathy in F344 male rats with lindane was used as a positive control and this response was contrasted to male NBR and female F344 rats treated with lindane. Five to seven 11-week-old male NBR rats were exposed to TMP (500 mg/kg/day), DCB (500 mg/kg/day), IP (1000 mg/kg/day), UG (500 mg/kg/day), d-L (1650 mg/kg/day), or lindane (10 mg/kg/day) and five 11-week-old male and female F344 rats were exposed to lindane (10 mg/kg/day) by oral gavage on 4 consecutive days. NBR male and F344 male and female rats gavaged with corn oil were incorporated in the study as vehicle controls. The presence of hyaline droplets was assessed in perfusion-fixed kidneys by staining paraffin sections with Mallory-Heidenhein stain and in GMA sections with Lee's methylene basic blue fuchsin stain. Paraffin sections were also analyzed immunohistochemically for the presence of alpha 2u. Under exposure conditions that clearly induce alpha 2u-nephropathy in male F344 rats, no lesions, hyaline droplets, or alpha 2u were detectable in treated or control male NBR and female F344 rats. It is thus concluded that the presence of alpha 2u is causal to the development of renal disease in rats exposed to TMP, DCB, IP, UG, d-L, and lindane.

Alpha-Globulins↗
PubMed1991

Metabolism of antidepressants: urinary metabolites of trimipramine in the rat.

1. Studies on the metabolism of the tricyclic antidepressant trimipramine (TMP) in the rat are described. 2. Twenty metabolites of TMP were isolated from rat urine after enzymatic hydrolysis and their structures were determined by a gas chromatographic-mass spectrometric (GC-MS) method. 3. Twelve TMP metabolites were the result of alicyclic (C10 or C11) oxidation in addition to the other metabolic pathways.

Animals↗
PubMed1979

Fluorescence studies of the interaction between 1,N6-ethenoadenosine monophosphate and nucleotides.

AMP, GMP, TMP and CMP quench the fluorescence of 1,N6-ethenoadenosine monophosphate (epsilon-AMP). The fluorescence spectrum of epsilon-AMP-nucleotide system is identical with that of epsilon-AMP itself, and the fluorescence decay kinetics follow a single-exponential decay law. The dependence of fluorescence yields and lifetimes upon the concentration of nucleotides shows that the fluorescence of epsilon-AMP is principally quenched in a dynamic process by AMP, TMP and CMP, while it is quenched in both dynamic and static processes by GMP. The quenching constants increase in the following order: GMP greater than AMP greater than TMP greater than CMP.

Adenosine Monophosphate↗
PubMed1984

Formation of phosphodiesters in thymidine monophosphate by styrene oxide.

Three products were isolated by high-performance liquid chromatography (HPLC) from the reaction between thymidine-5'-monophosphate (TMP) and styrene oxide in aqueous solution. None of the products was digested by alkaline phosphatase, but each was digested by vernom phosphodiesterase. The digestion products were identified by their mobility in HPLC and UV-spectra as phenylethylene glycol, thymidine, TMP, and hydroxyethylphenyl phosphoric acid, of which phenylethylene glycol and TMP were most abundant.

Alkaline Phosphatase↗
PubMed1993

Pyrazine derivatives affect membrane fluidity of vascular smooth muscle microsomes in relation to their biological activity.

We have previously demonstrated that several structurally similar pyrazine derivatives, tetramethylpyrazine (TMP), triethylpyrazine (3EP) and tetraethylpyrazine (TEP) consistently inhibited a wide spectrum of plasmalemma-associated biological activities of vascular smooth muscles in contractility and radioligand binding studies in the following order of increasing potency, TMP < 3EP < TEP. We speculated that these pyrazine derivatives elicit multiple effects in the above order of potency by affecting, at least in part, the bulk physical properties of the lipid bilayers in the cell membrane. This hypothesis was tested in the current study using plasmalemma-enriched microsomes isolated from dog aortic smooth muscle using two different biophysical techniques: fluorescence polarization and electron spin resonance. The calculated membrane fluidity values obtained as a function of temperature by both methods are consistent with the above order of potency. The amount of incorporation of these pyrazine derivatives into the vascular smooth muscle membranes also increased with the increasing hydrophobicity of these drugs, i.e., TMP < 3EP < TEP. Our results are consistent with the contention that these pyrazine derivatives not only interact with receptor protein molecules in the biological membranes, but also modulate these receptor properties via their interaction with the lipid bilayer altering the membrane microviscosity.

