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Biomedical subjects

J M McCall

Publications and source records attributed to J M McCall.

At least 37 records · Page 2Linked to original sources
PubMed1989

Comparative neuroanatomical distribution of the kappa and mu opioid receptors in guinea pig brain sections.

The opiate family of receptors is believed to consist of the mu, delta, kappa and sigma subtypes. Autoradiographic studies have been conducted to define the distribution of the mu and delta receptors. However, due to the lack of a selective ligand definitive studies have not been reported for the kappa receptor. Recently such a ligand was discovered and characterized. Results are presented in which the distribution of kappa receptors in guinea pig brain slices were determined using autoradiographic techniques and its distribution compared to that of a typical mu ligand. The results demonstrate numerous differences between the two opioid systems. The kappa receptors predominate in the prefrontal cortex, the nucleus accumbens, and deep cortex; whereas the mu receptors have a more intense, broader and different distribution.

Animals↗
PubMed1988

Attenuation of hemorrhagic shock by the non-glucocorticoid 21-aminosteroid U74006F.

The ability of the novel non-glucocorticoid 21-aminosteroid U74006F to protect against the development of hemorrhagic shock was examined in pentobarbital-anesthetized cats. The animals were hemorrhaged to a mean arterial blood pressure (MAP) of 45-50 mm Hg where they were held for 2 h. At the end of the hemorrhage period, either vehicle, a 30 mg/kg dose of methylprednisolone sodium succinate, or a 10 mg/kg dose of U74006F was administered i.v. followed by reinfusion of the shed blood. In vehicle-treated animals, there was a progressive post-reinfusion decline in the MAP over the subsequent 2 h. In the methylprednisolone-treated cats, the post-reinfusion decrease in the MAP was only slightly and not significantly better. In contrast, U74006F administration resulted in a significant maintenance of the MAP. These results suggest that U74006F may be efficacious for the attenuation of hemorrhagic shock and superior to conventional high dose glucocorticoid therapy in that context.

Animals↗
PubMed1988

Arylformamidines with antinociceptive properties.

A series of formamidines structurally related to clonidine were synthesized and investigated as potential nonopiate analgesics. Several of these compounds showed potent analgesic activity (ED50 on HCl writhing less than 1.0 mg/kg) with low potential for hypotensive effects. A qualitative description of the structure-activity relationship of this series reveals that the 2,4- and 2,6-dimethylphenyl compounds are more potent analgesics than are the corresponding dichlorophenyl compounds.

Analgesia↗
PubMed1988

New pharmacological treatment of acute spinal cord trauma.

Numerous experimental studies of blunt spinal cord injury have shown that while a variable degree of immediate mechanical damage occurs to spinal blood vessels and axons in proportion to the magnitude of the injury force, a considerable amount of post-traumatic tissue degeneration is due to a secondary pathophysiological process that may be modifiable by appropriate therapeutic intervention. A growing body of biochemical, physiological, and pharmacological evidence has suggested that oxygen free radical-induced lipid peroxidation, working in concert with aberrant calcium fluxes and eicosanoid generation in particular, plays a key role in progressive post-traumatic spinal cord degeneration. Of particular importance, lipid peroxidation has been linked to microvascular damage and hypoperfusion which, if severe enough, can lead to a secondary ischemic insult to the tissue. The ability of intensive dosing with the glucocorticoid steroid methylprednisolone to beneficially affect post-traumatic ischemia and to promote chronic neurologic recovery in spinal cord injured animals has been correlated not with its glucocorticoid activity, but rather with the ability to inhibit post-traumatic spinal lipid peroxidation. In view of this, a novel series of non-glucocorticoid 21-aminosteroids has been developed which lack glucocorticoid activity but are more effective inhibitors of nervous tissue lipid peroxidation than the glucocorticoid steroids. One of these, U74006F, has now been studied in some detail and appears to be a promising new agent for the acute treatment of spinal cord (and brain) trauma. The background and pre-clinical development of this compound to date is reviewed.

Humans↗
PubMed1988

Effects of the 21-aminosteroid U74006F on experimental head injury in mice.

