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Biomedical subjects

R Roser

Publications and source records attributed to R Roser.

At least 37 records · Page 2Linked to original sources
PubMed1988

Pharmacological profile of droxicam.

In Studies of anti-inflammatory activity, droxicam has shown itself to be as active as piroxicam and much more active than phenylbutazone, isoxicam and suprofen, both in acute studies such as carrageenin oedema, nystatin oedema and ultraviolet erythema, and in longer-term tests such as that of the cotton pellet. In the studies of anti-arthritic activity, which require long-term treatment, droxicam was as effective as piroxicam, both on primary and on secondary lesions. The study of analgaesic activity, conducted by means of the tests of protective activity against writhing induced by phenylbenzoquinone and acetylcholine bromide in the mouse and by acetic acid in the rat, droxicam activity was superior to that of acetylsalicylic acid, dipyrone, isoxicam and phenylbutazone. Droxicam also showed antipyretic activity in the rat, greater than that of acetylsalicylic acid, dipyrone and 4-aminoantipyrine, in the brewer's yeast and Salmonella typhi tests. Droxicam also acts as an ex vivo platelet aggregation inhibitor in the dog. In the study of inhibition of peritoneal capillary permeability in the mouse, droxicam was considerably more potent than isoxicam or phenylbutazone. Studies of general pharmacology have demonstrated that droxicam, at high doses, has no cardiovascular or respiratory effects, and that neither does it modify behaviour in rats and mice, determined by the Irwin test. Gastrointestinal tolerance of droxicam has been compared with that of piroxicam, and it has been found that droxicam is far better tolerated. The study of induction of gastrointestinal lesions in the rat demonstrated that the gastrolesive potential of droxicam is 10 times inferior to that of piroxicam.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1988

Comparative study of the multiple dose pharmacokinetics and the tolerance of a new NSAID (droxicam) versus piroxicam in healthy volunteers.

A controlled, randomized, double-blind, clinical trial has been performed in healthy volunteers in order to study the pharmacokinetics and tolerability of droxicam in comparison with piroxicam, when both drugs were administered at a dose of 20 mg/day for 20 days. Since transformation into piroxicam takes place in the gastrointestinal tract, unchanged droxicam was not detected in plasma. Steady state of plasma piroxicam concentrations was reached in all volunteers during the course of the study. Absorption kinetics of droxicam were delayed with respect to those of piroxicam (t1/2 a = 7.55 h for droxicam and 1.78 h for piroxicam). The remaining pharmacokinetical parameters studied showed no statistically significant differences. The bioavailability of both drugs was equal. Tolerability of droxicam and piroxicam was as usual for the NSAIDs, and no clinical or analytical side effects which could hinder its administration to wider populations were detected. Statistically significant differences in the number and type of side effects detected in the two treatment groups were not encountered.

Administration, Oral↗
PubMed1987

Effects of droxicam on in vivo prostaglandin synthesis and ex vivo platelet aggregation.

Droxicam, similar to piroxicam, inhibits in vivo renal synthesis of PGF2 alpha. This study was performed in rats; droxicam and piroxicam were administered orally at doses of 0.5, 1.2 and 8 mg/kg. Inhibitory activity of the two compounds was similar (40-60%) but showed no dose-effect relationship. Maximum inhibition was obtained with the 1 mg/kg dosage. In dogs droxicam has shown a clear inhibitory effect on arachidonic acid induced ex vivo platelet aggregation. Droxicam was administered orally at a dose of 2 mg/kg. Maximum inhibition (-40%) was achieved 24 hr post-administration and the effect was sustained up to 72 hr (-23%).

Animals↗
PubMed1987

Pharmacological properties of besulpamide, a new diuretic, in rats and dogs.

Besulpamide, a newly synthesized compound, has demonstrated significant diuretic activity in rats and dogs, similar to that of chlorthalidone, clopamide and xipamide. Antihypertensive activity of besulpamide is similar to that of hydrochlorothiazide and was demonstrated in rat one-kidney desoxycorticosterone acetate (DOCA)-salt hypertension. In addition, besulpamide, like hydrochlorothiazide, potentiated the antihypertensive activity of captopril in spontaneously hypertensive rats (SHR). Doses of besulpamide exceeding those normally required for pharmacological activity did not evoke adverse reactions in rats and mice.

Animals↗
PubMed1987

Acute, subacute and subchronic toxicity of besulpamide.

