Tacrine hydrochloride

Multifunctional liposomes for nasal delivery of the anti-Alzheimer drug tacrine hydrochloride.[Pubmed:24807822]

J Liposome Res. 2014 Dec;24(4):323-35.

The purpose of this study was the development of multifunctional liposomes for nasal administration of Tacrine hydrochloride. Liposomes were prepared using traditional excipients (cholesterol and phosphatidylcholine), partly enriched with alpha-tocopherol and/or Omega3 fatty acids. This approach was chosen in order to obtain at the same time two positive results: an enhanced drug permeation through nasal mucosa and a concomitant neuroprotective effect. Several liposome formulations were prepared using the Reverse Phase Evaporation technique followed by membrane filter extrusion. In particular, liposome capacity to enhance drug permeation was evaluated by means of membrane permeation and cellular uptake studies. Furthermore, liposome effect on neuronal viability and intracellular ROS production was evaluated as well as their cytoprotective effect against oxidative stress. All liposome formulations showed a mean diameter in the range of 175 nm to 219 nm with polydispersity index lower than 0.22, a lightly negative zeta potential and excellent encapsulation efficiency. Moreover, along with good mucoadhesive properties, multifunctional liposomes showed a markedly increase in tacrine permeability, which can be related to liposome fusion with cellular membrane, a hypothesis, which was also supported by cellular uptake studies. Finally, the addition of alpha-tocopherol without Omega3 fatty acids, was found to increase the neuroprotective activity and antioxidant properties of liposomes.

Transdermal iontophoretic delivery of tacrine hydrochloride: Correlation between in vitro permeation and in vivo performance in rats.[Pubmed:27633278]

Int J Pharm. 2016 Nov 20;513(1-2):393-403.

The aim of present investigation is to evaluate the feasibility of transdermal iontophoretic delivery of Tacrine hydrochloride in Sprague Dawley (SD) rats using anodal iontophoretic patches and to correlate plasma tacrine concentration profiles to in vitro tacrine permeation flux. In vitro skin permeation studies were carried out across artificial membrane CELGRAD((R)) 2400, freshly excised SD rat abdominal skin, freshly excised hairless rat abdominal skin, and frozen pig skin to examine the role of permeation membranes. Furthermore, plasma profiles with an application of 0.1-0.3mA current strength and tacrine concentration loading of 5-20mg/ml were obtained in SD rats. The tacrine plasma profiles were fitted to one-compartmental model using WinNonlin and in vivo transdermal absorption rates were then correlated to in vitro permeation profiles using various approaches. Tacrine permeation across membranes revealed current dependent interspecies differences at lower current strength application which diminished at higher current strength application, whereas, no significant difference in tacrine permeation was observed across fresh and frozen SD rat skin under 0.2mA current application. In vivo studies confirmed current and concentration dependent tacrine plasma profiles with possible tacrine depot formation under the skin in-line with earlier in vitro results. Correlation of in vivo transdermal absorption rates to in vitro permeation profiles revealed higher in vitro permeation fluxes compare to in vivo transdermal absorption rates at varied combination of current strength and concentrations. Present in vivo studies support the earlier published in vitro findings and tacrine plasma profiles show a potential to reach therapeutic effective concentration of Tacrine hydrochloride to provide a platform for pre-programmed tacrine delivery.

Application of design of experiments for formulation development and mechanistic evaluation of iontophoretic tacrine hydrochloride delivery.[Pubmed:27100474]

Drug Dev Ind Pharm. 2016 Nov;42(11):1894-902.

OBJECTIVE: The objective of this investigation is to develop mathematical equation to understand the impact of variables and establish statistical control over transdermal iontophoretic delivery of Tacrine hydrochloride. In addition, possibility of using conductivity measurements as a tool of predicting ionic mobility of the participating ions for the application of iontophoretic delivery was explored. METHODS: Central composite design was applied to study effect of independent variables like current strength, buffer molarity, and drug concentration on iontophoretic tacrine permeation flux. Molar conductivity was determined to evaluate electro-migration of tacrine ions with application of Kohlrausch's law. RESULTS: The developed mathematic equation not only reveals drug concentration as the most significant variable regulating tacrine permeation, followed by current strength and buffer molarity, but also is capable to optimize tacrine permeation with respective combination of independent variables to achieve desired therapeutic plasma concentration of tacrine in treatment of Alzheimer's disease. Moreover, relative higher mobility of sodium and chloride ions was observed as compared to estimated tacrine ion mobility. CONCLUSIONS: This investigation utilizes the design of experiment approach and extends the primary understanding of imapct of electronic and formulation variables on the tacrine permeation for the formulation development of iontophoretic tacrine delivery.

