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Biomedical subjects

C F Smith

Publications and source records attributed to C F Smith.

At least 19 recordsLinked to original sources
PubMed1992

Selectivity profile of the alpha 2-adrenoceptor antagonist efaroxan in relation to plasma glucose and insulin levels in the rat.

The effects of efaroxan (RX 821037A; 2-[2-(2-ethyl-2,3-dihydrobenzofuranyl)]-2-imidazoline HCl) at alpha 1- and alpha 2-adrenoceptors were investigated in isolated tissues, pithed rats and conscious rats. In isolated tissues, efaroxan competitively antagonised the inhibitory effects of p-aminoclonidine in the electrically stimulated (0.1 Hz) rat vas deferens, (pA2 = 8.89) and the contractile effects of phenylephrine on the rat anococcygeus muscle (pA2 = 6.03). Efaroxan had a selectivity ratio (alpha 2/alpha 1) of 724 compared to a value of 182 for idazoxan. In pithed rats, the i.v. doses of efaroxan (mumol/kg) producing 2-fold shifts in dose-response curves for UK-14,304 at prejunctional cardiac alpha 2-adrenoceptors and postjunctional vascular alpha 2-adrenoceptors, and for cirazoline at postjunctional vascular alpha 1-adrenoceptors, were 0.05, 0.13 and 2.96, respectively. In conscious fasted rats, prazosin (5 mg/kg p.o.) increased resting glucose levels and exacerbated the hyperglycaemic effects of UK-14,304 and adrenaline. In contrast, efaroxan (1-5 mg/kg p.o.) had little effect on resting plasma glucose but markedly antagonised the hyperglycaemic actions of UK-14,304 and adrenaline. Efaroxan increased resting plasma insulin levels and markedly potentiated the rise in insulin levels produced by adrenaline; this latter effect was prevented by the co-administration of propranolol. These results demonstrate that efaroxan is a potent and selective alpha 2-adrenoceptor antagonist and provide further support for the involvement of alpha 2-adrenoceptors in glucose homeostasis.

Adrenergic alpha-Antagonists↗
PubMed1991

Synthesis and biological evaluation of 14-alkoxymorphinans, V: 6-Deoxyocyprodime, an opioid antagonist with decreased mu receptor selectivity in comparison to cyprodime.

N-Cyclopropylmethyl-4,14-dimethoxymorphinan (4) and N-cyclopropylmethyl-4-hydroxy-14-methoxymorphinan (5) have been prepared from cyprodime (1) by Wolff-Kishner reduction. Pharmacological studies (mouse vas deferens and guinea pig ileum preparations) revealed that there was no significant decrease of 4 in antagonist activity but in mu selectivity when compared with 1. The phenol 5 showed partial agonism at mu, kappa and delta receptors.

Animals↗
PubMed1991

(-)-N,N'-but-2-ene-1,4-diylbimorphinans.

N,N'-But-2-ene-1,4-diylbimorphinans 1-3 have been synthesized and pharmacologically evaluated. Bimorphinans 1 and 3 show opioid antagonist activity and preference for mu and kappa opioid receptors in mouse vas deferens and guinea pig ileum preparations.

Animals↗
PubMed1991

The effect of total-body irradiation on corneal neovascularization in the Fischer 344 rat after chemical cauterization.

Previous investigations of corneal neovascularization after irradiation yielded discordant results. Most studies indicated that new blood vessel formation in the cornea is inhibited by irradiation. However, others reported that angiogenesis after corneal cauterization is similar in both irradiated and nonirradiated animals. To assess the effect of total-body irradiation on neovascularization further, the amount of angiogenesis was determined in irradiated rats after chemically induced corneal injury. Corneal tissue was evaluated quantitatively with computerized image analysis 2, 3, or 4 days postcautery in rats perfused with India ink and gelatin immediately after death. The rats were exposed to a single dose (9 Gy) of total-body irradiation 6 days before corneal cauterization. In both the nonirradiated and irradiated rats, neovascularization increased with the duration of the postcautery interval. The amount of corneal neovascularization was not significantly different in the irradiated and nonirradiated rats at any of the postcautery intervals studied. This investigation suggests that endothelial cell migration plays a more important role than cell replication in the pathogenesis of corneal angiogenesis in the Fischer 344 rat. Moreover, the suppression of corneal angiogenesis by irradiation may be dependent on the experimental conditions and species examined.

Animals↗
PubMed1990

Proteoglycan biosynthesis by human corneas from patients with types 1 and 2 macular corneal dystrophy.

