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PubMed1983

A study of the relationship between photosensitizing and therapeutic activity of 4,5',8-trimethylpsoralen, and its major metabolite 4,8-dimethyl, 5'-carboxypsoralen.

The molecular basis for the clinically observed differences in the skin photosensitizing activity and therapeutic effectiveness of the topically applied and orally administered drug trimethylpsoralen (TMP) was investigated. TMP, when tested topically, is a very potent photosensitizing and therapeutically effective furocoumarin in the treatment of psoriasis. When administered orally, however, it is significantly less photosensitizing and therapeutically a less effective drug than the commonly used furocoumarin 8-methoxypsoralen. This decreased reactivity of oral TMP is attributable to its poor solubility and rapid in vivo metabolic transformation to several inactive (nonphotosensitizing) metabolites, one of which is referred to as 4,8-dimethyl,5'-carboxypsoralen (DMeCP). The supporting evidence has been obtained by: (a) isolation of the urinary metabolite DMeCP and subsequent comparison of its properties with the synthetically prepared DMeCP and its methyl ester; (b) examining the dark and photochemical interactions of TMP, DMeCP, and DMeCP methyl ester with DNA and determining their ability to form interstrand cross-links with DNA; and (c) studying the inhibition of DNA and RNA synthesis in Ehrlich ascites tumor cells and the killing of bacteria and T2 bacteriophages. The structure-activity relationship of TMP and DMeCP also has been examined in normal human subjects and in patients with psoriasis. The order of topical therapeutic effectiveness in terms of ability to clear psoriasis plaques appeared to be: TMP greater than 8-MOP greater than DMeCP methyl ester greater than DMeCP. The data also suggest the methyl ester of DMeCP to be an interesting nonphotosensitizing furocoumarin that photoconjugates to DNA better than 8-MOP and is therapeutically effective in psoriasis.

Animals↗
PubMed1981

Proliferative response patterns of human fibroblasts after photoinjury with 4,5',8-trimethylpsoralen.

The extent of growth suppression and recovery following exposure to 4,5',8-trimethylpsoralen (TMP) plus UV-A irradiation was studied in 3 diploid human fibroblast strains. Inhibition of cellular proliferation was dose-dependent within the concentration range of TMP that was tested (1-4 X 10(-7) M), using a constant level of UV-A (0.24 J/cm2). The population generation (doubling) times for all cell strains were progressively lengthened under these conditions while maximal cell densities were reduced. At 2-4 X 10(-7) M TMP in the presence of UV-A, there was a triphasic pattern of growth which consisted of (1) proliferative activity during the first 24-36 hr, followed by; (2) complete growth inhibition for variable periods of time and; (3) a recovery period of log phase proliferation that was not as vigorous as measured for untreated cells. There were also declines in the percentage of cells labeled with 3H-Tdr at various times after TMP-UV-A treatment. These measurements were essentially identical for the three fibroblast strains evaluated. In that the cells employed for these investigations were derived from embryonic pulmonary tissue, neonatal foreskin and the buttock skin of an adult male, it seems unlikely that donor age and tissue source were important variables in determining growth response patterns after TMP-UV-A exposure. Because proliferative recovery was attenuated after this photochemical injury, we conclude that the biologic effect(s) of TMP-UV-A extend beyond the known period of psoralen-DNA cross-link removal.

Adult↗
PubMed1982

Action spectra of topical psoralens: a re-evaluation.

The action spectra for producing minimal phototoxic erythema with topical 0.I% trimethyl psoralen (TMP) and 8-methoxypsoralen (8-MOP) were determined with a double monochromator in the range of 295-380 nm. both psoralens induced photosensitivity in the range of 313-365 nm; TMP was 54% more effective than 8-MOP. There was no difference in the dose needed to produce minimal UV erythema or phototoxic erythema with 8-MOP and TMP at 295 and 305 nm, but at 313 nm with 8-MOP, photosensitivity was enhanced 3.5 times, and with TMP, sensitivity was enhanced 5.5 times. The peak sensitivity with 8-MOP was at 330 nm and for TMP it was 335 nm. No photosensitivity occurred above 380 nm. Results suggest that TMP and 8-MOP are significantly photoreactive at 320-335 nm. Commonly used UV-A light sources show peak emission around 360 nm. If there is a relationship between development of erythema and therapeutic effectiveness than this raises the possibility of alternative UV light sources for phototherapy with psoralens.

