Obstruction of the renal pelvis due to an insoluble blood clot after epsilon-aminocaproic acid therapy: resolution with intraureteral streptokinase instillations.

PURPOSE: We demonstrate the effectiveness of intraureteral streptokinase instillations for the resolution of an insoluble blood clot in the renal pelvis. MATERIALS AND METHODS: A patient with renal adenocarcinoma had prolonged hematuria related to involvement of the "pyelum" by the tumor. An insoluble blood clot obstruction of the left renal collecting system developed as a consequence of epsilon aminocaproic acid therapy, which was treated with low dose streptokinase through a ureteral catheter. RESULTS: Complete resolution of the clot and obstruction occurred within 3 days of therapy. CONCLUSIONS: This relatively simple approach should be used for the treatment of obstruction before radical surgery is performed.

Sustained release properties of the once daily theophylline capsule BY912 as compared with Theo-24 capsules.

In a multiple dose cross-over experiment in 12 healthy male adults the bioavailability and sustained release characteristics of new once daily BY912 400 mg theophylline capsules (= B, Byk Gulden Research Laboratories, FRG) were studied using Theo-24 capsules (= T, Searle & Co., USA) as reference. Both products were given once daily for a period of 7 days as an 800 mg theophylline dose at 8 am, half an hour after a standardized breakfast. Theophylline concentrations in plasma were measured on days 1, 6, and 7 using high-performance liquid chromatography. Significantly better sustained release characteristics, resulting in longer plateau time (t75%, 11.6 vs 9.2 h on day 6 and 13.1 vs 8.8 h on day 7) and smaller per cent peak-trough fluctuation in the steady state (per cent PTF, 80 vs 103 per cent on day 6 and 66 vs 100 per cent on day 7), were found for B in comparison with T. The extent of absorption on both days, however, was smaller for B compared with T (relative bioavailability 84 per cent and 81 per cent, respectively). In conclusion, the absorption of theophylline from B resulted in a more extended shape of the plateau phase, indicating better sustained release characteristics. The extent of absorption, however, over the dosing intervals was more complete with T.

Theophylline-terbutaline, a steady state study on possible pharmacokinetic interactions with special reference to chronopharmacokinetic aspects.

1. The pharmacokinetic interaction of terbutaline and theophylline and chronopharmacokinetics of both drugs were studied in a three-way crossover study with repeated administration of terbutaline (Bricanyl Depot) 7.5 mg twice daily, theophylline (Theo-Dur) 300 mg twice daily alone or the combination of both for 7 days to 12 healthy volunteers (six male and six female). 2. After the morning dose on day 7, blood and urine were sampled for 12 h, and after the evening dose on day 7, blood and urine were sampled for 48 h. Theophylline concentrations in plasma and concentrations of unchanged drug and metabolites in urine were determined by two selective high performance liquid chromatography methods. Terbutaline concentrations in plasma and urine were measured with a gas chromatography-mass spectrometry method. Area under the plasma concentration-time curve, fluctuations in plasma concentration, mean residence time, elimination half-life, renal clearance as well as maximal, minimal and average plasma concentration at steady state were evaluated. 3. The addition of terbutaline to the repeated administration of theophylline lowered the relative bioavailability of theophylline by approximately 11% during the night interval. The rate of elimination of theophylline and mean residence time were influenced accordingly. No significant changes in excretion of the theophylline metabolites were observed, but the excretion of 3-methylxanthine was slightly reduced by the concomitant terbutaline administration. None of the observed changes should be of any clinical importance. 4. The addition of theophylline did not influence any of the calculated pharmacokinetic parameters of terbutaline. 5. It can be concluded that no dosage adjustment is necessary when terbutaline and theophylline are given together.(ABSTRACT TRUNCATED AT 250 WORDS)

Comparison of the in vitro dissolution properties and in vivo steady-state pharmacokinetics of two sustained-release theophylline preparations.

