Experiences with the rectal use of trimethoprim.

The possibility of rectal use of trimethoprim was studied. The in-vitro liberation of the drug from 24 different suppository bases was examined and the results used to select bases for in-vivo examination. The in-vitro liberation from the suppositories containing 50-200 mg trimethoprim was studied by the method of dynamic diffusion, and the released drug content was measured spectrophotometrically. The in-vivo examinations were performed in anaesthetized rats. The concentration of trimethoprim in blood was determined by bioassay. The absorption of the drug in the form of oral suspension, rectal solution and suppository was also studied. The pharmacokinetic parameters obtained after blood-level curve fitting were compared by use of the MedUSA 1.6 program. The best in-vivo results were achieved with the lipohydrophilic Witepsol W 35 vehicle containing 10% polysorbate 20 and 10% polysorbate 61 (bioavailability = 63.8%) and with Witepsol W 35 containing 10% polysorbate 60 (bioavailability = 63.8%). The results for hydrophilic Macrogol 1540 vehicle containing 5% of Macrogol 400 were only slightly worse (bioavailability = 52.9%). In the case of the lipohydrophilic Witepsol W 35 vehicle with 10% polysorbate 20 and 10% polysorbate 61 content a significant negative exponential relationship was found between the administered doses and their respective bioavailability values; this tendency was also observed during in-vitro examinations. When incorporated in the appropriate vehicle trimethoprim was absorbed well. With three vehicles the extent of absorption exceeded that for oral administration on the same model (bioavailability = 38.8%). Trimethoprim rectal suppositories, which are formulated with the vehicles having the best in-vitro and in-vivo results, are suitable for clinical pharmacological investigation.

[Calcium antagonism by papaverine in isolated rat gastric fundus strips in a model system]. / Papaverin-Calcium-Antagonismus an isolierten Ratten-Magenfundusstreifen und in Modellversuchen.

Examining isolated strips of gastric fundus tissue of rats the authors observed that papaverin up to 7.8 X 10(-8) to 6.25 X 10(-7) mol/l increased the intensity of convulsions induced by constant amounts of barium chloride (9.5 X 10(-4); with further increase of the concentration the intensity of convulsions gradually sank under the initial value. An increased proneness to cramping was also observed when the calcium content of the Tyrode solution was reduced. In this case the proneness to cramping was highest between 1 and 1.3 mmol/l calcium content. When the calcium content was 1 mmol/l, papaverin increased the proneness to cramping only to a smaller degree, in agreement with the effect measured when the calcium content of the organ bath was reduced below 1 mmol/l. In model experiments, calcium antagonized the potential difference-increasing effect of papaverin at the ether/NaCl (0.1 mol/l) phase boundary. From this the authors infer an interaction (complex formation) between papaverin and calcium at the phase boundary, which is independent of the biological medium. Their findings and the papaverin -calcium antagonism first observed by Benigni [2] can be interpreted in this way.

The effect of E. coli infection on the prostaglandin synthesizing capacity of postobstructive rat kidney.

The PGE2, PGI2, PGF2 alpha and TxA2 synthesizing activities were studied in an isolated microsomal fraction of rat kidney after temporary, unilateral ureter obstruction and E. coli infection. In the early phase of regeneration the synthesis of vasodilatory PGI2 was increased, whereas that of vasoconstrictory PGF2 alpha was decreased. An increased PGE2 synthesizing activity was observed when renal obstruction was associated with infection. The role of these changes in regenerating the haemodynamics and function of postobstructive kidney is discussed.

Indomethacin and gentamycin treatment in experimental kidney infection.

Experiences in experimental renal infection of rats treated with gentamycin, indomethacin, and by the combination of both drugs are reported. Urine osmolality of animals treated with combined therapy normalized after the first dose of indomethacin; their antibody titers against the pathogenic bacteria, as compared to the controls, decreased significantly. When drugs were administered separately the above immunologic changes could not be observed. Indomethacin did not inhibit the antibacterial effect of gentamycin and, administered alone, it increased the renal concentration ability.

[Experiences with the rectal use of a chemotherapeutic agent. 1. In vitro biopharmaceutical examinations; selection of the optimal vehicle]. / Kemoterápiás szer rektális alkalmazásának tapasztalatai. 1. Rész. In vitro biofarmáciai vizsgálatok; optimális vehikulum kiválasztása.

The factors influencing in vitro liberation (Part 1) and in vivo absorption (Part 2) from trimethoprim-containing rectal suppositories and the authors' results related to them are reported in this two-part publication. Special emphasis was laid on selecting the optimal suppository base which is harmless physiologically yet not indifferent pharmacologically. From among the 24 compositions studied, a lipophilic mixture containing a surface active additive (Witepsol W 35) and a hydrophilic (Macrogolum) mixture were found to be the best in all respects. Liberation from the trimethoprim-containing rectal suppositories was measured with in vitro dynamic diffusion and spectrophotometrically. A power relation was found to exist between the quantity of the released pharmacon and the diffusion time, and a significant negative exponential relation was observed between the doses and their respective in vitro availability values.

[Experiences with the rectal use of chemotherapeutic agents. 2. Pharmacokinetic examinations with animals]. / Kemoterápiás szer rektális alkalmazásanak tapasztalatai. 2. Rész. Allatkísérletes farmakokinetikai vizsgálatok.