The orthorhombic pseudopolymorph of tacrine hydrochloride.[Pubmed:27698319]

Acta Crystallogr B Struct Sci Cryst Eng Mater. 2016 Oct 1;72(Pt 5):771-774.

Crystallization of Tacrine hydrochloride, an acetylcholinesterase inhibitor used during treatment of mild to moderate Alzheimer's disease, from a water:ethanol solution has resulted in an orthorhombic pseudopolymorph. This orthorhombic form which occurs as a dihydrate shows columns of stacking acridines together with continuous Cl-Owater-Owater-Cl chains and ladder-like ribbons composed of squares and hexagons.

A comparative study in rats of the in vitro and in vivo pharmacology of the acetylcholinesterase inhibitors tacrine, donepezil and NXX-066.[Pubmed:10193909]

Neuropharmacology. 1999 Jan;38(1):181-93.

The in vitro and in vivo effects of the novel acetylcholinesterase inhibitors donepezil and NXX-066 have been compared to tacrine. Using purified acetylcholinesterase from electric eel both tacrine and donepezil were shown to be reversible mixed type inhibitors, binding to a similar site on the enzyme. In contrast, NXX-066 was an irreversible non-competitive inhibitor. All three compounds were potent inhibitors of rat brain acetylcholinesterase (IC50 [nM]; tacrine: 125 +/- 23; NXX-066: 148 +/- 15; donepezil: 33 +/- 12). Tacrine was also a potent butyrylcholinesterase inhibitor. Donepezil and tacrine displaced [3H]pirenzepine binding in rat brain homogenates (IC50 values [microM]; tacrine: 0.7; donepezil: 0.5) but NXX-066 was around 80 times less potent at this M1-muscarinic site. Studies of carbachol stimulated increases in [Ca2+]i in neuroblastoma cells demonstrated that both donepezil and tacrine were M1 antagonists. Ligand binding suggested little activity of likely pharmacological significance with any of the drugs at other neurotransmitter sites. Intraperitoneal administration of the compounds to rats produced dose dependent increases in salivation and tremor (ED50 [micromol/kg]; tacrine: 15, NXX-066: 35, donepezil: 6) with NXX-066 having the most sustained effect on tremor. Following oral administration, NXX-066 had the slowest onset but the greatest duration of action. The relative potency also changed, tacrine having low potency (ED50 [micromol/kg]; tacrine: 200, NXX-066: 30, donepezil: 50). Salivation was severe only in tacrine treated animals. Using in vivo microdialysis in cerebral cortex, both NXX-066 and tacrine were found to produce a marked (at least 30-fold) increase in extracellular acetylcholine which remained elevated for more than 2 h after tacrine and 4 h after NXX-066.

Tetrahydro-9-aminoacridine has mixed actions on muscarinic currents and blocks opioid currents in rat locus ceruleus neurons.[Pubmed:8558423]

J Pharmacol Exp Ther. 1996 Jan;276(1):137-42.

Actions of tetrahydro-9-aminoacridine (THA) on membrane properties of locus ceruleus neurons were examined using intracellular recording in superfused brain slices. Low concentrations of THA (300 nM-3 microM) caused a small inward current and a 10-fold increase in the potency of ACh to produce inward (excitatory) currents. No effect was seen on currents activated by carbachol, a muscarinic agonist not degraded by cholinesterases. High concentrations of THA (30-300 microM) caused larger inward currents and a decrease in cell conductance. At these concentrations THA inhibited inward currents induced by carbachol (IC50 = 33 microM) and by substance P, which reportedly excites locus ceruleus neurons via the same ionic mechanism as muscarinic agonists. Furthermore, outward currents activated by opioids could be completely blocked (IC50 = 15 microM). Also affected was the action potential waveform, which was slower to rise, longer in duration and smaller in amplitude. The results suggest that THA has predominantly excitatory effects on locus ceruleus neurons--both by greatly enhancing the actions of ACh and by producing a small inward current. At high concentrations effects are mixed and include inhibition of muscarinic currents, as well as of resting and agonist-induced inwardly rectifying potassium currents. The block of opioid currents by THA was not consistent with inhibition of a cationic conductance as recently proposed.