The acute oral and intraperitoneal toxicity of besulpamide has been studied in the rat and mouse, together with the subacute and subchronic oral toxicity in the rat at doses of 0, 125, 500 and 2000 mg/kg/day. The LD50 is in excess of 12,800 mg/kg by the oral route and in excess of 5,000 mg/kg intraperitoneally. Toxic signs were very slight and autopsy did not reveal lesions which could be attributed to the test substance. In the subacute and subchronic toxicities the characteristic effects of the diuretic activity were observed. In the subchronic toxicity study significant, although not dose-related, increases were observed in calcium, alkaline phosphatase, GPT and GOT levels. A decrease in liver-weight of the female animals with respect to controls was also noted. Histopathological studies did not reveal any changes which could be attributed to administration of the test substance. Besulpamide has demonstrated the typical effects of diuretics which are derivatives of 3-sulfamoyl-4-chlorobenzoic acid and in acute, subacute and subchronic tests by the oral route in the rat it has shown itself to be a substance of very low toxicity.

Administration, Oral↗
PubMed1987

Pharmacokinetics of besulpamide in rats and dogs.

The pharmacokinetics of besulpamide were studied in rats and its urinary excretion in rats and dogs. Kinetic characteristics were the same for both male and female rats according to a two-compartment open model. Biological half-life was 1-4 hr, absorption half-life was approximately 10 min and absolute bioavailability was nearly complete (F = 86.4%). In rats, urinary excretion of unchanged besulpamide was 30% after i.v. administration and 7% after oral administration, whereas in dogs after oral administration it was 54%. Values of the area under the plasma concentration-time curve in rats and percent of urinary excretion in dogs show that the kinetics of besulpamide are not dose-related when the drug is administered at doses of 10-50 mg/kg.

Animals↗
PubMed1987

Comparative light and electron microscopic observations of the lesive effects of two non-steroid anti-inflammatory drugs plus stress on rat gastric mucosa.

In this histological study it has been demonstrated that a single-dose administration of piroxicam, at the same dosage (4 mg/kg) as droxicam, has a greater erosive potential on the gastric mucosa of rats later exposed to cold stress. For this purpose the depth of all lesions found was evaluated by light microscopy and results showed that piroxicam produces lesions deeper and more numerous than those of droxicam. The transmission and scanning electron microscopic studies showed that the lesive mechanism was very similar for both drugs and that both local and general factors induced by these drugs and stress come into play. Absorption or penetration and uptake by the cells of the mucosa have been considered among the most important local factors in the development of erosive gastric lesions caused by non-steroid anti-inflammtaory drugs. As this absorption is in direct relation to the depth of the lesions, it can be considered from the results of this study that the lesser lesive effect of droxicam on the gastric mucosa when compared to that of piroxicam is due to the fact that, owing to its hydrolysis to piroxicam the absorption rate is slower.

Animals↗
PubMed1986

Pharmacological properties of droxicam, a new non-steroidal anti-inflammatory agent.

Droxicam showed high antiinflammatory activity in carrageenin-induced edema in rat. At doses of 0.25 and 0.5 mg/kg, droxicam was as active as piroxicam and more active than phenylbutazone given at 2.5 and 5 mg/kg. Against nystatin-induced edema, droxicam (ED50, p.o., 5, 6, 7, 8 h: 7.5, 12.9, 4.8, 8.4 mg/kg) was 4-11 times more active than phenylbutazone and more than 12 times more active than isoxicam. In cotton pellet-induced granuloma in rats, title compound was as active as suprofen. In U.V. light-induced erythema in guinea pigs, droxicam (ED50, p.o., 1, 2, 3, 4 h: 0.51, 0.94, 1.56, 4.88 mg/kg) was 5-9 times more active than phenylbutazone. At doses of 0.1, 0.33 and 1.0 mg/kg/day, droxicam, similar to piroxicam, showed good antiarthritic activity in rats injected with Mycobacterium butyricum against primary and secondary lesions. Droxicam demonstrated strong analgesic activity in protecting against writhings: induced by phenylbenzoquinone in mice: ED50: droxicam = 5.3, phenylbutazone = 61.5, acetylsalicylic acid = 90.7, dipyrone = 83.6, isoxicam = 88.3 mg/kg, p.o.; induced by acetylcholine bromide in mice: ED50: droxicam = 1.1, phenylbutazone = 32.1, acetylsalicylic acid = 32.2, isoxicam = 32.7 mg/kg, p.o.; induced by acetic acid in rat: ED50: droxicam = 0.94, acetylsalicylic acid = 8.72, isoxicam = 4.70 mg/kg, p.o. Antipyretic activity of title compound was demonstrated in rats with pyresis induced by brewer's yeast, being 4-13 times more active than dipyrone. In pyresis induced by Salmonella typhi, droxicam was more active than acetylsalicylic acid and 4-aminoantipyrine at all times and doses. In a study of protection against diarrhea induced by castor oil in rats, droxicam and piroxicam showed equal activity (ED50 = 0.081 and 0.079 mg/kg, p.o., respectively) and were 3.9 and 15.6 times more active than isoxicam and phenylbutazone, respectively. Droxicam significantly inhibited peritoneal capillary permeability in mice at a dose of 5 mg/kg, p.o., while isoxicam and phenylbutazone required 100 and 200 mg/kg, p.o., respectively. Droxicam did not exhibit uricosuric activity in rats. It did not show cardiovascular or respiratory effects in anesthetized cats, nor modify their response to administration of acetylcholine, norepinephrine and histamine. In the Irwin's test, droxicam did not alter rat behavior (80 mg/kg, i.p.) nor that of mice (160 mg/kg, p.o.). Induction of gastrointestinal injuries in rats by droxicam was 10 times less than by piroxicam (UD50: droxicam, 57 mg/kg, p.o.; piroxicam, 5.6 mg/kg, p.o.). The potentiation of gastric injuries induced by stress through cold in rats was also studied.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1986

