Tramiprosate

Tramiprosate is a small, orally-administered compound that binds to soluble Aβ and reduces amyloid aggregation and subsequent deposition target: Aβ In vitro: Tramiprosate provides neuroprotection against Aβ-induced neurotoxicity in neuronal and mouse organotypic hippocampal cultures, and reverses Aβ-induced long-term potentiation (LTP) inhibition in rat hippocampus, in part, through activation of β-aminobutyric acid A (GABA-A) receptors. Tramiprosate dose-dependently provides neuroprotection against ischemic stroke. In vivo: Tramiprosate produced dose-dependent reductions of Aβ in the brain of transgenic mice (hAPP-TgCRND8). Clinical studies show that tramiprosate was safe and tolerable. In mild-to-moderate AD patients tramiprosate also reduced Aβ42 levels in CSF. The reference for animal administration is 50 mg/kg.

References:
[1]. Wu S et al. Tramiprosate protects neurons against ischemic stroke by disrupting the interaction between PSD95 and nNOS. Neuropharmacology. 2014 Aug;83:107-17. [2]. Aisen PS et al. Tramiprosate in mild-to-moderate Alzheimer's disease - a randomized, double-blind, placebo-controlled, multi-centre study (the Alphase Study). Arch Med Sci. 2011 Feb;7(1):102-11.

The potential protective effect of tramiprosate (homotaurine) against Alzheimer's disease: a review.[Pubmed:22961121]

Aging Clin Exp Res. 2012 Dec;24(6):580-7.

Due to the progressive aging of the population and to the age-associated increase in its incidence, Alzheimer's disease (AD) will become in near future one of the major challenges that healthcare systems will have to face with in developed countries. Since the pathophysiological process of AD is thought to begin many years before the clinical diagnosis of dementia, in theory there is an opportunity for preventive therapeutic interventions. In recent years, there has been a growing interest, supported by a large number of experimental and epidemiological studies, in the beneficial effects of some natural compounds in preventing various age-related pathologic conditions, including brain aging and neurodegeneration. Homotaurine, a small aminosulfonate compound that is present in different species of marine red algae, has been shown, in both in vitro and in vivo models, to provide a relevant neuroprotective effect by its specific anti- amyloid activity and by its gamma-aminobutyric acid type A receptor affinity. The therapeutic efficacy of homotaurine in AD has been investigated in a pivotal Phase III clinical study that did not reach its pre-defined primary endpoints. However, post-hoc analyses have shown positive and significant effects of homotaurine on secondary endpoints and subgroups of patients, including a reduction in hippocampal volume loss and lower decline in memory function in the overall cohort, as well as a reduction in global cognitive decline in APOE4 allele carriers, suggesting a disease-modifying effects. In this review, we will examine the pre-clinical and clinical evidence supporting the potential role of homotaurine as a promising candidate for both primary and secondary prevention of AD.

Precolumn derivatization followed by liquid chromatographic separation and determination of tramiprosate in rat plasma by fluorescence detector: application to pharmacokinetics.[Pubmed:21324628]

J Pharm Biomed Anal. 2011 May 15;55(2):282-7.

Alzheimer disease (AD) is characterized pathologically by extracellular amyloid deposits composed of amyloid beta (Abeta) protein. A simple and rapid method using HPLC with fluorescence detector was developed and validated for determination of Tramiprosate in rat plasma. Pre-column derivatization of the deproteinized rat plasma was carried out using o-phthaldialdehyde (OPA) as a fluorescent reagent in presence of 3-mercaptopropionic acid. The liquid chromatographic separation was achieved on a Kromasil C18 column using methanol:acetonitrile: 20 mM phosphate buffer pH 7.5 (8.0:17.5:74.5 v/v/v) as a mobile phase in an isocratic elution mode. The eluents were monitored by a fluorescence detector set at 330 and 450 nm of excitation and emission wavelength respectively. Vigabatrin was used as an internal standard. The method was linear within the range 30.0-1000.0 ng/mL. Design of experiments (DOE) was used to evaluate the robustness of the method. The developed method was applied to study the pharmacokinetics of Tramiprosate in rats.

Tramiprosate in mild-to-moderate Alzheimer's disease - a randomized, double-blind, placebo-controlled, multi-centre study (the Alphase Study).[Pubmed:22291741]

Arch Med Sci. 2011 Feb;7(1):102-11.

INTRODUCTION: The aim of the study was to assess the clinical efficacy, safety, and disease-modification effects of Tramiprosate (homotaurine, ALZHEMED(TM)) in mild-to-moderate Alzheimer's disease (AD). MATERIAL AND METHODS: Double-blind, placebo-controlled, randomized trial in 67 clinical centres across North America. Patients aged >/= 50 years, with mild-to-moderate AD (Mini-Mental State Examination score between 16 and 26) and on stable doses of cholinesterase inhibitors, alone or with memantine. INTERVENTION: 78-week treatment with placebo, Tramiprosate 100 mg or Tramiprosate 150 mg BID. MEASUREMENTS: Alzheimer Disease Assessment Scale - cognitive subscale (ADAS-cog) and Clinical Dementia Rating - Sum of Boxes (CDR-SB) assessments were performed at baseline and every 13 weeks. Baseline and 78-week magnetic resonance imaging (MRI) hippocampus volume (HV) measurements were conducted in a subgroup of patients. RESULTS: A total of 1,052 patients were enrolled and 790 (75.1%) completed the 78-week trial. Patient discontinuation and reasons for withdrawal were similar across groups. Planned analyses did not reveal statistically significant between-group differences. Lack of adequate statistical validity of the planned analysis models led to the development of revised predictive models. These adjusted models showed a trend toward a treatment effect for ADAS-cog (P = 0.098) and indicated significantly less HV loss for Tramiprosate 100 mg (P = 0.035) and 150 mg (P = 0.009) compared to placebo. The incidence of adverse events was similar across treatment groups. CONCLUSIONS: The primary planned analyses did not show a significant treatment effect, but were confounded by unexplained variance. Post-hoc analyses showed a significant treatment-related reduction in HV loss. However, there was only a trend towards slowing of decline on the ADAS-cog and no slowing of decline on the CDR-SB. These results must be interpreted in consideration of the limitations of clinical and disease-modification outcome measures and their relationship, the heterogeneity of the disease and the impact of confounding demographic and clinical variables.

