Diversity-directed synthesis based on the cascade allylation chemistry of indigo, with its embedded 2,2’-diindolic core, has resulted in rapid access to new examples of the hydroxy-8a,13-dihydroazepino[1,2-a:3,4-b']diindol-14(8H)-one skeleton in up to 51% yield. Additionally a derivative of the novel bridged heterocycle 7,8-dihydro-6H-6,8a-epoxyazepino[1,2-a:3,4-b']diindol-14(13H)-one was produced when the olefin of the allylic substrate was terminally disubstituted. Further optimisation also produced viable one-pot syntheses of derivatives of the spiro(indoline-2,9'-pyrido[1,2-a]indol)-3-one (65%) and pyrido[1,2,3-s,t]indolo[1,2-a]azepino[3,4-b]indol-17-one (72%) heterocyclic systems. Ring-closing metathesis of the N,O-diallylic spiro structure and subsequent Claisen rearrangement gave rise to the new (1R,8aS,17aS)-rel-1,2-dihydro-1-vinyl-8H,17H,9H-benz[2',3']pyrrolizino[1',7a':2,3]pyrido[1,2-a]indole-8,17-(2H,9H)-dione heterocyclic system.

Chlorpromazine is a phenothiazine-derived antipsychotic drug (APD) that inhibits clathrin-mediated endocytosis (CME) in cells by an unknown mechanism. We examined whether its action and that of other APDs might be mediated by the GTPase activity of dynamin. Eight of eight phenothiazine-derived APDs inhibited dynamin I (dynI) in the 2–12 µm range, the most potent being trifluoperazine (IC50 2.6 ± 0.7 µm). They also inhibited dynamin II (dynII) at similar concentrations. Typical and atypical APDs not based on the phenothiazine scaffold were 8- to 10-fold less potent (haloperidol and clozapine) or were inactive (droperidol, olanzapine and risperidone). Kinetic analysis showed that phenothiazine-derived APDs were lipid competitive, while haloperidol was uncompetitive with lipid. Accordingly, phenothiazine-derived APDs inhibited dynI GTPase activity stimulated by lipids but not by various SH3 domains. All dynamin-active APDs also inhibited transferrin (Tfn) CME in cells at related potencies. Structure–activity relationships (SAR) revealed dynamin inhibition to be conferred by a substituent group containing a terminal tertiary amino group at the N2 position. Chlorpromazine was previously proposed to target AP-2 recruitment in the formation of clathrin-coated vesicles (CCV). However, neither chlorpromazine nor thioridazine affected AP-2 interaction with amphiphysin or clathrin. Super-resolution microscopy revealed that chlorpromazine blocks neither clathrin recruitment by AP-2, nor AP-2 recruitment, showing that CME inhibition occurs downstream of CCV formation. Overall, potent dynamin inhibition is a shared characteristic of phenothiazine-derived APDs, but not other typical or atypical APDs, and the data indicate that dynamin is their likely in-cell target in endocytosis.

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The objective of this study was to investigate the effect of polypharmacy and high doses of amoxicillin/clavulanate on warfarin response in hospitalized patients. This was a prospective cross-sectional observational study on 120 patients from July 2013 to January 2014. Potentially interacting drugs were classified according to their tendency of increasing international normalized ratio (INR) or bleeding risk. The 87.5% of patients prescribed high-dose amoxicillin/clavulanate (10-12 g daily) compared with 28.9% of patients prescribed a normal dose (up to 3.6 g daily) had INR values ≥ 4 during the hospital stay (P ≤ .001). Increased number of potentially interacting drugs that are known to increase INR was a significant predictor of having INR values ≥ 4 (OR, 2.5; 95%CI, 1.3-4.7), and increased number of potentially interacting drugs that are known to increase bleeding risk was a significant predictor of experiencing bleeding episodes (OR, 3.1; 95%CI, 1.3-7.3). High doses of amoxicillin/clavulanate were associated with a higher risk of over-anticoagulation when combined with warfarin than were normal doses. Increased risk of having INR ≥ 4 and bleeding events was associated with increased numbers of potentially interacting drugs prescribed, indicating that polypharmacy is a problem of concern. Frequent monitoring of warfarin therapy along with patients' medications is necessary to avoid complications.

The objective of this study was to investigate the effect of polypharmacy and high doses of amoxicillin/clavulanate on warfarin response in hospitalized patients. This was a prospective cross-sectional observational study on 120 patients from July 2013 to January 2014. Potentially interacting drugs were classified according to their tendency of increasing international normalized ratio (INR) or bleeding risk. The 87.5% of patients prescribed high-dose amoxicillin/clavulanate (10-12 g daily) compared with 28.9% of patients prescribed a normal dose (up to 3.6 g daily) had INR values ≥ 4 during the hospital stay (P ≤ .001). Increased number of potentially interacting drugs that are known to increase INR was a significant predictor of having INR values ≥ 4 (OR, 2.5; 95%CI, 1.3-4.7), and increased number of potentially interacting drugs that are known to increase bleeding risk was a significant predictor of experiencing bleeding episodes (OR, 3.1; 95%CI, 1.3-7.3). High doses of amoxicillin/clavulanate were associated with a higher risk of over-anticoagulation when combined with warfarin than were normal doses. Increased risk of having INR ≥ 4 and bleeding events was associated with increased numbers of potentially interacting drugs prescribed, indicating that polypharmacy is a problem of concern. Frequent monitoring of warfarin therapy along with patients' medications is necessary to avoid complications.