Pharmacokinetics of droxicam in rat and dog.

A study was made of the oral absorption of droxicam in the rat. Five minutes after administration of 1 mg/kg droxicam, only piroxicam levels (its active metabolite) were detected at the portal vein and caudal vena cava. The transformation of droxicam into piroxicam takes place in the gastrointestional tract. A pharmacokinetic test to compare the plasma levels of piroxicam obtained in rat and dog was then made after oral administration of droxicam and piroxicam. In both animal species the oral absorption of droxicam was not dose-related. However, droxicam given at therapeutic doses (0.2-0.3 mg/kg) was bioequivalent to piroxicam. The elimination half-life of piroxicam after oral administration of droxicam and piroxicam was 8 +/- 2 h in the male rat, 27 +/- 12 h in the female rat and 38 +/- 18 h in the male dog, whilst the half-life of oral absorption of piroxicam did not vary from one animal species to another. In the case of droxicam, however, this value was higher than that after oral administration of piroxicam, as a consequence of the process of transformation of droxicam into piroxicam. It is concluded that droxicam is a prodrug of piroxicam with a slower rate of absorption, but with the same bioavailability within the range of therapeutic doses.

Animals↗
PubMed1977

Recirculating, suppressor T cells in transplantation tolerance.

An adoptive transfer system was used to examine the capacity of cellular inocula from rats fully tolerant of Ag-B antigens to transfer tolerance to irradiated recipients. Permanent tolerance in these irradiated recipients involved specific suppression of the regenerating immune response. Cells obtained from tissues rich in recirculating lymphocytes were the most effective suppressors. Highly purified inocula of T cells from tolerant donors were potent suppressors in irradiated hosts, but were not capable of direct suppression of peripheral antigen-sensitive T cells.. The role of the thymus in maintaining the complement of recirculating suppressor T cells in tolerant animals was examined after adult thymectomy. Thymectomized tolerant rats did not reject their tolerated grafts, and the longevity of the suppression in tolerant rats was confirmed by showing that adoptive transfer of cells from thymectomized tolerant donors was effective in suppressing irradiated recipients up to 180 days after thymectomy. Cellular inocula from these donors appeared to lose their suppressor function marginally faster than they lost effector function (as measured by their capacity to mediate rejection of third party control grafts). Thymectomy made tolerant rats more vulnerable to the termination of tolerance by challenge with normal cells. Transplantation tolerance is maintained in adult rats by long-lived rapidly recirculating suppressor T cells. The target for the suppressor action of these cells is probably the precursor of alloantigen-sensitive lymphocytes, and the effect of suppression may be deletion or inactivation of the relevant clone of these cells.

Animals↗
PubMedDate not supplied

Single and multiple dose pharmacokinetics of sultosilic acid in humans.