Animals↗
PubMed1993

Skin concentration of 8-methoxypsoralen, 5-methoxypsoralen and 4,5,8-trimethylpsoralen in guinea pigs.

The skin concentrations of 8-methoxypsoralen (8-MOP), 5-methoxypsoralen (5-MOP) and 4,5,8-trimethylpsoralen (TMP) were studied in the albino guinea pig following oral administration and intraperitoneal injection. The skin concentration of phototoxic drugs after oral administration peaked at 1.5 h, and the concentration of 8-MOP was 3.5 times greater than that of 5-MOP. The skin concentration of TMP was not detected in our study (limit of sensitivity 5 ng/ml). The highest skin concentrations of 8-MOP and 5-MOP after intraperitoneal injection were achieved for both drugs at 0.5 h, with the level of 8-MOP approximately 1.3 times higher than that of 5-MOP. The level of TMP could not be measured even in the case of intraperitoneal injection.

5-Methoxypsoralen↗
PubMed1996

Pyrrolo[2,3-d]pyrimidines and pyrido[2,3-d]pyrimidines as conformationally restricted analogues of the antibacterial agent trimethoprim.

Conformationally restricted analogues of the antibacterial agent trimethoprim (TMP) were designed to mimic the conformation of drug observed in its complex with bacterial dihydrofolate reductase (DHFR). This conformation of TMP was achieved by linking the 4-amino function to the methylene group by one- and two-carbon bridges. A pyrrolo[2,3-d]pyrimidine, a dihydro analogue, and a tetrahydropyrido[2,3-d]pyrimidine were synthesized and tested as inhibitors of DHFR. One analogue showed activity equivalent to that of TMP against DHFR from three species of bacteria. An X-ray crystal structure of this inhibitor bound to Escherichia coli DHFR was determined to evaluate the structural consequences of the conformational restriction.

Animals↗
PubMed2005

Photo-polymerized microarchitectural constructs prepared by microstereolithography (muSL) using liquid acrylate-end-capped trimethylene carbonate-based prepolymers.

Precision microarchitectural constructs made of acrylated trimethylene carbonate (TMC)-based liquid prepolymers were photo-polymerized using a custom-designed microstereolithographic apparatus. In this study, three different photo-polymerizable liquid prepolymers were prepared by the polymerization of TMC with a low molecular weight poly(ethylene glycol) (PEG) (mol. wt. 200 or 1000); designated as PEG200 or PEG1000, respectively or trimethylolpropane (TMP) as an initiator, and subsequently end-capped with an acrylate group. As a result of layer-by-layer photo-irradiation of the prepolymer with a movable ultraviolet light pen driven by computer-aided design, a three-dimensional (3D) micropillar array, a microbank array, a microcone array, and multi-microtunnels formed on a platform plate or a glass plate were precisely fabricated. The PEG-based polymers exhibited a very low cell adhesion potential, whereas the TMP-based hydrophobic polymer exhibited high cell adhesion and proliferation potentials. The microbank array, which consisted of a plate made of the TMP-based polymer and microbanks made of the PEG200-based polymer, caused cell adhesion and proliferation only on the plate. Upon the implantation of microcone arrays under the subcutis of rats, the photo-polymerized construct made of the poorly swellable PEG200-based polymer exhibited only surface erosion and limited drug loading and releasing potentials. On the other hand, the photo-polymerized construct made of the highly swellable PEG1000-based polymer exhibited not only surface erosion but also bulk erosion and high drug loading and releasing potentials. In this paper, we discuss their potential biomedical applications.