The objective of this study was to investigate the effect of polypharmacy and high doses of amoxicillin/clavulanate on warfarin response in hospitalized patients. This was a prospective cross-sectional observational study on 120 patients from July 2013 to January 2014. Potentially interacting drugs were classified according to their tendency of increasing international normalized ratio (INR) or bleeding risk. The 87.5% of patients prescribed high-dose amoxicillin/clavulanate (10-12 g daily) compared with 28.9% of patients prescribed a normal dose (up to 3.6 g daily) had INR values ≥ 4 during the hospital stay (P ≤ .001). Increased number of potentially interacting drugs that are known to increase INR was a significant predictor of having INR values ≥ 4 (OR, 2.5; 95%CI, 1.3-4.7), and increased number of potentially interacting drugs that are known to increase bleeding risk was a significant predictor of experiencing bleeding episodes (OR, 3.1; 95%CI, 1.3-7.3). High doses of amoxicillin/clavulanate were associated with a higher risk of over-anticoagulation when combined with warfarin than were normal doses. Increased risk of having INR ≥ 4 and bleeding events was associated with increased numbers of potentially interacting drugs prescribed, indicating that polypharmacy is a problem of concern. Frequent monitoring of warfarin therapy along with patients' medications is necessary to avoid complications.

The objective of this study was to investigate the effect of polypharmacy and high doses of amoxicillin/clavulanate on warfarin response in hospitalized patients. This was a prospective cross-sectional observational study on 120 patients from July 2013 to January 2014. Potentially interacting drugs were classified according to their tendency of increasing international normalized ratio (INR) or bleeding risk. The 87.5% of patients prescribed high-dose amoxicillin/clavulanate (10-12 g daily) compared with 28.9% of patients prescribed a normal dose (up to 3.6 g daily) had INR values ≥ 4 during the hospital stay (P ≤ .001). Increased number of potentially interacting drugs that are known to increase INR was a significant predictor of having INR values ≥ 4 (OR, 2.5; 95%CI, 1.3-4.7), and increased number of potentially interacting drugs that are known to increase bleeding risk was a significant predictor of experiencing bleeding episodes (OR, 3.1; 95%CI, 1.3-7.3). High doses of amoxicillin/clavulanate were associated with a higher risk of over-anticoagulation when combined with warfarin than were normal doses. Increased risk of having INR ≥ 4 and bleeding events was associated with increased numbers of potentially interacting drugs prescribed, indicating that polypharmacy is a problem of concern. Frequent monitoring of warfarin therapy along with patients' medications is necessary to avoid complications.

The aim of this study was to improve the bioavailability of water-insoluble, anti-emetic drug; domperidone (DMP) which has a poor oral bioavailability (13-17%) due to its extensive first pass metabolism. Solid dispersions of DMP with pluronic F-68 were prepared at different weight ratios by fusion method and they were tested for their in-vitro dissolution rate to select the best ratio for tablet formulation. Then, the selected solid dispersions were incorporated into sublingual tablets together with different water-soluble excipients. Sublingual tablets were prepared by direct compression technique and they were evaluated for their physical properties and in-vitro dissolution rate. Sublingual tablets formulae S4 (containing fructose and 10% w/w Ac-Di-Sol) and S8 (containing fructose and 10% w/w Explotab) showed the best results and thus; they were selected for in-vivo studies in rabbits in comparison with the commercially-available oral tablets; Motinorm®. The selected formulae showed marked enhancement of DMP bioavailability compared with the marketed oral tablets, with relative bioavailability values of 432.49 ±10.13% and 409.32 ±11.59 % for S4 and S8, respectively. The results confirmed that sublingual tablets were promising tool for DMP delivery with marked enhancement of bioavailability.

The aim of this study was to improve the bioavailability of water-insoluble, anti-emetic drug; domperidone (DMP) which has a poor oral bioavailability (13-17%) due to its extensive first pass metabolism. Solid dispersions of DMP with pluronic F-68 were prepared at different weight ratios by fusion method and they were tested for their in-vitro dissolution rate to select the best ratio for tablet formulation. Then, the selected solid dispersions were incorporated into sublingual tablets together with different water-soluble excipients. Sublingual tablets were prepared by direct compression technique and they were evaluated for their physical properties and in-vitro dissolution rate. Sublingual tablets formulae S4 (containing fructose and 10% w/w Ac-Di-Sol) and S8 (containing fructose and 10% w/w Explotab) showed the best results and thus; they were selected for in-vivo studies in rabbits in comparison with the commercially-available oral tablets; Motinorm®. The selected formulae showed marked enhancement of DMP bioavailability compared with the marketed oral tablets, with relative bioavailability values of 432.49 ±10.13% and 409.32 ±11.59 % for S4 and S8, respectively. The results confirmed that sublingual tablets were promising tool for DMP delivery with marked enhancement of bioavailability.

The aim of this study was to improve the bioavailability of water-insoluble, anti-emetic drug; domperidone (DMP) which has a poor oral bioavailability (13-17%) due to its extensive first pass metabolism. Solid dispersions of DMP with pluronic F-68 were prepared at different weight ratios by fusion method and they were tested for their in-vitro dissolution rate to select the best ratio for tablet formulation. Then, the selected solid dispersions were incorporated into sublingual tablets together with different water-soluble excipients. Sublingual tablets were prepared by direct compression technique and they were evaluated for their physical properties and in-vitro dissolution rate. Sublingual tablets formulae S4 (containing fructose and 10% w/w Ac-Di-Sol) and S8 (containing fructose and 10% w/w Explotab) showed the best results and thus; they were selected for in-vivo studies in rabbits in comparison with the commercially-available oral tablets; Motinorm®. The selected formulae showed marked enhancement of DMP bioavailability compared with the marketed oral tablets, with relative bioavailability values of 432.49 ±10.13% and 409.32 ±11.59 % for S4 and S8, respectively. The results confirmed that sublingual tablets were promising tool for DMP delivery with marked enhancement of bioavailability.