Furocoumarins↗
PubMed1994

A comparative study of the pharmacokinetics of intravenous and oral trimethoprim/sulfadiazine formulations in the horse.

The biopharmaceutical properties of four fixed trimethoprim/sulfonamide combinations were investigated in the horse. Eight fasted horses were dosed at 1 week intervals in a sequentially designed study with one intravenous (i.v.) and three oral trimethoprim/sulfadiazine (TMP/SDZ) formulations (1, 2 and 3) administered at a dose of 5 mg/kg trimethoprim (TMP) and 25 mg/kg sulfadiazine (SDZ). Plasma concentrations of each compound were monitored for 48 h. Pharmacokinetic parameters (volume of distribution, bioavailability and total body clearance) for TMP and SDZ were calculated and compared. After oral administration plasma concentrations of TMP and SDZ increased rapidly. With all three paste formulations, TMP peak plasma concentrations were attained within 2 h. SDZ mean peak plasma concentrations were reached at 2.59 +/- 0.48 h for a commercial paste (1), and at 1.84 +/- 0.66 h and 1.95 +/- 0.61 h for the two self-made formulations (2 and 3). Mean peak plasma TMP concentrations (+/- SD) were 1.72 +/- 0.36 micrograms/ml, 1.42 +/- 0.37 micrograms/ml and 1.31 +/- 0.36 micrograms/ml, and mean peak plasma SDZ concentrations 12.11 +/- 4.55 micrograms/ml, 12.72 +/- 3.47 micrograms/ml and 15.45 +/- 4.74 micrograms/ml for preparations 1, 2 and 3. The bioavailability of TMP was 67.0 +/- 20.3%, 57.7 +/- 21.6% and 60.9 +/- 18.9% and of SDZ 57.6 +/- 14.8%, 59.3 +/- 19.5% and 65.9 +/- 5.8% for SDZ for 1, 2 and 3, respectively. Following i.v. administration TMP/SDZ plasma concentration ratios approached the optimal 1:20 ratio (+/- 10%) for about 5 h, but following the oral administrations this ratio was only achieved for a very short time-span.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed1994

Trimethoprim/sulfonamide combinations in the horse: a review.

The indications for use, side-effects, and pharmacokinetic parameters of trimethoprim, sulfonamides and their combinations in the horse are reviewed. Trimethoprim/sulfonamide (TMPS) combinations are used for the treatment of various diseases caused by gram-positive and gram-negative bacteria, including infections of the respiratory tract, urogenital tract, alimentary tract, skin joints and wounds. TMPS combinations can be administered orally, since absorption from the gastrointestinal tract is relatively good. However, peak serum concentrations can vary significantly between individual horses. Feed intake affects serum concentrations after oral administration. Concentrations of non-bound trimethoprim (TMP) and sulfadiazine (SDZ) in synovial fluid and peritoneal fluid are equal to serum concentrations after intravenous (i.v.) administration, and high concentrations are found in urine. Concentrations of TMP and sulfamethoxazole (SMX) in cerebrospinal fluid after i.v. administration exceed the minimum inhibitory concentration for common equine pathogens. The volume of distribution is 1.5-2.7 l/kg for TMP and 0.3-0.7 l/kg for various sulfonamides. The plasma half-life of TMP is 1.9-4.3 h, whereas the plasma half-lives of the different sulfonamides vary between 2.7 and 14.0 h. About 50% of total TMP is bound to plasma proteins. The binding of sulfadoxine to plasma proteins depends on total plasma concentration and varies between 14% and 72%. The binding of other sulfonamides to plasma proteins may range from 33% for sulfaphenazole (SPZ) to 93% for sulfadimethoxine (SDM). Sulfonamides are metabolized by acetylation of the para-amino (N4) group and by hydroxylation of the methyl group and the pyrimidine ring. The metabolic pathways of TMP in the horse are not fully known. Bacterial resistance to TMPS combinations is still relatively low. The sensitivity of different micro-organisms may vary with the relative activity of the sulfonamide used in the combination. The advised oral and i.v. dose rate is 15-30 mg/kg (in a 1:5 TMP/S ratio) with a dose interval of 12 h. The acute toxicity of TMPS is low, but there have been several reports of death after i.v. administration, probably due to vagal stimulation and subsequent bradycardia and vasodilatation caused by the pharmaceutical formulation (excipients, solvents) used. Future research should concentrate on establishing the optimum pyrimidine/sulfonamide combination and its dosing regimen for antimicrobial therapy in horses.

