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Biomedical subjects

J R Robinson

Publications and source records attributed to J R Robinson.

At least 19 recordsLinked to original sources
PubMed1992

Drug delivery via the mucous membranes of the oral cavity.

The delivery of drugs via the mucous membranes lining the oral cavity (i.e., sublingual and buccal), with consideration of both systemic delivery and local therapy, is reviewed in this paper. The structure and composition of the mucosae at different sites in the oral cavity, factors affecting mucosal permeability, penetration enhancement, selection of appropriate experimental systems for studying mucosal permeability, and formulation factors relevant to the design of systems for oral mucosal delivery are discussed. Sublingual delivery gives rapid absorption and good bioavailability for some small permeants, although this site is not well suited to sustained-delivery systems. The buccal mucosa, by comparison, is considerably less permeable, but is probably better suited to the development of sustained-delivery systems. For these reasons, the buccal mucosa may have potential for delivering some of the growing number of peptide drugs, particularly those of low molecular weight, high potency, and/or long biological half-life. Development of safe and effective penetration enhancers will further expand the utility of this route. Local delivery is a relatively poorly studied area; in general, it is governed by many of the same considerations that apply to systemic delivery.

Administration, Buccal↗
PubMed1992

Transport of thyrotropin releasing hormone in rabbit buccal mucosa in vitro.

The transport of thyrotropin releasing hormone (TRH) in rabbit buccal mucosa in vitro has been investigated with respect to (a) rate and type of metabolism of TRH on mucosal and serosal sides of buccal mucosa, (b) mechanism of TRH transport including charge effect on its permeability, and (c) pathway and rate-limiting regions of TRH movement. In addition, the integrity of excised buccal mucosa has been evaluated for purposes of in vitro solute diffusion experiments using tissue ATP level data, transmission electron microscopy, and TRH transport kinetic data. The results indicate that excised rabbit buccal mucosa can be used for TRH diffusion studies for approximately 6 hr. In addition, TRH apparently traverses buccal mucosa by simple diffusion with a steady-state permeability of about 10(-7) cm/sec, and this permeability is independent of pH. Moreover, the primary pathway appears to be via the intercellular space in the rate-limiting barrier, i.e., the upper 50 microns of the epithelium. Finally, TRH is degraded predominantly by deamidase activity, which is followed by, to a lesser degree, carboxypeptidase metabolism.

Adenosine Triphosphate↗
PubMed1991

Anomalous molecular form of acetylcholinesterase in cerebrospinal fluid in histologically diagnosed Alzheimer's disease.

The possibility that the different molecular forms of acetylcholinesterase (AChE) in cerebrospinal fluid (CSF) which can be revealed by isoelectric focusing may reflect changes in AChE in pathologically affected neurons in Alzheimer's disease was tested in a retrospective study. CSF samples obtained at necropsy from 33 patients with clinically diagnosed dementia, 9 with possible dementia, and 19 without a diagnosis of dementia were examined by isoelectric focusing. An additional band indicating an anomalous molecular form of AChE was present in CSF from 19 of 23 patients with a histological diagnosis of Alzheimer's disease and no other central nervous system disorder but in none of the 19 non-demented patients (without a histological diagnosis of Alzheimer's disease). The band was also present in 2 of 8 patients with histologically defined Alzheimer's disease plus other neurological disorders and in 4 of 8 patients with possible dementia who did not meet histopathological criteria for Alzheimer's disease. The absence of the anomalous form of AChE from the CSF of non-demented patients and its presence in the CSF of the majority of patients with Alzheimer's disease has implications for our understanding of the biological basis of the disease and might form the basis of an antemortem diagnostic test.

Acetylcholinesterase↗
PubMed1991

Natural history of the cavernous angioma.

The incidence and natural history of the cavernous angioma have remained unclear in part because of the difficulty of diagnosing and following this lesion prior to surgical excision. The introduction of magnetic resonance (MR) imaging has improved the sensitivity and specificity of diagnosing and following this vascular malformation. Seventy-six lesions with an MR appearance typical of a presumed cavernous angioma were discovered in 66 patients among 14,035 consecutive MR images performed at the Cleveland Clinic between 1984 and 1989. Follow-up studies in 86% of the cases over a mean period of 26 months provided 143 lesion-years of clinical survey of this condition. The most frequent presenting features were seizure, focal neurological deficit, and headache. While most lesions exhibited evidence of occult bleeding on MR imaging, there was overt hemorrhage in seven of the 57 symptomatic patients and only one overt hemorrhage occurred during the follow-up interval. The annualized bleeding rate was 0.7%. Analysis of the hemorrhage group revealed a significantly greater risk of overt hemorrhage in females. Pathological confirmation of cavernous angioma was obtained in all 14 surgical cases. This information assists in rational therapeutic planning and prognosis in patients with MR images showing lesions suggestive of cavernous angioma.

Adolescent↗
PubMed1990

Bioadhesive polymers in peptide drug delivery.

