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Recent structural studies on libraries of cyclic hexapeptides led to the identification of common backbone conformations that may be instrumental to the oral availability of peptides. Furthermore, the observation of differential Caco-2 permeabilities of enantiomeric pairs of some of these peptides strongly supports the concept of conformational specificity driven uptake and also suggests a pivotal role of carrier-mediated pathways for peptide transport, especially for scaffolds of polar nature. This work presents investigations on the Caco-2 and PAMPA permeability profiles of 13 selected N-methylated cyclic pentaalanine peptides derived from the basic cyclo(-D-Ala-Ala4 -) template. These molecules generally showed moderate to low transport in intestinal epithelia with a few of them exhibiting a Caco-2 permeability equal to or slightly higher than that of mannitol, a marker for paracellular permeability. We identified that the majority of the permeable cyclic penta- and hexapeptides possess an N-methylated cis-peptide bond, a structural feature that is also present in the orally available peptides cyclosporine A and the tri-N-methylated analogue of the Veber-Hirschmann peptide. Based on these observations it appears that the presence of N-methylated cis-peptide bonds at certain locations may promote the intestinal permeability of peptides through a suitable conformational preorganization.

Seven 4-phenoxybenzenesulfonamidopolymethylene carbamoylphosphonates (CPOs) bearing two to eight methylene units in the polymethylene chain were synthesized and evaluated as matrix metalloproteinase (MMP) inhibitors. The five lowest homologues [(CH₂)₂-₆] are selective MMP-2 inhibitors, whereas the two with the longest linkers [(CH₂)₇,₈] lack inhibitory activity. The most potent homologues are those with (CH₂)₅,₆; these two were evaluated for antimetastatic activity in a murine melanoma model and showed good potency both by oral and intraperitoneal administration without any toxic--including musculoskeletal--side effects. In contrast to the previously reported cis-ACCP, which was shown to inhibit MMP-2 for ∼30 min, the new compounds inhibit MMP activity for the duration of measurement, lasting several hours. Pharmacokinetic evaluation revealed, on the one hand, low oral bioavailability; on the other hand, a relatively large calculated volume of distribution, consistent with the observed reversible absorption of CPO 5 to hydroxyapatite, as a model for bone.

Beta-lactam antimicrobials, commonly used in both veterinary and human medicine, generally present short biologic half-lives, whereas their activity is enhanced as pathogen exposure is prolonged. These properties necessitate multiple-dose regimens of standard dosage forms, thereby hampering pet owner adherence, frequently resulting in therapeutic failure. This study presents a novel controlled-release gastroretentive oral drug delivery system for beta-lactams with which single-dose administration provides an effective antimicrobial course, optimizing pharmacokinetic (PK)-pharmacodynamic (PD) profiles, minimizing adverse effects and emergence of antimicrobial resistance and facilitating adherence. Our prototype sustained-delivery swelling-tablet (SDST), based on a degradable hydrophilic polymeric matrix, was designed to enable continuous input of these drugs to their absorption sites over several days. Several SDST formulations of the beta-lactam amoxicillin were evaluated in in vitro dissolution studies. Two formulations were selected for further in vivo canine studies, for determination of gastric retention and PK-PD profiling. Prolonged gastric retention times maintaining allowed for maintained effective drug concentrations against many clinically relevant pathogens for more than 48 h for one formulation and more than 5 days for the other. Both SDST formulations offer significant advantages over standard immediate-release therapy in achieving PK-PD goals and enhancing adherence. The prototypical formulations represent a novel platform which may be modified to meet various clinical requirements.

Dosage forms of antimicrobials play a critical role in facilitating the attainment of pharmacokinetic-pharmacodynamic (PK-PD) targets as well as adherence in both veterinary and human medicine. The purpose of this study was to develop and evaluate a controlled-release subcutaneous amoxicillin implant for single-dose therapy of large ruminants such as goats, sheep, and deer. The degradable implant, designed to attain PK-PD targets following single administration, was evaluated for amoxicillin release rate and time-concentration profile. In vitro release studies demonstrated constant-rate release of approximately 40% of amoxicillin content within 96 h. In an in vivo study in goats, serving as a model for target animals, a serum concentration of approximately 0.4 mg/L was achieved within 8 h of implant insertion and maintained for >6 days. In comparison, in control goats given a standard single intramuscular amoxicillin dose of 15 mg/kg, amoxicillin peaked at 1.2 mg/L after 1 h, rapidly dropping to below detection level at 8 h. These results suggest that the proposed implant offers a unique modality for animal caregivers to conveniently administer a full antimicrobial course following a single dose of an efficient PK-PD-optimized dosage form. Furthermore, modifications of implant composition may allow for tailoring of its characteristics to various PK, PD, microbiological, and clinical requirements.

