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PubMed1990

[Effect of induced hypotension on arterial blood ketone body ratio (AKBR)].

Arterial blood ketone body ratio (AKBR; acetoacetate/beta-hydroxybutyrate) is known as a parameter to indicate the function of the liver cells. We evaluated the effects of induced hypotension with prostaglandin E1 (PGE1) or trimetaphan (TMP) on AKBR in patients without liver disease undergoing mastectomy. Almost no change was observed in AKBR before, during and after hypotension with PGE1, but slight diminution was observed during hypotension with TMP. No hepatic dysfunction, however, developed in these patients postoperatively. These findings suggest that usual hypotension with TMP may provoke no postoperative hepatic dysfunction in patients without liver disease. For the patient who required either hypotension of long duration or hypotension with other factors affecting function of liver (surgical procedures, drugs and others), we prefer PGE1 to TMP as a hypotensive drug. We should also adopt PGE1 when cardiovascular control with hypotensive drug is necessary in patients with liver disease.

Alprostadil↗
PubMed1975

Long-term therapy of chronic bacterial prostatitis with trimethoprim-sulfamethoxazole.

Trimethoprim (TMP) meets all of the theoretical requirements of diffusion into, and actual concentration in, human prostatic fluid. When TMP is combined with the sulfonamide sulfamethoxazole (SMX), potentiation of antibacterial activity is achieved and the development of resistant bacterial strains is less likely to occur. In our initial use of TMP-SMX in the treatment of 13 men with chronic bacterial prostatitis due to gram-negative organisms, patients were given two tablets of TMP-SMX twice daily for only 14 days. The results were that two patients (15%) were cured, nine patients (70%) were improved (sterile prostatic fluid during therapy) but eventually relapsed, and two patients (15%) were unchanged by therapy. In our present study 19 patients (31.6%) were totally cured and 9 of 23 (39.1%) gram-negative organisms were permanently cleared from prostatic fluid; 8 of the 9 patients (42.1%) were improved but eventually relapsed with the same organism; 5 of the 19 patients (26.3%) were considered unchanged by therapy.

Acinetobacter Infections↗
PubMed1987

PUVA therapy for photosensitive psoriasis.

The purpose of this study was to assess the prophylactic effect of oral photochemotherapy with psoralens and UVA (PUVA) on patients with light-sensitive psoriasis. Of fifteen patients with photosensitive psoriasis, ten with a history of polymorphous light eruption (PMLE) slowly developing into psoriasis were treated with trimethylpsoralen (TMP) and UVA. Five patients with no preceding PMLE reaction were similarly treated; two with 8-methoxypsoralen (8-MOP), two with TMP and one in whom 8-MOP was later changed to TMP. Good to excellent results were obtained in 9/10 of the first category and in 3/5 of the second, giving an overall efficacy of 80%. Preexisting psoriatic lesions did not, however, heal during TMP therapy but did so when treated with 8-MOP. The results confirm, for light-sensitive psoriatics, the efficacy of PUVA in photosensitive disorders.

Female↗
PubMed1989

Effectiveness of different methods to eliminate interference by thyroglobulin antibodies in the ELISA for thyroid microsomal autoantibodies.

Thyroid microsomal autoantibodies (TMA) have been mostly detected by means of either immunofluorescence (IF), tanned red cell haemagglutination (TRCH), or radioimmunoassay (RIA) until the recent development of ELISA. False positives in the ELISA for the detection of TMA due to interference by thyroglobulin antibodies (TGA) present in some test sera reacting with thyroglobulin (Tg) present as a contaminant in the thyroid microsomal preparation (TMP) appears to be common. In this study we tried various ways of removing any Tg contaminant in the TMP by further gel filtration, affinity chromatography of the microsomal preparation or preincubation of the test sera with either Tg or Tg-sepharose 4B immunoadsorbent to absorb out TGA present in the sera. Further gel filtration and affinity purification of the TMP failed to totally remove all the contaminating Tg. Preincubation with Tg effectively removed any TGA present in the test sera but resulted in inhibition of the TMA-thyroid microsomal antigen reaction in the test sera including those without TGA. Preincubation with Tg-immunoadsorbent equally effectively absorbed out any TGA present in the test sera but without significant inhibition of the assay reaction in TGA-free sera. The preincubation of the TMP with Tg-immunoadsorbent is an effective way of removing TGA present in sera without inhibiting the test reaction and thus resulting in false negatives especially in low-titre sera as occurs with the presence of free Tg in the test system.

Autoantibodies↗
PubMed1989

Pneumocystis carinii pneumonia in patients with the acquired immunodeficiency syndrome: pathophysiology, therapy, and prevention.

