Environmental Interaction
Craniofacial disorders have high variance in phenotypic expression, and researchers have suggested this variance could be due to interactions between the mutated/deviated genes and other genes, along with interactions with environmental factors. Environmental causes have been found to contribute to craniofacial clefting, however, these are still influenced by and supported by genetic factors. Many studies, for example, have linked maternal smoking to increased CLP risk; however, the increased risk suggests that genes in metabolic pathways could still contribute to susceptibility or formation of CL/P. Development and Inheritance
The craniofacial complex begins its progress in the fourth week of development, and results from neural crest cells migrating to form and fuse the facial primordia. Failures or deviations in this process result in craniofacial clefts, either CL or CP. The range of variation in phenotype aligns with ancestry. Studies have found increased amounts of clefting in the relatives of patients with clefts, suggesting genetic factors are the underlying cause for CL/P. Inheritance has a known and significant role in human craniofacial morphology. This is supported through cephalometric and anthropometric comparisons of family members including between triplets, twins, siblings, and parents and children. Genetic Experimentation
Genetic factors of craniofacial clefting can be investigated and tracked through several methods including sequencing in humans, Genome-wide association studies (GWAs), fate mapping, expression analysis, and animal studies (knockout experiments or models with clefting from chemical mutagenesis). Twin studies and familial clustering have also revealed that facial structure and formation are genetically linked.
It was found that paroxetine, an inhibitor of CYP2D6, increased the bioavailability of galantamine by 40%. The CYP3A4 inhibitors ketoconazole and erythromycin increased the bioavailability of galantamine by 30% and 12%, respectively. Synthesis
Galantamine is produced from natural resources, but also has many industrial syntheses. Companies such as Janssen, Ortho-McNeil Pharmaceutical, Sanochemia Pharmazeutika, Shire, and Takeda Pharmaceutical Company have industrial processes for synthesizing Galantamine. Research
Organophosphate poisoning
The toxicity of organophosphates results primarily from their action as irreversible inhibitors of acetylcholinesterase. Inhibiting acetylcholinesterase causes an increase in acetylcholine, as the enzyme is no longer available to catalyze its breakdown. In the peripheral nervous system, acetylcholine accumulation can cause an overstimulation of muscarinic receptors followed by a desensitization of nicotinic receptors. This leads to severe skeletal muscle fasciculations (involuntary contractions). The effects on the central nervous system include anxiety, restlessness, confusion, ataxia, tremors, seizures, cardiorespiratory paralysis, and coma. As a reversible acetylcholinesterase inhibitor, galantamine has the potential to serve as an effective organophosphate poisoning treatment by preventing irreversible acetylcholinesterase inhibition. Additionally, galantamine has anticonvulsant properties which may make it even more desirable as an antidote.Research supported in part by the US Army has led to a US patent application for the use of galantamine and/or its derivatives for treatment of organophosphate poisoning. The indications for use of galantamine in the patent application include poisoning by nerve agents "including but not limited to soman, sarin, and VX, tabun, and Novichok agents".