A software for quantification of vessel density in glaucoma: An OCT-Angiography study.

PURPOSE: To assess the capillary vessel density in the peripapillary region of glaucoma patients in comparison to controls using automated software. METHODS: We performed an observational, cross-sectional case-control study with 72 eyes of glaucoma patients (with strict selection criteria) and 30 age-matched healthy controls. We used an optical coherence tomography angiography device (Triton, Topcon) with scans of 4.5×4.5mm centered on the optic nerve head, excluding images of poor quality. Since this device does not quantify vessel density, we wrote software (with Visual Studio©) that allowed us to remove large blood vessels and quantify the capillary density in the peripapillary region. We tested the ability of OCT-A to differentiate glaucoma from controls using the receiver operating characteristic curve (ROC). We also verified whether VD was correlated with visual field mean deviation. RESULTS: VD was significantly lower in glaucoma than in controls, notably the whole-image VD of 72.45±7.45% in glaucoma and 77.87±3.77% in controls (P<0.001). VD values were correlated with visual fields (Spearman correlation of 0.33; P 0.0017). ROC was moderate (color VD of 0.629±0.143), but better than that of the visual field (0.229±0.077) or the retinal nerve fiber layer thickness assessed by OCT (0.326±0.064). CONCLUSIONS: This software is useful for quantifying vessel density at the optic disc, peripapillary and capillary levels and for documenting glaucomatous changes in vascularization. OCT-A might be useful in diagnosis of glaucoma.

[Is the clinical profile of women treated with tibolone similar to that of women receiving a classical estrogen-progestogen therapy? Data from a nationwide survey in France]. / Le profil clinique des femmes qui utilisent la tibolone est-il le même que celui des femmes utilisant un traitement hormonal classique ? Données d'une enquête nationale en France.

OBJECTIVES: To compare the pre-existing risk profiles for breast or endometrial cancer of menopaused women receiving tibolone or another hormone replacement therapy in France, with a view to examining the possibility of biases of selection of patients and of detection of these cancers in the Million Women Study. PATIENTS AND METHODS: Nationwide survey conducted in France among a representative sample of 153 gynaecologists. The particulars of the last two consulting menopaused women treated with tibolone (N = 306) and of the last two treated with a classical estrogen-progestogen therapy (N = 306) were collated then analysed. RESULTS: Compared to those treated with a classical estrogen-progestogen therapy, more women receiving tibolone were aged 60 years or over (40 vs 31%; P < 0.01). More of them had risk factors for breast cancer (history of mastodynia or mastopathy, elevated mammographic breast density) (6 vs 50%; P < 0.01). More of them had a history of uterine investigation or exploration or of irregular bleeding (61 vs 53% of women with a history of irregular bleeding; P < 0.05). Overall, 84% of women treated with tibolone had at least one risk factor for breast or endometrial cancer vs 75% of those receiving a classical estrogen-progestogen therapy (P < 0.01). DISCUSSION AND CONCLUSION: Owing to its specific properties, tibolone is generally prescribed to women with a higher risk profile for breast or endometrial cancer than those receiving a classical estrogen-progestogen therapy, which may entail patient selection and cancer detection biases in non-randomised, open-label, observational studies.

Bioequivalence study of alpha-dihydroergocryptine: utility of metabolite evaluation.

Metabolite assessment is an open question in bioequivalence studies. In situations of low absorption, high first-pass metabolism, and intrasubject variability, metabolites may reflect absorption more adequately than the parent drug, and their determination may help decision-making in bioequivalence issues. Treating alpha-dihydroergocryptine (DHECT) as a model, we used both unchanged DHECT and a pool of DHECT metabolites to evaluate the bioequivalence of 2 oral DHECT formulations (reference-R and test-T) in 12 subjects. DHECT and its metabolites were immunoassayed. There was no difference between the 2 formulations in terms of the AUC0-infinity (area under the curve) values determined from unchanged DHECT or DHECT with metabolites profiles: 572 +/- 490 pg/ml.h (R) and 442 +/- 276 pg/ml.h (T) for unchanged DHECT, and 7,141 +/- 2,936 pg/ml.h (R) and 6,941 +/- 1,462 pg/ml.h (R) for DHECT with metabolites. Confidence intervals were within the ranges 0.8-1.25 (AUC0-infinity) and 0.7-1.43 (Cmax) for DHECT with metabolites but not for unchanged DHECT. This study describes a particular case where only measurements on the basis of the metabolites can justify the assumption of bioequivalence.