Corneal buttons were obtained from patients with types 1 and 2 macular corneal dystrophy (MCD) and from control patients with Fuchs' dystrophy or keratoconus. Buttons were incubated for 20 h in the presence of [3H]glucosamine or [2-3H]mannose. Radiolabeled proteoglycans and lactosaminoglycan-glycoproteins (L-GPs) were purified using chromatography on Q-Sepharose, Superose 6, and octyl-Sepharose. They were identified using chondroitinase ABC, keratanase or endo-beta-galactosidase digestion, and sodium dodecyl sulfate-polyacrylamide gel electrophoresis or Superose 6 chromatography. This study confirms previous reports that type 1 MCD corneas synthesize a normal dermatan sulfate-proteoglycan (DS-PG) and an abnormal keratan sulfate-proteoglycan (KS-PG). The data indicate that typ 1 MCD corneas synthesize L-GP instead of KS-PG. This L-GP has a core protein of similar hydrophobicity (elution from octyl-Sepharose) and nearly similar mass (42 kDa) as the core protein of the KS-PG. It has identical glycoconjugates as those of the KS-PG except that they lack sulfate. Thus, type 1 MCD fails to synthesize keratan sulfate as a result of a defect in a sulfotransferase specific for sulfating lactosaminoglycans. Further, proteoglycans synthesized by a cornea from a patient with type 2 MCD were studied. This cornea synthesized a normal ratio of KS-PG to DS-PG although net synthesis of proteoglycans was approximately 30% below normal. The KS-PG appeared normal whereas the DS-PG had dermatan sulfate chains that were approximately 40% shorter than normal.

Cells, Cultured↗
PubMed1990

Synthesis and biological evaluation of 14-alkoxymorphinans. 3. Extensive study on cyprodime-related compounds.

A series of cyprodime-related compounds (2, 4-12, and 26) has been synthesized and evaluated for opioid agonist and antagonist activity with the mouse vas deferens and guinea pig ileum preparations. None of the changes to cyprodime, including the introduction of a 3-OMe group, increasing and decreasing the size of or completely removing the substituent in position 4, replacing the N-cyclopropylmethyl group with an N-allyl group, or replacing the 14-OMe with an 14-OEt substituent, resulted in an improved mu antagonist profile and most were detrimental either in terms of mu selectivity and potency or increased agonist activity. Increasing the length of the substituent in position 4 resulted in a compound (6a) with a very similar profile to that of cyprodime.

Animals↗
PubMed1989

Synthesis and biological evaluation of 14-alkoxymorphinans. 2. (-)-N-(cyclopropylmethyl)-4,14-dimethoxymorphinan-6-one, a selective mu opioid receptor antagonist.

(-)-N-(Cyclopropylmethyl)-4,14-dimethoxymorphinan-6-one (2) was synthesized with 4,14-dimethoxy-N-methylmorphinan-6-one (1) as starting material. In vivo and in vitro experiments show 2 (cyprodime) to be a pure opioid receptor antagonist. Some of these tests (opioid receptor binding assays, guinea pig ileal longitudinal muscle preparation, rat and mouse vas deferens preparation, acetic acid writhing antagonism test) indicate that 2 is a selective mu opioid receptor antagonist.

Animals↗
PubMed1989

Heteroaromatic analogues of the alpha 2-adrenoreceptor partial agonist clonidine.

A 1,4-dioxane analogue (1) of the alpha 2-adrenoreceptor partial agonist clonidine (2) has previously been shown to possess an interesting but complex pharmacological profile. In this study, from a series of other heterocyclic analogues of clonidine, the 1,4-oxazines 6 and 12 were found to resemble 1 in that they are partial alpha 2-agonists in the periphery and are excluded from the central nervous system. However, when given directly into the brain, they behave as pure alpha 2-antagonists.

Adrenergic alpha-Agonists↗
PubMed1989

The carbon dioxide laser. A potential tool for orthopedic surgery.

Arthroscopic laser surgery was performed in 325 knee joints between January 1985 and August 1988 with no significant lasting complications. The CO2 laser is especially effective in the "tight knee" for high surface area, low volume lesions, and chondromalacia. Arthroscopic laser surgery is also being performed as part of a multicenter study. Although the results are satisfactory to date, the use of the laser on the spine and joints other than the knee and for PMMA removal is experimental.

Ankle Joint↗
PubMed1988

Indoline analogues of idazoxan: potent alpha 2-antagonists and alpha 1-agonists.

