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l-Type amino acid transporter 1 (LAT1) is an interesting protein due to its peculiar expression profile. It can be utilized not only as a carrier for improved or targeted drug delivery, e.g., into the brain but also as a target protein by which amino acid supply can be restricted, e.g., from the cancer cells. The recognition and binding processes of LAT1-ligands, such as amino acids and clinically used small molecules, including l-dopa, gabapentin, and melphalan, are today well-known. Binding to LAT1 is crucial, particularly when designing the LAT1-inhibitors. However, it will not guarantee effective translocation across the cell membrane via LAT1, which is a definite requirement for LAT1-substrates, such as drugs that elicit their pharmacological effects inside the cells. Therefore, in the present study, the accumulation of known LAT1-utilizing compounds into the selected LAT1-expressing cancer cells (MCF-7) was explored experimentally over a time period. The differences found among the transport efficiency and affinity of the studied compounds for LAT1 were subsequently explained by docking the ligands into the human LAT1 model (based on the recent cryo-electron microscopy structure). Thus, the findings of this study clarify the favorable structural requirements of the size, shape, and polarity of the ligands that support the translocation and effective transport across the cell membrane via LAT1. This knowledge can be applied in future drug design to attain improved or targeted drug delivery and hence, successful LAT1-utilizing drugs with increased therapeutic effects., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Spirocyclic 1-oxa-9-azaspiro[5.5]undecan-4-amine scaffold was explored as a basis for the design of potential inhibitors of soluble epoxide hydrolase (sEH). Synthesis and testing of the initial SAR-probing library followed by biochemical testing against sEH allowed nominating a racemic lead compound (±)-22. The latter showed remarkable (> 0.5 mM) solubility in aqueous phosphate buffer solution, unusually low (for sEH inhibitors) lipophilicity as confirmed by experimentally determined logD 7.4 of 0.99, and an excellent oral bioavailability in mice (as well as other pharmacokinetic characteristics). Individual enantiomer profiling revealed that the inhibitory potency primarily resided with the dextrorotatory eutomer (+)-22 (IC 50 4.99 ± 0.18 nM). For the latter, a crystal structure of its complex with a C-terminal domain of sEH was obtained and resolved. These data fully validate (+)-22 as a new non-racemic advanced lead compound for further development as a potential therapeutic agent for use in such areas as cardiovascular disease, inflammation and pain., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Mutations in SNCA are rare causes of familial Parkinson's disease (PD). We have previously described a novel p.Ala53Glu mutation in 2 Finnish families. To assess this mutation's frequency among Finnish PD patients, we screened 110 PD patients (mean age-of-onset 60 years) from Western Finland by Sanger sequencing of the third coding exon of SNCA. In addition, a sample of 47 PD subjects (mean age-of-onset 53 years) originating from Southern and Eastern Finland were studied using next-generation sequencing covering SNCA. Only one new individual with the p.Ala53Glu mutation was identified, confirming that this mutation is a rare cause of PD in the Finnish population. To search for a possible common origin of the p.Ala53Glu mutation, haplotype analysis was conducted in 2 families and in a patient from a third family (6 affected subjects) using both STR markers and a genome-wide SNP array. The results show that patients with the p.Ala53Glu mutation share a haplotype spanning a minimum of 5.7 Mb suggesting a common founder., (Copyright © 2016 Elsevier Inc. All rights reserved.)

In the present study, a previously described sulfenamide prodrug of a basic antidiabetic drug, metformin, was evaluated further. This sulfenamide prodrug was designed to improve the permeability and consequently the oral absorption and bioavailability (F) of the highly water-soluble metformin. Bioactivation of the prodrug was mediated by reduced glutathione, but it has been reported that sulfenamide prodrugs can also be bioactivated by other endogenous thiols like cysteine, and free thiol-containing proteins. Consistent with earlier findings for a sulfenamide prodrug of a weakly acid drug, linezolid, the permeability studies indicated that the metformin prodrug was also prematurely bioactivated on the apical surface of the Caco-2 cell monolayer. Nevertheless, the bioavailability of metformin was increased by approximately 25% after oral administration of the prodrug in rats, most probably because of better oral absorption. This indicates that the sulfenamide prodrug approach may be used to improve the moderate oral bioavailability of metformin, which may help to decrease the uncomfortable gastrointestinal adverse effects associated with metformin therapy as the daily doses of metformin can be reduced. Furthermore, the present study confirms that the applicability of the sulfenamide prodrug approach can be successfully extended from weak NH acids to very basic guanide-type drugs., (Copyright © 2012 Wiley Periodicals, Inc.)