The sustained-release properties and relative bioavailability of Theolin Retard and Pharphylline Retard were studied in eight healthy adults after treatment for five days with twice daily 450 mg, respectively 425 mg. During the day-time dosing interval on the fourth and fifth day theophylline plasma concentrations were assayed by HPLC. After intake of Theolin Retard, minimum theophylline plasma concentrations were significantly higher, fluctuations in theophylline plasma concentrations were significantly smaller and t75 (the period within a dosing interval during which the plasma concentration exceeds 75% of the maximal concentration) was significantly longer than after Pharphylline Retard. Maximal concentrations and AUC values were not significantly different. For both products the plasma concentration time-curves on day 5 were significantly lower than on day 4. In vitro dissolution tests confirmed the more sustained release of theophylline from Theolin Retard. These results indicate an equal extent of absorption from the two products but better sustained-release properties for Theolin Retard.

Single dose bioavailability of two different digoxin tablets.

In a single dose bioequivalence study in 10 healthy young adults the absorption profiles and bioavailability of two digoxin containing tablets (A = digoxin-Pharbita 0.25 mg and reference drug B) were compared and related to the in vitro dissolution rate of both tablets. Two tablets of each product (= 0.50 mg of digoxin) were taken at random on an empty stomach; two weeks elapsed between the two treatments. Frequent blood sampling was performed up to 24 h after intake of the dose. Digoxin plasma concentrations were measured by means of radioimmunoassay. No significant differences (p greater than 0.05) were found in the mean values of the peak plasma concentration (cmax), time to peak (tmax) and area under the plasma concentration versus time curve for the period of 0-10 h after drug intake (AUC0-10), although in most subjects the absorption process after intake of product A was slightly faster, with slightly higher peak. This might be related to a slightly faster release of digoxin from the product A dosage form, as was seen from the dissolution test data. The relative bioavailability of product A as compared to product B, accounted for 97.7 +/- 28.7% (mean +/- S.D.). These results indicate, that both products can be considered as being bioequivalent.

Single dose absorption profiles and bioavailability of two different salbutamol tablets.

In a single dose cross-over experiment in twelve healthy adults a comparison of the absorption profiles and the relative bioavailability was made between a new salbutamol containing tablet (preparation A = Salbutax) and a commercially available and accepted formulation as reference (preparation B), both containing 4 mg salbutamol. Salbutamol plasma concentrations were measured frequently during a period of 16 h post dosing. Maximum salbutamol plasma concentrations after intake of product A and product B on an empty stomach were reached after 2.3 +/- 0.9 (= mean +/- S.D.) and 2.4 +/- 1.1 h, respectively, and accounted for 14.3 +/- 2.5 and 12.8 +/- 2.6 micrograms X l-1, respectively. The differences were not found to be significant (p greater than 0.05). The areas under the plasma concentration-time curves (AUC0----16), as obtained after administration of tablet A and tablet B, accounted for 73.5 +/- 14.0 and 65.0 +/- 11.8 micrograms X l-1 X h, respectively, the difference being marginally significant (p = 0.05). This results in a relative bioavailability of 114.3 +/- 15.7% for the product A 4-mg tablets. It is concluded that both products can be considered as having comparable bioavailability.

Clinical pharmacokinetics of theophylline during co-treatment with cefaclor.