A frequently encountered problem with the peptide-based drugs which are becoming available is that these agents must generally be administered by injection. There is therefore considerable research interest in alternative delivery routes, such as the buccal and nasal mucosae, and the conjunctiva. This paper reports some quantitative considerations of peptide delivery via the buccal, nasal, ocular and gastrointestinal routes, based on estimates of permeability coefficients and other necessary parameters. Rates of delivery and the resulting systemic levels are calculated for some peptide drugs, and compared to therapeutic levels: situations are identified in which bioadhesive formulations may be of benefit.

Adhesiveness↗
PubMed1990

The development of USP dissolution and drug release standards.

Dissolution tests have been in use in the pharmaceutical industry for over 20 years, and they are official in The United States Pharmacopeia since the early 1960s. The dissolution test, reviewed primarily as a quality control tool, replaced the use of disintegration tests which had been official in The United States Pharmacopeia since 1950. Refinements in the dissolution test equipment and methodology have occurred over the years in order to enhance its relevance. The Subcommittees of the USP Committee of Revision dealing with these issues have developed and refined compendial dissolution standards and policies for conventional solid-oral dosage forms and modified-release dosage forms.

Delayed-Action Preparations↗
PubMed1990

Increased tau messenger RNA in Alzheimer's disease hippocampus.

The microtubule-associated protein tau is present in the pathologic hallmarks of Alzheimer's disease and its production and deposition have been implicated in the pathogenesis of the disease. We detected tau mRNA using in situ hybridization histochemistry in the hippocampus, visual cortex, and cerebellum, and compared its level in Alzheimer's disease with controls. The amount of tau mRNA also was determined as a ratio of total polyadenylated mRNA in each area. A significant and gene-specific increase in tau mRNA hybridization was found in hippocampal fields CA4 and CA3, with a similar trend in the dentate gyrus. In contrast, no change was found in the visual cortex or cerebellum in Alzheimer's disease. Increased hippocampal expression of tau mRNA also was present in cases of non-Alzheimer's dementia. Enhanced tau mRNA may be a marker of attempted plasticity involving the cytoskeleton in neuronal populations affected by various neurodegenerative disorders.

Aged↗
PubMed1989

Comparison of different models for the testing of pilocarpine eyedrops using conventional eyedrops and a novel depot formulation (nanoparticles).

An objective in the development of ophthalmic formulations is the use of in vitro or animal models that closely resemble the clinical situation. For this reason, experiments with conventional pilocarpine nitrate eyedrops and a depot formulation of pilocarpine nitrate sorbed to poly (butylcyanoacrylate) nanoparticles were carried out. In vitro, the diffusion of pilocarpine through bovine cornea was measured using Edelhauser cells. In vivo, the rabbit aqueous humor concentration of pilocarpine and miosis were determined after application of the above formulations. In addition, intraocular pressure was measured. Since pilocarpine has little influence on intraocular pressure in healthy rabbits, the pressure had to be increased artificially. Three models were employed that are described in the literature, namely, the betamethasone model, the alpha-chymotrypsin model, and the water-loading model. Pilocarpine could be loaded onto nanoparticles by 15% but was rapidly released from the nanoparticles based on the bovine corneal experiment. Nanoparticles only enhanced the aqueous humor concentration at 30 min; this increase, however, led to a considerably extended period of miosis as well as a reduction in intraocular pressure. The duration of the action and the intensity of the response were different among the three models tested. According to the present results, the betamethasone model seems to represent the best correlation to the clinical situation.

Animals↗
PubMed1989

The natural history of mental disorder in old age. A long-term study.

In a prospective study, 153 consecutive new referrals to a psychogeriatrician in Oxfordshire in 1973 were followed up for 15 years. The percentage of the over-65 population at risk was 0.27 and, of those aged over 80, 0.6. Alzheimer's dementia and depressive illness comprised over two-thirds of referrals. A quarter became permanent admissions, half of them with Alzheimer's dementia, 19% of whom were alive five years later. Depressive illness, at ten years, had a mortality 1.2-1.6 times that of the population at risk. The distinction between Alzheimer's dementia and depressive illness, based on their natural history and causes of death, was reinforced.

Activities of Daily Living↗
PubMed1988

Mechanisms of corneal drug penetration. I: In vivo and in vitro kinetics.