Several case reports indicate that carbapenem antibiotics, especially meropenem, may decrease the plasma concentrations of valproic acid (VPA), thus decreasing its therapeutic activity. To investigate the onset, severity, and dose dependency of the interaction between meropenem and VPA, the authors carried out a retrospective evaluation of data collected during 24 months from patients hospitalized in a tertiary medical center. The analysis included 36 patients. VPA mean +/- SEM plasma concentration decreased from of 50.8 +/- 4.5 microg/mL to 9.9 +/- 2.1 microg/mL (P < .001) following meropenem administration. After discontinuation of meropenem, VPA plasma concentrations remained low for 7 days and then gradually increased after 8 to 14 days, reaching values comparable to those before meropenem initiation. Different daily VPA doses showed a similar pattern of decreased VPA concentrations. The mean decrease in individual plasma VPA concentration was 82.1% +/- 2.7%. The mean VPA plasma concentration of patients in whom samples were drawn within 24 hours of meropenem initiation was 9.9 +/- 3.2 microg/mL. In conclusion, the interaction between meropenem and VPA causes a significant decrease in VPA plasma concentration, apparently within 24 hours. As the therapeutic effects of VPA are plasma concentration dependent, the data suggest that these drugs should not be administered concomitantly.

Objective Metformin is a polar positively charged compound. The aim of the study was to characterize its permeability across the human placenta using the ex vivo placental perfusion model. Methods Selected cotyledons from term placentas were cannulated and dually perfused. Metformin (10 mg/L, 1000 mg/L) and a permeability reference, antipyrine (50 mg/L), were added to the maternal circulation. Samples from maternal and fetal compartments were analyzed for metformin and antipyrine by high performance liquid chromatography (HPLC). The permeation of metformin was also studied using the parallel artificial membrane permeation assay (PAMPA) that was designed to predict passive transcellular permeability of drugs. Results In this study, 15 complete placental perfusion experimental set-ups were performed. The mean percent transport increased as metformin concentrations were raised and it was 11 ± 1.32 and 16.92 ± 0.98 for 10 mg/L and 1000 mg/L, respectively. The transport rate of metformin across the placenta was asymmetric yet, an active efflux against the gradient concentration could not be observed. Using the PAMPA assay, we confirmed that metformin does not cross by passive diffusion. Conclusion The data suggest that metformin permeability across the placenta is mediated by a carrier that transport cationic compounds bi-directionally, with a higher transfer rate from the fetal to the maternal side. Copyright © 2008 John Wiley & Sons, Ltd.

The potential of peptides as drug candidates is limited by their poor pharmacokinetic properties. Many peptides have a short half-life in vivo and a lack of oral availability. Inspired by the excellent pharmacokinetic profile of cyclosporine, a natural, multiply N-methylated cyclic peptide, we envisioned multiple N-methylation as a promising way to rationally improve key pharmacokinetic characteristics. In this Account, we summarize our efforts toward modulating the properties of peptides by multiple N-methylation. As a first step, we simplified the synthesis of N-methylated amino acids in solution, by employing very mild conditions that could be tolerated by the diverse protecting groups required when working with naturally occurring amino acids. We also report the rapid and inexpensive syntheses of N-methylated peptides on a solid support; this facilitated the N-methyl scanning of bioactive peptides. Because of a lack of information regarding the conformational behavior of multiply N-methylated peptides...

The present study aimed to investigate whether the pharmacodynamics of a lipophilic barbiturate, heptabarbital, is altered by liver dysfunction. Heptabarbital was slowly infused i.v., to rats with liver necrosis induced by carbon-tetrachloride, until the rats lost their righting reflex. The concentrations of the drug in serum, brain and CSF were determined in both the diseased animals and solvent-treated controls. Although the concentrations of heptabarbital in the CSF, serum and brain were not significantly different between controls and diseased rats, the total heptabarbital dose required to induce sleep was markedly lower in the diseased animals. Accordingly, the pharmacodynamics of heptabarbital is unaffected in experimental liver dysfunction in rats.