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Biomedical subjects

C A Hunt

Publications and source records attributed to C A Hunt.

At least 55 records · Page 3Linked to original sources
PubMed1986

A decrease in the number of GABAergic somata is associated with the preferential loss of GABAergic terminals at epileptic foci.

Previous studies have indicated that a loss of GABAergic terminals occurs at epileptic foci. The present study was undertaken to investigate if this loss is associated with a loss of GABAergic neuronal somata. Seven juvenile monkeys (M. mulatta) received alumina gel injections to the pre-central gyrus of the left cerebral hemisphere to produce epileptic foci. Four of these monkeys were chosen for further quantitative study. One was sacrificed prior to seizure onset ('pre-seizure'), one had seizures for 3 days ('acute'), and two had a seizure record of one month ('chronic'). Sections of tissue from the epileptic cortex and from the contralateral, non-epileptic cortex were processed for glutamate decarboxylase (GAD) immunocytochemistry at the light microscopic level. Quantitative analysis revealed that a loss of GAD-positive neuronal somata ranging from 24 to 52% occurred at epileptic foci for all monkeys. This decrease was significant (P less than 0.01) for the two chronic monkeys. There was also a slight decrease in GAD-positive neurons 1 cm distal to the focus ('parafocus') in the chronic monkeys, but not in the acute or pre-seizure animals. In addition, small GAD-positive somata (50-150 micron2) were more severely decreased in number at epileptic foci than larger ones (200-250 micron2). As an experimental control, an additional monkey was given a surgical lesion in area 4 of one cerebral hemisphere. It did not display seizure activity prior to sacrifice and did not show a loss of GAD-positive neurons proximal to the control lesions. The results of this study indicate that a loss of GABAergic neuronal somata is associated with a loss of GABAergic terminals at epileptic foci, and that this loss may be more specific for the small GABAergic neurons.

Animals↗
PubMed1985

Synthesis and evaluation of a prototypal artificial red cell.

A new process allows microencapsulation of purified human hemoglobin and 2,3-diphosphoglycerate to form neohemocytes. The microcapsule membrane is composed of phospholipids and cholesterol. Neohemocytes are substantially smaller than erythrocytes, contain 15.1 grams per decaliter of hemoglobin, and have a P50 value (the partial pressure of oxygen at which the hemoglobin is half-saturated) of 24.0 torr. All rats given 50-percent exchange transfusions survived with only limited evidence of reversible toxicity. Normal serum glutamate-pyruvate-transaminase values at 1, 7, and 30 days after transfusion were consistent with minimal hepatotoxicity. The concentration of blood urea-nitrogen was elevated by 35 percent after 1 day but returned to normal by day 7. However, histopathology revealed normal kidneys on day 1 as well as on days 7 and 30. Neohemocytes cleared from the circulation of transfused rats with an apparent half-life of 5.8 hours.

Alanine Transaminase↗
PubMed1985

Transarticular pinning for repair of hip dislocation in the dog: a retrospective study of 40 cases.

Transarticular pinning was used for the repair of hip dislocation in 40 dogs. The mean follow-up period was 18.4 months. Satisfactory results were achieved in 80% of the cases. Body weight, ipsilateral femoral head fracture, and hip dysplasia appeared to affect long-term prognosis. The most frequent complication was pin breakage, but this did not affect final outcome and could be avoided by using pins of larger diameter. Osteonecrosis was observed in two cases.

Animals↗
PubMed1985

Lymphatic transport of liposome-encapsulated agents: effects of liposome size following intraperitoneal administration.

Liposomal encapsulation can limit passage of a drug from a peritoneal administration site to blood, while enhancing lymphatic transport. We evaluated the effects of liposome size on lymphatic transport after intraperitoneal administration. Liposomes tested had mean diameters of either 0.72, 0.46, 0.17, or 0.048 micron and identical compositions. [14C]Sucrose was the aqueous space marker (model drug). Doses were given to thoracic-duct-cannulated rats. The subsequent 0-5 h time-course of carbon-14 was quantified in thoracic lymph, several lymph nodes, blood, and urine. Calibration studies indicated a maximum of approximately 30% of the absorbed dose could be collected in thoracic lymph. Carbon-14 levels in the various nodes covered a 1000-fold range, and relatively high levels were observed in the left mediastinal, parathymic, cisternal, and renal lymph nodes. Liposome stability in vivo and in vitro increased with decreasing size. Absorption from the peritoneal cavity was independent of size. The smallest liposomes were collected in lymph with little lymph node retention. The largest liposomes were retained most by lymph nodes, and would be the best prototypical carrier of the group if increased therapeutic availability within both lymph and lymph nodes is desired. The results implicate other, unexplored physical and physiological variables as potentially of equal importance.