Objectives: To compare 6-year-old children with unilateral cleft lip and palate (UCLP) and children with unilateral cleft lip and a separate cleft palate (CL+CP), cephalometrically and to evaluate the need for orthognathic surgery of these children in later life., Materials and Methods: One hundred and seven cleft children (67 UCLP, 40 CL+CP) were compared retrospectively using lateral cephalograms taken at a mean age of 6.2 years (range 5.7-7.3). The need for maxillary or bimaxillary osteotomies in these patients was evaluated from the hospital records at the mean age of 18.1 years (range 15.6-20.5)., Results: The craniofacial morphology of children with UCLP and CL+CP was similar except for a more retrusive maxilla in children with UCLP. The frequency of orthognathic surgery was 40% (27/67) in the UCLP group and 18% (7/40) in the CL+CP group. The patients who needed orthognathic surgery (UCLP and CL+CP combined) had smaller mean values of ANB angle at the age of 6 years when compared to those who did not (1.8 versus 3.9°). None of the children whose ANB angle was greater than 4.5 needed orthognathic surgery whereas all the children whose ANB angle was less than -1 needed osteotomies., Conclusion: Six-year-old children with UCLP have more retruded maxillae and require orthognathic surgery later in life more often than the children with CL+CP., (Copyright © 2010 European Association for Cranio-Maxillo-Facial Surgery. Published by Elsevier Ltd. All rights reserved.)

A series of acyloxyalkyl esters of ketoprofen and naproxen were synthesized and investigated as topical prodrugs with the aim of improving the dermal delivery of the drugs. In addition, some hydroxyalkyl esters of ketoprofen and naproxen were synthesized as possible intermediates of acyloxyalkyl prodrugs. All of the prodrugs were more lipophilic than their parent molecules, as evaluated by drug partitioning between 1-octanol and phosphate buffer at pH 7.4 (log Papp). However, their solubilities in aqueous solutions decreased markedly compared with the parent molecules. The prodrugs were stable toward chemical hydrolysis in aqueous solutions (pH 7.4), but were hydrolyzed to the parent drug both in 80% human serum and in human skin homogenate, with half-lives ranging from 4 to 137 min and from 13 to 403 min, respectively. The abilities of the selected naproxen acyloxyalkyl prodrugs to deliver naproxen through excised human skin were evaluated. Generally, the prodrugs showed similar dermal delivery as the parent drug through cadaver skin. In the present series of lipophilic prodrugs of naproxen, the prodrug with the highest aqueous solubility was the most effective prodrug to deliver naproxen through the skin.

The initial treatment of complicated fractures several days old when first seen in Afghan war wounded is reported for 52 limbs in 47 patients. External fixation was the method of choice for stabilizing fractures in adults. In children, traction and plaster-of-Paris were preferred. In 30 cases (58 per cent) tissue damage was classified as moderate. With radical wound toilet and delayed closure, infection could be controlled in most of these limbs. In 15 fractures (29 per cent) there was severe laceration and exposure of bone. After operation, deep infection persisted in three-quarters of these cases and the fate of these limbs often seemed doubtful. The patients usually refused amputation. However, of seven limbs (13 per cent) in which the fracture was associated with an arterial injury, only one could be saved. The brief period of observation of only 11 weeks does not permit assessment of time to healing, frequency of late osteitis or definitive amputation rate. It seems, however, that in spite of the lack of any proper first aid for these severe injuries, a functional limb could be salvaged in over two-thirds of the cases, even with our modest resources.