3T3 Cells↗
PubMed2004

Preliminary in vitro studies on two potent, water-soluble trimethoprim analogues with exceptional species selectivity against dihydrofolate reductase from Pneumocystis carinii and Mycobacterium avium.

2,4-Diamino-5-[3',4'-dimethoxy-5'-(5-carboxy-1-pentynyl)]benzylpyrimidine (6) and 2,4-diamino-5-[3',4'-dimethoxy-5'-(4-carboxyphenylethynyl)benzylpyrimidine (7) were synthesized from 2,4-diamino-5-(5'-iodo-3',4'-dimethoxybenzyl)pyrimidine (9) via a Sonogashira reaction with appropriate acetylenic esters followed by saponification, and were tested as inhibitors of dihydrofolate reductase (DHFR) from Pneumocystis carinii (Pc), Toxoplasma gondii (Tg), Mycobacterium avium (Ma), and rat in comparison with the widely used antibacterial agent 2,4-diamino-5-(3',4',5'-trimethoxybenzyl)pyrimidine (trimethoprim, TMP). The selectivity index (SI) for each compound was calculated by dividing its 50% inhibitory concentration (IC(50)) against rat DHFR by its IC(50) against Pc, Tg, or Ma DHFR. The IC(50) of 6 against Pc DHFR was 1.0 nM, with an SI of 5000. Compound 7 had an IC(50) of 8.2 nM against Ma DHFR, with an SI of 11000. By comparison, the IC(50) of TMP was 12000 nM against Pc, 300 nM against Ma, and 180000 against rat DHFR. The potency and selectivity values of 6 and 7 were not as high against Tg as they were against Pc or Ma DHFR, but nonetheless exceeded those of TMP. Because of the outstanding selectivity of 6 against Pc and of 7 against Ma DHFR, these novel analogues may be viewed as promising leads for further structure-activity optimization.

Folic Acid Antagonists↗
PubMed2005

Metabolism of chlorpyrifos in relation to its effect on the availability of some plant nutrients in soil.

A laboratory experiment was conducted to study the persistence and metabolism of chlorpyrifos in Gangetic Alluvial soil of West Bengal and also to evaluate their effect on the availability of the major plant nutrients (N, P and K) in soil following the application of chlorpyrifos @ 1 kg (T1), 10 kg (T2) and 100 kg (T3) a.i.ha(-1). The dissipation followed first order kinetics and the calculated half-life (T1/2) values ranged from 20 to 37 days. The primary metabolite of chlorpyrifos, 3,5,6-trichloropyridinol (TCP) was detected from 3rd day after application and was at maximum on 30th day which decreased progressively to non-detectable level (NDL) on 120th day for all the treatment doses. The secondary metabolite 3,5,6-trichloro-2-methoxy pyridine (TMP) was detected on 30th, 15th and 7th day in T1, T2 and T3 doses respectively which decreased to NDL during 90-120th day. ANOVA study revealed significant decrease in the available N and P content in soil treated with chlorpyrifos in comparison to the control set. The inhibitory effect on available N was attributable to TMP and for P it was due to the presence of TCP and TMP rather than chlorpyrifos itself as revealed by the step wise multiple regression technique. In the later stage of incubation, however the average N and P status was recovered significantly at 120 days which might be due to the disappearance of the metabolites. The variation due to time of observations or treatment doses was minimum in case of available K in soil.

Biological Availability↗
PubMed2004

Effect of trimethoprim-sulfamethoxazole prophylaxis in AIDS patients on the formation of the small colony variant phenotype of Staphylococcus aureus.

Emergence of Staphylococcus aureus small colony variants (SCVs) has been associated with antibiotic use, particularly with trimethoprim-sulfamethoxazole (TMP-SMZ). In this study, 634 specimens of 125 patients with AIDS were prospectively screened for S. aureus with normal phenotype and for S. aureus SCVs. Charts of these patients were reviewed for previous prophylaxis with TMP-SMZ often used as long-term pneumocystosis prophylaxis. Thirty-seven patients (29.6%) harbored S. aureus in their anterior nares, three of these patients (8.1%) had S. aureus SCVs. Interestingly, TMP-SMZ does not appear to select for S. aureus SCVs in nasal swabs of these patients.