Animals↗
PubMed1984

Liposome disposition in vivo. VI: Delivery to the lung.

The effect of negatively charged liposome components and vesicle size on the time course and dose dependency of liposome disposition in mice was studied with a view to optimizing liposome delivery to the lung. The disposition of large multilamellar liposomes was followed using 125I-labeled p-hydroxybenzamidine phosphatidyl ethanolamine. Of the three negatively charged liposome compositions studied (phosphatidyl choline-X-cholesterol-alpha-tocopherol, molar ratio: 4:1:5:0.1; X = phosphatidyl serine, dipalmitoyl phosphatidic acid, or phosphatidyl glycerol), phosphatidyl serine liposomes resulted in the greatest accumulation in lungs. Lung levels decreased up to 95 h postdose, at which time 6% of the liposome dose present at 2 h still remained. The disposition of phosphatidyl serine-containing liposomes was independent of dose for the range 0.04-21 mumol/animal. When liposomes containing phosphatidyl choline were prepared using a variety of extrusion and dialysis conditions, a strong link between liposome size and lung accumulation was revealed. A maximum lung accumulation of 30.9% of the administered dose was achieved with no detectable gross pathological lung lesions up to 24 h postdose.

Animals↗
PubMed1984

Adrenoceptor and tetrabenazine antagonism activities of some pyridinyltetrahydropyridines.

A series of pyridinyltetrahydropyridine derivatives was synthesized and evaluated as adrenoceptor and tetrabenazine antagonists. 4-(3-Fluoro-2-pyridinyl)-1,2,5,6-tetrahydropyridine proved to be the most potent and selective alpha 2-adrenoceptor antagonist of the series as measured in vitro by displacement of [3H]clonidine and [3H]prazosin from membrane binding sites of calf cerebral cortex and by antagonism of the effects of clonidine and methoxamine in the rat isolated, field-stimulated vas deferens. In addition, this compound, and the corresponding desfluoro derivative, blocked tetrabenazine-induced ptosis in the mouse.

Animals↗
PubMed1983

Ion pair absorption of ionized drugs--fact or fiction?

The lipophilicity of some highly ionized drugs at physiological pH is very low. Gastro-intestinal absorption of such compounds cannot be explained by the 'pH-partition' hypothesis. Ion pair formation between a drug and an endogenous counter ion alone resulting in an electrically neutral and potentially more lipophilic species has been proposed as a mechanism to explain the observed, though deficient, absorption of ionic drugs. The concept of ion pair formation between an ionic drug and an exogenous counter ion has been the rationale for attempts to improve penetration of biological membranes and, specifically, result in increased absorption from the gastro-intestinal tract. The validity of the 'ion pair absorption hypothesis' is re-evaluated in the context of a conceptual review of relevant literature.

Animals↗
PubMed1983

Delivery of therapeutic doses of doxorubicin to the mouse lung using lung-accumulating liposomes proves unsuccessful.

Addition of solid doxorubicin or solutions to pre-formed liposomes proved to be the optimal method for incorporating the drug into liposomes whilst maintaining their size distribution and hence ability to accumulate in the lung. Liposomes prepared in this way lost doxorubicin only slowly on dialysis but dilution with an equal volume of saline at 37 degrees C resulted in the loss of 80% of the incorporated doxorubicin within 30 min. These liposomes were thus ineffective in altering doxorubicin disposition in vivo and produced no enhanced activity compared with free drug and a non-lung-accumulating carrier liposome in the EMT6 cell-Balb/c mouse model lung tumour.

Animals↗
PubMed1983

Synthesis and receptor binding studies relevant to the neuroleptic activities of some 1-methyl-4-piperidylidene-9-substituted-pyrrolo[2,1-b][3]benzazepine derivatives.