The ability of a novel non-glucocorticoid 21-aminosteroid U74006F to inhibit lipid peroxidation of central nervous system tissue in vitro and to enhance the early neurological recovery and survival of mice after a severe concussive head injury is described. In the in vitro studies, U74006F was found to be an extremely potent inhibitor of lipid peroxidation in an assay system where the glucocorticoid steroid methylprednisolone and the non-glucocortoid steroids U72099E and U75718A were almost completely ineffective. In the head-injury studies, unanesthetized male CF-1 mice were subjected to a 900 gm-cm closed head injury produced by a 50-gm weight being dropped 18 cm. This concussive injury resulted in immediate unconsciousness (loss of righting reflex) in all animals and death in approximately 30%. Survivors received a tail vein injection of either vehicle or U74006F (0.001 to 30 mg/kg) within 5 minutes postinjury. Their neurological status was evaluated 1 hour later using a grip test. The grip-test score indicated that intravenous administration of a single dose of U74006F resulted in a significant improvement by as much as 168.6% in the neurological status 1 hour postinjury over a broad dose range (0.003 to 30 mg/kg). A 1-mg/kg dose given intravenously within 5 minutes and again at 1 1/2 hours after a severe injury, in addition to improving early recovery, also increased the 1-week survival rate to 78.6% compared to 27.3% in vehicle-treated mice (p less than 0.02). The compound was also effective in enhancing early recovery after a more moderate injury. This study demonstrates that early treatment after severe concussive head injury with a potent inhibitor of iron-dependent lipid peroxidation can significantly benefit the injured brain in mice and promote both early neurological recovery and long-term survival.

Animals↗
PubMed1988

Effects of treatment with U-74006F on neurological outcome following experimental spinal cord injury.

The compound U-74006F is one of a series of 21-aminosteroids that lack glucocorticoid or mineralocorticoid activity. These potent inhibitors of lipid peroxidation have been specifically developed for the acute treatment of central nervous system trauma and ischemia. This study evaluated the dose-response characteristics and capability of U-74006F to promote functional recovery in cats subjected to compression trauma of the upper lumbar (L-2) spinal cord. Thirty minutes following injury, randomized and investigator-blinded treatment was initiated with the intravenous administration of either vehicle (citrate-buffered saline) or one of eight doses of U-74006F. Initial doses of U-74006F ranged from 0.01 to 30 mg/kg. Subsequent doses consisted of intravenous bolus injections followed by a continuous 42-hour intravenous infusion. Over the 48-hour treatment period, cats received total U-74006F doses ranging from 0.048 to 160 mg/kg. The animals were evaluated weekly for neurological recovery based upon an 11-point behavioral scale. With the exception of two cats in one group, the animals receiving accumulated doses of U-74006F (ranging from 1.6 to 160.0 mg/kg/48 hrs) exhibited nearly 75% of normal neurological function by 4 weeks after injury. Lower total doses of 0.16 and 0.48 mg/kg/48 hrs were associated with approximately 50% return of normal function, which was not significantly better than the recovery in the vehicle-treated control group. The lowest total dose tested (0.048 mg/kg/48 hrs) gave results indistinguishable from those in vehicle-treated cats, which had recovered only 20% of their preinjury neurological function by 4 weeks. These findings demonstrate that over a 100-fold range of doses, U-74006F has a remarkable capacity to promote functional recovery in spinal cord-injured cats.

Animals↗
PubMed1987

Novel 21-amino steroids as potent inhibitors of iron-dependent lipid peroxidation.

Two representative compounds from a novel chemical series of potent inhibitors of lipid peroxidation are described. The compounds 21-[4-(2,6-di-1-pyrrolidinyl-4-pyrimidinyl)-1-piperazinyl]-16 alpha-methylpregna-1,4,9(11)-triene-3,20-dione monomethane sulfonate (U74006F) and 21-[4-(3,6-bis(diethylamino)-2-pyridinyl)-1-piperazinyl]-16 alpha-methylpregna-1,4,9(11)triene-3,20-dione hydrochloride (U74500A) inhibited lipid peroxidation in brain homogenates and purified brain synaptosomes under a variety of conditions involving iron. With IC50 values ranging from 2 to 60 microM, U74006F and U74500A were comparable in potency to alpha-tocopherol or butylated hydroxytoluene and were nearly 100 times as potent as desferrioxamine. Some specificity for intact phospholipid membranes is suggested since the ability of U74006F or U74500A to inhibit lipid peroxidation was greatly reduced in methanol solutions of arachidonic acid. Despite close similarities in their structures, their response to increasing concentrations of Fe2+ in lipid peroxidation assays differed qualitatively. One of the compounds, U74500A, may act as a membrane localized chelator of iron.

Animals↗
PubMed1987

A nonglucocorticoid steroid analog of methylprednisolone duplicates its high-dose pharmacology in models of central nervous system trauma and neuronal membrane damage.