AIDS-Related Opportunistic Infections↗
PubMed2005

Antibiotic combinations significantly more active than monotherapy in an in vitro infection model of Stenotrophomonas maltophilia.

The goal of this study was to investigate clinical doses of trimethoprim-sulfamethoxazole (TMP-SMX) alone and in combination against Stenotrophomonas maltophilia in an in vitro pharmacodynamic infection model. A 1-compartment model was established using 4 clinical isolates of S. maltophilia susceptible to TMP-SMX and susceptible or intermediately susceptible to at least one other agent (ie, ceftazidime, ciprofloxacin, gentamicin, tobramycin). Antibiotics alone and in combination were tested by simulating unbound serum concentration profiles achieved with multiple-dose regimens in humans. Despite susceptible minimum inhibitory concentrations, TMP-SMX alone was bacteriostatic at best against all isolates. All antibiotic combinations were more active than monotherapy as determined by bacterial reductions at both 24 and 48 h (P < 0.0001). Significant benefit was observed even with agents inactive alone or only intermediately susceptible based on minimum inhibitory concentrations. These preclinical data support further investigation of antibiotic combinations in the management of serious S. maltophilia infections.

Anti-Bacterial Agents↗
PubMed2006

Rheolytic thrombectomy with percutaneous coronary intervention for infarct size reduction in acute myocardial infarction: 30-day results from a multicenter randomized study.

OBJECTIVES: The goal of this work was to determine whether rheolytic thrombectomy (RT) as an adjunct to primary percutaneous coronary intervention (PCI) reduces infarction size and improves myocardial perfusion during treatment of ST-segment elevation myocardial infarction (STEMI). BACKGROUND: Primary PCI for STEMI achieves brisk epicardial flow in most patients, but myocardial perfusion often remains suboptimal. Distal embolization of thrombus during treatment may be a contributing factor. METHODS: This prospective, multicenter trial enrolled 480 patients presenting within 12 h of symptom onset and randomized to treatment with RT as an adjunct to PCI (n = 240) or to PCI alone (n = 240). Visible thrombus was not required. The primary end point was infarct size measured by sestamibi imaging at 14 to 28 days. Secondary end points included final Thrombolysis In Myocardial Infarction (TIMI) flow grade, tissue myocardial perfusion (TMP) blush, ST-segment resolution, and major adverse cardiac events (MACE), defined as the occurrence of death, new Q-wave myocardial infarction, emergent coronary artery bypass grafting, target lesion revascularization, stroke, or stent thrombosis at 30 days. RESULTS: Final infarct size was higher in the adjunct RT group compared with PCI alone (9.8 +/- 10.9% vs. 12.5 +/- 12.13%; p = 0.03). Final TIMI flow grade 3 was lower in the adjunct RT group (91.8% vs. 97.0% in the PCI alone group; p < 0.02), although fewer patients had baseline TIMI flow grade 3 in the adjunct RT group (44% vs. 63% in the PCI alone group; p < 0.05). There were no significant differences in TMP blush scores or ST-segment resolution. Thirty-day MACE was higher in the adjunct RT group (6.7% vs. 1.7% in the PCI alone group; p = 0.01), a difference primarily driven by very low mortality rate in patients treated with PCI alone (0.8% vs. 4.6% in patients treated with adjunct RT; p = 0.02). CONCLUSIONS: Despite effective thrombus removal, RT with primary PCI did not reduce infarct size or improve TIMI flow grade, TMP blush, ST-segment resolution, or 30-day MACE.

Adult↗
PubMed2005

Determination of thiamine and its phosphate esters in rat tissues analyzed as thiochromes on a RP-amide C16 column.

