A Full Computerized Workflow for Planning Surgically Assisted Rapid Palatal Expansion and Orthognathic Surgery in a Skeletal Class III Patient

: In the present case report, we present and discuss the digital workflow involved in the orthodontic/orthognathic combined treatment of a skeletal malocclusion correction in a 17-year-old male patient affected by a skeletal class III, facial asymmetry, sagittal and transversal deficiency of the medium third of the skull, dental crowding, and bilateral cross-bite. The first stage of the treatment involved surgically assisted rapid palatal expansion and occlusal decompensation, using fixed self-ligating appliance. An orthodontic software package (i.e., Dolphin 3D Surgery module) was used to perform virtual treatment objective evaluation by integrating data from cone beam computer tomography acquisition, intraoral scan, and extraoral photographs. The software allowed a comprehensive evaluation of skeletal, dento-alveolar, and soft-tissue disharmonies, qualitative and quantitative simulation of surgical procedure according to skeletal and aesthetic objectives, and, consequently, the treatment of the malocclusion. Using a specific function of the software, the surgical splint was designed according to the pre-programmed skeletal movements, and subsequently, the physical splint was generated with a three-dimensional (3D) printing technology. Once a proper occlusal decompensation was reached, a Le Fort I osteotomy of the maxilla and a bilateral sagittal surgical osteotomy of the mandible were executed to restore proper skeletal relations. The whole treatment time was 8 months. The orthodontic/orthognathic combined treatment allowed to correct the skeletal and the dental imbalance, as well as the improvement of facial aesthetics. Accordingly, the treatment objectives planned in the virtual environment were achieved. Virtual planning offers new possibilities for visualizing the relationship between dental arches and surrounding bone and soft structures in a single virtual 3D model, allowing the specialists to simulate different surgical and orthodontic procedures to achieve the best possible result for the patient and providing an accurate and predictable outcome in the treatment of challenging malocclusions

Design and Mechanism of (S)-3-Amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic Acid, a Highly Potent γ-Aminobutyric Acid Aminotransferase Inactivator for the Treatment of Addiction

© 2018 American Chemical Society. γ-Aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the central nervous system. Inhibition of GABA aminotransferase (GABA-AT), a pyridoxal 5′-phosphate (PLP)-dependent enzyme that degrades GABA, has been established as a possible strategy for the treatment of substance abuse. The raised GABA levels that occur as a consequence of this inhibition have been found to antagonize the rapid release of dopamine in the ventral striatum (nucleus accumbens) that follows an acute challenge by an addictive substance. In addition, increased GABA levels are also known to elicit an anticonvulsant effect in patients with epilepsy. We previously designed the mechanism-based inactivator (1S,3S)-3-amino-4-difluoromethylenyl-1-cyclopentanoic acid (2), now called CPP-115, that is 186 times more efficient in inactivating GABA-AT than vigabatrin, the only FDA-approved drug that is an inactivator of GABA-AT. CPP-115 was found to have high therapeutic potential for the treatment of cocaine addiction and for a variety of epilepsies, has successfully completed a Phase I safety clinical trial, and was found to be effective in the treatment of infantile spasms (West syndrome). Herein we report the design, using molecular dynamics simulations, synthesis, and biological evaluation of a new mechanism-based inactivator, (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid (5), which was found to be almost 10 times more efficient as an inactivator of GABA-AT than CPP-115. We also present the unexpected crystal structure of 5 bound to GABA-AT, as well as computational analyses used to assist the structure elucidation process. Furthermore, 5 was found to have favorable pharmacokinetic properties and low off-target activities. In vivo studies in freely moving rats showed that 5 was dramatically superior to CPP-115 in suppressing the release of dopamine in the corpus striatum, which occurs subsequent to either an acute cocaine or nicotine challenge. Compound 5 also attenuated increased metabolic demands (neuronal glucose metabolism) in the hippocampus, a brain region that encodes spatial information concerning the environment in which an animal receives a reinforcing or aversive drug. This multidisciplinary computational design to preclinical efficacy approach should be applicable to the design and improvement of mechanism-based inhibitors of other enzymes whose crystal structures and inactivation mechanisms are known

Evaluation of hypothermia on the in vitro metabolism and binding and in vivo disposition of midazolam in rats

The effect of hypothermia on the in vivo pharmacokinetics of midazolam was evaluated, with a focus on altered metabolism in the liver and binding to serum proteins. Rat primary hepatocytes were incubated with midazolam (which is metabolized mainly by CYP3A2) at 37, 32 or 28℃. The Michaelis?Menten constant (Km) and maximum velocity (Vmax) of midazolam were estimated using the Michaelis?Menten equation. The Km of CYP3A2 midazolam remained unchanged, but the Vmax decreased at 28℃. In rats, whose temperature was maintained at 37, 32 or 28℃ by a heat lamp or ice pack, the plasma concentrations of midazolam were higher, whereas those in the brain and liver were unchanged at 28℃. The tissue/plasma concentration ratios were, however, increased significantly. The unbound fraction of midazolam in serum at 28?°C was half that at 37℃. These pharmacokinetic changes associated with hypothermic conditions were due to reductions in CYP3A2 activity and protein binding