The effect of cefaclor on the steady state pharmacokinetics of theophylline was investigated in healthy young adults by comparing the pharmacokinetic parameters as found during a nine days course of theophylline alone and as obtained during co-medication with the antibiotic cefaclor. The pharmacokinetic parameters obtained on Day 9 during the two periods of drug treatment accounted for the following figures respectively: minimum plasma concentration 5.0 +/- 1.7 mg X 1(-1) (mean +/- SD) and 6.0 +/- 2.0 mg X 1(-1); maximum plasma concentration 9.7 +/- 2.6 mg X 1(-1) and 9.0 +/- 2.6 mg X 1(-1); time to peak 3.2 +/- 0.4 h and 3.9 +/- 0.8 h; AUC 132.54 +/- 41.73 mg X 1(-1) X h and 126.90 +/- 40.45 mg X 1(-1) X h; half-life of elimination 6.6 +/- 1.6 h and 7.1 +/- 1.2 h; clearance 0.059 +/- 0.011 1 X h-1 X kg-1 and 0.063 +/- 0.014 1 X h-1 X kg-1; volume of distribution 0.54 +/- 0.09 1 X kg-1 and 0.64 +/- 0.17 1 X kg-1. Only the values for cmax and tmax after cefaclor co-treatment were slightly, but significantly (p less than 0.05) different from the values found after administration of theophylline alone. As the volume of distribution and the clearance were not affected by cefaclor, it is concluded that both drugs can be given concomitantly without any dosage adjustment of theophylline.

Lack of influence of co-trimoxazole on theophylline pharmacokinetics.

In an open cross-over experiment, the influence of the antimicrobial agent co-trimoxazole on the single-dose pharmacokinetics of theophylline was studied in six healthy adults by comparing the pharmacokinetic parameters found after intravenous administration of theophylline without and with co-medication of co-trimoxazole for the previous 8 d. Theophylline concentrations in plasma were measured by high-performance liquid chromatography (HPLC) analysis. During each treatment, a concentration-time curve was evaluated. No influence of co-trimoxazole on the rate of elimination and volume of distribution of theophylline could be found, as a result of which theophylline concentrations in plasma were not significantly different in both periods of drug administration. A similar lack of influence of co-trimoxazole may apply to the steady-state pharmacokinetics of theophylline. The present study suggests that both drugs can be given concomitantly without the need for dosage adjustment of theophylline.

Lack of effect of amoxicillin on theophylline pharmacokinetics.

The effect of the antibiotic drug amoxicillin on steady state pharmacokinetics of theophylline was studied in healthy adults by comparing the pharmacokinetic parameters as found during a 9 day course of theophylline alone and as obtained during comedication with amoxicillin. Theophylline plasma concentrations were measured by means of h.p.l.c. analysis. On the ninth day of each of the two periods of drug administration a concentration-time curve was evaluated. It showed no influence of amoxicillin on absorption, elimination and volume of distribution of theophylline, as a result of which mean steady state plasma concentrations were not significantly different during both treatments. It is concluded that both drugs can be given concomitantly without any dosage adjustment of theophylline.

Food reduces the rate but not the extent of the absorption of theophylline from an aqueous solution.

The effect of food on the rate and extent of absorption of theophylline was studied in healthy adults given a single dose of theophylline (aqueous solution of choline theophyllinate containing 270 mg of theophylline) in the evening either on an empty stomach or together with supper. Food appeared to decrease the absorption rate of theophylline significantly, tmax being prolonged from 1.34 h (mean) to 4.40 h and cmax decreased from 7.82 mg . l-1 to 5.47 mg . l-1. The area under the plasma concentration-time curve (AUC) after drug intake with supper was slightly but not significantly smaller, indicating that theophylline (as a solution of choline theophyllinate) can be taken together with food without substantial loss of the quantity of drug absorbed. The elimination rate was not influenced by concomitant intake of supper.

Clinical pharmacokinetics of amoxycillin and theophylline during cotreatment with both medicaments.

The influence of amoxycillin and theophylline on their mutual steady-state pharmacokinetics was studied in healthy adults by comparing the pharmacokinetic parameters as obtained during a 10-day course of each drug alone and after giving the drugs in combination. Amoxycillin and theophylline plasma concentrations were measured by means of HPLC methods. On the 9th day of each of the two periods of drug administration, a concentration-time curve was evaluated. These showed no influence of theophylline on absorption, elimination or volume of distribution of amoxycillin, demonstrating that the mean steady-state plasma concentrations were not significantly different during the two treatments. Amoxycillin also has no significant effect on theophylline steady-state pharmacokinetics. It is concluded that both drugs can be given concomitantly without any dosage adjustment.

