The drug interaction potential of daprodustat when coadministered with pioglitazone, rosuvastatin, or trimethoprim in healthy subjects.

This study was conducted to evaluate the likelihood of daprodustat to act as a perpetrator in drug-drug interactions (DDI) with the CYP2C8 enzyme and OATP1B1 transporter using the probe substrates pioglitazone and rosuvastatin as potential victims, respectively. Additionally, this study assessed the effect of a weak CYP2C8 inhibitor, trimethoprim, as a perpetrator of a DDI with daprodustat. This was a two-part study: Part A assessed the effect of coadministration of daprodustat on the pharmacokinetics of pioglitazone and rosuvastatin in 20 subjects; Part B assessed the coadministration of trimethoprim on the pharmacokinetics of daprodustat in 20 subjects. Coadministration of 100 mg of daprodustat with pioglitazone or rosuvastatin had no effect on the plasma exposures of either probe substrate. When trimethoprim was coadministered with 25-mg daprodustat plasma daprodustat AUC and Cmax increased by 48% and 28%, respectively. Additionally, AUC and Cmax for the metabolite GSK2531401 were decreased by 32% and 40%, respectively. Cmax for the other metabolites was slightly decreased (~8-15%) but no changes in AUC were observed. As 100-mg daprodustat exceeds the planned top therapeutic dose, interaction potential of daprodustat as a perpetrator with substrates of the CYP2C8 enzyme and OATP1B1 transporters is very low. Conversely, daprodustat exposure (AUC and Cmax) is likely to increase moderately with coadministration of weak CYP2C8 inhibitors.

Concentrations of sulfadoxine and trimethoprim in plasma, lymph fluids and some tissues 24 h after intramuscular administration to Angora goats.

This study was carried out to determine the concentrations of sulfadoxine and trimethoprim in plasma, lymph, and some tissues in goats after administration of a single recommended therapeutic dose. Five healthy, adult Angora goats were used. The drug combination, containing 200 mg sulfadoxine and 40 mg trimethoprim per millilitre, was given as a single IM injection at the recommended dose level, 15 mg/kg body weight for sulfadoxine and 3 mg/kg body weight for trimethoprim. The goats were slaughtered 24 hours after drug administration and samples were taken from liver, bone marrow, pelvic limb muscles, hepatic, thoracic duct, and the pelvic limb lymph fluids for analysis of drug concentrations by HPLC. The concentrations of trimethoprim in bone marrow, liver, pelvic limb muscles, hepatic lymph, the pelvic limb lymph, and thoracic duct lymph were found to be 6, 5, 4, 2, 5 and 15 times higher than those of plasma, respectively. Although the sulfadoxine concentrations in bone marrow, pelvic limb muscles, and liver were 2, 3 and 2 times higher than the plasma concentrations, respectively, the sulfadoxine concentrations in hepatic lymph, the pelvic limb lymph, and thoracic duct lymph were lower than those of plasma. The results show that the trimethoprim concentrations in lymph fluids were quite similar to those in tissues. However, the sulfadoxine concentrations in lymph fluids were different in each tissue.

Activity of epiroprim (Ro 11-8958), a dihydrofolate reductase inhibitor, alone and in combination with dapsone against Toxoplasma gondii.