Single and multiple oral doses of Sultosilic acid were administered to four healthy volunteers. Plasma and Urine levels of unchanged Sultosilic acid (I) and its major metabolite (II) were measured. I and II were extracted from plasma and urine with chloroform after ion-pair formation and analysed by HPLC using a U.V. detector. Sultosilic acid was well absorbed and the plasma concentrations declined bioexponentially with mean half-lives of 1.9 h (fast disappearance phase, alpha) and 17.6 h (slow disappearance phase, beta) for I and 2.0 h (alpha) and 17.0 h (beta) for II. Renal clearances of I and II were 50.5 ml/min and 74.8 ml/min respectively. 60% of the administered dose was excreted in urine, 28% unchanged (I), the remainder as carboxylic derivative (II). Minimal drug concentrations in plasma in the range of those detected in steady state conditions were already found within the first day of treatment.

Adult↗
PubMedDate not supplied

Single and multiple dose pharmacokinetics of a new NSAID (droxicam) in healthy volunteers.

The pharmacokinetics of droxicam, both as a single 10 mg dose and as a multidose regimen of 10 mg/day for 20 consecutive days, have been studied in healthy volunteers. The study was performed in two separate groups of volunteers. Following a single dose the Cmax was 0.82 +/- 0.15 micrograms/ml, the Tmax was achieved at 6.1 +/- 3.5 h, the elimination half life was 65.7 +/- 17.6 h, the Clt/F was 2.04 +/- 0.53 ml/min, the Vd/F was 11.0 +/- 1.7 l and the AUC infinity was 86.9 +/- 24.6 mugh/ml, which was similar to results reported in other study from piroxicam (10 mg). Following multiple doses the Cmed(ss) was 2.06 +/- 0.42 microgram/ml, the Tmax(ss) was 8.2 +/- 6.0 h, the elimination half life was 41.4 +/- 12.4 h, the Clt/F was 3.30 +/- 0.63 ml/min, the Vd/F was 11.8 +/- 4.3 l and the AUC infinity was 52.4 +/- 11.3 mugh/ml. The differences encountered between single and multiple dose administration in elimination kinetics are due to the wide interpersonal variation described for the elimination half life of piroxicam. It may be concluded from these results that absorption, elimination and bioavailability kinetics of droxicam are independent of the administered dose.

Administration, Oral↗
PubMedDate not supplied

Cross-over study of the bioavailability of a new NSAID (droxicam) versus piroxicam in healthy volunteers following single and multiple dose administration.

Droxicam is a new anti-inflammatory drug which is a pro-drug of piroxicam and possesses delayed absorption kinetics. In this study, the comparative bioavailability of the two compounds was investigated. The study was performed following a cross-over design with single (20 mg) and multiple (20 mg/day for 30 consecutive days) administration in 25 healthy volunteers. The peak plasma concentrations of piroxicam, obtained following administration of droxicam, were lower than those calculated for administration of piroxicam, and the time taken to reach these peak concentrations was increased by approximately 5-7 h. There was no significant difference in either the elimination kinetics of piroxicam or the AUC values found following administration of the two products. Bioavailability of droxicam is equal to that of piroxicam, with a slower rate of absorption.

Administration, Oral↗
PubMedDate not supplied

A direct, highly sensitive fluorometric assay for a microsomal cytochrome P450-mediated O-demethylation using a novel coumarin analog as substrate.

A highly sensitive fluorometric assay for the determination of monooxygenase activity in liver microsomes is described. The assay is based on the use of 3-chloro-7-methoxy-4-methylcoumarin which is demethylated to 3-chloro-7-hydroxy-4-methylcoumarin. The rate of formation of 3-chloro-7-hydroxy-4-methylcoumarin was recorded as an increase of fluorescence (lambdaA = 380 nm, lambdaF = 480 nm) with time. When 3-chloro-7-methoxy-4-methylcoumarin was incubated in the presence of MgCl2 and NADPH with rat liver microsomes, a continuous increase of the fluorescence could be measured. The reaction proceeded linearly for about 10 min and at least up to a concentration of 0.1 mg/ml of microsomal protein. Besides 3-chloro-7-hydroxy-4-methylcoumarin a hydroxylated derivative of the substrate was formed as a second metabolite during the incubation. Using an excitation wavelength of 380 nm and a fluorescence/emission wavelength of 480 nm, the fluorescence of this substance (lambdaA = 338 nm, lambdaF = 422 nm) amounted only to about 1% of the fluorescence of the main product. The use of 3-chloro-7-methoxy-4-methylcoumarin as substrate enables the fluorometric determination of the O-dealkylation activity of a cytochrome P450-dependent monooxygenase system in rat liver which is inducible by phenobarbital but not by 3-methylcholanthrene.

Animals↗