No influence of doxycycline on theophylline pharmacokinetics.

The influence of the antibiotic drug doxycycline on steady-state pharmacokinetics of theophylline was studied in nine healthy adults by comparing the pharmacokinetic parameters measured during a 9-day course of theophylline alone and during comedication with doxycycline. Theophylline plasma concentrations were measured by means of high performance liquid chromatography analysis. Trough theophylline plasma concentrations were measured on days 1-8. On day 9 of each of the two periods of drug administration, a plasma concentration-time curve was evaluated. No influence of doxycycline on absorption, elimination, and volume of distribution of theophylline was found. Mean steady-state plasma concentrations were not significantly different during the two treatments. It is concluded that the drugs can be given concomitantly without any dosage adjustment of theophylline.

No effect of cefaclor on theophylline pharmacokinetics.

The effect of the antibiotic drug cefaclor on steady state pharmacokinetics of theophylline was studied in healthy adults by comparing the pharmacokinetic parameters as found during a 9 days course of theophylline alone and as obtained during comedication with cefaclor. Theophylline plasma concentrations were measured by means of HPLC analysis. On the ninth day of each of the 2 periods of drug administration, a concentration-time curve was evaluated. It showed no influence of cefaclor on volume of distribution and clearance of theophylline and only a slight, but significant (p less than 0.05) influence on the values for Cmax and tmax after cefaclor co-treatment. It is concluded that both drugs can be given concomitantly without any dosage adjustment of theophylline.

The absolute bioavailability of a new pediatric sustained release theophylline tablet, when given as whole or divided tablets.

Absorption characteristics and absolute bioavailability of a new sustained release theophylline tablet for pediatric use were investigated in seven volunteers, both after administration of whole tablets and tablets broken into four equal parts. An intravenous infusion of 200 mg theophylline (as aminophylline) was also administered to the same panel of subjects. Theophylline plasma concentrations were measured frequently during a period of 33 h post dosing. Both after intake of the whole and the broken tablets steadily increasing theophylline plasma concentrations were found. The maximum concentration was found after 5.2 +/- 0.6 h (mean +/- S.D.) and 5.3 +/- 2.2 h and measured 2.00 +/- 0.28 mg.1-1 and 2.46 +/- 0.60 mg.1-1, respectively. The absorption process continued for a considerable period. As a consequence the theophylline plasma concentrations remained above 75% of the maximum value during a period of 8.9 +/- 2.1 h and 8.6 +/- 2.0 h. The absolute bioavailability of the whole tablets was 91.8 +/- 24.7% and that of the broken tablets was 95.8 +/- 9.7%.

Chronopharmacokinetics of theophylline after sustained release and intravenous administration to adults.

The influence of time of drug administration on pharmacokinetics of theophylline was studied both after ingestion of a sustained-release tablet, containing choline theophyllinate ( Zy 15061-S. R.; Teovent ; Sabidal ; ZYMA S.A.) and after intravenous infusion of aminophylline to eight healthy volunteers. Both drugs were administered in the morning (10 a.m.) and on a separate occasion in the evening (10 p.m.) after a 12 h period of fasting. After oral administration of a dose of 540 mg theophylline, the drug was steadily absorbed, both during day-time and during night-time. In some subjects absorption was slower in the evening. Maximum theophylline plasma concentrations were reached after 3.3 +/- 0.4 h (mean +/- SD) and 3.9 +/- 1.4 h respectively (not significantly different p greater than 0.05). The maximum plasma concentrations were almost identical after administration in the morning and in the evening (12.6 +/- 3.3 mg X l-1 and 13.1 +/- 1.4 mg X l-1 respectively). There was also no significant difference (p greater than 0.05) between the areas under the plasma concentration-time curves after oral and intravenous administration, both at day-time and at night-time. This finding indicates complete bioavailability of the sustained release tablets on both occasions. After administration of the tablets in the morning the plasma concentration 12 h post dosing was significantly lower than after administration in the evening: c1 12 accounted for 6.0 +/- 2.0 mg X l-1 after intake at 10 a.m. and for 7.9 +/- 2.1 mg X l-1 after ingestion at 10 p.m. (p less than 0.01). A similar observation was done after intravenous administration of the drug: c12 was 6.6 +/- 1.6 mg X l-1 after starting the infusion in the morning and 8.0 +/- 1.8 mg X l-1 after infusing the drug in the evening (p less than 0.01). This phenomenon could be explained by the finding of a significantly prolonged half-life of theophylline during night-time, provided that the plasma concentrations were in the range of 5 to 15 mg X l-1 (which coincides approximately with the therapeutic range of the drug).(ABSTRACT TRUNCATED AT 250 WORDS)