We examined the effect of epiroprim (Ro 11-8958), a dihydrofolate reductase inhibitor, alone and in combination with dapsone, against Toxoplasma gondii. In vitro, the anti-T. gondii effects of epiroprim and dapsone were observed at nanogram-per-milliliter levels when a 72-h uracil assay and an infection rate of one parasite per 120 macrophages were used. In combination, these drugs exerted a synergistic effect that, however, was only parasitostatic. In a model of acute infection, mice were infected intraperitoneally with 10(4) parasites of the RH strain of T. gondii and were treated for 14 days by gavage (therapy divided into two daily dosages), starting 24 h after infection. Used alone, dapsone and epiroprim, each at a dose of 50 mg/kg of body weight per day, protected 10 and 0% of the mice, respectively. When these drugs were administered simultaneously, a 100% survival rate was observed. Pyrimethamine-sulfadiazine (4 and 250 mg/kg/day, respectively) protected 100% of the mice. A 3-week therapy of chronically infected mice with either epiroprim (50 mg/kg/day), dapsone (50 mg/kg/day), or pyrimethamine (15 mg/kg/day) reduced the numbers of T. gondii cysts and the inflammation in their brains. A combination of epiroprim and dapsone, both at 50 mg/kg/day, further reduced the number of brain cysts in comparison with the number after the corresponding monotherapies. Epiroprim may have a role in the prophylaxis or therapy of human toxoplasmosis, especially when combined with other drugs active against T. gondii, such as dapsone.

Trimethoprim-sulfamethoxazole prophylaxis in granulocytopenic patients with acute leukemia: evaluation of serum antibiotic levels in a randomized, double-blind, placebo-controlled Department of Veterans Affairs Cooperative Study.

Despite widespread use of trimethoprim-sulfamethoxazole (TMP-SMZ) for prophylaxis in neutropenic patients, questions remain regarding its efficacy, toxicity, the risk of selection of resistant isolates, and the relation of its activity to selective decolonization vs. the attainment of direct inhibitory levels within blood and tissues. We evaluated the effect of TMP-SMZ (160/800 mg orally every 12 hours) in 42 adult granulocytopenic patients (< 100 absolute neutrophils/mm3, mean duration 13.3 days) undergoing chemotherapy for acute leukemia at 11 participating Veterans Administration Medical Centers in a randomized, double-blind, placebo-controlled trial. No significant differences in survival, frequency of bacteremia, overall infections, use of systemic antimicrobial therapy, or adverse effects, including myelosuppression, were observed between patients receiving TMP-SMZ vs. those receiving placebo. All patients acquired trimethoprim-resistant organisms. Concentrations of trimethoprim in serum were significantly lower before febrile episodes than when patients were afebrile. These results suggest that the purported activity of TMP-SMZ may be related to the serum concentration achieved. Moreover, the results highlight the need for additional study of the value of antibiotic prophylaxis in neutropenic patients.

Disposition of drugs in cystic fibrosis. I. Sulfamethoxazole and trimethoprim.

The disposition of sulfamethoxazole and trimethoprim, after constant rate intravenous administration (10 mg/kg/hr sulfamethoxazole and 2 mg/kg/hr trimethoprim for 1 hour), was investigated in adult patients with cystic fibrosis (n = 7) and in age-matched healthy subjects (control subjects, n = 8). The total plasma clearance of sulfamethoxazole was found to be increased in cystic fibrosis (0.0262 +/- 0.0064 L/hr/kg) when compared with that found in control subjects (0.0188 +/- 0.0043 L/hr/kg). This increase in clearance was found to be primarily attributable to an increase in the metabolic clearance of sulfamethoxazole to N4-acetylsulfamethoxazole (0.00903 +/- 0.00247 versus 0.00355 +/- 0.00049 L/hr/kg) with the renal clearance of sulfamethoxazole remaining unchanged. These conclusions were not altered when the pharmacokinetic parameters were computed for the unbound drug or when they were normalized with respect to body surface area. These data indicate that, in cystic fibrosis, the enzymes mediating the metabolism of sulfamethoxazole to N4-acetylsulfamethoxazole, N-acetyltransferase(s), may be induced, activated, or both, or that the uptake of sulfamethoxazole by cells that metabolize sulfamethoxazole to N4-acetylsulfamethoxazole is enhanced. The total plasma clearance of trimethoprim was also found to be increased in cystic fibrosis (0.1808 +/- 0.0440 L/hr/kg) when compared with that found in control subjects (0.1139 +/- 0.0193 L/hr/kg). In contrast to sulfamethoxazole, this increase in clearance was found to be primarily attributable to an increase in the renal clearance of trimethoprim (0.1240 +/- 0.0299 versus 0.0720 +/- 0.0166 L/hr/kg). These data indicate that the tubular secretion of trimethoprim may be enhanced in cystic fibrosis.

