Physicochemical determinants of passive membrane permeability: role of solute hydrogen-bonding potential and volume.

The relationship of solute structure with cellular permeability was probed. Two series of dipeptide mimetics consisting of glycine, alanine, valine, leucine, phenylalanine, and cyclohexylalanine with amino acids in the D-configuration were prepared. Partition coefficients for the peptidemimetics were obtained in the octanol/water (log P(octanol/water)), hydrocarbon/octanol (Delta log P), and heptane/ethylene glycol (log P(heptane/glycol)) systems in order to explore the contributions of solute volume, or surface area, and hydrogen-bond potential to the permeability of the solutes. Permeability coefficients were obtained in Caco-2 cell monolayers as a model of the human intestinal mucosa. The results were interpreted in terms of a partition/diffusion model for solute transport where membrane partitioning into the permeability-limiting membrane microdomain is estimated from the solvent partition coefficients. Neither log P(octanol/water) nor Delta log P alone correlated with cellular permeability for all the solutes. In contrast, log P(heptane/glycol) gave a qualitatively better correlation. With regard to solute properties, log P(octanol/water) is predominantly a measure of solute volume, or surface area, and hydrogen-bond acceptor potential, while Delta log P is principally a measure of hydrogen-bond donor strength. Log P(heptane/glycol) contains contributions from all these solute properties. The results demonstrate that both hydrogen-bond potential and volume of the solutes contribute to permeability and suggests that the nature of the permeability-limiting microenvironment within the cell depends on the properties of a specific solute. Collectively, these findings support the conclusion that a general model of permeability will require consideration of a number of different solute structural properties.

Central pontine myelinolysis as a complication of partial ornithine carbamoyl transferase deficiency.

Central pontine myelinolysis (CPM) is a demyelinating condition of the central pons with or without associated foci of demyelination in extrapontine areas. We present a case of partial ornithine carbamoyl transferase deficiency in a 5-year-old girl which was complicated by CPM. The patient was a previously undiagnosed girl who presented with mild hyperammonemic encephalopathy with a maximum plasma ammonia level of 376 microM on admission. Laboratory testing established the diagnosis of OCT deficiency, and therapy with hydration and protein restriction was successful in returning the plasma ammonia levels to normal. Five days after correction of her hyperammonemia, the patient developed intractable seizures and coma. Serial MRI scans of the brain revealed the evolution of the characteristic findings of CPM. Plasma ammonia and electrolyte concentrations were well controlled throughout this time. This represents the first description of CPM in a patient with a urea cycle defect.

Blinded prospective evaluation of sensitivity of MR angiography to known intracranial aneurysms: importance of aneurysm size.

PURPOSE: To determine the sensitivity of time-of-flight and phase-contrast MR angiography for the detection of intracranial aneurysms. METHODS: Sixteen patients with 27 intracranial aneurysms previously identified with conventional angiography and 19 control patients were examined with three-dimensional time-of-flight, three-dimensional phase-contrast MR angiography, and standard MR imaging. Subvolumes of the carotid and posterior circulations, source images, and standard MR images were blindly interpreted by three experienced neuroradiologists. RESULTS: Detection of an aneurysm by a given sequence was defined as at least two of the three blinded readers identifying the aneurysm. The sensitivities of the sequences based on all 27 aneurysms were: transaxial T1, 25.9%; T2, 48.1%; PC, 44.4%; and TF, 55.6%. Two of 3 aneurysms detected with T2 but not MR angiography had adjacent blood products. Five millimeters appeared to be a critical size; the sensitivities for aneurysms greater than or equal to 5 mm were: T1, 37.5%; T2, 62.5%; PC, 75%; and TF, 87.5%. CONCLUSIONS: Three-dimensional time-of-flight MR with 512 x 256 matrix is more sensitive than three-dimensional phase-contrast or standard MR imaging for detection of aneurysms. Retrospectively, aneurysms 3 mm or larger can be identified with MR angiography; however, prospectively, 5 mm is the critical size for detection.

Maintaining zebu Maure cattle in a tsetse infested area of Mali. II. Epidemiological considerations.

Scheduled monitoring of tsetse and other biting flies at Tienfala Forest, Republic of Mali from December 1979 until June 1981 yielded more than 14,500 specimens. Comparisons of the monthly totals of tsetse and other biting flies with the monthly incidence of bovine trypanosomiasis in sentinel cattle suggested that biological transmission by a single riverine species of tsetse, Glossina palpalis gambiensis, accounted for most if not all disease transmission at the study site. The data obtained also suggested that human decisions had contributed to the magnitude if not the degree of the disease problem at the study site and that viable solutions to the disease problem exist.