Animals↗
PubMed1999

Effect of trimethoprim-sulfamethaxazole in Blastocystis hominis infection.

OBJECTIVE: Blastocystis hominis (B. hominis) is a common intestinal parasite that has long been considered nonpathogenic. Recently there have been many reports supporting a role for the organism as a potential pathogen. We performed a study to examine the pathogenicity of B. hominis and the effect of trimethoprim-sulfamethaxazole (TMP-SMX) on this organism. METHODS: Stool samples of patients, who came to the Department of Parasitology, Faculty of Medicine, Celal Bayar University, were examined by direct wet-mount, trichrome staining, formalin-ethyl acetate concentration, and Kinyoun acid fast techniques for intestinal parasites, and bacteriological stool cultures were performed. Fifty-three symptomatic patients (38 children and 15 adults) with two consequent stool samples positive for abundant B. hominis (five or more organisms per x400 field) and negative for other parasitic and bacterial pathogens were treated with TMP-SMX for 7 days, children 6 mg/kg TMP, 30 mg/kg SMX, and adults 320 mg TMP, 1600 mg SMX, daily. On the seventh day, at the end of treatment, stool samples of all patients were examined by same methods, and clinical symptoms were again evaluated. RESULTS: B. hominis was eradicated in 36 of 38 (94.7%) children, and 14 of 15 (93.3%) adults. Clinical symptoms disappeared in 39 (73.6%), decreased in 10 (18.9%), and no change was observed in one (1.9%) patient, whereas symptoms persisted in all three (5.7%) patients in whom B. hominis could not be eradicated. Mean number of stools per day was significantly decreased from 4.3 to 1.2 in the 33 children (p < 0.001), and decreased from 3.5 to 1.0 in the four adults (p = 0.06) with diarrhea. CONCLUSIONS: These results suggested that B. hominis may be pathogenic, especially when it is present in large numbers, and TMP-SMX is highly effective against this organism. Although there are some anecdotal reports, to our knowledge this is the first study examining the effect of TMP-SMX on B. hominis in humans.

Abdominal Pain↗
PubMed1999

PUVA-induced lymphocyte apoptosis: mechanism of action in psoriasis.

Psoralen plus ultraviolet A (PUVA), utilizing oral 8-methoxypsoralen (8-MOP), is a widely utilized and effective treatment for psoriasis vulgaris. Previous studies have suggested that PUVA's mechanism of action in psoriasis is a result of its direct lymphotoxic effects. Trimethylpsoralen (TMP), a potentially safer compound, has been found to be effective in psoriasis during bath water delivery. In this study we examined the relative antilymphocytic effects of TMP and 8-MOP through both flow cytometry and tissue analysis on lesional skin during clinical treatment. Based on FACS analysis on phytohemagglutinin-activated lymphocytes, we found TMP to be nearly 10,000 fold more lymphotoxic compared to 8-MOP. In addition, lymphocytes treated with 8-MOP or TMP with UVA displayed DNA degradation patterns typical of apoptotic cell death. These findings were consistent with our investigation of treated psoriatic skin, with virtual elimination of epidermal CD3+ T-cells following bath water treatment with TMP or 8-MOP. These results support the theory that the therapeutic effects of PUVA stem from its toxic effects on activated lymphocytes. If further investigation supports TMP's lack of carcinogenicity, this potent lymphotoxic treatment may prove to be one of the safest and most effective treatments for psoriasis.

