Biomedical subjects

M J Winn

Publications and source records attributed to M J Winn.

26 records · Page 2Linked to original sources

PubMed1990

Gonadal influence on the metabolism and haematological toxicity of dapsone in the rat.

Administration of dapsone (33 mg kg-1) to intact rats resulted in a marked elevation of methaemoglobin levels in male (435.0 +/- 105.2% met Hb h) compared with female rats (59.0 +/- 17.2% met Hb h). However, the clearance of dapsone was significantly faster in males compared with females. Female rats showed very low levels of methaemoglobin which were accompanied by significantly higher blood concentrations of parent drug. Clearance of dapsone in castrated animals was less than one-third of that of the intact sham-operated males (252.2 +/- 67.2 vs 81.4 +/- 33.0 mL h-1). Likewise, clearance of dapsone in ovarectomized rats was approximately half that of intact females. There were no significant differences in the disposition of dapsone between the ovarectomized (AUC 431.0 +/- 31.7 micrograms h mL-1; t1/2, 15.62 +/- 1.8 h) and castrated (AUC, 450.6 +/- 150.9 micrograms h mL-1; t1/2, 17.6 +/- 7.9 h) animals. However, methaemoglobin levels in castrated males, although less than a third of those of intact males, significantly exceeded those of ovarectomized animals. There was no significant difference between the four groups of animals with respect to red cell sensitivity to the methaemoglobin-forming capacity of the toxic metabolite of dapsone, the hydroxylamine. Metabolic conversion of dapsone to the hydroxylamine in the presence of NADPH was 7.6 +/- 1.5% for liver microsomes from intact males and was significantly greater (P less than 0.05) than the corresponding values for liver microsomes from castrated rats (5.3 +/- 0.59%). Conversion of dapsone to dapsone-NOH by liver microsomes from intact females and ovarectomized animals was below 1% in both cases.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylation↗

PubMed1989

The disposition of the enantiomers of warfarin following chronic administration to rats: relationship to anticoagulant response.

A model of chronic anticoagulation has been used to investigate the whole liver and subcellular disposition of the individual enantiomers of warfarin in the Wistar rat in relation to anticoagulant response. Consistent pharmacodynamic responses were achieved by dosing daily with R-warfarin (0.4, or 0.8 mg kg-1 day-1 i.p.) or S-warfarin (0.1 mg kg-1 day-1 i.p.). After the administration of increasing doses of R-warfarin, prothrombin times were dose-dependent (16.3 +/- 0.5 s, 0.1 mg kg-1 day-1; 21.6 +/- 1.7 s, 0.4 mg kg-1 day-1; 55.1 +/- 9.0 s, 0.8 mg kg-1 day-1; results all measured 24 h after the final dose). Increasing doses of R-warfarin also produced increases in plasma, whole liver, and cytosolic concentrations of warfarin. However, there were no significant differences between the microsomal concentrations of R-warfarin in the three groups. The dose of S-warfarin required to produce a consistent and significant increase in the prothrombin time was four-fold lower than the dose of R-warfarin required to cause a similar effect. Plasma concentrations of S-warfarin were not significantly different from those seen after 0.4 mg kg-1 day-1 R-warfarin. Whole liver and cytosolic concentrations of the S-enantiomer were lower than those observed after a dose of 0.4 mg kg-1 day-1 R-warfarin. However, consistent with microsomal concentrations following increasing doses of R-warfarin, there was no significant difference between microsomal concentrations of R(+)- and S(-)-warfarin.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1989

The bioavailability of a mixed micellar preparation of vitamin K1, and its procoagulant effect in anticoagulated rabbits.

