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Journal of Analytical Toxicology 1985A specific, reliable, and accurate high performance liquid chromatographic method is described for the determination of physostigmine in plasma and brain using carbaryl...
A specific, reliable, and accurate high performance liquid chromatographic method is described for the determination of physostigmine in plasma and brain using carbaryl as an internal standard. Plasma and brain containing physostigmine were first precipitated with TCA, and then carbaryl was added. This was followed by chloroform extraction and then evaporation. The residue was reconstituted in the mobile phase. Physostigmine, its hydrolyzed product eseroline, and carbaryl were separated on a reversed-phase column eluted with mobile phase containing octanesulfonic acid with phosphate buffer in a methanol and water solution. The eluted compounds were detected at 245 nm, and physostigmine was quantified from the ratio of the area of physostigmine to carbaryl peaks. The chromatography was complete within 15 min. The dynamic range of quantitation of physostigmine was 0.05 micrograms to 0.5 micrograms/mL plasma or per gram of brain. Analytical recoveries varied from 95 to 107% over this range. Coefficient of variation ranged from 1.7 to 9.5%. This method was applied to study plasma and brain concentration in rats after 650 micrograms/kg intramuscular administration of physostigmine. The ratio of brain to plasma was found to be 0.48 and 1.97 at 15 and 30 min, respectively.
Topics: Animals; Brain Chemistry; Carbaryl; Chromatography, High Pressure Liquid; Indoles; Physostigmine; Rats
PubMed: 3921763
DOI: 10.1093/jat/9.2.71 -
Neurology Dec 1988Minimal short-term benefits with oral physostigmine have been reported in Alzheimer's disease. We examined long-term oral physostigmine therapy in 14 patients with... (Clinical Trial)
Clinical Trial Randomized Controlled Trial
Minimal short-term benefits with oral physostigmine have been reported in Alzheimer's disease. We examined long-term oral physostigmine therapy in 14 patients with probable Alzheimer's disease in an extended double-blind crossover trial in which they received physostigmine for five intervals of 4 to 6 weeks in length and placebo for one interval determined at random. At each interval a Selective Reminding Test was administered and three indexes were examined: total recall, long-term recall, and intrusions. As a group, patients' memory test scores were significantly better during the drug period. Two patients who previously had performed worse on drug than on placebo in a short-term trial continued to do so. Nine of the remaining 12 patients performed better on two or more measures on physostigmine compared with placebo. In some cases scores improved up to 50% over placebo values. This improvement was not predicted by response to medication in the earlier short-term trial. Seven patients completed an additional six-interval crossover trial. All but one continued to have improved performance with oral physostigmine and, in grouped data, memory measures remained significantly improved. These results suggest that long-term administration of physostigmine in Alzheimer's disease may be more effective than short-term. This benefit can be sustained for up to a year in some patients.
Topics: Administration, Oral; Aged; Alzheimer Disease; Clinical Trials as Topic; Humans; Memory; Middle Aged; Neuropsychological Tests; Physostigmine; Time Factors
PubMed: 3057398
DOI: 10.1212/wnl.38.12.1837 -
Neuropharmacology Jul 1987The time course of physostigmine (Phy), its metabolites and activity of cholinesterase (ChE) in plasma were studied after intravenous bolus administration of [3H]Phy... (Comparative Study)
Comparative Study
The time course of physostigmine (Phy), its metabolites and activity of cholinesterase (ChE) in plasma were studied after intravenous bolus administration of [3H]Phy (100 micrograms/kg) to beagle dogs. The maximal inhibition of ChE (78%) in plasma at 2 min correlated with the largest concentration of physostigmine (124 ng/ml). The concentration of physostigmine decreased by 88% to 16 ng/ml at 45 min when the activity of ChE was still 59% inhibited. Acetylcholinesterase activity in four regions of the brain (medulla, striatum, cerebellum and cortex) was not significantly different from controls at 70 +/- 5 min after administration of physostigmine. Concentrations of physostigmine and its metabolites determined by HPLC were not significantly different in different regions. In plasma, physostigmine was found, together with eseroline and two other metabolites M1 and M2. At 45 min, only 18% of total radioactivity was due to physostigmine and 52% was due to the major metabolite M1. On the contrary, in regions of the brain, metabolite M1 represented only 1.9-3.37% of total radioactivity at 70 +/- 5 min. Pharmacokinetic parameters, obtained in the dog, were compared to previously published data in rat and man. The elimination half-life (beta) was 30.7 min in the dog as compared to 15 min in rat and and 21.7 min in man. The Vd (ml/kg) was higher than total body water volume in all three species: dog (1832), rat (1352) and man (664), indicating sequestration of the drug in body compartments. Clearance (ml/min/kg) was found to be 41.2 in dog, which compares to 62 in rat and 22 in man.(ABSTRACT TRUNCATED AT 250 WORDS)
Topics: Animals; Body Water; Brain; Cholinesterases; Dogs; Half-Life; Humans; Indoles; Injections, Intravenous; Male; Mathematics; Physostigmine; Rats; Tissue Distribution
PubMed: 3658115
DOI: 10.1016/0028-3908(87)90059-1 -
Organic Letters Aug 2021The alkaloid physostigmine is an approved anticholinergic drug and an important lead structure for the development of novel therapeutics. Using a complementary approach...
The alkaloid physostigmine is an approved anticholinergic drug and an important lead structure for the development of novel therapeutics. Using a complementary approach that merged chemical synthesis with pathway refactoring, we produced a series of physostigmine analogues with altered specificity and toxicity profiles in the heterologous host . The compounds that were generated by applying a simple feeding strategy include the promising drug candidate phenserine, which was previously accessible only by total synthesis.