From TgO/GABA-AT, GABA, and T-263 Mutant to Conception of Toxoplasma

Toxoplasma gondii causes morbidity, mortality, and disseminates widely via cat sexual stages. Here, we find T. gondii ornithine aminotransferase (OAT) is conserved across phyla. We solve TgO/GABA-AT structures with bound inactivators at 1.55 Å and identify an inactivator selective for TgO/GABA-AT over human OAT and GABA-AT. However, abrogating TgO/GABA-AT genetically does not diminish replication, virulence, cyst-formation, or eliminate cat's oocyst shedding. Increased sporozoite/merozoite TgO/GABA-AT expression led to our study of a mutagenized clone with oocyst formation blocked, arresting after forming male and female gametes, with “Rosetta stone”-like mutations in genes expressed in merozoites. Mutations are similar to those in organisms from plants to mammals, causing defects in conception and zygote formation, affecting merozoite capacitation, pH/ionicity/sodium-GABA concentrations, drawing attention to cyclic AMP/PKA, and genes enhancing energy or substrate formation in TgO/GABA-AT-related-pathways. These candidates potentially influence merozoite's capacity to make gametes that fuse to become zygotes, thereby contaminating environments and causing disease

From TgO/GABA-AT, GABA, and T-263 mutant to conception of Toxoplasma

Toxoplasma gondii causes morbidity, mortality, and disseminates widely via cat sexual stages. Here, we find T. gondii ornithine aminotransferase (OAT) is conserved across phyla. We solve TgO/GABA-AT structures with bound inactivators at 1.55 Å and identify an inactivator selective for TgO/GABA-AT over human OAT and GABA-AT. However, abrogating TgO/GABA-AT genetically does not diminish replication, virulence, cyst-formation, or eliminate cat’s oocyst shedding. Increased sporozoite/merozoite TgO/GABA-AT expression led to our study of a mutagenized clone with oocyst formation blocked, arresting after forming male and female gametes, with “Rosetta stone”-like mutations in genes expressed in merozoites. Mutations are similar to those in organisms from plants to mammals, causing defects in conception and zygote formation, affecting merozoite capacitation, pH/ionicity/sodium-GABA concentrations, drawing attention to cyclic AMP/PKA, and genes enhancing energy or substrate formation in TgO/GABA-AT-related-pathways. These candidates potentially influence merozoite’s capacity to make gametes that fuse to become zygotes, thereby contaminating environments and causing disease

Synthesis And Manipulation Of Carbasugars And Natural Product Scaffolds

My doctoral studies have focused on the construction of natural products and diversification of complex natural product scaffolds. A specific natural product with interesting bioactivity, sch202596, an antagonist for the galinin receptor, contains two moieties that formed the basis for my graduate studies: a carbasugar and a spirocoumaranone (dienone). Work, therefore, focused on two areas: (1) asymmetric regio-resolution of allylic oxides for the synthesis and incorporation of spirocyclization. carbasugars; and (2) asymmetric hypervalent iodide oxidative A system was developed in which a racemic allylic oxide underwent a Tsuji-Trost allylation to yield four different enantioenriched regioisomers which were carried onto four different carbasugar natural products: streptol, MK7607, cyathiformine B and polyporapyranone G. This method, termed allylic oxide regio resolution (AORR), allowed for the control of product distribution through prudent ligand and protecting group selection. Additionally, AORR allowed for the incorporation of carbasugars into phenolic natural product scaffolds. Rubiyunnanin B, a glycosidic macrocyclic peptide with an interesting bioactivity profile was one particular natural product scaffold which could be subjected to AORR. A short synthesis of the rubiyunnanin B aglycone was developed and 1H NMR analysis was used to determine the overall structure of the core. The second area of research resulted in the synthesis of arnottin II through hypervalent iodine mediated oxidative spirocyclization

Synthesis of ( S)-3-Amino-4-(difluoromethylenyl)-cyclopent-1-ene-1-carboxylic Acid (OV329), a Potent Inactivator of γ-Aminobutyric Acid Aminotransferase

( S)-3-Amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid (OV329, 1) is being developed for the treatment of epilepsy and addiction. The previous 14-step synthesis of OV329 was low yielding, involved an unselective α-elimination to form the cyclopentene, required the use of tert-butyllithium, and produced toxic selenium byproducts in the penultimate step. A new synthesis, which avoids the aforementioned issues, was carried out on large scale, reducing the step count from 14 to 9 steps and increasing the overall yield from 3.7% to 8.1%

Syntheses of Arnottin I and Arnottin II

Short total syntheses of arnottin I and II were accomplished in 5 and 6 steps, respectively. A sesamol-benzyne cycloaddition with a 3-furyl-benzoate followed by regiospecific lactonization provided rapid, large-scale access to the core of arnottin I. Saponification of arnottin I and hypervalent iodide mediated spirocyclization provided an efficient and direct preparation of racemic arnottin II

Regiodivergent Addition of Phenols to Allylic Oxides

The regiodivergent addition of substituted phenols to allylic oxides has been demonstrated using <i>C</i>₂-symmetric palladium complexes. Complex phenol donors tyrosine, estradiol, and griseofulvin follow the predictive model