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Biomedical subjects

L W King

Publications and source records attributed to L W King.

At least 19 recordsLinked to original sources
PubMed1998

Protective effect of oral xemilofiban in arterial thrombosis in dogs: increased activity in combination with aspirin.

BACKGROUND: Inhibition of platelet aggregation by preventing the binding of fibrinogen to glycoprotein (GP) IIb/IIIa on activated platelets results in antithrombotic activity. We report on the antithrombotic effect of xemilofiban (SC-54684A), an oral GP IIb/IIIa antagonist, administered alone or with aspirin (ASA) in an acute thrombosis model. METHODS AND RESULTS: Conscious dogs were treated with xemilofiban (1.25, 2.5, 5.0, or 6 mg/kg, n=6); low-dose (LD, 81 mg) ASA, n=7; high-dose (HD, 162 mg) ASA, n=6; xemilofibran 1.25 mg/kg plus LD ASA, n=6; xemilofibran 1.25 mg/kg plus HD ASA, n=6; or placebo, n=7. Dogs were anesthetized 60 minutes later, and the effects of the treatments were evaluated after electrolytic injury (250 microA for 180 minutes) in the left circumflex coronary artery. Bleeding time (BT) was assessed in a separate study. Incidence of thrombosis was reduced (P<0.05) by xemilofiban > or =2.5 mg/kg, HD ASA, or xemilofiban 1.25 mg/kg plus HD ASA compared with placebo. Xemilofiban > or =2.5 mg/kg or xemilofiban 1.25 mg/kg plus HD ASA significantly increased time to occlusion, inhibited ex vivo platelet aggregation to collagen >90%, and prevented or decreased (P<0.05) cyclic flow variations (CFVs) compared with placebo. BT was increased (P<0.05) with xemilofiban > or =2.5 mg/kg but not with xemilofiban 1.25 mg/kg plus HD ASA. CONCLUSIONS: Xemilofiban > or =2.5 mg/kg, HD ASA, or xemilofiban 1.25 mg/kg plus HD ASA significantly reduced the incidence of thrombosis. These doses of xemilofiban or xemilofiban 1.25 mg/kg plus HD ASA increased time to occlusion, inhibited ex vivo platelet aggregation by >90%, and prevented or reduced CFVs. Xemilofiban > or =2.5 mg/kg but not xemilofiban 1.25 mg/kg plus HD ASA significantly increased BT.

Administration, Oral↗
PubMed1996

The protective dose of the potent GPIIb/IIIa antagonist SC-54701A is reduced when used in combination with aspirin and heparin in a canine model of coronary artery thrombosis.

BACKGROUND: Fibrinogen receptor antagonists block the fibrinogen-platelet interaction at the GPIIb/IIIa receptors and inhibit thrombus formation. SC-54701 is the active metabolite of SC-54684A, an orally fibrinogen receptor antagonist. We compared the efficacy of SC-54701A (SCa, hydrochloride salt) with that of aspirin (ASA) or heparin and with combination therapy in a canine model of continuous current injury. METHODS AND RESULTS: Sixty-six dogs were used (6 per treatment). SCa (15-minute loading dose followed by [//] infusion [microgram/kg per minute]: (0.87//0.39=1 X SCa; 0.52//0.23=0.6 X SCa; and 0.425//0.20= 0.5 X SCa), ASA (2.8 mg/kg), heparin (200 U/kg plus 1000 U/h), or saline (0.1 mL/kg) was administered intravenously. Experimental time was 180 minutes of current. Time to occlusion was increased (P < .05) by SCa (T=incidence of thrombosis) (1 X SCa, >180 minutes [T=0]; 0.6 X SCa, 158 +/- 15 minutes [T=2]; 0.5 X SCa, 130 +/- 22 minutes [T=4]), heparin (114 +/- 16 minutes [T=5]), and ASA plus heparin (130 +/- 11 minutes [T=5]) relative to saline (58 +/- 7 minutes [T=6]). Time to occlusion for the SCa treatments was increased compared with ASA (64 +/- 7 minutes [T=6]). When 0.5 X SCa was administered with ASA plus heparin, time to occlusion was >180 minutes [T=0]. SCa provided complete protection at > or = 90% inhibition of ex vivo collagen-induced platelet aggregation. Cyclic flow variations were minimal with SCa or any treatment involving 0.5 X SCa and ASA. CONCLUSIONS: SCa has dose-dependent antithrombotic efficacy and inhibits ex vivo platelet aggregation. ASA, heparin, or saline was ineffective in this model. SCa (0.5X) plus ASA and heparin maximized the antithrombotic effect of this lower dose of SCa.