Corneal penetration studies were conducted in unanesthetized albino rabbits using various organic compounds representing both polar and nonpolar species. Very low molecular weight compounds demonstrate rapid uptake into the aqueous humor despite the lipid-like barrier imposed by the corneal epithelium. Evidence that these compounds may have access to a diffusional channel for corneal transport is presented. In vitro permeability studies were also conducted in an effort to quantitate the corneal diffusion of compounds covering a range of molecular weights and partition coefficients; the results corresponded well with the results of in vivo experiments. Calculations of energies of activation, taken from Arrhenius plots, indicate that the diffusion of drug across the cornea may be by two different mechanisms that depend on the physical-chemical characteristics of the perfusant. One mechanism appears similar to drug movement in an aqueous environment and is characterized by an activation energy similar to that for diffusion in water. The other relates to the expected partitioning of a compound across cellular membranes represented by a relatively high activation energy for diffusion. For hyrdophilic compounds, the epithelium appears to be rate limiting to drug movement, whereas for hydrophobic compounds, the stroma is rate limiting. In the presence of calcium-chelating agents, glycerol demonstrated an increase in corneal penetration in vivo. This effect appears to be reversible at specific concentrations of chelator. In contrast, divalent cations reduced corneal penetration of glycerol. The known calcium chelator EDTA was shown to penetrate the cornea, conjunctiva, and iris/ciliary body from a topically applied dose. The implications of this observation pertain to toxicity effects when EDTA is incorporated into ocular drug products for stability purposes, or novel stratagems for improving ocular bioavailability of topically applied drugs are employed. The addition of calcium-chelating agents to in vivo mounted corneas demonstrated increases in permeability of the cornea to glycerol which were directly related to the concentration of chelating agent used. These results paralleled the findings of similar in vivo studies. The results of these studies are consistent with a currently proposed 'pore' model for the penetration of drugs through the cornea which demonstrates both a partition coefficient and molecular weight dependency on the permeability of the cornea to transported compounds.

Alcohols↗
PubMed1988

Mechanisms of corneal drug penetration. II: Ultrastructural analysis of potential pathways for drug movement.

Ultrastructure analysis was conducted in an effort to augment the results of classical kinetic studies. Scanning electron microscopy (SEM) allowed visual inspection of cellular junctions on corneal epithelium and endothelium. The addition of calcium-chelating agents to in vivo and in vitro mounted corneas demonstrated a concentration-dependent progressive expansion of the intercellular spaces of epithelium and endothelium, as seen by SEM. The expansion of these cellular junctions correlates with increases in permeability of the cornea to glycerol under similar conditions. The size of the intercellular space was estimated by transmission electron microscopy. Use of lanthanum as a marker of aqueous diffusional pathways demonstrated that the epithelial surface is not a totally occlusive barrier to transport of small hydrophilic compounds. Development of a method whereby an administered drug could be visualized in its actual pathway of movement through the cornea was undertaken, involving precipitation of specific compounds in the tissue with osmium tetroxide vapor. Results suggest that separate pathways of drug movement exist in the cornea for hydrophilic and hydrophobic compounds. Hydrophilic compounds were preferentially located in intercellular spaces, whereas hydrophobic compounds were associated with the lipid structures of the tissue. The results of these studies are consistent with a currently proposed 'pore' model for the penetration of drugs through the cornea.

Animals↗
PubMed1988

Mechanisms of corneal drug penetration. III: Modeling of molecular transport.

A model relating the parameters of permeability coefficient in the cornea with partition coefficient and molecular weight of the penetrating species is presented. The development of the model is unique in that it includes the availability of a "pore" pathway with the corresponding kinetic data to substantiate this premise. The "pore" pathway is applied to small hydrophilic compounds and assumes that an aqueous diffusional space is available for transport of these compounds. This is in contrast to an alternate "partitioning" mechanism which is the most probable route of transport for larger or more lipophilic entities. The model is consistent with published data from this and other laboratories.

Animals↗
PubMed1988

Improved intestinal cannula for drug delivery studies in the dog.

A modified light-weight intestinal cannula, based on the modified Thomas type (Thomas, 1941; Jones et al., 1971) was fabricated and tested. The design extends the useful life of the cannula and expands the versatility of the canine gastrointestinal (GI) system for pharmaceutical and physiological research. The cannula permits easy administration of pharmaceutical dosage forms directly into or access to ingested substances anywhere along the small intestine.

Animals↗
PubMed1988

Immunohistochemical detection of steroid binding in rabbit cornea.

An indirect immunoperoxidase technique was used to demonstrate progesterone binding in rabbit cornea as a measure of steroid absorption into corneal tissues. Tissue preparation prior to immune staining was prepared by both a pre-fixed, paraffin-embedding method and a post-fixed, cryostat sectioning method. Rabbit antiprogesterone antiserum and peroxidase conjugated goat antirabbit antiserum were used as a primary and secondary antibody respectively. The immune staining of the antibody-treated sections was then developed in a solution of 3-3' diaminobenzidine-hydrogen peroxide system. The resulting, brown colored, end-products at the site of reaction indicate the location of bound steroid in the sections. Paraffin-embedded sections showed negative staining in both steroid treated and untreated control corneas while fixed frozen sections showed only positive staining for the treated corneas. The results suggest the preservation of the immunogenicity in the treated frozen sections. The negative result observed in the paraffin-embedded sections may be attributed to the loss of steroid from the tissues during the dehydration and paraffin embedding processes. It was found that the immunoreactive progesterone localized mainly in the epithelial cells and the bottom portion of the stroma. Prior application with an excess of triamcinolone acetonide, to the treated corneas gave negative results indicating the reversible and competitive nature of the binding.

Animals↗