China
Africa
Explore chapters and articles related to this topic
Battlefield Chemical Inhalation Injury
Published in Jacob Loke, Pathophysiology and Treatment of Inhalation Injuries, 2020
Signs and symptoms of exposure generally are limited to the effects of cholinesterase inhibition. Generally within minutes of a topical exposure and within 30 sec or less of an inhalational exposure symptoms of nervousness, headache, blurred vision, weakness, nausea, intestinal cramping, diarrhea, chest tightness, and incoordination may be seen. The signs of excessive oropharyngeal secretions, tearing, sweating, increased respiratory secretions, vomiting, muscle twitching, cyanosis, muscle weakness, convulsions, loss of sphincter competence, areflexia, heart block, and cardiac arrest are seen. There may be rapid progression through these signs and symptoms to death within 5-15 min. Alternatively, with lower dose exposure and, depending on degree and competence of medical support, life may be sustained for days to weeks with ultimate full recovery unless a major organ system (liver, kidney, heart, CNS) has suffered hypoxic damage. It is difficult to separate the effects of atropine from the effects of OP compound on the quantity of saliva. Furthermore, the contribution of such thick saliva to the observed respiratory obstruction has not been well evaluated. Bronchospasm secondary to OP exposures has been shown to increase pulmonary resistance and decrease dead space. A report of severe dyspnea without measurable increase in airways resistance was thought to be due to changes in chest wall mechanics. Respiratory center inhibition may be of relatively short duration.
Pharmacological Management of Alzheimer’s Disease
Published in Sahab Uddin, Rashid Mamunur, Advances in Neuropharmacology, 2020
Rakesh Kumar, Rajan Kumar, Abhinav Anand, Neha Sharma, Navneet Khurana
Ladostigil has both neuroprotective effects cholinesterase inhibitory and monoamine oxidase MAO-A and MAO-B activities in one molecule. Ladostigil has observed about 25–40% cholinesterase inhibitor in rats. When ladostigil was administered orally at the doses range from 12–35 mg per kg it antagonizes scopolamine-induced spatial memory impairments. Ladostigil has successfully completed a preclinical study and entered in clinical trial phase II. The researchers hypothesized that an increase in the level of synaptic AChE induced by ladostigil might be one of the mode of action involved in cognitive function improvement. However, salivation, diarrhoea, and muscle weakness are the symptoms arise due to access cholinergic stimulation in the periphery until the high dose of 139 mg per kg was administered orally, which inhibited 50–60% cholinesterase. Such a wide therapeutic ratio was probably observed due to the relatively enhanced small rate in cholinesterase inhibition with increasing drug doses over the ranges of 17–69 mg per kg. This increase in cholinesterase inhibition with oral administration of ladostigil at dose 17–69 mg per kg was markedly lower and compared to subcutaneous injection of ladostigil at the doses range of 8.6–17 mg/kg; 40% increase in cholinesterase inhibition. Ladostigil was observed to inhibit both AChE and BuChE in an in vitro study. In which, the inhibitory effect was 100 times more potent against AChE than BuChE (Weinstock et al., 2000).
Dermal and Transdermal Drug Delivery Systems
Published in Tapash K. Ghosh, Dermal Drug Delivery, 2020
Kenneth A. Walters, Majella E. Lane
An alternative cholinesterase inhibitor that has been considered for transdermal delivery in Alzheimer’s patients is donepezil (Figure 1.8, Table 1.3) (Choi et al., 2012; Sozio et al., 2012; Saluja et al., 2013; Galipoglu et al., 2015; Madan et al., 2015). With a maximum dose of 10 mg/day, a molecular weight of 380 and an estimated (EPISuite) logP of 4.86, donezipil is certainly a feasible candidate for the transdermal route. Kim et al. (2015) evaluated the single dose tolerability and pharmacokinetics of patches containing 43.75 mg, 87.5 mg or 175 mg donepezil in healthy volunteers. The patches were designed for three-day application periods. Sustained dose-dependent plasma concentrations were achieved over the wear period with Cmax varying between 5.24 ng/mL to 20.36 ng/mL for the low and high dose patches, respectively. Skin reactions were mild and the patches were well tolerated. This initial study confirmed the potential of transdermal donepezil as a candidate for the treatment of Alzheimer’s disease.
Advances in prodrug design for Alzheimer’s disease: the state of the art
Published in Expert Opinion on Drug Discovery, 2022
Valentin Travers--Lesage, Serge M. Mignani, Patrick Dallemagne, Christophe Rochais
We have discussed, for now in this chapter, prodrugs that are precursors of pleiotropic action through the release of two different active compounds or one MTDL. But what if the prodrug already contains one of the biological activities of the whole drug candidate? Through this literature study, a variety of associations of activities have been discussed, and cholinesterase inhibition is very frequently found. Yet, as we discussed in the preamble of this chapter, some cholinesterase inhibitors can act in a covalent and pseudo-irreversible mode of action. We will see that the last years have seen the possibility to target a specific biological target for the activation of prodrugs, leading then to a first activity beside liberating a second bioactive molecule (Figure 3D). Some recent examples will be given in the next chapter.
Design, synthesis, and evaluation of 3,7-substituted coumarin derivatives as multifunctional Alzheimer’s disease agents
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2021
Sheunopa C. Mzezewa, Sylvester I. Omoruyi, Luke S. Zondagh, Sarel F. Malan, Okobi E. Ekpo, Jacques Joubert
Of the multiple theories underlying AD’s pathophysiology, the roles of oxidative stress, toxic amyloid-β (Aβ) plaques, and the cholinergic hypothesis have gained momentum in explaining the disease’s pathology and in guiding treatment options8–10. The cholinergic hypothesis postulates that the symptoms present in AD (particularly cognitive decline and amnesia) can be linked to declining function in the cholinergic neurotransmitter system. The cholinergic system is modulated by the neurotransmitter acetylcholine, metabolised by acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) in the brain11,12. The primary therapeutic approach has been to counter cholinergic depletion using acetylcholinesterase inhibitors (AChEIs). This has thus far been done by using the second-generation AChEIs such as donepezil, galantamine, and rivastigmine (Figure 1)5,13. The clinical application of these agents has demonstrated that cholinesterase inhibition leads to modest improvement in cognitive functions14–16.
1,2,4-Triazole-based anticonvulsant agents with additional ROS scavenging activity are effective in a model of pharmacoresistant epilepsy
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2020
Barbara Kaproń, Robert Czarnomysy, Mariusz Wysokiński, Rudolf Andrys, Kamil Musilek, Andrea Angeli, Claudiu T. Supuran, Tomasz Plech
Cognitive improvements, particularly in learning and memory formation, are also observed during treatment with cholinesterase inhibitors. These drugs can delay the loss of cognitive functions and therefore are prescribed for patients with mild to moderate Alzheimer’s disease. However, cholinesterase inhibition in peripheral tissues (mainly in smooth muscles and myocardium) may result in adverse effects associated with the hyperactivity of cholinergic system. The investigated drug candidates seem not to elevate acetylcholine concentration through cholinesterase inhibition since they possess very weak inhibitory effect against hrAChE and have no inhibitory effect on hrBChE. Taking into account that main mechanism of anticonvulsant action of the compounds tested is associated with VGSC blocking, lack of AChE/BChE affinity suggests their minimal off-target cholinergic effects.