We have investigated the pharmacokinetics and procoagulant activity of a new, mixed-micellar preparation of vitamin K1 (MM-K) in male New Zealand White rabbits. Oral administration of MM-K alone caused a significant (P less than 0.01) increase in the plasma concentrations of vitamin K1 as measured by normal-phase high-performance liquid chromatography (HPLC). Maximum plasma concentrations of vitamin K1 (450 ng mL-1, range 133-824 ng mL-1) were recorded at 3.3 h (range 3-5 h), and were significantly (P less than 0.05) greater than those seen after administration of an existing polyethoxylated castor oil preparation (PE-K; Konakion), which were 260 ng mL-1, range 198-390 ng mL-1 (tmax 0.8 h, range 0.4-1.2 h). AUC after MM-K (4.6 micrograms mL-1 h-1, range 2.1-6.3 micrograms ML-1 h-1) was also significantly (P less than 0.05) greater than after PE-K (1.6 micrograms mL-1 h-1, range 1.0-2.1 micrograms ML-1 h-1). However, the bioavailability of vitamin K1 after administration of MM-K was poor (9.4%), and there was considerable intra-individual variability between the concentrations of vitamin K1 recorded in the plasma samples. Both preparations of vitamin K1 stimulated clotting factor synthesis in rabbits anticoagulated with the potent and long-acting coumarin, brodifacoum. Maximum stimulation of clotting factor synthesis by vitamin K1 after MM-K was 87%, range 44-124% (%PCA). The maximum was seen later (tmax 12 h) than after PE-K (PCA 82%, range 47-125%; tmax 5 h). However, there was considerable intra-individual variability in response to both MM-K and PE-K.(ABSTRACT TRUNCATED AT 250 WORDS)

4-Hydroxycoumarins↗

PubMed1989

Plasma vitamin K1 concentrations in cystic fibrosis.

Plasma concentrations of vitamin K1 were similar in 37 patients with cystic fibrosis (median 46 ng/l) and 16 controls (49 ng/l). The plasma concentrations were lower than those previously described in adults, but higher than in neonates. There was no association between an increase in prothrombin time and vitamin K1 plasma concentration.

Adolescent↗

PubMed1988

An investigation of the pharmacological response to vitamin K1 in the rabbit.

1. The relationship between pharmacological response and disposition of a dose of vitamin K1 (10 mgkg-1, i.v.) in normal rabbits and in rabbits treated with the coumarin anticoagulant brodifacoum, has been studied. 2. High performance liquid chromatography (h.p.l.c.) with electrochemical detection (EC) was used to determine concentrations of vitamin K1 in plasma, whole liver homogenate, and liver microsomes. 3. After intravenous administration of vitamin K1, plasma concentrations of the vitamin declined in a tri-exponential fashion. There were no differences between the two groups over the first 24 h of the experiment. However, between 24 h and the end of the study, plasma concentrations of vitamin K1 in the presence of brodifacoum were significantly (P less than or equal to 0.05) below those of vehicle-treated rabbits. 4. Seventy-two hours after administration of vitamin K1, plasma concentrations of the vitamin were not different from normal. 5. Three hours after administration of vitamin K1, the concentrations of the vitamin in whole liver were 46.6 +/- 4.3 micrograms g-1 in the presence of brodifacoum, and 32.8 +/- 6.4 micrograms g-1 in the absence of brodifacoum; and were significantly (P less than or equal to 0.05) greater than normal (127.7 +/- 44.3 ng g-1). Likewise, microsomal concentrations of vitamin K1 (4.00 +/- 2.38 micrograms mg-1 protein, and 2.65 +/- 1.01 micrograms mg-1 protein, in the presence and absence of brodifacoum, respectively) were significantly (P less than or equal to 0.01) greater than normal (16.0 +/- 3.5 ng mg-1 protein). 6 In conclusion, there appears to be no direct effect of coumarins on clearance of vitamin K1 from either plasma or liver; the need for large doses of vitamin K1 during coumarin poisoning is due to a greatly increased requirement for the vitamin.

4-Hydroxycoumarins↗

PubMed1987

The effects of 17 beta-oestradiol or testosterone on the response to S-warfarin in castrated male rats.

The effects of castration alone, or followed by administration of 17 beta-oestradiol or testosterone, on the action of S-warfarin have been investigated in male Wistar rats castrated at 4 weeks of age. Six to 10 weeks later, blood samples were taken before, and at 24 h and 7 days after onset of administration of either 17 beta-oestradiol (50 to 500 micrograms kg-1 day-1 i.p.), testosterone (500 micrograms kg-1 day-1 i.p.), or vehicle (polyethylene glycol 200 i.p.). On the seventh day of these interventions, S-warfarin (6.3 mg kg-1 i.p.) was given; prothrombin complex activity (PCA) was then measured over the next 72 h. In addition, a group of sham-operated rats were given S-warfarin, alone. The control prothrombin times were lower in castrated rats (17.9 +/- 0.4 s) than in sham-operated rats (19.1 +/- 0.6 s). Warfarin, over the first 24 h of its administration, caused a significant (P less than or equal to 0.01) fall in PCA in each group of rats, the fall in PCA in castrated rats pretreated with vehicle being significantly (P less than or equal to 0.05) less than that seen in the sham-operated rats. The fall was the same in castrated rats given vehicle or those given 17 beta-oestradiol. In contrast, warfarin caused a greater fall in PCA in the presence of testosterone than in the other groups of castrated rats.