The synthesis of a series of 1-methyl-4-(9-substituted-11H-pyrrolo[2,1-b]benzazepin-11-ylidene)piperidines (4a-f) and 1-methyl-4-(9-substituted-6,11-dihydro-5H-pyrrolo[2,1-b][3]benzazepin-11-ylidene)piperidines (4g-l) is described. As with th e 3-substituted cyproheptadine compounds 1b-e, atropisomerism exists in 4b-f, but unlike the enantiomers of 1b-e, the pyrrolobenzazepine enantiomers racemize at room temperature. Thus, the bromo compound (+)-4b has a half-life of 128 +/- 1 min at 25 degrees C, while the chloro compound (-)-4c has a half-life of 114 +/- 9 min at 25 degrees C. Compounds 4a-l have been examined for receptor binding affinities in assays that have been recognized as predictive for antipsychotic activity. The displacement of specifically bound tritiated ligands, comprising the dopamine antagonist [3H]spiperone, the dopamine agonist [3H]apomorphine, the muscarinic cholinergic antagonist [3H]quinuclidinyl benzilate (QNB), the alpha-adrenergic antagonist [3H]prazosin, the alpha-adrenergic agonist [3H]clonidine, the serotonin-1 binding agent [3H]serotonin, and the mixed serotonin agonist-antagonist [3H]lysergic acid diethylamide (LSD), by 4a-l has been measured utilizing membrane preparations of mammalian brain. Certain of the features of the receptor binding of these compounds have been shown to be common to several of the receptor sites. Data from these binding studies have been compared to corresponding data previously obtained for a series of chiral 3-substituted cyproheptadine analogues, and the receptor binding data of the two classes of compounds are discussed with respect to their molecular geometries.

Animals↗
PubMed1983

Pyridinylpiperazines, a new class of selective alpha 2-adrenoceptor antagonists.

A series of 1-(2-pyridinyl)piperazine derivatives was synthesized and evaluated for adrenergic activity. In vitro activity was assessed through the antagonism of clonidine's effect in the rat, isolated, field-stimulated vas deferens and by the displacement of [3H]clonidine from membrane binding sites of calf cerebral cortex. Antagonism of clonidine-induced mydriasis in the rat was used as an in vivo assay. Several members of the series proved to be potent, selective alpha 2-adrenoceptor antagonists. 1-(3-Fluoro-2-pyridinyl)piperazine was more potent than either yohimbine or rauwolscine in displacement of [3H]clonidine and had a higher affinity for this binding site (alpha 2) than for the [3H]prazosin site (alpha 1). In vivo, the 3-F derivative was more potent than the reference standards in reversing clonidine-induced mydriasis. None of the members of this series was more selective or potent than rauwolscine in antagonizing clonidine in the rat vas deferens.

Adrenergic alpha-Antagonists↗
PubMed1983

Metabolic disposition of N,N-dibenzyldaunorubicin in the rat.

The more efficacious and less cardiotoxic analogue of daunorubicin, N,N-dibenzyldaunorubicin (B2D), was found to be metabolized in rats by stepwise debenzylation that was superimposed on the known anthracycline metabolism via 13-ketone reduction and deglycosidation. Using high-pressure liquid chromatography for resolution and fluorescence for detection, we observed a series of metabolites in plasma, liver, heart, muscle, and lungs of rats receiving 10 mg B2D per kg, i.v., i.p., and p.o. Rats receiving 40 mg B2D per kg, i.v., died immediately, but this dose given p.o. was not lethal during 24 hr. Patterns of B2D and metabolites varied quantitatively with tissue and route of administration. Rat liver perfusion studies indicated extensive metabolism of B2D compared with limited metabolism of doxorubicin. These observations were consistent with an observed major first-pass effect on B2D in intact rats given B2D p.o. The predominant metabolites of B2D were the glycosidic derivatives, N-benzyldaunorubicin, daunorubicin, and their 13-dihydro derivatives. These metabolites of B2D had exhibited activity against mouse leukemia P388 as did B2D and were active in in vitro tests in which B2D was essentially inactive. These results indicate that B2D acts as a prodrug for a series of active metabolites. Conversion of B2D to these metabolites was relatively more efficient after p.o. administration than following i.v. or i.p. treatments.

Animals↗
PubMed1983

Neohemocytes.

The neohemocytes described in this report average approximately 0.4 microns in diameter. The microcapsule membrane is composed of biodegradable lipids, including phospholipids, and has a structure similar to liposomes. In a suspension having an apparent hematocrit of 0.5, the neohemocytes occupy 50% of the volume, the neohemocyte membrane accounts for approximately 2%, and the hemoglobin suspension accounts for about 48% of the volume. The encapsulated hemoglobin suspension averages 15.8g%. The P50 averages 26, the Hill Number averages 2.1, and methemoglobin is typically less than 5%. Transfusions in rats of neohemocyte suspensions, where the RBC hematocrit is lowered below 0.03, consistently give a fivefold-or-better increase in survival time relative to transfusions of equal concentrations of unencapsulated hemoglobin. Many of the problems of hemoglobin microencapsulation have been overcome, and the results strongly indicate that neohemocytes may become the functional component of a resuscitative fluid for use in man.