Animals↗
PubMed1995

SC-54684A: an orally active inhibitor of platelet aggregation.

BACKGROUND: Intravenous therapy has been shown to be beneficial in the prevention of acute platelet-associated thrombotic events. However, orally active agents would be advantageous for chronic therapy. Fibrinogen receptor antagonists block the fibrinogen/platelet interaction and thus inhibit a step required for thrombus formation. To date, no orally active fibrinogen binding inhibitors have been characterized. SC-54684A, now in clinical trial, is the orally active prodrug of a potent and specific fibrinogen binding antagonist. METHODS AND RESULTS: We measured inhibition of 125I-fibrinogen binding to activated platelets and inhibition of aggregation in platelet-rich plasma to selected agonists and showed IC50s of 1.0 x 10(-8) and 3 to 7 x 10(-8) mol/L, respectively. Specificity of the active moiety was determined by studying its effect on the binding of (1) neutrophils to interleukin (IL)-1 beta-stimulated endothelial cells, (2) endothelial cells to fibronectin, and (3) vitronectin to isolated vitronectin and fibrinogen receptors. No effect was observed on the binding neutrophils to IL-stimulated endothelial cells or endothelial cell binding to fibronectin. There was a fivefold separation between binding to isolated receptors of vitronectin and fibrinogen. Collagen-induced aggregation was inhibited by 80%, and bleeding time was increased approximately 2.5-fold when the active moiety was infused to steady state at 0.2 micrograms/kg per minute in dogs. When the ester prodrug was given orally and the active moiety was given intravenously, the oral systemic activity was approximately 20%. Pharmacokinetic analysis after intravenous infusion of the prodrug or active moiety showed that the prodrug was rapidly converted to the active moiety; the active moiety had a t1/2 of 6.5 hours. When the prodrug was administered both orally and intravenously, the systemic availability of the active moiety was 62%. CONCLUSIONS: SC-54684A, an orally active antiplatelet drug now in clinical trial, is shown to be a potent, specific fibrinogen binding inhibitor that blocks platelet aggregation to a wide variety of known stimuli and has good bioavailability in animals.

Administration, Oral↗
PubMed1994

SC-49992--a potent and specific inhibitor of platelet aggregation.

Fibrinogen binding is required for platelet aggregation and subsequent thrombus formation. SC-49992 (SC), an RGDF mimetic, is a potent and specific inhibitor of the binding of fibrinogen to its receptor on activated platelets, glycoprotein IIb/IIIa (IC50 0.7 microM). SC was more potent (1-5 microM) than either RGDS, RGDF or the gamma chain dodecapeptide in blocking platelet aggregation to a variety of agonists in both dog and human platelet rich plasma. SC was more potent as an inhibitor of GP IIb/IIIa on platelets than it was against other integrin and non-integrin receptors, including the RGD-dependent vitronectin receptor and other non-RGD-dependent integrins such as CDII/CD18. SC had little effect on ristocetin induced agglutination. SC blocked ex vivo collagen induced aggregation in dogs and collagen induced thrombocytopenia in rats. These data suggest that elimination of the Arg-NH2 and the Arg-Gly amide bond of RGDF provided increased inhibitory potency and specificity. This structural modification may be of value in the development of other more potent RGDF mimetics for the inhibition of platelet aggregation.

Amino Acid Sequence↗
PubMed1993

SC-49992, a mimetic of the peptide arginine-glycine-aspartic acid-phenylalanine that blocks platelet aggregation, enhances recombinant tissue plasminogen activator-induced thrombolysis and prevents reocclusion in a canine model of coronary artery thrombosis.

