The bioavailability of griseofulvin from microsized and ultramicrosized tablets in nonfasting volunteers

Tablets of either microsized or ultramicrosized griseofulvin (2 x 125 mg), were administered to 6 healthy volunteers of either sex just before a breakfast containing 4o g. of butter. The plasma concentration of griseofulvin were determined 1, 3, 5, 7, 9, 24, and 32 h. after dosing using a spectrofluorometric method, and pharmacokinetic parameters (Cp max, t max, AUC 0 - greater than 32) were calculated. These parameters were found to be; Cp max = 0.0.681 +/- 0.1 mu/ml, t max. = 2.51 +/- 0.33 h. and AUC = 14.14 +/- 2.33 micrograms h/ml for microsized tablets and Cp max = 0.80 +/- 0.08 +/- g/ml, t max = 2.44 +/- 0.54 and AUC = 16.25 +/- 1.16 microgram h/ml for ultramicrosized tablets. Our results show that mean peak plasma level and AUC (0 - greater than 32) are only slightly higher for the ultramicrosized preparation and the time to peak plasma level is similar in two preparations. Therefore, it is concluded that coadministration of griseofulvin with food will tend to reduce the difference between the bioavailability of the two type of preparations.     

Vasodilator effects of sarafotoxins and endothelin-1 in spontaneously hypertensive rats and rat isolated perfused mesentery

Sarafotoxins (SRTa, SRTb and SRTc) and ET-1 produced a potent vasodilator effect in spontaneously hypertensive rats in vivo and in rat isolated perfused mesenteries in vitro. Among these peptides SRTc demonstrated the most potent vasodilator activity, and was three times more active than SRTa in both preparations. These peptides induced endothelium-dependent vasodilatation in vitro and pretreatment with methylene blue inhibited this effect, while exposure to the antagonists of other vasodilators did not. In contrast, [nitrophenylsulfenylated Trp21]SRTc, SRTc(1-18) and reduced and S-carboxymethylated SRTc caused no vasodilatation in either animal model; the vasodilator effect of acetylated SRTc was less potent than that of SRTc. These results suggest that (i) the vasodilatations of these peptides may be exerted through the release of endothelium derived relaxing factor; (ii) the C-terminal Trp21 and disulfide bonds are essential; and (iii) the N-terminal amino group plays an important role in vasodilator activity.     

Evaluation of drugs for treatment of urinary bladder dysfunction in conscious rats with intact pelvic nerve and after resection of the left pelvic nerve

We studied the effects of drugs used for treatment of bladder dysfunction in conscious rats with intact pelvic nerves and also in rats at one or two weeks after nerve decentralization on the left side. Bladder contraction accompanying micturition was continuously induced by infusion of solution at a constant rate. When the effects of oxybutynin (3 mg/kg, i.p.) and terodiline (3 and 10 mg/kg, i.p.) on the cystometrogram were studied for about 2 hr, these drugs shortened and then prolonged the micturition interval (MI), but atropine (1 and 5 mg/kg, i.p.), butylscopolamine (20 mg/kg, i.p.) and nifedipine (3 mg/kg, i.p.) exhibited only a shortening effect on the MI. After injection of oxybutynin (10 mg/kg, i.p.), solution dribbled from the urethra for about 30 min. Terodiline (3 mg/kg) caused ischuria in the rats one week after resection of the left pelvic nerve, but not in the rats two weeks after surgery. Physostigmine (0.3 mg/kg, i.p.) improved micturition in the rats one week after surgery, but the effect was not evident in the rats with intact pelvic nerves. It was found that the drugs used for treating failure to store or expel urine exhibited a beneficial effect on micturition in rats with intact pelvic nerves and also in rats one week after nerve decentralization, respectively.     

DNA-directed alkylating agents. 3. Structure-activity relationships for acridine-linked aniline mustards: consequences of varying the length of the linker chain

Four series of acridine-linked aniline mustards have been prepared and evaluated for in vitro cytotoxicity, in vivo antitumor activity, and DNA cross-linking ability. The anilines were attached to the DNA-intercalating acridine chromophores by link groups (-O-, -CH2-, -S-, and -SO2-) of widely varying electronic properties, providing four series of widely differing mustard reactivity where the alkyl chain linking the acridine and mustard moieties was varied from two to five carbons. Relationships were sought between chain length and biological properties. Within each series, increasing the chain length did not alter the reactivity of the alkylating moiety but did appear to position it differently on the DNA, since cross-linking ability (measured by agarose gel assay) altered with chain length, being maximal with the C4 analogue. The in vivo antitumor activities of the compounds depended to some extent on the reactivity of the mustard, with the least reactive SO2 compounds being inactive. However, DNA-targeting did appear to allow the use of less reactive mustards, since the S-linked acridine mustards showed significant activity whereas the parent S-mustard did not. Within each active series, the most active compound was the C4 homologue, suggesting some relationship between activity and extent of DNA alkylation.     

The role of microsomal oxidation processes in the development of haloperidol tolerance during melatonin administration and epiphysectomy in rats

A pineal hormone melatonin (1 mg/kg, 24 days) facilitated the formation of tolerance to haloperidol and eliminated the changes produced by it in the processes of microsomal oxidation in rats. Pinealectomy yielded the opposite result. After pinealectomy the normalizing effect of the hormone on the condition of the liver monoxygenase system and the effects of haloperidol weakened.     

Interaction of midazolam and morphine in the spinal cord of the rat

The antinociceptive properties, as measured by the tail-flick and hot-plate tests, and the motor effects of an intrathecally-administered benzodiazepine agonist midazolam, alone, and in combination with morphine, was examined in rats. Midazolam alone produced a weak but dose-dependent (20-60 micrograms) antinociceptive effect in addition to a clear motor dysfunction at larger doses (60-100 micrograms). An inactive dose of intrathecally-administered midazolam (20 micrograms) produced a leftward shift in the dose-response curve for intrathecally administered morphine, in the thermal antinociceptive tests. This supra-additive effect was antagonized by naloxone (1 mg/kg). The data suggest a synergistic interaction between mu- and GABAA-receptors in the spinal processing of thermally-evoked pain.