Topics: Molecular Structure; Myxococcus xanthus; Physostigmine
PubMed: 34355569
DOI: 10.1021/acs.orglett.1c02374 -
The New England Journal of Medicine Mar 1978
Topics: Aged; Amantadine; Humans; Male; Physostigmine
PubMed: 622150
DOI: 10.1056/nejm197803022980919 -
Molecular Interventions Feb 2010
Topics: Cholinesterase Inhibitors; History, 18th Century; History, 19th Century; History, 20th Century; History, 21st Century; Humans; Physostigmine
PubMed: 20124558
DOI: 10.1124/mi.10.1.1 -
Clinical Pharmacology and Therapeutics Dec 1993We evaluated a double-blind, placebo-controlled, and double-crossover trial of oral physostigmine salicylate for a 9-month period in 13 of 25 patients with sporadic... (Clinical Trial)
Clinical Trial Comparative Study Randomized Controlled Trial
We evaluated a double-blind, placebo-controlled, and double-crossover trial of oral physostigmine salicylate for a 9-month period in 13 of 25 patients with sporadic amyotrophic lateral sclerosis (ALS). A large dropout rate of 48% was secondary to eight deaths and four exclusions attributed to the incapability to swallow the tablets (physostigmine) and capsules (lecithin) or to attend the clinic. Parameters used for assessment of the drug efficacy included body weight, ALS score, Jamar grip strength, forced vital capacity, and maximum voluntary ventilation. It revealed slight benefit in reduced loss of grip strength compared with the pretrial and placebo periods. However, the rates of decline for body weight, ALS score, forced vital capacity, maximum voluntary ventilation, and megascore did not differ significantly between the pretrial, placebo, and physostigmine periods. We therefore concluded that overall no significant alteration in the clinical course was gained by oral physostigmine therapy in the 13 patients with ALS who were included in this study.
Topics: Administration, Oral; Amyotrophic Lateral Sclerosis; Double-Blind Method; Humans; Nausea; Physostigmine; Placebos
PubMed: 8275623
DOI: 10.1038/clpt.1993.206 -
Pflugers Archiv : European Journal of... Jun 1976Physostigmine in 15 mM concentration at pH 8.4 produces reversible contractures of up to 0.3 Po tension output in frog's whole toe muscle or in 7-10 fiber bundles of...
Physostigmine in 15 mM concentration at pH 8.4 produces reversible contractures of up to 0.3 Po tension output in frog's whole toe muscle or in 7-10 fiber bundles of these muscles, At pH 7.2, the 15 mM physostigmine contracture output is only about 0.10 Po. The 15 mM, pH 8.4 contractures are essentially unaffected by lack of external Ca2+, complete depolarization of the fibers, detubulation by glycerol treatment, and 0 degrees C ambient temperature. These results and other evidence indicate that physostigmine produces contracture by directly releasing activator Ca2+ from the sarcoplasmic reticulum (SR). Pretreatment of muscles with 4 mM procaine reduces physostigmine's capacity to produce contracture, evidently by means of a competitive inhibition at SR sites. The above results indicate similarities between physostagmine and caffeine contractures. But the physostigmine action differs in that it is reversible, and, especially, it lacks the ability, strongly characteristic of caffeine, to sensitize a muscle to produce a rapid cooling contracture. The internal action of physostigmine requires that it be permeant, and, since it is a weak base (pKa = 8.2), this property is provided by its uncharged base. But, once internal, where the pH = 6.8, most of the drug will be protonated and it may act on the SR in this form, in contrast with caffeine which, since its pKa is about 1.0, acts on the SR as uncharged base.
Topics: Animals; Caffeine; Calcium; Cold Temperature; Hydrogen-Ion Concentration; Membrane Potentials; Muscle Contraction; Physostigmine; Potassium; Procaine; Rana pipiens; Sarcoplasmic Reticulum
PubMed: 8761
DOI: 10.1007/BF00594605 -
British Journal of Clinical Pharmacology Jan 19951. The pharmacokinetics of physostigmine were investigated in a three-way cross-over design in six healthy, male volunteers comparing a physostigmine transdermal system... (Clinical Trial)
Clinical Trial Comparative Study Randomized Controlled Trial
1. The pharmacokinetics of physostigmine were investigated in a three-way cross-over design in six healthy, male volunteers comparing a physostigmine transdermal system (PTS), an oral solution and an i.v. infusion. 2. A single application of the patch over 24 h produced detectable plasma drug concentrations after a mean lag-time of 4 h. Thereafter, the drug was absorbed continuously from the PTS and putative therapeutic plasma concentrations were measured over approximately 18 h. 3. A mean absolute bioavailability of 36% was determined for the transdermal system and 3% for the oral solution. In comparison with the oral solution, interindividual variability of pharmacokinetics was less with the PTS. 4. The mean amount of physostigmine released from the transdermal system after 24 h was 5.7 mg. Because of extensive metabolism, only 2.2 mg of physostigmine were detected systemically. 5. After removing the PTS, the mean apparent half-life of elimination was 4.9 h, compared with 0.5 h for the i.v. infusion. This indicates continued drug absorption from a skin depot. 6. Physostigmine was well tolerated by the volunteers. With the PTS, a mild erythema was observed at the area of application, disappearing within a few hours.
Topics: Administration, Cutaneous; Administration, Oral; Adult; Biological Availability; Cross-Over Studies; Half-Life; Humans; Infusions, Intravenous; Male; Physostigmine; Skin; Skin Absorption; Solutions
PubMed: 7756100
DOI: 10.1111/j.1365-2125.1995.tb04410.x -
Lancet (London, England) Jun 1985
Topics: Administration, Oral; Adult; Humans; Male; Physostigmine
PubMed: 2861349
DOI: 10.1016/s0140-6736(85)91827-6