Apoptosis↗
PubMed2005

Substrate specificity of vaccinia virus thymidylate kinase.

Anti-poxvirus therapies are currently limited to cidofovir [(S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine], but drug-resistant strains have already been characterized. In the aim of finding a new target, the thymidylate (TMP) kinase from vaccinia virus, the prototype of Orthopoxvirus, has been overexpressed in Escherichia coli after cloning the gene (A48R). Specific inhibitors and alternative substrates of pox TMP kinase should contribute to virus replication inhibition. Biochemical characterization of the enzyme revealed distinct catalytic features when compared to its human counterpart. Sharing 42% identity with human TMP kinase, the vaccinia virus enzyme was assumed to adopt the common fold of nucleoside monophosphate kinases. The enzyme was purified to homogeneity and behaves as a homodimer, like all known TMP kinases. Initial velocity studies showed that the Km for ATP-Mg2+ and dTMP were 0.15 mm and 20 microM, respectively. Vaccinia virus TMP kinase was found to phosphorylate dTMP, dUMP and also dGMP from any purine and pyrimidine nucleoside triphosphate. 5-Halogenated dUMP such as 5-iodo-2'-deoxyuridine 5'-monophosphate (5I-dUMP) and 5-bromo-2'-deoxyuridine 5'-monophosphate (5Br-dUMP) were also efficient alternative substrates. Using thymidine-5'-(4-N'-methylanthraniloyl-aminobutyl)phosphoramidate as a fluorescent probe of the dTMP binding site, we detected an ADP-induced conformational change enhancing the binding affinity of dTMP and analogues. Several thymidine and dTMP derivatives were found to bind the enzyme with micromolar affinities. The present study provides the basis for the design of specific inhibitors or substrates for poxvirus TMP kinase.

Amino Acid Sequence↗
PubMed2005

Tetramethylpyrazine protected photoreceptor cells of rats by modulating nuclear translocation of NF-kappaB.

AIM: To evaluate the effect of tetramethylpyrazine (TMP) injection on retinal damage induced by N-methyl-N-nitrosourea (MNU) in rats and on nuclear factor-kappa B (NF-kappaB) family members. METHODS: Female Sprague-Dawley (SD) rats were randomly divided into groups: (i), control group; (ii), model group; and (iii), TMP-injection groups, in which the rats were subdivided into 40 mg/kg, 80 mg/kg and 160 mg/kg groups. Drugs were injected ip into 47-day-old SD rats once a day. At 50 days of age, all rats in the model group and drug groups also received a single ip injection of 60 mg/kg MNU. Rats in group 1 received ip injection of physiological saline. All rats were killed at different times after MNU or physiological saline treatment. The apoptotic index of photoreceptor cells was calculated by TUNEL labeling; retinal damage was evaluated based on retinal thickness and the expression of NF-kappaB family members was detected by Western blot. RESULTS: TMP injections, in a dose-dependent manner, suppressed photoreceptor cell apoptosis and decreased its loss in the peripheral retina. As compared with the MNU-treated group, TMP injection at a dose of 160 mg/kg also time-dependently upregulated the NF-kappaB/p65 protein level in the nucleus and downregulated the IkappaBalpha protein level in the cytoplasm. However, no protective effect of TMP injection on MNU-induced central retinal damage was found. CONCLUSION: TMP injection partially protects against MNU-induced retinal damage by upregulating the nuclear translocation of p65 to inhibit photoreceptor cells apoptosis.

Animals↗
PubMed1993

The role of cyclic AMP and phosphodiesterase activity in the mechanism of action of tetramethylpyrazine on human and dog cardiac and dog coronary arterial tissues.

