Nanostructured lipid carriers engineered for intranasal delivery of teriflunomide in multiple sclerosis: optimization and in vivo studies.

BACKGROUND: Multiple sclerosis (MS) is one of the most severe autoimmune disorder of the central nervous system (CNS). OBJECTIVE: The present research work was aimed to formulate and investigate teriflunomide (TFM)-loaded intranasal (i.n.) nanostructured lipid carriers (NLC) for the treatment of multiple sclerosis (MS). METHODS: The TFM-loaded NLC (TFM-NLC) nanoparticles were prepared by melt emulsification ultrasonication method using biodegradable and biocompatible polymers. The Box-Behnken statistical design was applied to optimize the formulation. The optimized NLC formulation was subjected to evaluate for particle size, entrapment efficiency (%), in vitro and ex vivo permeation. The safety and efficacy of optimized formulations were demonstrated using pharmacodynamic, subacute toxicity and hepatotoxicity data. RESULTS: Experimental data demonstrated that optimized NLC formulation (F17) showed significant size (99.82 ± 1.36 nm), zeta potential (-22.29 ± 1.8 mV) and % entrapment efficiency (83.39 ± 1.24%). Alternatively, ex vivo permeation of TFM mucoadhesive NLC (TFM-MNLC) and TFM-NLC was observed 830 ± 7.6 and 651 ± 9.8 µg/cm2, respectively. Whereas, TFM-MNLC shows around 2.0-folds more Jss than the TFM-NLC. Finally, TFM-MNLC (i.n.) formulation produced the rapid remyelination in cuprizone-treated animals and decreases the number of entries in open compartment of EPM when compared with negative control and TFM-NLC (oral) animals. Simultaneously, the nanoformulation did not reflect any gross changes in hepatic biomarkers and subacute toxicity when compared with control. CONCLUSIONS: Hence it can be inferred that the nose-to-brain delivery of TFM-MNLC can be considered as effective and safe delivery for brain disorders.

Rebound after discontinuation of teriflunomide in patients with multiple sclerosis: 2 case reports.

Teriflunomide is an oral first-line disease modifying treatment (DMT) for patients with relapsing-remitting multiple sclerosis (RRMS). It can take up to two years to achieve systemic clearance of teriflunomide to an acceptable level, but this washout period may be accelerated by administration of cholestyramine. Relapse of multiple sclerosis (MS) during washout of teriflunomide or other first-line DMT is not as common. We report two patients with RRMS who experienced a relapse after the accelerated elimination period (AEP) of teriflunomide and confirmation of negative plasmatic levels (<0.02 µg/ml). In cases of risk of MS activity, we should not wait for teriflunomide negative plasmatic levels confirmation before starting the next DMT to reduce the risk of relapse.

Facile functionalization of Teriflunomide-loaded nanoliposomes with Chondroitin sulphate for the treatment of Rheumatoid arthritis.

This research aims to coat Teriflunomide (TEF) loaded conventional nanoliposomes (CON-TEF-LIPO) with Chondroitin sulphate (CS) to produce CS-TEF-LIPO for the effective treatment of Rheumatoid arthritis (RA). Both CON-TEF-LIPO and CS-TEF-LIPO were produced, characterized and evaluated for their active targeting potential towards CD44 receptors. Cell cytotoxicity, cell viability and intracellular uptake study on differentiated U937 and MG-63 cells demonstrated the active targeting of CS-TEF-LIPO towards CD44 receptors. Furthermore, in vivo pharmacodynamic, biochemical, radiological and histopathological studies performed in adjuvant induced arthritic (AIA) rat model showed a significant (P < 0.05) reduction in inflammation in arthritic rat paw in CS-TEF-LIPO group compared to TEF and CON-TEF-LIPO groups. Moreover, liver toxicity study revealed that CS-TEF-LIPO showed no signs of toxicity and biodistribution study revealed the accumulation of CS-TEF-LIPO in synovial region of arthritic rat. Taken together, results suggest that CS-TEF-LIPO could provide a new insight for an effective treatment of RA.

Tolerability and efficacy of colestipol hydrochloride for accelerated elimination of teriflunomide.

BACKGROUND: Teriflunomide is an oral disease modifying therapy approved for the treatment of relapsing forms of multiple sclerosis. Teriflunomide' s pharmacokinetics (PK) contribute to its slow elimination, on average taking 6-8 months, though it can take up to 2 years in some instances. This slow elimination can become problematic in certain clinical situations - such as during pregnancy, when teriflunomide has potential teratogenic effects. In such scenarios, an accelerated elimination procedure (AEP) is recommended. Currently, AEPs with oral cholestyramine or activated charcoal are available but are restricted by adverse effects, limited administration routes, and dosing frequencies. METHODS: A single-center, PK interaction study was performed in a total of 14 healthy volunteers, to investigate colestipol hydrochloride (HCl) as an alternative to cholestyramine for the elimination of teriflunomide. Participants received teriflunomide for 14 days, followed by an AEP with colestipol HCl for 15 days. RESULTS AND CONCLUSIONS: The administration of colestipol HCl for 15 days was sufficient to reduce plasma teriflunomide concentrations by greater than 96%. Although colestipol HCl did not completely eliminate teriflunomide with the same effectiveness as cholestyramine, it may offer an alternative method for accelerated elimination of teriflunomide with potentially improved tolerability and more favorable dosing and administration options.

Parallel analysis of stimulants in saliva and urine by gas chromatography/mass spectrometry: perspectives for "in competition" anti-doping analysis.

Stimulants are banned by the World Anti-Doping Agency (WADA) if used "in competition". Being the analysis of stimulants presently carried out on urine samples only, it might be useful, for a better interpretation of analytical data, to discriminate between an early intake of the substance and an administration specifically aimed to improve the sport performance. The purpose of the study was to investigate the differences, in terms of excretion/disappearance of drugs, between urine and oral fluid, a sample that can reflect plasmatic concentrations. Oral fluid and urine samples were collected following oral administration of the following stimulants: modafinil (100 mg), selegiline (10 mg), crotetamide/cropropamide (50 mg each), pentetrazol (100 mg), ephedrine (12 mg), sibutramine (10 mg), mate de coca (a dose containing about 3mg of cocaine); analysis of drugs/metabolites was carried out by gas chromatography/mass spectrometry (GC/MS) in both body fluids. Our results show that both the absolute concentrations and their variation as a function of time, in urine and in oral fluid, are generally markedly different, being the drugs eliminated from urine much more slowly than from oral fluid. Our results also suggest that the analysis of oral fluid could be used to successfully complement the data obtained from urine for "in competition" anti-doping tests; in all those cases in which the metabolite(s) concentration of a substance in urine is very low and the parent compound is not detected, it is indeed impossible, relying on urinary data only, to discriminate between recent administrations of small doses and remote administrations of higher doses.