The metabolic fate of 14C-ximoprofen in rats, baboons and humans.

1. The metabolic fate of 14C-ximoprofen was compared in rat (2 mg/kg), baboon (2 mg/kg) and human (approx. 0.4 mg/kg). An oral dose was well absorbed in all three species as indicated by urinary excretion of 80%, 86% and 94% dose respectively in 5 days: excreted in the faeces were 14%, 2% and 2% dose respectively. 2. Total 14C in plasma reached peak concentrations at 1-1.5 h in humans and earlier in animals. In humans, plasma 14C was initially associated mainly with unchanged drug which declined with a half-life of about 2 h (plasma 14C t1/2 about 8 h; cf. about 6 h in animals). 3. Tissue 14C concentrations in rats were generally similar to those in baboons at 1 h after dosing, decreasing substantially at later times. The distribution of 14C was consistent with that of a compound readily eliminated. 4. The major biotransformation products of ximoprofen were formed by hydrolysis to the keto-analogue followed by reduction to the hydroxy-analogue and conjugation of these two compounds. The same major metabolites were detected in urine of rat, baboon and humans but there was (a) complete biotransformation of ximoprofen in the rat, (b) an apparent difference in the nature of the conjugated component(s) in rat urine and those in baboon and human urine, (c) only one hydroxy-analogue detected in human urine but two such compounds in animal urine as indicated by mass spectrometry. 5. In human plasma at peak concentrations, the relative importance of circulating components was ximoprofen greater than keto-analogue greater than hydroxy-analogue, whereas in the plasma of the animal species this order was reversed, consistent with the more extensive biotransformation of ximoprofen observed in rat or baboon.

The effects of dihydroergocryptine on the neurological and enzyme disorders induced by cerebral ischaemia in rats.

Ergot alkaloids are commonly used as cerebroprotective drugs. Their efficacy has been demonstrated experimentally in animals submitted to acute cerebral anoxia or ischaemia, at dose levels hugely superior to dose levels usually administered in humans. In the present experiments, dihydroergocryptine (DHEC), a constituent of dihydroergotoxine (DHET), was administered at doses closely related to human doses, preventively (in experiments where animals survived only for a short while after ischaemic insult) or curatively, and its efficacy tested through refined neurological and biochemical evaluation of experimental cerebral ischaemia sequelae. DHEC was administered orally (30 micrograms or 150 micrograms/kg body weight (bwt) twice daily) for 3 days, following transient cerebral ischaemia induced by a 60-min carotid occlusion plus sodium nitroprusside (1.1 mg/rat s.c.) injection, or, in a second experiment, prophylactically (60 micrograms or 300 micrograms/kg bwt/day) for 4 days prior to multiple cerebral infarct induced by sodium arachidonate injection into the left internal carotid artery. The neurological sequelae were evaluated by the Irwin visual placing response or by a battery of behavioural tests. Na-K-ATPase enzyme activity in cerebral homogenates was measured; decreases in this enzyme activity are considered to reflect the neuronal membrane consequences of the neurocell energetic metabolism alterations caused by cerebral ischaemia. Low dose oral DHEC treatment prevented the behavioural abnormalities and memory impairment arising after transient cerebral ischaemia and there was a marked trend in improving the behavioural abnormalities observed in animals submitted to massive cerebral infarction, in spite of the model severity. DHEC prevented reduction in cerebral Na-K-ATPase activity after cerebral multiinfarction. These effects of DHEC were observed with doses and administration route close to the usual therapeutic regimen.