Tramiprosate protects neurons against ischemic stroke by disrupting the interaction between PSD95 and nNOS.[Pubmed:24769446]

Neuropharmacology. 2014 Aug;83:107-17.

Tramiprosate, a small aminosulphonate compound, is present in various species of red marine algae. In this study, we examined whether Tramiprosate protects neurons and improves functional recovery following ischemic stroke in rats subjected to the intraluminal filament model of MCAO and further explored the underlying mechanisms. Tramiprosate dose-dependently reduced the infarct volume after MCAO, and the therapeutic time window of Tramiprosate (50 mg/kg) for cerebral ischemia was at least 6 h. Moreover, functional assays and histochemical staining were performed. Significant neurological functional recovery was found after Tramiprosate (50 mg/kg) administration in all three functional assays performed (modified neurological severity score, foot-fault test and adhesive-removal somatosensory test). Tramiprosate significantly attenuated OGD- or NMDA-induced injury in NGF-differentiated PC12 cells and primary cortical neurons. Furthermore, the neuroprotective effect of Tramiprosate was partially blunted by the NMDA receptor (NMDAR) antagonist MK801 both in vitro and in vivo, indicating that Tramiprosate might confer neuroprotection against stroke via the NMDAR. Based on co-immunoprecipitation and western blotting, Tramiprosate decreased the intensity of the association between nNOS and PSD95, and Tramiprosate also inhibited the translocation of nNOS from the cytosol to the membrane without affecting the total nNOS expression level both in vitro and in vivo. In conclusion, Tramiprosate dose-dependently provides neuroprotection in vitro and in vivo against ischemic stroke, and the neuroprotective effect of Tramiprosate may be partially attributed to disruption of the interaction between PSD95 and nNOS and inhibition of nNOS translocation.

Targeting soluble Abeta peptide with Tramiprosate for the treatment of brain amyloidosis.[Pubmed:16675063]

Neurobiol Aging. 2007 Apr;28(4):537-47.

Amyloid beta-peptide (Abeta) is a major constituent of senile plaques in Alzheimer's disease (AD). Neurotoxicity results from the conformational transition of Abeta from random-coil to beta-sheet and its oligomerization. Among a series of ionic compounds able to interact with soluble Abeta, Tramiprosate (3-amino-1-propanesulfonic acid; 3APS; Alzhemedtrade mark) was found to maintain Abeta in a non-fibrillar form, to decrease Abeta(42)-induced cell death in neuronal cell cultures, and to inhibit amyloid deposition. Tramiprosate crosses the murine blood-brain barrier (BBB) to exert its activity. Treatment of TgCRND8 mice with Tramiprosate resulted in significant reduction (approximately 30%) in the brain amyloid plaque load and a significant decrease in the cerebral levels of soluble and insoluble Abeta(40) and Abeta(42) (approximately 20-30%). A dose-dependent reduction (up to 60%) of plasma Abeta levels was also observed, suggesting that Tramiprosate influences the central pool of Abeta, changing either its efflux or its metabolism in the brain. We propose that Tramiprosate, which targets soluble Abeta, represents a new and promising therapeutic class of drugs for the treatment of AD.

Homotaurine (3 aminopropanesulfonic acid; 3APS) protects from the convulsant and cytotoxic effect of systemically administered kainic acid.[Pubmed:7199633]

Neurology. 1982 Mar;32(3):241-5.

Pretreatment of rats with homotaurine (3 aminopropanesulfonic acid; 3APS), a synthetic gamma-aminobutyric acid (GABA) analog, protected from the convulsant and cytotoxic action of systemically injected kainic acid (KA). Wet dog shaking (WDS) behavior was significantly reduced. Taurine, an inhibitory non-GABA-mimetic amino acid, and muscimol (another direct GABA-agonist) reduced the number of seizures and lesions in the brain but were less effective than homotaurine. Progabide (a GABA-agonist) did not modify kainic acid effects. The neurotoxicity of kainic acid could have been due to repetitive convulsive activity. Activation of GABA-mediated inhibition is an effective, but not the determinant means of preventing KA-induced abnormalities.

Tramiprosate is a small, orally-administered compound that binds to soluble Aβ and reduces amyloid aggregation and subsequent deposition target: Aβ In vitro: Tramiprosate provides neuroprotection against Aβ-induced neurotoxicity in neuronal and mouse organotypic hippocampal cultures, and reverses Aβ-induced long-term potentiation (LTP) inhibition in rat hippocampus, in part, through activation of β-aminobutyric acid A (GABA-A) receptors.

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