Maintaining zebu Maure cattle in a tsetse infested area of Mali.

A study was initiated to evaluate two trypanocidal drugs, the prophylactic isometamidium chloride (Trypamidium) and the curative diminazene aceturate (Berenil) as to their potential for long-term maintenance of zebu cattle in a tsetse infested area of Mali. Trypamidium was administered quarterly and Berenil was administered only as animals were found to be positive for trypanosomes. During the 21-month study trypanosomiasis was the most frequently encountered disease in the cattle in the Berenil treatment group with an average of 5.5 reinfections. The predominant trypanosome species encountered was Trypanosoma vivax and the most important vector was Glossina palpalis gambiensis. The results indicate that, even though the direct costs for drugs under the two maintenance regimens were almost identical, the use of Trypamidium resulted in a significantly greater annual weight gain, prevented death loss due to trypanosomiasis and resulted in a herd with a greater market value.

Strategies toward predicting peptide cellular permeability from computed molecular descriptors.

The therapeutic efficacy of an orally administered drug is dictated not only by its pharmacological properties such as potency and selectivity, but also its pharmacokinetic properties such as its access to the site of activity. Thorough evaluation of the physicochemical and biological barriers to drug delivery is essential to the selection and successful development of drug candidates. We have demonstrated previously that cellular permeability, as a primary component of drug delivery, is principally dependent upon the desolvation potential of the polar functionalities in the molecule and, secondarily, upon the solute lipophilicity [Conradi, R.A., Hilgers, A.R., Ho, N.F.H., Burton, P.S. (1992). The influence of peptide structure on transport across Caco-2 cells. II. Peptide bond modification which results in improved permeability. Pharm. Res. 9, 473-479]. Increasingly sophisticated computational methods are becoming available for describing molecular structural features proposed to correlate with such molecular physicochemical determinants of permeability. Herein we examine the relationships of various computationally derived molecular geometric descriptors for a set of peptides and peptidomimetics, in the context of experimentally measured hydrogen-bond potentials and lipophilicities, with their cellular permeabilities. These descriptors include molecular volume, polar and non-polar surface areas and projected molecular cross-sectional areas. Particular attention is paid to the roles of solvation treatments and other computational factors in descriptor generation, deconvolution of cellular transport mechanisms and statistical analyses of the resulting data for the development of valid, structure-based and mechanistically meaningful models of cellular permeability. No significant correlation of cellular permeability with computed descriptors was found. This was primarily because of our inability to identify surrogates for hydrogen-bond desolvation potential for the solutes from among these descriptors.

An NMR study of conformations of substituted dipeptides in dodecylphosphocholine micelles: implications for drug transport.

Efficient transport of intact drug (solute) across the intestinal epithelium is typically a requirement for good oral activity. In general, the membrane permeability of a solute is a complex function of its size, lipophilicity, hydrogen bond potential, charge, and conformation. In conjunction with theoretical/computational and in vitro drug transport studies, seven dipeptide (R(1)-D-Xaa-D-Phe-NHMe) homologues were each dissolved in a micellar d(38)-dodecylphosphocholine solvent system. In this homologous dipeptide series, factors such as size, lipophilicity, hydrogen-bond potential, and charge were either tightly controlled or well-characterized by other methods in order to investigate by nmr how conformational factors relate to transport. Nuclear Overhauser effect spectroscopy experiments and amide-NH-H(2)O chemical exchange rates showed that the five more lipophilic dipeptides were predominately associated with micelle, whereas the two less lipophilic analogues were not. Rotating frame nuclear Overhauser effect spectroscopy derived interproton distance restraints for each analogue, along with (3)J(HH)-derived dihedral restraints, were used in molecular dynamics/simulated annealing computations. Our results suggest that-other factors being equal-flexible dipeptides having a propensity to fold together nonpolar N- and C-terminal moieties allow greater segregation of polar and nonpolar domains and may possess enhanced transport characteristics. Dipeptides that were less flexible or that retained a less amphiphilic conformation did not have comparably enhanced transport characteristics. We suggest that these conformational/transport correlations may hold true for small, highly functionalized solutes (drugs) in general.