A new reversed-phase chromatographic method is described for the separation and quantification of thiamine (T), thiamine monophosphate (TMP) and diphosphate (TDP) in rat tissues. Sample extraction with perchloric acid (HClO(4)) was found more suitable than extraction with trichloroacetic acid (TCA), as regards convenience and background fluorescence. Derivatization of thiamine vitamers to thiochromes was optimized and complete separation of TDP and TMP thiochromes was obtained on a RP-amide C16 column in isocratic elution, with T thiochrome eluting in less than 10 min. The precision and the accuracy of the HPLC procedure were assessed: ranging from 0.5 to 7.7% for intra-day and from 2.0 to 9.4% for inter-day precision, a recovery average of 101% was determined (range 90-111%). Mean values of recovery for TDP, TMP or T were 91, 96 and 90% for liver extracts, respectively. Analysis of vitamers in tissues of rat submitted to 8 days thiamin deficiency, followed by a 14 days repletion, showed a significant reduction of TPP after 8 days of depletion in liver (-67%), brains (-50%), kidneys (-60%), followed by a complete recovery upon repletion.

Animals↗
PubMed2006

Delivery of photosensitisers and light through mucus: investigations into the potential use of photodynamic therapy for treatment of Pseudomonas aeruginosa cystic fibrosis pulmonary infection.

Respiratory disease is the main cause of morbidity and mortality in patients with cystic fibrosis (CF). In such patients chronic Pseudomonas aeruginosa infection is virtually impossible to eradicate using antibiotic therapy. Photodynamic antimicrobial chemotherapy (PACT) could be one potential alternative antimicrobial method. As photosensitisers could be delivered to the lungs of CF patients via inhalation, the current in vitro study investigated the potential use of PACT in the treatment of P. aeruginosa CF pulmonary infection. Delivery of red light (635 nm) and two photosensitisers (toluidine blue O (TBO) and meso-tetra (N-methyl-4-pyridyl) porphine tetra tosylate (TMP)) across artificial CF mucus was successfully achieved. Artificial CF mucus reduced the measured fluence of incident light in an almost exponential manner with increasing depth. The presence of dissolved photosensitisers also reduced light fluence. TMP diffused more efficiently across artificial CF mucus than TBO. However, receiver compartment concentrations of both drugs after 6 h were of the same order as those required to achieve high rates of kill (>99%) of P. aeruginosa isolates growing both planktonically and in biofilms. TMP required significantly higher concentrations (2.5 mg ml(-1)) than TBO to achieve high rates of kill (>99%) of P. aeruginosa isolates growing planktonically. Higher concentrations (5.0 mg ml(-1)) of both photosensitisers were required to achieve high rates of kill (>99%) of P. aeruginosa isolates growing in biofilms. When photosensitisers were prepared in artificial mucus, higher concentrations were required to achieve reasonably high kill rates (>80%) of P. aeruginosa (PAO1) growing both planktonically and in biofilm.

Cystic Fibrosis↗
PubMed2005

Equilibrium studies for trimethoprim adsorption on montmorillonite KSF.

In this study, the adsorption of trimethoprim (TMP) on montmorillonite KSF was studied under different conditions (pH, ionic strength, temperature). The results indicate that a pH value of 5.04 is optimum value for the adsorption of TMP on KSF. The adsorption kinetics was interpreted using pseudo-first-order kinetic model, pseudo-second-order kinetic model and intraparticle diffusion model. The pseudo-second-order model provides the best correlation with the experimental data of KSF adsorption. The adsorption data could be fitted with Freundlich, Langmuir and Dubinin-Radushkevich equation to find the characteristic parameters of each model. It was found that linear form of Langmuir isotherm seems to produce a better model than linear form of Freundlich equation. From the Langmuir and Freundlich equation, the adsorption capacity values raised as the solution temperature decreased. From DR isotherm, it was also determined that the type of adsorption can be considered as ion-exchange mechanism. Determination of the thermodynamic parameters DeltaH(0), DeltaS(0) and DeltaG(0) showed that adsorption was spontaneous and exothermic in nature. It was also added that adsorption of TMP by KSF may involve physical adsorption.