The aim of the present experiments was to explore the underlying cellular mechanisms responsible for the actions of tetramethylpyrazine (TMP) on atrial, ventricular and coronary arterial tissues. Transmembrane potentials of cardiac tissues were detected by means of the glass microelectrode technique and contractile tension by a force transducer. Tissue cyclic (c) AMP level was determined by protein binding assay. Results show that in human atrial and dog Purkinje fibres, high concentration of TMP (3 mM) induced a persistent positive inotropic effect only in the presence of adrenaline. Also, 3 mM TMP increased the cAMP level of the atrial muscle fibres, especially in the presence of adrenaline. Determination of the activity of cAMP-phosphodiesterase revealed that 0.3 and 3 mM TMP inhibited the phosphodiesterase activity of dog coronary artery and human atrial tissues in a concentration-dependent manner. When compared at the lower concentration (0.3 mM), the inhibitory effect of TMP was about 60% that of theophylline. The above findings indicate that the cardiovascular effects of TMP are related to the inhibition of phosphodiesterase activity and the subsequent elevation of the cAMP concentration.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1994

Hemolysis during membrane plasma separation with pulsed flow filtration enhancement.

The use of pulsed blood flow in membrane plasmapheresis permits enhancement of plasma filtration yet may result in high levels of hemolysis due to large increases in instantaneous transmembrane pressure (TMP). This work investigates the occurrence of hemolysis as a function of TMP and wall shear rates (gamma w) for both steady and pulsed blood flow conditions. Two types of hollow fiber filters with identical polypropylene membranes but different lengths and membrane areas (0.1 and 0.25 m2) were tested. Fresh citrated bovine blood was circulated through the fibers at various blood flowrates and TMP in a single pass circuit using a pulsation generator, made of a single roller peristaltic pump. The free hemoglobin concentration of the plasma, Hbm, was measured from permeate samples collected at each set of TMP and gamma w conditions. It was found that the net hemolysis generated by the filtration was proportional to the membrane area. This justified the introduction of an hemolysis index, IH, equal to the plasma hemoglobin per unit membrane area. The boundary for the occurrence of hemolysis was thus defined by setting IH = 30 mg/dl.m2. For both steady and pulsed flow conditions the hemolysis boundaries were found to be straight lines in the TMP-gamma w plane. They were identical for the two filters under steady flow but different for pulsed flow. At the same time mean wall shear rates hemolysis occurred at a lower time mean TMP under pulsed flow conditions than under steady flow conditions.

Animals↗
PubMed1979

Clinical pharmacology of intravenously administered trimethoprim-sulfamethoxazole.

Pharmacokinetic studies of intravenously administered trimethoprim-sulfamethoxazole (TMP-SMX) were conducted in 11 patients with cancer while they received therapy with this drug combination for infection. Each patient received 160 mg of TMP and 800 mg of SMX every 8 h. The highest plasma concentrations of both agents were attained at the end of a 1-h infusion period, and the levels were maintained above 38 mug of free SMX and 2 mug of TMP per ml for 2 to 4 h on day 1. On day 4, these concentrations were exceeded at all time intervals of blood sampling. High concentrations of TMP and free SMX were recovered in the urine during the 8-h period. The plasma half-lives of TMP and free SMX, as determined during the first 8-h period, were 7.6 and 8.6 h, respectively. Compared with SMX, TMP had an approximately 2.5 times higher volume of distribution. This drug combination was well tolerated by the patients and unaccompanied by drug-related toxicity.

Adolescent↗
PubMed1985

Reversal of the in vitro susceptibility of enterococci to trimethoprim-sulfamethoxazole by folinic acid.

The in vitro susceptibilities of 21 clinical isolates of Streptococcus faecalis to trimethoprim (TMP) in combination with sulfamethoxazole (SMX) was evaluated in Mueller-Hinton broth (MHB) in the presence and absence of folinic acid as well as in urine. The mean MIC and MBC in MHB, expressed as the TMP concentration, was 0.13 and 0.32 micrograms of TMP-SMX per ml, respectively. In MHB supplemented with folinic acid, the mean MIC and MBC was 3.3 and 5.5 micrograms of TMP-SMX per ml, respectively. In urine the mean MIC of TMP-SMX for these isolates was 8.1 micrograms/ml (range, 1.6 to 50 micrograms/ml). All isolates were inhibited by less than 0.01 micrograms of TMP-SMX per ml when methotrexate was added to the urine.