The continuing growth of the acquired immunodeficiency syndrome (AIDS) epidemic has caused a parallel increase in patients with Pneumocystis carinii pneumonia (PCP). PCP has a wide spectrum of severity, from mild disease to severe parenchymal lung damage. Outcome is determined by severity of lung injury, the underlying physical condition of the patient, and concomitant infections. Both trimethoprim-sulfamethoxazole (TMP-SMX) and pentamidine are effective therapeutic agents; however, both cause a high incidence of adverse reactions. TMP-SMX therapy can be made safer by careful monitoring and dose adjustment. Pentamidine toxicity, especially hypoglycemia, appears to be cumulative dose-dependent. Experimental therapies, including TMP-dapsone and aerosolized pentamidine, appear promising in mild to moderate disease, while trimetrexate may be more effective in severe disease. Corticosteroids are unproven in decreasing mortality. Prophylaxis of PCP is possible with TMP-SMX but the high rate of adverse reactions make long-term therapy difficult. Other oral therapies such as dapsone, pyrimethamine/sulfadoxine are also promising but not yet tested. Aerosolized pentamidine is effective and safe for prophylaxis regimen when administered correctly. Airway irritation as manifested by cough and/or wheezing is a common adverse effect of aerosolized pentamidine.

Acquired Immunodeficiency Syndrome↗
PubMed1989

[Cefaclor and trimethoprim-sulfamethoxazole for recurrent otitis media].

The efficacy of cefaclor and of trimethoprim-sulfamethoxazole (TMP-SMX) in the management of recurrent otitis media was evaluated in a randomized single-blind controlled trial. The median age of the patients was 12 months (range 5-37); there were 37 boys and 19 girls. All had received 1 or more courses of antibacterials for acute otitis media in the previous 2-3 weeks. 27 were treated with oral cefaclor suspension, 40 mg/kg/day in 3 divided doses, and 29 with 1 mg/kg/day of TMP-SMX (trimethoprim 8 mg, sulfamethoxazole 40 mg) in 2 divided doses, each group for 10 days. 70% of the cefaclor group and 90% of the TMP-SMX group were cured after the 10 days of therapy (0.1 greater than p greater than 0.05). Results were not better on the 21st day as compared with the 10th. Our data indicate a mild preference for TMP-SMX (although p was not less than 0.05), since it needs to be given only twice a day and costs less than cefaclor.

Acute Disease↗
PubMed1989

Pharmacokinetics of sulfadiazine/trimethoprim in neonatal male calves: effect of age and penetration into cerebrospinal fluid.

Sulfadiazine (SDZ)/trimethoprim (TMP; 30 mg of SDZ/TMP/kg of body weight) was given IV to the same 6 male calves at 1, 7, and 42 days of age and to 2 additional calves at 7 days of age. Serum concentrations of SDZ and TMP were best represented by a 2-compartment open model, but in 42-day-old calves, CSF concentrations of both drugs were best represented by a 1-compartment open model with first-order input. Between 1 and 42 days of age, the elimination half-life (t1/2(beta)) of SDZ decreased from 5.7 to 3.6 hours, and total body clearance (CLtot) increased from 1.43 to 1.88 ml/min/kg; the area under the curve (AUC0----infinity) decreased from 291.5 to 225.4 mg/L.h. The distribution coefficient (Vd(area)/kg of body weight) decreased with age, changing from 0.72 to 0.59 L/kg, between 1 and 42 days of age. Therapeutic concentrations of SDZ in serum (greater than 2 micrograms/ml) were maintained for 24 hours in 1-day-old calves and for about 15 hours in 7- and 42-day-old calves. The elimination rate of TMP increased about 9-fold; t1/2(beta) was 8.4, 2.1, and 0.9 hours, respectively, at 1, 7, and 42 days of age. Other values also reflected an increase in TMP elimination rate with age: CLtot increased from 2.8 to 12 to 28.9 ml/min/kg, k13 increased from 0.336 to 0.654 to 1.664/h and AUC0----infinity decreased from 32.8 to 7.9 to 3.1 mg/L.h, respectively. Therapeutic concentrations (greater than 0.1 microgram/ml) were maintained for 15 hours, 8 hours, and about 6 hours in 1-, 7-, and 42-day-old calves, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Age Factors↗
PubMed1988

[Electrogenic character of the functioning of H+-ATPase of synaptic vesicles in the rat brain].