Adsorption↗
PubMed2004

Psoralen derivatives and longwave ultraviolet irradiation are active in vitro against human melanoma cell line.

Cutaneous malignant melanoma is a very serious form of skin cancer that arises from melanocytes. Currently there is no effective treatment for metastatic melanoma so intense clinical trials are evaluating new drugs for this human malignancy. Psoralens are a group of compounds that bind to DNA in rapidly dividing cells and with ultraviolet light in the A band (UVA) cause DNA crosslinking, thereby preventing cellular division. They are used in the treatment of psoriasis and cutaneous T-cell lymphoma among other skin and blood diseases. We have investigated the cytotoxic potential of three psoralen derivatives plus UVA exposure (PUVA) on a established cell line of human melanoma. Cells were treated with different concentrations of 8-methoxypsoralen (8-MOP), 4,5',8-trimethylpsoralen (TMP) and 7-methylpyridopsoralen (MPP), for 1 h and after exposure to UVA light (0.3 J/cm(2)) were allowed to recover over a 24-72 h period. Viability was assessed by the microculture 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) colorimetric assay. Cisplatin, one of the most important drugs in the chemotherapy of melanoma, was included for comparative studies. All the psoralen derivatives tested were markedly cytotoxic in a dose and post-exposure-time dependent manner. The IC(50) values for 72 h of post-exposure time were as follows: MPP=0.05+/-0.01, TMP=0.13+/-0.003 and 8-MOP=10.79+/-1.85 micromol/L. Regardless of the limitations of the in vitro model, our results suggested that the lower IC(50) values of TMP and MPP might be of clinical importance.

Cell Division↗
PubMed2006

Dietary nucleotides and human immune cells. II. Modulation of PBMC growth and cytokine secretion.

OBJECTIVE: The immune system is dependent on purines and pyrimidines as building blocks for DNA and RNA synthesis to enable rapid cell proliferation and protein synthesis. Emerging evidence suggests that dietary nucleotides optimize immune function. We investigated whether growth and function of human immune cells were affected by an exogenous source of nucleotides during specific antigen challenge. METHODS: Peripheral blood mononuclear cells from healthy individuals (n = 10) were stimulated with influenza virus antigen and either DNA sodium from fish soft roe (DNA), RNA from bakers yeast (Saccharomyces cerevisiae) (RNA), 2' deoxyadenosine 5'-monophosphate sodium (dAMP), 2' deoxycytidine 5'-monophosphate sodium (dCMP), 2' deoxyguanosine 5'-monophosphate sodium (dGMP), 2' deoxyuridine 5'-monophosphate sodium (dUMP) or thymidine sodium (TMP). Growth effects were ascertained by measuring the amount of tritium-labeled thymidine, incorporated into cell DNA. Cell function was measured by detection of IFN-gamma, TNF-alpha and IL-10 production. RESULTS: Specific nucleotide derivatives alone did not affect the growth of healthy peripheral blood mononuclear cells. However, the nucleotide derivatives influenced immune cell growth and cytokine secretion when cocultured with specific antigen. DNA, RNA, dAMP, dCMP and dUMP increased influenza virus antigen induced immune cell proliferation. In contrast dGMP and TMP inhibited the antigen-induced growth response. RNA and dAMP cocultured with virus antigen significantly increased peripheral blood mononuclear cell secretion of IFN-gamma, IL-10 and TNF-alpha. DNA increased virus antigen-induced immune cell secretion of IFN-gamma only, whereas dUMP significantly increased secretion of IL-10 only. dGMP completely inhibited virus-triggered IFN-gamma secretion, whereas TMP did not change the virus induced secretion pattern of measured cytokines. CONCLUSION: Nucleotide derivatives affect growth and function of specific virus antigen-stimulated human immune cells in vitro.

Antigens, Viral↗