The effect of laquinimod, a novel immuno-modulator in development to treat Huntington disease, on the pharmacokinetics of ethinylestradiol and levonorgestrel in healthy young women.

PURPOSE: Laquinimod is an orally dosed immuno-modulator currently under development for Huntington's disease (HD). Preclinical findings suggest potential teratogenicity of laquinimod, thus the reproductive ability of females with HD treated with laquinimod needs to be closely managed. Because combined oral contraceptives (COC) are often used in this context, the pharmacokinetics of COC containing ethinylestradiol (EE) and levonorgestrel (LNG) in combination with laquinimod (0.6 mg/day) was evaluated. METHODS: In this randomized, phase-1 single-center, double-blind, placebo-controlled, 2-way crossover drug-drug interaction (DDI) study in 48 healthy premenopausal women, COC were administered in a 28-day regimen of 21 days followed by 7 pill-free days for 4 cycles and laquinimod or placebo was administered for 28 days in cycle 1 and cycle 3 starting 7 days prior to COC administration. Blood samples for pharmacokinetic profiling of laquinimod, EE and LNG were collected on day 21 and day 22 of Cycles 1 and 3 pre-dose and multiple times post-dose. RESULTS: The ratio of geometric means and 90% confidence intervals for AUC0-24 and Cmax of EE and LNG with and without laquinimod were all within the bioequivalence range (80 to 125%). Laquinimod pharmacokinetics was consistent with those observed in previous studies. The adverse event profile was in line with the current knowledge on the safety profile of both drugs, with headache as the most frequently reported treatment-related adverse event. CONCLUSION: The combination of COC and laquinimod treatment was found to be safe, tolerable, and devoid of any noticeable pharmacokinetic interaction.

Rasagiline prevents neurodegeneration in thiamine deficient rats-a longitudinal MRI study.

Neuroprotection is a therapeutic approach for the management of neurodegenerative diseases. Experimental thiamine deficiency (TD) in rats provides a model for selective neurodegeneration accompanied by chronic oxidative deficits. Rats exhibit neurological and cognitive impairments, which can be partially reversed by thiamine administration, enabling the study of mechanisms of neurodegeneration as well as neuroprotection. In this magnetic resonance (MR) study we used various techniques to characterize the neuroprotective effects of rasagiline, a selective MAO-B inhibitor. TD was induced by a thiamine-deficient diet and daily injections of the central thiamine antagonist, pyrithiamine. Daily injections of either saline or rasagiline (3mg/kg) were also administered to untreated-TD rats and rasagiline-treated TD rats respectively. With the appearance of neurological symptoms, all injections were terminated and thiamine was restored. MRI scans were performed before induction of TD (control values), on days 10, 12 (before symptoms appear), 14 (symptomatic stage) and during the recuperation period. Both groups were assessed using in-vivo serial T2-weighted imaging and diffusion tensor imaging (DTI), from which apparent diffusion coefficient (ADC) and fractional anisotropy (FA) maps were calculated. A histopathological evaluation was correlated with the MRI analysis. Thalamic hyperintensities were significantly smaller and less severe in the rasagiline-treated TD rats. Enlargement of the lateral ventricles was significantly less pronounced in the rasagiline-treated TD group. FA values of the untreated-TD group decreased significantly in the thalamic on days 12 and 14 and in the corpus callosum on day 14. These results demonstrate significant neuroprotection by rasagiline which could have implications for clinical neurodegenerative disorders.

Neurodegeneration in thiamine deficient rats-A longitudinal MRI study.

Selective neurodegeneration accompanied by mitochondrial dysfunction characterizes neurodegenerative disorders such as Alzheimer's and Parkinson's diseases. Thiamine deficiency (TD) in rats is a model for the study of cellular and molecular mechanisms that lead to selective neuronal loss caused by chronic oxidative deficits. Neurodegeneration in TD-rats develops over a period of 12 to 14 days and can be partially reversed by thiamine administration. The aim of this study was to characterize the in-vivo progression of neurodegeneration and the neuronal rescue processes in TD using T(2) magnetic resonance mapping and diffusion tensor imaging (DTI). Each rat was scanned prior to TD induction (day 0), before the appearance of neurological symptoms (day 10), during the symptomatic stage (days 12 and 14) and during the recuperation period (days 31 and 87). Time-dependent lesions were revealed mainly in the thalamus and the inferior colliculi. Early decrease in the fractional anisotropy (FA) was found on day 10 in the inferior colliculi and to a lesser degree in the thalamus, while the earliest detectable changes in the T(2) parameter occurred only on day 12. FA values in the thalamus remained significantly low after thiamine restoration, suggesting irreversible disarrangement and replacement of neuronal structures. While T(2) values in the frontal cortex demonstrated no lesions, FA values significantly increased on days 14 and 31. An enlargement of the lateral ventricles was observed and persevered during the recovery period. This longitudinal MRI study demonstrated that in TD MRI can detect neurodegeneration and neuronal recovery. DTI is more sensitive than T(2) mapping in the early detection of TD lesions.

Neuroprotection by rasagiline in thiamine deficient rats.

Thiamine deficiency (TD) in rats is a model of chronic impairment of oxidative metabolism leading to neuronal loss. TD rats exhibit neuropathological, behavioral and cognitive abnormalities. The aim of this study was to use this syndrome to assess the neuroprotective potential of drugs in a whole animal model. TD was produced in rats using the following protocol: thiamine deficient diet, daily injections of the central thiamine antagonist, pyrithiamine (0.5 mg/kg), and the test drugs, the selective monoamine oxidase (MAO) B inhibitors, rasagiline (1 or 3 mg/kg/day) and selegiline (2.4 or 8 mg/kg/day). Normal rats and untreated TD rats served as controls. Upon the appearance of neurological symptoms, the TD protocol was suspended, rats were transferred to a regular diet, pyrithiamine and test drug injections were terminated and rats were injected with 3 daily doses of thiamine (100 mg/kg). Neuroprotective potential was assessed by: general behavioral observations, cognitive testing using the Morris water maze and histopathological examination of the brains. Rasagiline but not selegiline significantly delayed the onset and severity of the neurological symptoms of TD. In the Morris water maze, TD-untreated rats displayed severe cognitive impairment while rasagiline-treated rats were similar to control rats and significantly different from TD-untreated rats. The effects were dose related. Selegiline treatment had no significant protective effect. TD-untreated brains displayed extensive gliotic and necrotic lesions mainly in the thalamus and posterior collicular nucleus, which were significantly reduced in the rasagiline-treated TD rats. These findings demonstrate significant neuroprotection by rasagiline with possible implications for clinical neurodegenerative disorders.