Drug Combinations↗
PubMed1986

Role of a novel antidiarrheal agent, BW942C, alone or in combination with trimethoprim-sulfamethoxazole in the treatment of traveler's diarrhea.

The efficacy of BW942C, a novel enkephalinlike pentapeptide antidiarrheal agent, was compared with the efficacy of trimethoprim-sulfamethoxazole (TMP-SMX) and the combination of the two agents in a placebo-controlled trial of the 72-h treatment of acute diarrhea. Subjects with diarrhea but without bloody stools or fever greater than 102 degrees F (38.9 degrees C) were enrolled. Administered to 134 U.S. adults with diarrhea that developed shortly after their arrival in Guadalajara, Mexico, BW942C was more efficacious than TMP-SMX in relieving diarrhea and cramps in the first 12 h of therapy, especially among subjects with diarrhea caused by enterotoxigenic E. coli. In the BW942C treatment group, 25% of subjects eventually took additional therapy because their diarrhea did not respond to BW942C alone. Neurological side effects such as dizziness and light-headedness occurred more frequently among BW942C-treated subjects. Therapy for 3 days with TMP-SMX provided lasting relief comparable with previously reported 5-day therapy. Use of the combination of both agents provided the benefits of prompt relief afforded by BW942C and lasting relief afforded by TMP-SMX. BW942C might prove to be an agent suitable for the treatment of acute diarrhea, with TMP-SMX reserved for treatment of those who do not respond adequately. The empiric use of the combination of BW942C and TMP-SMX appears appropriate for the treatment of severe nondysenteric disease.

Antidiarrheals↗
PubMed1991

Comparative, double-blind, prospective, multicenter trial of temafloxacin versus trimethoprim-sulfamethoxazole in uncomplicated urinary tract infections in women.

In a double-blind, randomized, multicenter study, 400 women with symptoms of acute urinary tract infections were treated with either a 7-day course of temafloxacin hydrochloride (400 mg once a day; n = 204) or a 10-day course of trimethoprim (160 mg) and sulfamethoxazole (800 mg) (TMP-SMZ) twice daily (n = 196). The bacteriologic cure rates at 5 to 9 days posttherapy were 100% in the temafloxacin group and 97% in the TMP-SMZ group (P = 0.035). The clinical cure rates were 93% in the temafloxacin group and 95% in the TMP-SMZ group (P greater than 0.1). Adverse events, including nausea, vomiting, rash, headache, and dizziness, were experienced by 19.6% of the temafloxacin group and 23.5% of the TMP-SMZ group. Transient leukopenia occurred in 0.5 and 4.1% of the temafloxacin and TMP-SMZ groups, respectively. Temafloxacin, 400 mg once a day for 7 days, appears to be at least as safe and effective as a 10-day course of TMP-SMZ in the management of acute urinary tract infection in women.

4-Quinolones↗
PubMed1999

Comparative efficacies of antibiotics in a rat model of meningoencephalitis due to Listeria monocytogenes.

The antibacterial activities of amoxicillin-gentamicin, trovafloxacin, trimethoprim-sulfamethoxazole (TMP-SMX) and the combination of trovafloxacin with TMP-SMX were compared in a model of meningoencephalitis due to Listeria monocytogenes in infant rats. At 22 h after intracisternal infection, the cerebrospinal fluid was cultured to document meningitis, and the treatment was started. Treatment was instituted for 48 h, and efficacy was evaluated 24 h after administration of the last dose. All tested treatment regimens exhibited significant activities in brain, liver, and blood compared to infected rats receiving saline (P < 0.001). In the brain, amoxicillin plus gentamicin was more active than all of the other regimens, and trovafloxacin was more active than TMP-SMX (bacterial titers of 4.1 +/- 0.5 log10 CFU/ml for amoxicillin-gentamicin, 5.0 +/- 0.4 log10 CFU/ml for trovafloxacin, and 5.8 +/- 0.5 log10 CFU/ml for TMP-SMX; P < 0.05). In liver, amoxicillin-gentamicin and trovafloxacin were similarly active (2.8 +/- 0.8 and 2.7 +/- 0.8 log10 CFU/ml, respectively) but more active than TMP-SMX (4.4 +/- 0. 6 log10 CFU/ml; P < 0.05). The combination of trovafloxacin with TMP-SMX did not alter the antibacterial effect in the brain, but it did reduce the effect of trovafloxacin in the liver. Amoxicillin-gentamicin was the most active therapy in this study, but the activity of trovafloxacin suggests that further studies with this drug for the treatment of Listeria infections may be warranted.