8-Guanidino-octanoyl-aspartic acid-phenylalanine (SC-49992), a mimetic of the tetrapeptide arginine-glycine-aspartic acid-phenylalanine, is a potent inhibitor of platelet aggregation. In this study, the authors examined the effects of SC-49992 on the time to lysis of thrombi and the time to reocclusion in the canine coronary artery, which had been treated with tissue plasminogen activator. A lysis/reocclusion model was used that was originally designed so that the reoccluding thrombus was platelet rich. SC-49992 decreased the time to lysis in response to recombinant tissue plasminogen activator in a dose-dependent manner. The reduction of the lytic time was significant at the highest dose of 0.08 mg kg-1 min-1 (from 22.8 +/- 8.2 to 7.4 +/- 1.4 min, P < .05). The reocclusion time was prolonged at all doses of SC-49992 (from a control level of 3.4 +/- 0.6 min to more than 50 min at all doses of SC-49992, P < .05). At the 0.06- and 0.08-mg kg-1 min-1 doses, all but one animal in each group did not have a reocclusion during the time of the experiment. In those animals that did have reocclusions in the presence of SC-4992, ex vivo platelet aggregation was inhibited 100% at the time of reocclusion. The bleeding times were prolonged in these animals at the levels of inhibition in which the compound was the most effective.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗
PubMed1991

In vitro and in vivo effects of a peptide mimetic (SC-47643) of RGD as an antiplatelet and antithrombotic agent.

Platelet aggregation requires binding of fibrinogen (fgn) to activated platelets and inhibition of this binding blocks platelet aggregation. Synthetic peptides modeled after the platelet binding sequence on fgn block the platelet glycoprotein IIb/IIIa receptor and effectively inhibit aggregation. SC-47643 (SC) is a mimetic of the RGD-containing peptide sequence that is recognized by the platelet IIb/IIIa receptor. SC inhibited fgn binding to activated platelets (IC50: 1.0 x 10(-5) M) and prevented platelet aggregation in response to a variety of platelet agonists in both washed human platelets and platelet rich plasma (IC50's ranging from 4 x 10(-6) to 1 x 10(-5) M, respectively). SC inhibited collagen induced thrombocytopenia in the rat (ED50 0.07 mg/kg and t1/2 36 min). In dogs ex vivo collagen induced platelet aggregation was inhibited 50% after a bolus injection of 1.7 mg/kg. After a steady state infusion (2 hr), the ED50 was 0.03 mg/kg/min, with no effects on blood pressure, heart rate or platelet count. These data demonstrate that SC, a peptide mimetic of the natural fgn binding sequence, is capable of blocking platelet-fgn interactions and platelet aggregation.

Amino Acid Sequence↗
PubMed1991

Antiplatelet and antithrombotic effects of platelet glycoprotein IIb/IIIa (GPIIb/IIIa) inhibition by arginine-glycine-aspartic acid-serine (RGDS) and arginine-glycine-aspartic acid (RGD) (O-me)Y (SC-46749).

Arginine-glycine-aspartic acid (RGD) is the minimal sequence in fibrinogen that leads to recognition and binding to the glycoprotein IIb/IIIa platelet receptor during aggregation. Analogs of tetrapeptides containing the RGD sequence have been previously shown to block fibrinogen binding to activated platelets in vitro. SC-46749 is an analog of arginine-glycine-aspartic acid-phenylalanine in which the phenylalanine is replaced by O-methyltyrosine. In this study the biological activities of SC-46749 were examined and its actions compared with the tetrapeptide arginine-glycine-aspartic acid-serine (RGDS), one of the natural sequences on the fibrinogen alpha chain that binds to platelets. In vitro, SC-46749 was more potent than RGDS in inhibiting fibrinogen binding (IC50: SC-46749, 27 microM; RGDS, 47 microM), in preventing ADP-induced aggregation in human platelet-rich plasma (IC50: SC-46749, 32 microM; RGDS, 95 microM) and in inhibiting thrombin-induced aggregation in washed human platelets (IC50: SC-46749, 23 microM; RGDS, 64 microM). In rats, SC-46749 prevented collagen-induced thrombocytopenia with an ED50 of 0.87 mg/kg whereas RGDS did not inhibit the response by 50% at doses up to 10 mg/kg. SC-46749 inhibited thrombus formation in an electrically damaged rat carotid artery in a dose-dependent fashion whereas the effects of RGDS were biphasic. RGDS appeared to delay thrombus formation at lower doses but had no effect at higher doses. When infused in dogs for 15 min, SC-46749 prevented ex vivo collagen-induced aggregation at 4 mg/kg/min. These data demonstrate that SC-46749 is a potent inhibitor of platelet aggregation and platelet-dependent thrombus formation.