Transmembrane potential (TMP) of synaptic vesicles (SV) from the rat brain was registered by means of potential-sensitive fluorescent probe 3,3' dipropylthiocarbocyanine iodide (dis-C3-(5)). It was found that Mg-ATP generates TMP on the SV membrane suspended in sucrose-buffer medium. TMP did not appear if 0.25 M sucrose medium was replaced by 0.125 M KCl medium or 0.125 NaCl medium, or if the SV membrane was disrupted by triton X-100 or alamethicin, or if there was protonophore m-chlorophenylhydrazone or N-ethylmaleimide influence on SV. The data obtained indicate that functioning of SV proton pump is electrogenic and the level of TMP depends on the presence of anion Cl- in the incubation medium.

Adenosine Triphosphate↗
PubMed1986

Evaluation in dogs and humans of three potential technetium-99m myocardial perfusion agents.

The biodistribution of the three cationic 99mTc complexes [99mTc(TMP)6]+, [99mTc(POM-POM)3]+, and [99mTc(TBIN)6]+--where TMP represents trimethylphosphite, POM-POM represents 1,2-bis(dimethyoxyphosphino)ethane, and TBIN represents t-butylisonitrile--have been evaluated in humans and dogs. Each agent was studied in three normal volunteers at rest, while [99mTc(POM-POM)3]+ and [99mTc(TBIN)6]+ were each studied in one normal volunteer at exercise. Even though all three agents yield good myocardial images in dogs, none appear suitable for clinical use as myocardial perfusion imaging radiopharmaceuticals. In humans, [99mTc(TMP)6]+ and [99mTc(POM-POM)3]+ clear very slowly from the blood and provide myocardial images only several hours after injection. [99mTc(TBIN)6]+ clears rapidly from the blood, but accumulation in the lung obscures the myocardial image for the first hour after injection; at later times, activity in the liver and spleen masks the apical wall. These results correlate with the blood-binding properties of the three complexes. [99mTc(TMP)6]+ and [99mTc(POM-POM)3]+ bind tightly to the plasma of human blood, but not to the plasma of dog blood; [99mTc(TBIN)6]+ does not bind tightly to the plasma of either dog or human blood. Among the Tc(I) complexes studied to date in humans, [99mTc(TBIN)6]+ appears to be unique in biodistribution pattern, blood-binding properties, and the fact that exercise improves the ultimate myocardial image. All the Tc(I) complexes appear to undergo myocardial accumulation by a mechanism different from that utilized by Tc(III) complexes. Animal studies alone are not adequate to evaluate the potential utility of 99mTc cationic complexes for myocardial perfusion studies.

Animals↗
PubMed1986

[Diffusion of trimethoprim and sulfamethoxazole into the pleural fluid].

The level of Trimethoprim (TMP) and of Sulfamethoxazole (SMZ) in the fluid of both pleural effusion and plasma was determined in 7 patients on the first day of treatment consisting of two daily doses of 160 mg TMP and 800 mg SMZ. In 4 subjects, the levels were determined again on the third (J3) and fifth day of treatment (J5). Thus with TMP the ratio of pleural/plasma drug levels rose progressively from the first day of treatment to attain by 12 hours a mean value of 0.79 +/- 0.16; subsequently it stayed at about the same level for day 3 (J3) and day 5 (J5). As for SMZ, the ratio of the pleural plasma drug level reached a maximum at 8 hours on the first day of treatment (0.53 +/- 0.12) then rose progressively on day 3 (J3 0.58 +/- 0.06) and on day 5 to 0.71 (+/- 0.08). The levels of TMP in the pleural fluid were below those which are usually described in bronchial secretions. On the other hand those of SMZ are appreciably raised.

Drug Combinations↗
PubMed1985

Vasodilator drugs in patients with chronic ischaemic heart failure.

The effects of intravenous nitroglycerin (NTG), trimetaphan (TMP), and phentolamine (PTL) on pulmonary artery diastolic pressure (PADP), systemic arterial pressure (SAP), cardiac index (CI) and systemic vascular resistance (SVR) in patients (12 in each treated group) with chronic ischaemic heart failure are analyzed. Each group was divided into two subgroups according to the initial PADP taking into account the mean value in the whole group. A significant decrease in PADP (by 40%; p less than 0.001) was observed in the NTG-treated group, with no significant changes in CI and SVR except for patients with moderately elevated initial PADP, in whom SVR increased slightly in the early period of treatment, and CI decreased (by 25%; p less than 0.05). TMP and PTL reduced SVR (by 25 and 30% respectively; p less than 0.01) and increased CI irrespective of the initial PADP. TMP significantly decreased PADP in patients in whom its level was initially high. The results suggest that NTG is mainly a venodilating agent which should be used in patients with high PADP and normal or slightly decreased CI. PTL acts mainly by reducing SVR and increasing CI. TMP influences both PADP and SVR and is a drug of choice in patients with high or elevated PADP and low cardiac output.