Animals↗

PubMed1987

An investigation of sex-linked differences to the toxic and to the pharmacological actions of difenacoum: studies in mice and rats.

We have investigated the actions of the coumarin anticoagulant, difenacoum, in male and female rats and mice. In our first experiment difenacoum (0.5 mg kg-1) killed 50% of male mice within 9 days of its administration, whereas no female mice died during this study. In a second group of experiments, the anticoagulant effect of difenacoum in male and female rats was determined. Under resting conditions, the prothrombin complex activities (PCA) of male and female rats were not significantly different. Over the first 24 h after administration of difenacoum (0.4 mg kg-1 i.p.), there was a monoexponential fall in PCA in both sexes. However, 6, 12 and 24 h after difenacoum, the PCA in male rats was significantly (P less than 0.05) lower than in female rats. PCA began to recover over the subsequent 48 h in both sexes, during which time there was marked variability in recovery in female rats. The difference between the onset of action of difenacoum in male and female rats did not appear to be due to a greater rate of elimination of the drug in female rats, since the plasma concentrations of difenacoum 24 h after its administration were the same in both sexes. The concentration of vitamin K1 in rat liver was also investigated. Vitamin K1 levels were 35.1 +/- 18.6 ng (g liver)-1 (male), and 29.4 +/- 5.4 ng (g liver)-1 (females) in control rats, but 24 h after difenacoum, vitamin K1 levels were either very low, or undetectable in all rats.(ABSTRACT TRUNCATED AT 250 WORDS)

4-Hydroxycoumarins↗

PubMed1985

Functional involvement of vasopressin in the maintenance of systemic arterial blood pressures after phenoxybenzamine or phentolamine administration: studies in Long-Evans and Brattleboro rats.

The alpha adrenoceptor antagonists phenoxybenzamine and phentolamine are reported to have opposite effects on vasopressin release, the former inhibiting and the latter enhancing it. In this study we have assessed the functional involvement of vasopressin in the maintenance of blood pressure in conscious rats after administration of either phenoxybenzamine or phentolamine. In normal (Long-Evans) rats, phenoxybenzamine caused a small fall in arterial blood pressure, whereas phentolamine initially caused a profound hypotension which was followed by a fluctuating recovery back to normotensive levels. Similar effects were seen in rats deficient in hypothalamic vasopressin (Brattleboro strain). Administration of an antagonist of the cardiovascular actions of vasopressin [1-(beta-mercapto-beta, beta-cyclopentamethylenepropionic acid)-8-D-arginine vasopressin] in the presence of either alpha adrenoceptor antagonist alone was without effect in Long-Evans or Brattleboro rats, but, under these conditions, subsequent administration of captopril caused a profound and sustained hypotension in both strains. Administration of captopril in the presence of either alpha adrenoceptor antagonist alone caused a prompt fall in blood pressure which was sustained for the duration of the experiment in the Brattleboro rats. However, under these conditions, the blood pressure of the Long-Evans rats showed some recovery over the subsequent 45 min; this recovery was antagonized by [1-(beta-mercapto-beta, beta-cyclopentamethylenepropionic acid)-8-D-argine vasopressin]. It is concluded that after alpha adrenoceptor antagonism with either phenoxybenzamine or phentolamine, the renin-angiotensin system exerts a major pressor influence. However, after captopril administration in the presence of phenoxybenzamine or phentolamine, vasopressin contributes to the maintenance of arterial blood pressure in Long-Evans rats; the magnitude of this contribution is similar irrespective of the alpha adrenoceptor antagonist used.

Adrenergic alpha-Agonists↗