Animals↗
PubMed1986

Failure to confirm the existence of short-latency, short-loop feedback regulation (autoregulation) of growth hormone secretion in the human.

That growth hormone (GH) regulates its own secretion by negative feedback both directly and indirectly via somatomedins has been well-documented in the rat and assumed, on the basis of limited studies, to be true for man as well. Prior to proceeding with studies designed to investigate the nature of this feedback in various endocrine states, we sought first to confirm the existence of direct, short-latency GH feedback in normal individuals. Primed, continuous rate infusions of human GH in normal volunteers achieved a range of steady state GH levels. After 1 h of GH infusion, arginine HCl (500 mg/kg) was infused over 30 min and the GH response assessed. Seven of 8 subjects achieved steady state GH levels in the 8-21 ng/ml range with an infusion rate of 0.0045 U/min following a 0.277 U bolus. After arginine, there was a significant increment of GH levels (range 11.6-69.5 ng/ml) in all 7 subjects. With a higher infusion rate of 0.009 U/min following a 0.54 U bolus, 1 of 2 subjects reached a steady state of 31.0 ng/ml and no response to arginine was demonstrable. Two subjects reached steady state levels of 45.0 and 58 ng/ml during a 0.018 U/min infusion after a 1.08 U bolus and had increments of 26.2 and 25.9 ng/ml following arginine. In 3 subjects achieving levels of 64.5, 107.0 and 132.0 ng/ml, there were increments of 55.0, 61.7 and 13.0 ng/ml during infusions of 0.036 U/min following boluses of 2.16 U. However, only in the first of these 3 was a true steady state achieved.(ABSTRACT TRUNCATED AT 250 WORDS)

Arginine↗
PubMed1986

Cardiovascular actions and pharmacokinetics of desethyl-N-acetylprocainamide in the dog.

The pharmacokinetic profile and the cardiovascular actions of desethyl-N-acetylprocainamide (NAPADE) were studied in chloralose-urethane anesthetized dogs. NAPADE was given as a 15-min i.v. infusion in doses of 12 and 60 mg/kg. In all cases, the plasma concentration vs. time curve could be resolved into two exponential components, and the distribution and elimination of NAPADE were analyzed with a two-compartmental model. Total apparent volume of distribution was 0.4153 +/- 0.0301 liters/kg (mean +/- S.E.M.) for the 12-mg/kg group and 0.4946 +/- 0.0691 liters/kg for the 60-mg/kg group (P greater than .05). Elimination clearance was 0.0061 +/- 0.0006 liters/min/kg for the 12-mg/kg group and 0.0086 +/- 0.0013 liters/min/kg for the 60-mg/kg group (P greater than .05). The elimination phase half-life (T1/2 beta) was 57.0 +/- 4.1 and 53.1 +/- 3.2 min for the 12- and 60-mg/kg groups, respectively (P greater than .05). Thus, NAPADE exhibited first-order kinetics of distribution and elimination in the dose range studied. Renal clearance of unchanged NAPADE amounted to 45.9 +/- 4% of total plasma clearance. NAPADE had a dose- and concentration-related positive inotropic effect, as measured with a Walton-Brodie gauge sutured to the right ventricle. A 12-mg/kg infusion caused a peak increased in myocardial force of 18.4 +/- 3.6% over base line, whereas a 60-mg/kg infusion caused a peak increase in myocardial force of 48.9 +/- 10% over base line. The positive inotropic effect of NAPADE was sustained for 50 to 90 min.(ABSTRACT TRUNCATED AT 250 WORDS)

Acecainide↗
PubMed1986

The inotropic actions of N-acetylprocainamide: blockade and reversal by propranolol.