Aged↗
PubMed1979

Neisseriaceae, a group of bacteria with dihydrofolate reductases, moderately susceptible to trimethoprim.

Dihydrofolate reductases of five species of the family Neisseriaceae were compared by means of inhibition profiles, using several structurally different inhibitors, including trimethoprim (TMP) and pyrimethamine. All enzymes were seen to be highly susceptible to the folate analog aminopterin, but exhibited moderate susceptibility to all other inhibitors tested. Approximately 200-fold higher concentrations of TMP were needed to inhibit neisserial reductases as compared to the E. coli enzyme. Besides poor penetration this is assumed to be the main basis for the low susceptibility of neisseriae to TMP. In addition to TMP all other inhibitors were also moderately active or inactive in vitro. The enzymatic differences, as seen from inhibition profiles, were statistically significant but small among all species of the genus Neisseria. Branhamella catarrhalis on the other hand was seen to be far less related to the other neisseriae, as seen by the inhibition profile of its reductase, its dihydrofolate reductase conttent, as well as by its in vitro properties.

Drug Resistance, Microbial↗
PubMed1979

[New bacteriological results with Co-trimoxazole (author's transl)].

The current situation regarding resistance to cotrimoxazole and trimethoprim as well as the selected ratio of our combination and the resulting proportions of the two components in body fluids and tissues are discussed. Special attention will be paid to the relevant synergy in the respective proportions. Data on the development of resistance towards co-trimoxazole obtained from London, Zurich, Hamburg and Austria will be presented. In general, however, in Zurich a slight increase in resistance to staphylococci, Klebsiellae and Serratia can be seen. If we take an investigation in Hamburg as an example, we can show the importance of distinguishing between infectious hospitalism and a genuine development of resistance. Reference is made to Austria, because of claims that the resistance problem would be improved by combination with another sulfonamide (sulfametrole). The situation in Austria resembles that in Zurich. In order to deal with the problem as to whether the risk of the development of resistance to co-trimoxazole is still as significant as 10 years ago, the resistance frequency towards TMP alone will be further analysed. The chromosomal as well as the plasmidic transferable resistance is on slight increase in England, France and Italy. However, susceptibility to the combination has not yet adversely influenced. Accelerated deterioration of the susceptibility could occur if TMP alone were introduced in more countries. However, 30-50% of TMP-resistant organisms are still susceptible to sulfonamides and remain therefore sensitive to a strong synergistic influence of the combination, which is shown in many instances. As a result of various chemico-physical properties different ratios of both components, SMZ and TMP occur, in body fluids and tissues which differ from that in the plasma. However, many of these ratios are comprised by the large range of potentiation of the combination against many pathogens. A more complete synergistic inhibition however, would be achieved by the development of new supplementary combinations.

Austria↗
PubMed1983

[Effect of trimethoprim at a subinhibitory concentration on the appearance of mutants resistant to rifampicin].

Experiments have been performed to establish the effect of trimethoprim (Tmp) on the emergence of Staphylococcus aureus (S. aureus) mutants to rifampicin (Ramp). Four S. aureus strains were used: two strains with low MIC of Ramp (0,01 microgram/ml), two strains with enhanced MIC of Ramp (2 micrograms/ml). For each of them the frequency of mutants and the mutation rates to Ramp were determined when various concentrations of Tmp were added. Results showed that subinhibitory concentrations of Tmp reduced 10 to 100 folds the frequency of mutants and the rates of mutation to Ramp alone. The more the Tmp concentrations were near the MIC, the more this effect was important.

Drug Resistance, Microbial↗
PubMed1983

Antimicrobial therapy of travellers' diarrhoea.

Two trials were carried out to evaluate antimicrobial agents in the therapy of travellers' diarrhoea. In the first, 72 students were given 500 mg bicozamycin (BI), a poorly absorbable drug, q.i.d. for three days and 68 were given a placebo. In the second, 37 students were given trimethoprim/sulphamethoxazole (160 mg TMP-SMX 800 mg), 38 TMP (200 mg), and in 35 a placebo was given b.i.d. for five days. Diarrhoea lasted on average 28 hours in those receiving BI compared to 64 hours in the placebo group (p = 0.00009). Significant shortening of diarrhoea after taking BI was seen for all subjects with illness, as well as those with ETEC diarrhoea, shigellosis and for those with unknown causes of illness. A significant clinical response was also noted in all categories of diarrhoea for both TMP-SMX and TMP when compared to placebo group.