[In vivo kinetics of cotrimoxazole in alveolar macrophages]. / Cinétique in vivo du cotrimoxazole dans les macrophages alvéolaires.

The aim of this work was to study the kinetic of intramacrophage penetration of cotrimoxazole in guinea pigs which had received 100 mg/kg of sulfamethoxazole and 20 mg/kg of trimethoprim after a single intraperitoneal injection. 30 minutes, 1, 3, 6 and 24 hours after this injection an intra-cardiac blood sample was taken and pulmonary lavage was performed immediately after sacrificing the animal by cervical cord dislocation. The level of trimethoprim and sulfamethoxazole was measured in each sample by high performance liquid chromatography (HPLC). An estimation of the dilution of the supernatant was obtained by comparing the supernatant glucose with the serum glucose. The serum kinetics of trimethoprim and sulfamethoxazole progressed in a parallel fasion with time with a maximal concentration at 30 minutes (for trimethoprim: 6.7 +/- 0.9 micrograms/ml and for sulfamethoxazole 176.1 +/- 16.2 micrograms/ml). On the other hand their penetration capacity was different in the supernatant and in the alveolar macrophages: the maximal concentrations were obtained after one hour in the supernatant and after 3 hours in the cellular extract and were respectively for trimethoprim 0.43 +/- 0.07 microgram/ml and 20.9 +/- 8.06 micrograms/ml of intramacrophage water and for sulfamethoxazole 1.86 +/- 0.24 micrograms/ml and 23.8 +/- 12.7 micrograms/ml of intramacrophage water. A concentration around six times greater was noted for the trimethoprim inside the cells compared with serum and was only 0.25 time for sulfamethoxazole. On the other hand the supernatant/serum ratio showed a greater concentration for trimethoprim (4 to 10) than for sulfamethoxazole (0.6 to 1).(ABSTRACT TRUNCATED AT 250 WORDS)

[Study of the in vivo penetration of cotrimoxazole in alveolar macrophages]. / Etude de la pénétration in vivo du cotrimoxazole dans les macrophages alvéolaires.

Kinetic of cotrimoxazole was studied in serum, alveolar macrophages and BAL fluid from guinea pigs receiving sulfamethoxazole (SMX, 100 mg/kg) and trimethoprim (TMP, 20 mg/kg). Guinea pigs were killed by cervical dislocation 30 min, 1 h, 3 h, 6 h and 24 h after intraperitoneal injection. Lung lavage was performed to obtain alveolar macrophages and BAL fluid. TMP and SMX levels were assayed using high-performance-liquid chromatography. Highest SMX levels were obtained in serum at 30 min, in BAL fluid at 1 h and in alveolar macrophages at 3 h. Mean SMX/TMP ratios (30 min, 1 h, 3 h) was 26.5 +/- 0.8 in serum, 3.76 +/- 1.8 in BAL fluid and 1.15 +/- 0.02 in alveolar macrophages.

[Nocardial brain abscess: case report].

A 25-year-old man, who was slightly immunosuppressed, presented headache and right motor weakness due to multiple brain abscesses disseminated from lung abscess. They were diagnosed, by bacteriological examination, as nocardial brain abscesses (nocardia asteroides) 4 weeks after the first operation. In spite of delay in the diagnosis, he was relieved by operations (three times) and chemotherapy including high doses of Sulfamethoxazole-Trimethoprim. He was eventually discharged. We stress the necessity of early diagnosis and the efficacy of Sulfamethoxazole-Trimethoprim for nocardial brain abscess.

Trimethoprim interference in methotrexate assay by an enzyme inhibition assay kit.

Spurious methotrexate (MTX) concentrations in sera and cerebrospinal fluids from leukemia patients who were given trimethoprim (TMP) were estimated using an MTX assay kit which is based on its inhibition of dihydrofolate reductase. The interference of TMP with MTX was confirmed in the assay system. A concentration of 0.17 microgram/ml of TMP gave a value for an apparent MTX of 10 microM.