Behavioural and biochemical studies on 6-methylamino-4,5,6,7-tetrahydrobenzothiazole (14.839JL), a new potent dopaminergic agonist.

6-Methylamino-4,5,6,7-tetrahydrobenzothiazole monochlorhydrate (14.839JL) is a new, potent dopaminergic agonist. The stereotypy induced by this drug was greater than that induced by an equivalent dose of apomorphine, was antagonized by pretreatment with sulpiride and counteracted the hypomotility induced by reserpine. Striatal levels of the dopamine metabolites homovanillic acid (HVA), dihydroxyphenylacetic acid (DOPAC) and 3-methoxytyramine (3-MT) were significantly lowered for up to 4-6 h by doses from 0.05 to 1 mg/kg. The drug was also very effective in lowering prolactine secretion. 14.839JL displaced [3H]N-n-propylnorapomorphine [3H]NPA from striatal binding sites with an IC50 similar to dopamine (DA). Conversely, the ability of 14.839JL to displace 3H spiperone from its binding sites was 100 and 10 times lower than that of haloperidol and sulpiride, and similar to that of SCH 23390. Differently from the latter, however, 14.839JL did not modify adenylate cyclase activity. All these data suggest that 14.839JL is a new, potent, long-lasting direct DA agonist, probably acting on D2 receptors.

Antiarrhythmic and hemodynamic effects of prifuroline.

The antiarrhythmic activity of 4-(2-benzofuranyl)-2-(dimethylamino)-1-pyrroline (prifuroline) has been evaluated in rats, guinea-pigs and dogs. Prifuroline dose-dependently antagonizes the arrhythmogenic action of aconitine in rats, when administered either intravenously (5, 10 or 20 mg/kg) or intraduodenally (10, 20 or 50 mg/kg); it exhibits effectiveness by the digestive route at doses only twice as greater as the active i.v. doses: its intravenous anti-aconitine activity is comparable to that of disopyramide, and superior to that of quinidine; lidocaine is inactive in this test. Prifuroline also diminishes ventricular susceptibility to electrical stimulation in open-chest rats; its effect is comparable to that of disopyramide and amiodarone at the same dose levels; quinidine and lidocaine are less effective. Only prifuroline and propranolol were able to antagonize ouabain toxicity in guinea-pigs, quinidine showing only borderline activity, and disopyramide, lidocaine and verapamil being ineffective. In a model of arrhythmias induced by anoxic stress in rats, all the tested compounds were found active, with prifuroline and disopyramide providing complete protection at high dose levels. The arrhythmias induced in dogs by coronary artery ligation were markedly antagonized by prifuroline after doses of 5 and 10 mg/kg i.v. or 30 mg/kg intraduodenally; the duration of its antiarrhythmic activity in this model of arrhythmias in conscious dogs was much longer after intraduodenal than after i.v. administration. Prifuroline was also able to restore sinus rhythm in guinea-pigs after intracardiac conduction blockade with acetylcholine, although being devoid of anticholinergic activity. It also diminishes the maximal frequency of guinea-pig atria electrically stimulated in viro (EC25 = 5 X 10(-6) g/ml).(ABSTRACT TRUNCATED AT 250 WORDS)

Immediate and prolonged effects of dihydroergocryptine after experimental vascular microsurgery.

An animal model of limb replantation has been utilized in order to evaluate the effects of dihydroergocryptine (DHEC, 0.1 mg/kg I.V.) on arterial and peripheral tissular blood flows after reperfusion. DHEC is a partial agonist of adrenergic receptors and is therefore liable to exert an action on arteriovenous shunts that remain abnormally opened after ischaemia. DHEC showed important efficacy in this model, increasing, in low doses, blood flow in sutured artery and peripheral tissue.