Clinical pharmacokinetic comparison of two indometacin containing suppositories with different vehicula.

A single dose each of two brands of indometacin (INN; in some pharmacopoeias called indomethacin) containing suppositories, made with different vehicula , was administered rectally - in a cross over design - to ten healthy volunteers. Product A ( Dolcidium ) was made of a new waxy excipient which emulsifies at body temperature; product B was a leading brand of indometacin containing suppository, made of a hydrophilic polyethyleneglycol basis, which dissolves in body fluid. Plasma indometacin concentrations were measured frequently during a period of 9 h after dosing. Both products showed rather consistent absorption profiles. The maximum plasma indometacin concentration after administration of the product A 50 mg suppository was found after 62 +/- 18 min (mean +/- S.D.), and measured 2.0 +/- 0.5 mg X l-1. After dosing with the reference product those values were 66 +/- 21 min and 1.8 +/- 0.4 mg X l-1, respectively. The area under the plasma indometacin concentration-time curve was found to be 384 +/- 130 mg X l-1 X min for product A 50 mg suppositories and 372 +/- 62 mg X l-1 X min for the reference product. This results in a relative bioavailability of the product A 50 mg suppositories of 1.02, after correction for actual amount of indometacin in each dosage form. None of the above mentioned pharmacokinetic parameters were statistically significantly different (p greater than 0.05), indicating bioequivalence of the two products.

Plasma indomethacin assay by reversed-phase ion pair high pressure liquid chromatography.

A new rapid, selective and sensitive high pressure liquid chromatographic (HPLC) assay for indomethacin in plasma is described. The method involves precipitation of proteins with perchloric acid, followed by dichloromethane extraction using flurbiprofen as an internal standard. The organic solvent was evaporated and the residue dissolved in a water-methanol (2 + 3) phosphate buffer mixture with an apparent pH of 6.8. Aliquots of 100 microliters were injected automatically into the chromatograph. The separation of indomethacin was achieved on a reversed phase (C18, 10 micron) column with a mobile phase consisting of 65% (vol/vol) methanol in water solution of apparent pH 6.8 containing tetrabutylammonium hydrogensulfate as an ion pairing agent. Quantitation of indomethacin was performed by UV detection at 235 nm. At a 2.0 mg X l-1 concentration of indomethacin in plasma the analytical recovery was 82.9 +/- 3.4% (n = 7), the intra-day variability (CV) was 3.6% (n = 7) and the inter-day variability (CV) was 11.0% (n = 7). The calibration curve was linear (typical r-values greater than 0.990) in the range of plasma concentrations as usually found during indomethacin therapy (up to 6 mg X l-1). The limit of sensitivity is 0.025 mg X l-1. The metabolites O-desmethylindomethacin and O-desmethyldeschlorobenzoylindomethacin did not interfere with the method. The capacity of an analyst using this method with automated injection and peak integration is about forty samples in duplicate per day. The applicability of the method for pharmacokinetic studies is demonstrated.