Prior studies have demonstrated that intensive treatment with high doses of methylprednisolone (MP) can beneficially affect the acutely injured central nervous system by a variety of mechanisms and promote neurological recovery in experimentally injured animals. In view of the fact that these actions are associated only with MP doses greatly in excess of those required for classical glucocorticoid receptor-mediated actions of the steroid, the possibility was examined that this high-dose pharmacology of MP could be duplicated by a nonglucocorticoid analog. Accordingly, U-72099E (17,21-dihydroxy-11 alpha-t-butylacetoxy-1,4-pregnadiene-3,20-dione- 21-hemisuccinate, sodium salt) was synthesized and tested for its ability to duplicate the high-dose effects of MP in a concussive head injury model in mice and in an in vitro model of lipid peroxidation-induced membrane damage using rat brain synaptosomes. The absence of glucocorticoid-related activity of U-72099E was confirmed by its inability to either suppress body weight gain or cause thymic involution in mice treated with doses up to 100 mg/kg/day for 4 days. On the other hand, MP at 30 mg/kg/day for 4 days caused a complete inhibition of body weight gain and a 43.5% reduction in thymus weight. Moreover, U-72099E, at concentrations of 10(-5) M or lower, failed to suppress adrenocorticotropin secretion by mouse AtT-20 pituitary cells in culture, whereas dexamethasone or MP at concentrations of 10(-6) M and lower caused a marked suppression in adrenocorticotropin secretion.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenocorticotropic Hormone↗
PubMed1987

Lipid peroxidation and the role of oxygen radicals in CNS injury.

Lipid peroxidation is a radical induced chain reaction which is fundamentally linked to cellular destruction in the secondary injury process which is initiated by head and spinal injury and stroke. Injuries such as these begin a series of molecular events which lead to gradual vascular and neuronal degeneration. This process ultimately precludes neurological recovery. The secondary damage process is a combination of lipid peroxidation, calcium influx, arachidonic acid release and metabolism, transition metal redox reactions and tissue pH. Although CNS cells are particularly susceptible to lipid peroxidation, the process is common to many biological processes (e.g. inflammation, carcinogenesis, aging, radiation damage, transplant rejection, etc.).

Animals↗
PubMed1987

A new class of compounds for stroke and trauma: effects of 21-aminosteroids on lipid peroxidation.

The Lazaroids are the result of a blend of reasonable objectives which sprang from experience and hypothesis with a strong dose of serendipity. We believe that these compounds inhibit lipid peroxidation at a membrane level and, thus, blunt the damage from the secondary wave of injury which follows stroke, trauma and other insults to cell membranes. Certainly, these compounds are superior in animal models in potency and efficacy to older glucocorticoids. One compound, U74006F, has been selected for clinical development. Clinical trials in head injury will begin soon in selected centers in the United States.

Animals↗
PubMed1987

Isolation, identification and synthesis of a metabolite of tazadolene succinate.

Metabolism of tazadolene (1), a novel non-opioid analgesic with antidepressant properties, affords the 4-hydroxy and 3-methoxy-4-hydroxy derivatives (phenyl ring) of the drug, and N-[2-(phenylmethylene)cyclohexyl]-beta-alanine (4). The isolation, identification and synthesis of the latter metabolite is described.

Analgesics↗
PubMed1986

7-(Trifluoromethyl)-4-aminoquinoline hypotensives: novel peripheral sympatholytics.

A family of 7-(trifluoromethyl)-4-aminoquinolines that are hypotensive agents and that act by a novel sympatholytic mechanism is described. Structure-activity relationships in this series have been elucidated. Some of the more potent hypotensives were evaluated for safety in the mouse. A candidate, 1-[(4-fluorophenyl)sulfonyl]-4-[4-[[7-(trifluoromethyl)-4- quinolinyl]amino]benzoyl]piperazine hydrochloride (losulazine hydrochloride) has been selected for clinical development. Losulazine hydrochloride is a hypotensive agent in the rat, cat, and dog. At acute effective hypotensive doses, it does not block the response of the sympathetic nervous system to stimuli. Both animal pharmacology and clinical experience suggest that losulazine hydrochloride may be free of the clinically limiting side effects that often plague compounds that decrease blood pressure by interfering with autonomic neurogenic function.

Aminoquinolines↗
PubMed1985

[3H]U-69593 a highly selective ligand for the opioid kappa receptor.