The synthesis and alpha-adrenergic activity of a series of substituted 2-imidazolinylindolines are described. Substitution in the indoline ring generated compounds with a spectrum of adrenoceptor antagonist/agonist profiles that proved sensitive to both the nature and position of the substituent. Many of the derivatives possess greater presynaptic antagonist potency than the corresponding benzodioxan 1, dihydrobenzofuran 2, and indan 3 analogues; however, this alpha 2-antagonism is often accompanied by alpha 1-agonist activity. It was not possible to separate alpha 2-antagonist from alpha 1-agonist properties in this series. Compounds of most interest proved to be the N-ethyl 6, 5-chloro-N-methyl 18, and 5-chloro-N-ethyl 23 derivatives, all being potent alpha 2-antagonists and alpha 1-agonists. Substitution at the 4- and 7-position of the indoline ring generally gave compounds with nonselective agonist properties.

Adrenergic alpha-Agonists↗
PubMed1988

Quantitation of corneal neovascularization using computerized image analysis.

We have developed a method for quantitating corneal neovascularization, induced in anesthetized rats by silver nitrate/potassium nitrate cauterization, using a LeMont OASYS video input image analyzer. Corneal vessels are visualized by perfusing the upper half of deeply anesthetized animals with a mixture of 10% india ink, 11% gelatin in lactated Ringer's solution. The eyes are then rapidly cooled using a stream of compressed dichlorodifluoromethane (Freon) to solidify the gelatin mixture. Magnified images of flat preparations of the corneas are acquired using a television camera attached to a dissecting microscope. The images are electronically converted to digital form and the digitized data are stored in the image analyzer. The area of the cornea and blood vessels are independently determined by analyzing the digitized data as discrete values of varying shades of gray (gray-scale analysis). The area and gray scale of the injury and its distance from the corneoscleral limbus can also be measured to determine variability of location and intensity of the injury in different animals. This technique allows the area occupied by new blood vessels during studies on corneal neovascularization in rats to be rapidly quantitated.

Animals↗
PubMed1988

Comparison of seven methods of preparing and administering small-volume injections.

The time and costs associated with preparing and administering small-volume injections using seven infusion systems were compared. Thirteen demographically diverse hospitals were chosen as study sites, all under a common protocol. The systems compared were the CRIS controlled-release infusion, minibag, frozen ready-to-use minibag, drug manufacturer-supplied piggyback, syringe pump, volume-control set, and ADD-Vantage systems. Care was taken to ensure that similar drugs (i.e., drugs with equivalent preparation steps) were studied in the same test systems at the hospitals. The mean preparation time for the CRIS controlled-release infusion system was significantly longer than the times for the frozen ready-to-use minibags and ADD-Vantage system and significantly shorter than the times for the minibag and syringe pump systems. Medication administration time for initial doses was found to be significantly shorter with the CRIS system than with the volume-control and ADD-Vantage systems; the time required to administer subsequent doses of small-volume injections was shorter with CRIS than with all other systems except the ADD-Vantage system. When total material costs plus the cost of labor involved in both pharmacy and nursing were combined, CRIS proved to be the least expensive system to use, primarily because of the time and cost savings associated with its use for administration of subsequent doses. Of the seven admixture systems studied, the CRIS system proved to be the least expensive to use when labor and material costs associated with preparation and administration of six doses of an injectable drug were considered.

Cefazolin↗
PubMed1987

16-Me cyprenorphine (RX 8008M): a potent opioid antagonist with some delta selectivity.

16-Me cyprenorphine (RX 8008M) has been investigated in a number of isolated tissue preparations and found to be a pure opioid antagonist with Ke values at the delta, mu and kappa receptors of 0.73, 1.77 and 59.6 nM respectively. Comparisons of the mu, kappa and delta Ke values with a number of other antagonists in the mouse vas deferens have been made and show that the 16-Me substituent results in a marked enhancement of delta activity, making RX 8008M the most selective non-peptide delta antagonist available at the present time.

Animals↗
PubMed1986

Effect of methoxy substitution on the adrenergic activity of three structurally related alpha 2-adrenoreceptor antagonists.

We have recently reported the synthesis and alpha 2-antagonist activity of the methoxy derivative 2 [2-(2-methoxy-1,4-benzodioxan-2-yl)-2-imidazoline] and described the enhanced potency of this compound over the parent 1,4-benzodioxan, idazoxan, in reversing the inhibition caused by alpha 2-adrenoreceptor agonists of the electrically induced twitch in the rat or mouse vas deferens. It was of interest to us to discover whether a similar substitution in the structurally related alpha 2-adrenoreceptor antagonists piperoxan, prosympal, and fenmetazole would similarly enhance potency. We subsequently discovered that this was not so and potency was decreased markedly. In particular, that of the methoxy derivative of piperoxan was ca. 220 times less than the parent structure.

Adrenergic alpha-Antagonists↗