The inotropic actions of N-acetylprocainamide (NAPA) were studied in chloralose-urethane anesthetized dogs. Myocardial contractile force was measured with a Walton-Brodie strain gauge sutured to the right ventricle. A low-dose NAPA infusion (12 mg/kg i.v.) increased myocardial force by a maximum of 11.6 +/- 2.4% (mean +/- SEM), whereas a high dose of NAPA (60 mg/kg i.v.) increased myocardial force by 33.3 +/- 2.6% at the peak of the effect. The high-dose NAPA infusion also caused significant reductions in heart rate and blood pressure, while the low-dose NAPA infusion lacked significant chronotropic or hypotensive actions. Pretreatment with propranolol (0.5 mg/kg i.v. loading, followed by a 10 micrograms/kg/min infusion) did not block the positive inotropic actions of NAPA 12 mg/kg, but these actions were blocked in dogs pretreated with both propranolol and atropine (1 mg/kg). On the other hand, pretreatment with propranolol blocked and reversed the inotropic actions of NAPA 60 mg/kg, and potentiated its negative chronotropic effects. Thus, the positive inotropic actions of NAPA are indirect and more than one mechanism is involved; a component due to direct action related to the lengthening of cardiac repolarization is not discounted. At low doses, the increase in myocardial force seems related to NAPA's vagolytic properties, whereas at high doses the positive inotropic actions appear to be catecholamine-mediated. Furthermore, a negative inotropic action of high-dose NAPA is apparent after beta-adrenergic receptor blockade.

Acecainide↗
PubMed1984

Twenty-four-hour prolactin secretory patterns in women with galactorrhea, normal menses, normal random prolacting levels and abnormal sellar tomograms.

During a systematic study of women with idiopathic galactorrhea, we observed several patients with normal random serum prolactin (PRL) levels and normal menses, but abnormal sellar tomograms characteristic of a pituitary adenoma. To test the hypothesis that these women might have intermittent PRL hypersecretion, we studied PRL secretion by sampling blood every half hour for 24 h in 10 patients and for 17.5 h in another, and compared the findings to those of a group of 5 normal women. The mean 24-h PRL of the 10 patients (16.8 +/- 7.8 ng/ml; mean +/- SD) was not significantly different from that of the normal women (13.6 +/- 3.2 ng/ml), and each patient showed a normal sleep-associated PRL increment. Three individuals exhibited an abnormally elevated 24-h PRL (greater than 20 ng/ml). Increased PRL secretion occurred primarily at night or in the afternoon. Thyrotropin releasing hormone (TRH) administration caused normal or exaggerated PRL responses in all patients tested. High resolution CT scanning of two of the hypersecretors suggested a microadenoma in one case. In another case whose PRL was normal over 17.5 h, transsphenoidal surgery, carried out because of the tomographic findings and the symptom of headaches, demonstrated a 5-mm chromophobe adenoma that did not contain PRL by immunohistochemistry. Postoperatively the galactorrhea persisted. We conclude that most women with galactorrhea, normal PRL, normal menses, and abnormal tomograms have normal PRL secretion. However, a minority of patients with this syndrome do demonstrate intermittent PRL hypersecretion. The etiology of intermittent PRL hypersecretion and its relevance to galactorrhea have not been determined.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1983

Cavernous sinus syndrome due to prolactinoma: resolution with bromocriptine.

Cavernous sinus syndrome due to a pituitary tumor is quite rare. Our patient had a large prolacinoma that extended superiorly, causing bitemporal visual field defects, and laterally into the right cavernous sinus, causing tearing, dysesthesia in the distribution of the fifth cranial nerve, a loss of the corneal reflex, and a sixth cranial nerve palsy. Prolactin levels ranged between 800 and 1000 ng/mL. Treatment with 7.5 mg of bromocriptine daily caused a marked reduction in the size of the tumor and resolution of her visual field defects and cranial nerve dysfunction over 6 months. We feel that bromocriptine should be considered as initial therapy for patients with prolactinomas extending into the middle or posterior cranial fossae.

Bromocriptine↗
PubMed1982

Surgical cure of prolactinoma reverses abnormal prolactin repsonse to carbidopa/L-dopa.