Anti-Infective Agents↗
PubMed1984

Safety and therapeutic effectiveness of 8-methoxypsoralen, 4,5',8-trimethylpsoralen, and psoralen in vitiligo.

In this paper, we report on 366 East Indian patients with vitiligo who were treated for 2 to 3 years with either 8-methoxypsoralen (8-MOP), 4,5',8-trimethylpsoralen (TMP), or psoralen and sunlight. These patients with amelanotic macules had 10 to 70% skin involvement of 1 to 50 years duration. Male and female patients from ages 12 to 70 years were randomly assigned to 8 treatment groups; the study was conducted on a double-blind protocol. Patients in prone and supine positions were exposed to the sun for 45-60 minutes in gradually increasing doses between 11 a.m. and 2 p.m. thrice weekly and 2 hours after oral ingestion of the drug. The various drug dosage schedules investigated included 9 groups: 0.3 and 0.6 mg 8-MOP/kg; 0.8, 1.8, and 3.6 mg TMP/kg; a combination of 0.3 mg 8-MOP and 0.6 mg TMP/kg; 0.6 and 1.2 mg psoralen/kg, and a placebo. For ethical reasons, the placebo group was terminated after 9 to 12 months of therapy. All patients were photographed before enrollment and at intervals of 6, 12, 18, and 26 months during therapy. Of these patients treated for nearly 2 years, the faces of those 45% receiving the combination dose of 8-MOP plus TMP or low-dose 8-MOP (0.3 mg/kg) were fully repigmented, and nearly 60% achieved 75 to 100% repigmentation of the head and neck. The chest, abdomen, and back were repigmented nearly as well and better than the arms and legs. The patients receiving high-dose schedules of TMP and psoralen achieved better repigmentation response than those on lower dosage but still not as good as patients on 8-MOP or the combination group of 8-MOP plus TMP.(ABSTRACT TRUNCATED AT 250 WORDS)

Ficusin↗
PubMed1984

Psoralen pharmacology: studies on metabolism and enzyme induction.

Psoralens, tricyclic furocoumarins with potent photosensitizing properties in the skin, are now widely used in the treatment of several dermatologic diseases. In this study, the metabolism of 4,5',8-trimethylpsoralen (TMP) and 8-methoxypsoralen (8-MOP) was studied in mouse liver. Orally administered TMP is transformed into several metabolites, the major one of which is 4,8-dimethyl-5'-carboxypsoralen (DMCP) in both humans and mice. Orally administered 8-MOP is metabolized into at least 5 fluorescent moieties, including 8-hydroxypsoralen, the 4'5'-dihydro-diol of 8-MOP, and furocoumaric acid. The effects of 3 psoralens, 8-MOP, TMP, and isopsoralen (angelicin) on hepatic microsomal drug-metabolizing enzymes and cytochrome P-450 were assessed in mice and rats. Administered orally to CD-1 mice daily for 6 days, 8-MOP caused twofold to threefold increases in hepatic aryl hydrocarbon hydroxylase (AHH), ethylmorphine N-demethylase, and cytochrome P-450. The absorbance maximum of the induced cytochrome was at 450 nm. Aniline hydroxylase activity was unchanged. Chronic administration of 8-MOP to Skh:hairless-1 mice caused significant enhancement of hepatic ethylmorphine N-demethylase and cytochrome P-450 but had no effect on AHH, whereas chronically administered TMP had no significant effect on any of these parameters.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1984

Effect of trimethoprim administration on hepatic functions of albino rats.

The effects of chronic and high-dose administration of trimethoprim (TMP) i.p. for different periods on serum and hepatic functions of rats were studied at cellular and subcellular levels. Most of the parameters studied were unaffected after chronic administration of TMP (10 mg/kg/day) for 90 days except an increase in total lipid content of liver and liver microsomes. Administration of TMP in doses of 40 mg and 80 mg/kg/day for 21 days caused a significant increase in total lipid, cholesterol and transaminases activities of serum and liver. Protein, RNA and phospholipid contents of liver and microsomes decreased significantly while DNA content remained unchanged. Glycogen content of liver decreased significantly but alkaline phosphatase activity did not show any noticeable alteration. Histopathological findings showed fatty infiltration and distorted liver architecture. Administration of TMP in doses of 40 mg and 80 mg/kg/day for 14 days changed all the parameters and enzymes in a similar pattern but with less intensity. From the present study it is obvious that high doses of this drug cause harmful toxic effects on serum and hepatic function with liver injury whereas chronic administration has no effect so far.

Animals↗