Animals↗
PubMed1984

Prediction of sulfamethoxazole-trimethoprim synergistic action against members of the family Enterobacteriaceae with a two-plate agar dilution breakpoint MIC system.

Synergy between sulfamethoxazole (SMZ) and trimethoprim (TMP) was predicted by a two-plate agar dilution breakpoint MIC system. Comparison of the results of this new system with those of the disk diffusion system (P.M. Waterworth, Postgrad. Med. J. Suppl. 45:21-27, 1969) after tests with 1,518 Enterobacteriaceae isolates showed an overall correlation of 99.8%, a sensitivity of 99.7%, and a specificity of 100%. The method involves spot inoculation of 10(3) organisms onto each of two plates, one containing 160 micrograms of SMZ per ml and the other 8 micrograms of TMP per ml (in Oxoid IsoSensitest medium with 3% agar supplemented with 7% saponin-lysed horse blood), and then incubation overnight at 37 degrees C in air. All but three organisms for which SMZ-TMP was found to be synergistic by disk testing were inhibited on both plates. Three isolates of Proteus mirabilis, which failed to correlate with disk testing by this new system, all showed SMZ MICs of 1,000 micrograms/ml. The SMZ-TMP combination was falsely predicted to be nonsynergistic against these three organisms. There were no false synergy predictions by the breakpoint MIC system. Laboratories should report susceptibility to the SMZ-TMP combination only when there is synergy between the constituents. This simple, reliable agar dilution technique enables laboratories to accurately report synergy between SMZ and TMP.

Drug Resistance, Microbial↗
PubMed2004

Relation between coronary pressure derived collateral flow, myocardial perfusion grade, and outcome in left ventricular function after rescue percutaneous coronary intervention.

OBJECTIVE: To evaluate the relation between pressure derived coronary collateral flow (PDCF) index and angiographic TIMI (thrombolysis in myocardial infarction) myocardial perfusion (TMP) grade, angiographic collateral grade, and subsequent recovery of left ventricular function after rescue percutaneous coronary intervention (PCI) for failed reperfusion in acute myocardial infarction. METHODS: The pressure wire was used as the guidewire in 38 consecutive patients who underwent rescue PCI between December 2000 and March 2002. Follow up angiography was performed at six months. Baseline and follow up single plane ventriculograms were analysed off line by an automated edge detection technique. A linear model was fitted to assess the relation between 0.1 unit increase in PDCF and change in left ventricular regional wall motion. RESULTS: Patients with TMP 0 grade had significantly higher mean (SD) PDCF than patients with TMP 1-3 (0.30 (0.11) v 0.15 (0.07), p < 0.0001, r = -0.5). A similar relation was observed between TMP grade and coronary wedge pressure (mean (SD) 28 (16) mm Hg with TMP 0 v 9 (7) mm Hg with TMP 1-3, p = 0.001, r = -0.4). Higher PDCF was associated with increased left ventricular end diastolic pressures (0.28 (0.14) with end diastolic pressure > 20 mm Hg v 0.22 (0.09) with end diastolic pressure < 20 mm Hg, p = 0.08, r = 0.2). No correlation was observed between PDCF and Rentrops collateral grade (0.26 (0.13) with grade 0 v 0.25 (0.11) with grades 1-3, p = 0.4, r = -0.06). No linear relation existed between changes in PDCF and changes in left ventricular regional wall motion. CONCLUSION: PDCF in the setting of rescue PCI for failed reperfusion after thrombolysis does not predict improvement in left ventricular function. Increased PDCF and coronary wedge pressure in acute myocardial infarction reflect a dysfunctional microcirculation rather than good collateral protection.

Angioplasty, Balloon, Coronary↗