The aim of the investigations was to optimise vehicle for trimethoprim (TMP) suppositories ready for clinical trials. The rectal absorption of TMP was studied in anaesthetized rats. The drug liberation properties of the five mixed vehicles with promising in vitro results (Part 1.) were studied. The course of the blood level curves was monitored with serial sampling. The TMP concentration of blood was determined by bioassay. Individual bases were compared with the use of the pharmacokinetic parameters derived from the analysis of the obtained blood level curves, with special respect to biological availability (BA). The extent of bioavailability is influenced considerably by the hydro-, lipo- or lipohydrophilic property of the vehicle. TMP, if incorporated in the proper vehicle, is absorbed well. With three vehicles the extent of absorption exceeded the absorption seen with oral administration on the same model (BA = 38.8%). The best results were achieved with the lipophilic base Witepsol W 35 containing 10% of Polysorbate 20 and 10% of Polysorbate 61 (BA = 63.8%) and with Witepsol W 35 containing 10% of Polysorbate 60 (BA = 64.9%). The hydrophilic Macrogol 1540 vehicle containing 5% of Macrogol 400 had only slightly worse results (BA = 52.9%). In the case of the lipohydrophilic Witepsol W 35 vehicle with 10% of Polysorbate 20 and 10% of Polysorbate 61 content a significant negative exponential relation was found between the administered doses and their respective bioavailability values, this tendency had been observed during the in vitro examinations, too. No such relation was found in the case of the lipophilic Witepsol W 35 vehicle containing 10% of Miglyol 812.

Fatigue of three skeletal muscles in domestic and wild pigs. A comparative study in situ.

The semitendinosus, the gastrocnemius and the soleus muscle were stimulated in situ in young, female domestic pigs (Sus scrofa domestica, German Landrace) and in European wild pigs (Sus scrofa scrofa), by supramaximal impulses via the sciatic nerve. Fatigue indices of the whole muscles were registered during a continuous supramaximal stimulation with square wave impulses (0.3 ms) that were given for 10 s with a frequency of 100 Hz. In domestic pigs, fatigue indices of all three muscles were significantly (p less than 0.001) lower than in wild pigs. The extremely rapid fatigue of domestic pig muscles was remarkably different from that measured in wild pigs, comparing either pigs of nearly the same body weight (FI: 22.7/58.6 for the semitendinosus muscle; 28.5/63.7 for the gastrocnemius muscle; 37.7/81.2 for the soleus muscle), or pigs of nearly the same age (FI: 23.1/58.8 for the semitendinosus muscle; 25.9/65.1 for the gastrocnemius muscle; 33.6/81.4 for the soleus muscle). Doses of anaesthetics needed for appropriate general anaesthesia of young wild pigs were two to three times higher than doses used for domestic pigs. Differences in fiber type composition of the muscles, and alterations in signal transmission characteristics at neuromuscular junctions are discussed as to be associated with the extremely low fatigue resistance of the domestic pig muscles.

Neuromuscular transmission in the gastrocnemius muscle of young domestic and wild pigs.

The gastrocnemius muscle was stimulated in situ in young female domestic pigs (DP, Sus scrofa domestica, German Landrace; n = 24) and in European wild pigs (WP, Sus scrofa scrofa; n = 20), by short (0.1 ms) square-wave impulses via the sciatic nerve. Evoked compound action potentials were recorded from the sciatic nerve, from the Ramus muscularis distalis of the tibial nerve and from the end plate region of the muscle tissue. Maximum nerve conduction velocities (NCV) were 58.8 +/- 10.4 m/s in DP and 77.7 +/- 16.5 m/s in WP. Time of neuro-muscular transmission ("distal latency") for evoked compound action potentials from the Ramus gastrocnemius of the tibial nerve into the gastrocnemius muscle was 2.32 +/- 0.54 ms in DP and only 1.27 +/- 0.25 ms in WP. Electromechanical coupling time intervals in the gastrocnemius muscle were 11.95 +/- 2.26 ms in DP and 9.95 +/- 1.07 ms in WP. Motor end plates were visualized histochemically and classified as of the red, intermediate and white type according to their shape and arborization. High extrajunctional acetylcholinesterase activity was observed in the close vicinity of the junctions of muscles in young DP (3.5 month, 40 kg), which was absent in WP muscles and also in DP muscle at older age.

Mechanism of action of the spasmogenic activity of penthylenetetrazol and of 1,2,3,4-tetrahydroisoquinolines on rat stomach fundus strips.

Spasmogenic activity of penthylenetetrazol (PTZ) and 1,2,3,4-tetrahydro-isochinoline (THI) derivatives was gradually reduced during storage of their solutions as tested on rat isolated stomach fundus strips. Spasmogenic activity of both PTZ and THI derivatives could be modified by prior exposure of the solutions to electrostatic field and to rotating magnetic field or ultrasound treatment. As a consequence of rotating magnetic field treatment, ED50 values for 1-phenyl-6,7-dimethoxy-1,2,3,4-tetrahydro-isochinoline-hydrochloride (S-23), PTZ and for PTZ crystallized from an ether solution of PTZ (PTZA) doubled, i.e. their activity was reduced by 50 per cent. After an exposure to rotating magnetic field, intrinsic activity of S-23 fell only by 10 to 20 per cent, while after the same treatment the fall in intrinsic activity of PTZ was more pronounced (40 to 50 per cent). Activity of PTZA changed similarly as that of PTZ. Activity of S-23 was similarly modified by exposure of its solution to electrostatic or rotating magnetic field. On the other hand, intrinsic activity of PTZ solution exposed to electrostatic field was twice as high as that of the control PTZ solution. Affinity and intrinsic activity of PTZ solutions diminished after ultrasound treatment. The fall in the activity of PTZ solution of low concentration was greater after the same ultrasound treatment, but its convulsive activity measured in vivo remained unchanged. Spasmogenic activity of ultrasound-treated PTZ reappeared after the solution had been dried under vacuum and then the residue crystallized and redissolved in water. These findings allow the conclusion that the observed changes in activity could be the result of spontaneous or field-evoked alterations in molecular state (orientation, association etc.) conformation. The fact that the activity of PTZ solution measured in vivo did not change during storage supports this assumption.