Neostigmine methyl sulfate

Autonomic and cholinergic mechanisms mediating cardiovascular and temperature effects of donepezil in conscious mice

Donepezil is a centrally acting acetylcholinesterase (AChE) inhibitor with therapeutic potential in inflammatory diseases; however, the underlying autonomic and cholinergic mechanisms remain unclear. Here, we assessed effects of donepezil on mean arterial pressure (MAP), heart rate (HR), HR variability, and body temperature in conscious adult male C57BL/6 mice to investigate the autonomic pathways involved. Central versus peripheral cholinergic effects of donepezil were assessed using pharmacological approaches including comparison with the peripherally acting AChE inhibitor, neostigmine. Drug treatments included donepezil (2.5 or 5 mg/kg sc), neostigmine methyl sulfate (80 or 240 μg/kg ip), atropine sulfate (5 mg/kg ip), atropine methyl bromide (5 mg/kg ip), or saline. Donepezil, at 2.5 and 5 mg/kg, decreased HR by 36 ± 4% and 44 ± 3% compared with saline (n = 10, P < 0.001). Donepezil, at 2.5 and 5 mg/kg, decreased temperature by 13 ± 2% and 22 ± 2% compared with saline (n = 6, P < 0.001). Modest (P < 0.001) increases in MAP were observed with donepezil after peak bradycardia occurred. Atropine sulfate and atropine methyl bromide blocked bradycardic responses to donepezil, but only atropine sulfate attenuated hypothermia. The pressor response to donepezil was similar in mice coadministered atropine sulfate; however, coadministration of atropine methyl bromide potentiated the increase in MAP. Neostigmine did not alter HR or temperature, but did result in early increases in MAP. Despite the marked bradycardia, donepezil did not increase normalized high-frequency HR variability. We conclude that donepezil causes marked bradycardia and hypothermia in conscious mice via the activation of muscarinic receptors while concurrently increasing MAP via autonomic and cholinergic pathways that remain to be elucidated.

[CONTRIBUTION TO THE EVALUATION OF THE BROMIDE AND METHYL SULFATE OF THE M-TRIMETHYLAMINOPHENYL ESTER OF DIMETHYLCARBAMIC ACID (NEOSTIGMINE) WITH REFERENCE TO THE DEGRADATION PRODUCTS]

[Applications of A C oscillopolarographic titration in pharmaceutical analysis. I. Titration of neostigmine methyl sulfate injection with sodium tetraphenylborate]

Drug-1,3,4-Thiadiazole Conjugates as Novel Mixed-Type Inhibitors of Acetylcholinesterase: Synthesis, Molecular Docking, Pharmacokinetics, and ADMET Evaluation

A small library of new drug-1,3,4-thiazidazole hybrid compounds (3a?3i) was synthesized, characterized, and assessed for their acetyl cholinesterase enzyme (AChE) inhibitory and free radical scavenging activities. The newly synthesized derivatives showed promising activities against AChE, especially compound 3b (IC₅₀ 18.1 ± 0.9 nM), which was the most promising molecule in the series, and was substantially more active than the reference drug (neostigmine methyl sulfate; IC₅₀ 2186.5 ± 98.0 nM). Kinetic studies were performed to elucidate the mode of inhibition of the enzyme, and the compounds showed mixed-type mechanisms for inhibiting AChE. The Ki of 3b (0.0031 ?M) indicates that it can be very effective, even at low concentrations. Compounds 3a?3i all complied with Lipinski's Rule of Five, and showed high drug-likeness scores. The pharmacokinetic parameters revealed notable lead-like properties with insignificant liver and skin-penetrating effects. The structure?activity relationship (SAR) analysis indicated π?π interactions with key amino acid residues related to Tyr124, Trp286, and Tyr341.

Effect of acupuncture on rabbit bladder with urodynamic indexes

Objective: To study the effect of acupuncture on rabbit bladder with urodynamic indexes.
Methods: New Zealand male rabbits were divided into control group, model group, treatment group 1 treated by acupuncture at Shenshu (BL 23) and treatment group 2 treated by acupuncture at Zhongji (CV 3). The urine dynamic parameters through the urethral catheter were detected in each group in order: fluctuation of pressure at filling phase of urinary bladder and flow rate in urination phase, which were used as quantification indexes of urinary bladder function. The urinary bladder abnormal model was prepared by administration of cholinergic stimulant; Regulatory effects of acupuncture at Shenshu (BL 23) and Zhongji (CV 3) on the abnormal state of the urinary bladder were respectively observed.
Results: 1) In the filling phase of urinary bladder and in the urination phase, the intravesical pressure wave in infilling (IPWI) and intravesical discharge rate (IDR) could be respectively recorded. 2) IPWI and IDR could become abnormality by neostigmine methyl sulfate [stability type IPWI: the control group (n = 20, 80%) vs the model group (n = 15, 14.3%), P < 0.01; IDR and time regression equation: the control group (n = 20, y = 24.3 - 0.878x) vs the model group (n = 15, y = 40.0 - 5.15x), P < 0.01]. 3) Abnormal IPWI's could be normalized respectively by acupuncture at Shenshu (BL 23) and Zhongji (CV 3) [the stability type IPWI wave: the model group (n = 2, 14.3%) vs the treatment group 1 (n = 3, 30%), P > 0.05; the instability type IPWI wave: the model group (n = 13, 85.7%) in vs the treatment group 2 (n = 6, 60%), P > 0.05]; 4) Abnormal IDR also could be turned to normality by acupuncture at Shenshu (BL 23) and Zhongji (CV 3), respectively [IDR and the time regression equation: the model group (n = 15, y = 40.0 - 5.15x) vs the treatment group 1 (n = 10, y = 18.9 - 0.499x), P < 0.01; the model group (n = 15, y = 40.0 - 5.15x) vs the treatment group 2 (n = 10, y = 17.5 - 0.251x), P < 0.01].
Conclusion: 1) Urodynamic indexes can be used for study of mechanism of acupuncture effects; 2) The effect of acupuncture in the bladder filling phase is smaller than that in the urination phase; 3) Acupuncture has a very obvious effect on intravesical discharge rate.