Flupirtine attenuates sodium nitroprusside-induced damage to retinal photoreceptors, in situ.

Flupirtine has been shown to function as a neuroprotectant and is presently used in man to treat a number of conditions. The aim of this study was to investigate the specific antioxidant properties of flupirtine in relation to oxidant-induced damage to retinal photoreceptors. Initial in vitro studies on brain membranes showed that flupirtine was approximately 20 times more potent than trolox (vitamin E analogue) and 8 times more potent than metipranolol at attenuating lipid peroxidation caused by the nitric oxide donor, sodium nitroprusside (SNP). Subsequent immunohistochemical studies revealed that following an intraocular injection of SNP, retinal photoreceptors are the only retinal cell types that appear to be clearly affected. This was supported by electroretinogram (ERG) recordings which showed both the a- and b-wave amplitudes to be significantly reduced. Western blotting techniques showed that SNP caused a significant decrease in photoreceptor-specific markers (RET-P1, rhodopsin kinase), an increase in cleaved caspase-3, Bcl-2, and cleaved PARP proteins that are associated with apoptosis and no change in the ganglion cell specific marker, neurofilament (NF-L). This was supported by RT-PCR data where rhodopsin (photoreceptor specific) mRNA was reduced while Thy-1 and NF-L (ganglion cell specific) mRNAs were unaffected. In addition SNP caused an elevation of glial cell response mRNAs primarily associated with Müller cells (GFAP, CNTF, bFGF) as well as caspase-3 and Bcl-2. Importantly, when flupirtine was co-injected, the effects to the retina caused by SNP on retinal proteins and mRNAs were in most cases significantly blunted. The conclusion reached from this study is that flupirtine is a powerful antioxidant and when injected into the eye with SNP attenuates the detrimental influence of SNP to retinal photoreceptors. Since oxidative stress has been implicated in retinal diseases like age-related macular degeneration (AMD) this study provides "proof of principle" for the idea that flupirtine may help individuals suffering from such retinal diseases.

Conjunctival keratinisation, an abnormal reaction to an ocular beta-blocker.

Conjunctival leucoplakia was induced by the local beta-blocker metipranolol in one case. Withdrawal of the drug and application of all-trans retinoic acid ointment resulted in resolving of the keratinisation. A striking pharmacological resemblance is discovered between metipranolol and practolol. Metipranolol seems to be a less toxic phenol derivative of practolol. Nevertheless, it seems able to act as antigen.

[Pharmacokinetics of the beta-receptor blocker metipranolol in patients with liver cirrhosis (author's transl)]. / Pharmakokinetik des beta-Rezeptorenblockers Metipranolol bei Patienten mit Leberzirrhose.

The pharmacokinetics after oral administration of the beta-blocker metipranolol (Disorat) were investigated in 20 patients with liver cirrhosis, 8 of them with portocaval shunt. Twenty healthy persons were used as controls. Kinetic data in patients were not notably different from the normal group, in particular there was no significant difference in the mean serum concentration over 24 hours. In patients with advanced disease the only noteworthy difference was an increase of the linear rate of increase of serum concentrations. Maximal serum concentrations were found with a median of only 0,37 and 0,59 hours after intake, and in controls 0,76 hours after intake. It appears that metipranolol has no hepatic first-pass-effect and that its total clearance remains largely uninfluenced even in severe liver damage. A reduction of dosage in these diseases is thus not required from the pharmacological point of view.

Pharmacokinetics of metipranolol in normal man.

The pharmacokinetic parameters of deacetyl metipranolol were determined after i.v. infusion of increasing doses (6-25mg) in 17 normal volunteers. In a second cross-over trial, deacetyl metipranolol 10 and 20mg were infused in a further 10 subjects, and in a third trial another 20 volunteers received metipranolol 40mg orally. Metipranolol is very rapidly and completely deacetylated in man, so all pharmacokinetic data refer to deacetyl metipranolol, which was assayed by gas chromatography-mass spectrometry. The pharmacokinetic analysis was performed using a recently developed model, using a volume of distribution which is variable with time. The following data were obtained after oral administration: (mean values); lag-time 7.3 min; tmax 50 min, invasion half-life 6.3 min; elimination half-life 3 h; urinary excretion of unchanged drug approximately 4% of the dose. The experiments with infusion of increasing doses, as well as the cross-over study with 10 and 20mg i.v., showed dose-linearity of the kinetics. The respective mean half-lives of elimination were 2.6, 2.9 and 2.8 h. The mean total, renal and extra-renal clearances amounted to 1237 ml/min, 149 ml/min and 1068 ml/min, respectively. The distribution coefficient was 3.5 l/kg, and protein binding amounted to 70% within the range of therapeutic concentrations. Absolute bioavailability was found to be approximately 50% by several different evaluation procedures. Thus, the pharmacokinetic profile of metipranolol shares features of both the lipophilic and the hydrophilic groups of beta-blocking agents.