Rapid onset of co-trimoxazole induced interstitial nephritis.

An infant developed anuric renal failure within 18 hours of starting therapy with Co-trimoxazole for otitis media. There was no prior exposure to Co-trimoxazole, sulfonamides or trimethoprim. A renal biopsy revealed acute interstitial nephritis with eosinophilic infiltration (AIN). The lymphocyte blast transformation test revealed increased proliferation of the patient's lymphocytes on exposure to Co-trimoxazole (Bactrim). Both parents have clinically demonstrated hypersensitivity to sulfonamides. The extremely short latent period between ingestion of the offending drug and the onset of AIN in the absence of prior exposure to the drug has been reported previously. It suggests that drug induced AIN may develop more rapidly in patients with a strong genetic hypersensitivity to the drug.

Treatment of nonpulmonary infections due to Mycobacterium fortuitum and Mycobacterium chelonei on the basis of in vitro susceptibilities.

One hundred twenty-three patients with nonpulmonary infections due to Mycobacterium fortuitum or Mycobacterium chelonei were treated by wound debridement and with chemotherapy on the basis of in vitro susceptibilities of the organism. Of 76 patients with infections caused by M. fortuitum, 13 required no therapy or were adequately treated with surgery alone. Patients with active localized disease received single drug therapy (usually with a sulfonamide) for a mean period of 10.6 weeks for cellulitis and seven months for osteomyelitis. Patients with extensive disease received amikacin or amikacin plus cefoxitin (mean, four weeks) followed by a sulfonamide (mean, six months). The 47 patients with infections caused by M. chelonei received no therapy or were treated with surgery alone (6); with amikacin (10), erythromycin (6), doxycycline (3), or cefoxitin (1); or with amikacin plus cefoxitin followed by cefoxitin alone for a total of 10-12 weeks (20); or other multiple-drug regimens (1). Surgery was performed on 74 (60%) patients. Schlichter tests or serum drug levels were determined for 81 (66%) patients. Response to therapy was excellent; 68 (90%) infections with M. fortuitum and 34 (72%) with M. chelonei were successfully treated. Cultures became negative within six weeks of chemotherapy, except for sternal osteomyelitis, for which cultures were not negative until up to 14 weeks. Follow-up for a mean period of 12 months following therapy was possible in 80% of cases. Relapses were rare except in patients with disseminated disease, and drug resistance developed in only one patient. These studies demonstrate the value of routine susceptibility testing of these mycobacterial species and the benefit of chemotherapy on the basis of in vitro susceptibilities.

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.

[Lung tissue diffusion of intravenous trimethoprim-sulfamethoxazole combination (author's transl)]. / Diffusion pulmonaire de l'association triméthoprime-sulfaméthoxazole (TMP-SMZ).

In 13 cases of pneumonectomy, we have studied the concentration of TMP-SMZ in tissue and serum, after three days of treatment. Four hours after TMP-SMZ injection, the tissue's samples obtained from crushed and mixed ; the dosages were performed by a microbiological assay. As we previously described in bronchial secretions : the lung penetration of TMP is important ; the tissue concentrations were higher than in serum ; the diffusion of SMZ is low. The ratio of TMP to SMZ were diffusion of SMZ is low. The ratio of TMP to SMZ were different in serum and tissue, but the antibacterial activity is not affected in vitro by the value's modification.

Levels of trimethoprim and sulfamethoxazole in human oviduct mucosa and plasma.

The oviductal and plasma levels of trimethoprim (TMP) and sulfamethoxazole (SMZ) were studied in 9 women after oral and i.v. administration of a drug combination (Eusaprim R, Wellcome Foundation Ltd). The concentration of TMP in a healthy endosalpinx was found to be twice as high (4.7 microgram/g, range 2.8-8.3) as in plasma (2.6 microgram/ml, range 2.1-3.6). Conversely, the endosalpingeal level of SMZ (38 microgram/g, range 12-65) was about half that in plasma (77 microgram/ml, range 58-95). The agar well diffusion method was used for the concentration determinations. The specimens were collected during surgery for non-infectious genital diseases. The implication of treatment by the given drugs is discussed.