Animals↗
PubMed1982

Liposomes disposition in vivo. V. Liposome stability in plasma and implications for drug carrier function.

The kinetics of [14C]sucrose release from multilamellar liposomes of fixed diameter (approx. 0.23 micron) incubated in human plasma (serum and blood) were quantified. Composition was various ratios of phosphatidylcholine, phosphatidic acid and cholesterol with alpha-tocopherol included as antioxidant. Considerable intra-individual variability was noted for liposome stability in blood and its derived fluids, yet reproducible results were obtained for pooled samples. The destabilizing effects of plasma decreased with increasing lipid concentrations. Results of fitting a kinetic model to the data showed that four of five model parameters were linearly related to liposome cholesterol content. Liposomes depleted plasma of its destabilizing factors, and when pre-incubated with plasma were partially stabilized to the effects of a subsequent plasma addition. Plasma caused a rapid rise in liposome membrane permeability which then declined non-linearly, presumably because of a rearrangement of membrane lipids and adsorbed proteins to form their most stable configuration. The therapeutic availability of drugs administered encapsulated in liposomes, which can be governed by the kinetics of their in vivo extracellular release, may be directly proportional to--and predictable from--the time-course and extent of release in plasma. The kinetic model was used in conjunction with simple pharmacokinetic assumptions to show that the effectiveness of a liposome drug carrier cannot be predicted based simply on its plasma stability; more stable liposomes may not be more effective drug carriers. Interestingly, plasma-induced solute release from liposomes serendipitously mimics an important facet of ideal carrier behavior.

Cholesterol↗
PubMed1982

Liposome disposition in vivo II: Dose dependency.

The dose-dependent disposition of extruded multilamellar (diameter approximately 1 micrometer) negatively charged liposomes containing entrapped [14C]inulin was studied in mice. Mice received 1500, 300, or 15 mumoles of liposomal lipid/kg iv. Carbon 14 levels were measured in the blood, liver, spleen, and carcass for 72 hr. A pronounced saturation effect, consistent with the known dose behavior of other colloids, was seen at early times; it was manifested by higher dose values in the blood and spleen but by lower liver values as the dose increased. This dose effect was attenuated in the liver but was maintained in the spleen at later times, and percent dose values approached plateau values in all tissues for all doses at later times. [14C]Inulin was used at the liposomal marker because of its inability to enter cells (or, presumably, leave them if delivered there by liposomes) in its free form. An early decline in carbon 14 levels (over the first 48 hr) was seen in the liver for the low and medium doses. Because of the known ability of blood factors to cause liposomes to leak their contents, this decline was interpreted as being a loss of [14C]inulin from extracellularly bound liposomes during this period. Moreover, the plateau carbon 14 levels at later times were interpreted as approximating the true level of intracellular inulin delivery by the liposomes.

Animals↗
PubMed1982

Liposome dialysis for improved size distributions.

A technique is described which allows reproducible preparation of liposomes with improved size-frequency distributions. The recent procedure of extrusion of crude liposome dispersions through controlled-pore polycarbonate membranes is used to control the upper limit of liposome diameter. Subsequent dialysis, using the same type of membrane, can remove the majority of liposomes smaller than a predetermined size. The pattern of dialysis of a liposome preparation is a function of the size-frequency distribution (as well as the membrane pore size) and can be used to approximate the distribution and/or used to monitor the reproducibility of liposome preparations.

Chemical Phenomena↗
PubMed1982

Liposome disposition in vivo IV: the interaction of sequential doses of liposomes having different diameters.

In order to evaluate the degree to which liposomes of the same composition but of different size interact with organ binding sites, a series of pre-dose studies have been carried out in mice. Two sizes of multilamellar liposomes were used: large (L) liposomes averaging 0.5 micrometer in diameter and small (S) liposomes averaging 0.06 micrometer in diameter. Lipid composition was phosphatidylcholine/phosphatidic acid/cholesterol/alpha-tocopherol in the molar ratio 4:1:5:0.1. Experiments consisted of a saturating pre-dose of either non-radioactive L- or S-liposomes followed at various times by a test dose of radioactively labelled L- or S-liposomes. When pre-dose and test dose were of the same diameter, an interaction was observed. A pre-dose of L-liposomes also interacted with a test dose of S-liposomes but a pre-dose of S-liposomes did not interact with a test dose of L-liposomes. All disposition effects were reversible, returning to control values within 24 h. These results indicate that L- and S-liposomes of identical composition may associate with different hepatic binding sites and that a class of non-specific binding sites available to S-liposomes but not to L-liposomes may exist.

Animals↗