To determine whether the abnormalities in dopaminergic regulation of PRL secretion in patients with prolactinomas persist after resection of the adenoma, we evaluated PRL inhibitory responses to L-dopa alone and L-dopa given after pretreatment with the dopa decarboxylase inhibitor carbidopa before and after transsphenoidal selective resection of prolactinomas in 23 women. Eighteen women were cured by surgery (normal PRL, menses, no galactorrhea), while 5 women were not cured. Preoperatively, the PRL inhibitory responses to L-dopa cured, 4 .3 +/- 3.8%; uncured, 50.1 +/- 5.5% of baseline) was blunted by pretreatment with the decarboxylase inhibitor carbidopa (cured, 79.1 +/- 4.1%; uncured, 76.8 +/- 9.2%). Postoperatively, this blunting disappeared in the cured patients (L-dopa, 49.1 +/- 3.5%; carbidopa/L-dopa, 56.3 +/- 5.1%), but the blunting persisted in the uncured patients (L-dopa, 49.3 +/- 7.9%; carbidopa/L-dopa, 69.3 +/- 4.2%). The return to normal of the carbidopa/L-dopa test in cured prolactinoma patients after surgery is evidence that in these individuals, preoperative abnormalities of secretion are due to either intrinsic abnormalities of the tumor or alteration of hypothalamic function secondary to tumor secretion. In those patients not cured by surgery, dynamic tests of function remain abnormal, findings attributable to either incomplete tumor resection or the presence, in some patients, of underlying hypothalamic dysregulation.

Adenoma↗
PubMed1981

Differential effects of ibuprofen and indomethacin in the regional circulation of the dog.

The effects of indomethacin and ibuprofen on aortic blood pressure and regional vascular resistances were studied in pentobarbital-anesthetized dogs. In the mesenteric vascular bed, indomethacin produced severe, acute vasoconstriction when administered by i.v. infusion as well as by i.a. injections. Tachyphylaxis developed rapidly to this response. In contrast. ibuprofen did not alter mesenteric blood flow even when a large (50 mg) i.v. bolus was rapidly injected. The mesenteric vasoconstrictor response to indomethacin was not modified when prostaglandin synthesis was inhibited or in the presence of cyproheptadine. Phentolamine exerted only a minor influence on the mesenteric vascular effect of indomethacin. The effects of indomethacin and ibuprofen on aortic blood pressure and renal blood flow were similar. Both agents increased aortic pressure and decreased renal blood flow a small but significant amount, but these responses occurred slowly and were probably not related to the acute mesenteric vasoconstricting effect or indomethacin. The present study demonstrates that these nonsteroidal anti-inflammatory agents have different effects on the mesenteric vascular bed and the data suggest that the vasoconstricting effects of indomethacin are not related to the inhibition of prostaglandin synthesis in the intestine. The data also suggest that the acute vasoconstriction in the mesenteric circulation produced by indomethacin is not mediated to a significant degree by local release of alpha adrenergic agents or serotonin.

Animals↗
PubMed1976

A comparative evaluation of two day hospitals. Goal attainment scaling of behavior therapy vs. milieu therapy.

Previous attempts at program evaluation of partial hospitalization programs have consisted largely of descriptive and anecdotal reports of programs and patient characteristics. There have been no comparative or experimental studies of the effectiveness of differing day treatment programs. In the current study, Goal Attainment Scaling, a goal-oriented program evaluation system, was used with 56 randomly selected partial hospitalization patients who attended two day hospitals: one program was based on behavioral-educational methods, and the other was an eclectic program based on the concepts of a therapeutic community. Patients attending the behavioral-educational program showed greater attainment of their therapeutic goals than did the patients involved in the eclectic program. The greater effectiveness of the behavioral-educational day program increased from the 3-month follow-up to the 2-year follow-up.

Adolescent↗
PubMed1975

Behavior modification consultation in a Mexican-American school: a case study.

Following consultation by two psychologists with an elementary school populated primarily by Mexican-American students, absenteeism was chosen as the first problem area to attempt to change. A between-groups experimental design was used to evaluate the effect of contigent rewards on the students' attendance. Analysis of the data showed no improvement in attendance. The results of the study were discussed in terms of (1) a more thorough behavior analysis of the absenteeism problem, (2) methodological restraints of a between-groups experimental design, (3) the need for consultants to be familiar with the community in which they work, and (4) relatedly, the success of the local school psychologist in implementing behavior modification programs.

Behavior Therapy↗