[Pharmacokinetic of antibiotics in patients with mucoviscidosis (author's transl)]. / Pharmakokinetik von Antibiotika bei Patienten mit Mukoviszidose.

Inadequate therapeutic results in the treatment of bacterial infections in patients with Cystic Fibrosis prompted a reevaluation of pharmacokinetic parameters of orally and parenterally administered drugs in these patients. Gentamicin, Azlocillin and Ticarcillin are eliminated faster in patients with Cystic Fibrosis. Serum concentrations show a rapid decrease over 60 to 90 minutes and surpass MIC values of Pseudomonas isolates for a maximum of only 60 minutes. 70% to 90% of the administered amount of drug is eliminated within two hours in the urine. Concomitantly determined clearance rates for creatinine didn't show abnormalities, however they pointed towards an additional tubular secretion of Gentamicin which is not seen in healthy controls. Cephalexin, Epicillin and both components of Cotrimoxazol show a delay in oral absorption. The renal elimination of Cephalexin and Trimethoprim is unaltered, but the excretion of Epicillin and Sulfametrol is enhanced again. This is seen by a delay and decrease in the maximal serum concentration (Cmax), but increased urine recovery. Doubling of the dose of gentamicin administered as i. v. infusion over 45 to 60 minutes results in smooth serum curve, the MIC values of most encountered organisms are surpassed for 3 hours and more. The clinical applicability of this recommendation however awaits further investigations concerning efficacy and safety.

Trimethoprim interferes with serum methotrexate assay by the competitive protein binding technique.

Administration of Bactrim (a combination of trimethoprim and sulfamethoxazole) to a patient who also was receiving methotrexate caused a significant increase in apparent plasma methotrexate concentrations as determined by competitive protein binding assay with use of dihydrofolate reductase (EC 1.5.1.3) from Lactobacillus casei as the binding protein. This spurious increase was caused by trimethoprim in the patient's plasma. A plasma trimethoprim concentration of 0.1 mg/L inhibited binding of radiolabeled methotrexate to dihydrofolate reductase by 50%. In contrast, radioimmunoassay for methotrexate was not affected by concomitant administration of trimethoprim. The competitive protein binding assay for methotrexate should not be used in patients being treated with Bactrim or Septra (a similar combination). However, the L. casei competitive protein binding assay technique can be used to assay plasma trimethoprim concentrations with sensitivity to 0.02 mg of trimethoprim per liter.

Evaluation of slow infusions of co-trimoxazole by using predictive pharmacokinetics.

Digital computer simulations of plasma concentration-time profiles of single intravenous infusions of trimethoprim (160 mg)/sulfamethoxazole (800 mg) based on data from other workers showed that increasing the infusion period from the hitherto generally recommended 1 to 1.5 h to 6 h did not significantly affect the interval (approximately 10 h and 8.5 h, respectively) during which trimethoprim and sulfamethoxazole plasma concentrations were maintained above their minimum effective plasma concentrations (selected as 0.6 microgram/ml and 25 microgram/ml, respectively). For the 6-h infusion, the simulated peak plasma concentration of trimethoprim was only approximately 27% less than for the 1-h infusion, and that for sulfamethoxazole was approximately 30% less. The validity of these predictions was confirmed by plasma concentration measurements of trimethoprim and sulfamethoxazole in six patients undergoing gynecological surgery, who received co-trimoxazole (160 mg of trimethoprim, 800 mg of sulfamethoxazole) postoperatively by constant-rate intravenous infusion over a 4-h period. It is concluded that infusions of the dose of intravenous co-trimoxazole over periods from 1 to at least 6 h are therapeutically equivalent.