The selective kappa agonist U-50488 was recently discovered and characterized. In this study, the receptor binding properties of [3H]U-69593, an analog of U-50488, were characterized. [3H]U-69593 binds with high affinity (3 nM) to membranes prepared from guinea pig, mouse and rat brain. The number of kappa binding sites comprise only 13%, 9% and 4% of the total opioid sites, respectively. The benzmorphans, dynorphin, and compounds structurally related to U-50488 have high affinity for this kappa site.

Analgesics↗
PubMed1984

An aspirin-prednisolone combination to modify postadulticide lung disease in heartworm-infected dogs.

A combination of aspirin and prednisolone was used in an attempt to modify the pulmonary disease produced by thiacetarsamide treatment of heartworm-infected dogs. Results of 6 heartworm-infected dogs treated with prednisolone (1 mg/kg, daily for 4 weeks) and aspirin (10 mg/kg, daily for 4 weeks) after thiacetarsamide treatment were compared with previously published results of 3 groups of dogs (6 dogs/group). One of these 3 groups was a nontreated control group, another was treated with prednisolone, and the 3rd was treated with aspirin. All dogs, each with 9 adult heartworms transplanted, were treated with a 2-day, twice-a-day treatment of thiacetarsamide (1 mg/kg) 4 weeks after the transplant. Thoracic radiographs were taken before and at 1, 2, and 3 weeks after thiacetarsamide treatment to evaluate lung disease. Pulmonary arteriography was performed before and 3.5 weeks after thiacetarsamide treatment to evaluate pulmonary blood flow. After treatment, radiographs of the aspirin-prednisolone group were similar to radiographs of the prednisolone group, both with a marked attenuation of the parenchymal disease, as compared with the non-treated group. Addition of aspirin to prednisolone prevented the blood flow obstruction and intraluminal filling defects that were present in the groups not receiving aspirin. Sixteen of 54 transplanted heartworms survived thiacetarsamide treatment in both prednisolone-treated groups, in contrast to complete elimination of heartworms in the nontreated group. Aspirin may be considered for treatment of any heartworm-infected dog that does not have hemotypsis, but postthiacetarsamide use of prednisolone should be restricted to the dog that develops severe lung disease after the heartworms have been killed.

Animals↗
PubMed1983

Pyrimidine and triazine 3-oxide sulfates: a new family of vasodilators.

Di- and triaminopyrimidine 3-oxides (e.g., 2,4-diamino-6-piperidinylpyrimidine 3-oxide and 2,4-diamino-6-(diallylamino)triazine 3-oxide) react with sources of sulfur trioxide, such as sulfur trioxide trimethylamine or chlorosulfuryl chloride, to yield the corresponding heterocyclic O-sulfates. These sulfates are inner salts with unusual physical properties. The structure of the O-sulfate of 2,4-diamino-6-piperidinylpyrimidine 3-oxide was confirmed by X-ray. These O-sulfates are hypotensives. They apparently act by direct vasodilation.

Animals↗
PubMed1982

Sulfation of minoxidil by liver sulfotransferase.

The 100,000 g supernatant fraction of rat liver homogenate contains a sulfotransferase activity which catalyzes the sulfation of minoxidil. Synthetic minoxidil N-O sulfate and the enzyme synthesized product had identical chromatographic characteristics on high pressure liquid chromatography. Minoxidil sulfate, which yields minoxidil when treated with sulfatase, was slowly hydrolyzed in water. Several N-oxides of other heterocycles, including several other pyrimidines, triazines and imidazoles, were also substrates for this sulfotransferase.

Animals↗
PubMed1982

1-(alkylamino)isochromans: hypotensives with peripheral and central activities.

A series of 1-[1-(3,4-dimethoxy-1H-2-benzopyran-1-yl)alkyl]-4-arylpiperazines that shows hypotensive activity in the conscious rat has been investigated. Structure-activity relationships are described. A typical example that was investigated in greater detail is 1-[2-(3,4-dihydro-6,7-dimethoxy-1H-2-benzopyran-1-yl)ethyl]-4-(4-fluorophenyl)piperazine. This compound decreases sympathetic nerve activity recorded from the external carotid and splanchnic nerves of baroreceptor-denervated cats and, therefore, has a central component to its mechanism of action. It also blocks pressor effects of norepinephrine and phenylephrine and is thus an alpha-adrenergic antagonist. Binding data characterize this as alpha 1-adrenergic receptor blockade.

Adrenergic alpha-Antagonists↗