Effect of zatosetron on ipecac-induced emesis in dogs and healthy men.

Serotonin receptor (5-HT3) antagonists provide effective antiemetic therapy in cancer patients receiving emetogenic chemotherapy, such as cisplatin. Animal studies have shown that 5-HT3 receptor antagonists also have antiemetic activity in ipecac-induced emesis. The authors investigated the antiemetic activity of zatosetron maleate, a 5-HT3 receptor antagonist, on ipecac-induced emesis in dogs and healthy men.

Establishment of time-action profiles for regular and NPH insulin using pharmacodynamic modeling.

Objective: To provide distinct definitions and quantify the establishment of onset, peak, and duration of action for insulins.

Research Design And Methods: We administered single subcutaneous doses of 10 U regular insulin to 10 volunteer subjects and 25 U NPH insulin to 6 healthy male volunteer subjects on separate occasions. Each dose was given after an overnight fast during a glucose clamp to maintain an euglycemic state.

Disposition of zatosetron, a serotonin (5-HT3) receptor antagonist, in humans.

Zatosetron is being tested clinically as an antianxiety agent; it is a highly selective antagonist of the serotonin 5-HT3 receptor, with minimal agonist activity. The disposition of [14C]zatosetron was studied in five healthy men after a single oral dose (46.2 mg).

Effect of tibenelast (a phosphodiesterase inhibitor) and theophylline on isoproterenol-stimulated heart rate, cyclic AMP and norepinephrine levels.

The effect of the phosphodiesterase inhibitors (tibenelast, theophylline) and placebo on isoproterenol-induced changes in heart rate, cAMP and norepinephrine levels in normal male volunteers was studied. Heart rates in response to isoproterenol dosing were fitted by linear regression, and horizontal shifts in the regression lines were examined between the three treatments. The shift of the regression line after placebo compared to the preplacebo line was to the right by 2.

The effects of renal and hepatic disease on the pharmacokinetics, renal tolerance, and risk-benefit profile of fluoxetine.

Renal and hepatic diseases have a significant impact on the plasma concentration profiles and the dose requirements for almost all drugs. This paper reviews the effect of these diseases and their associated physiological derangements on the pharmacokinetics of fluoxetine and norfluoxetine. Metabolic studies of fluoxetine in man show that more than 70% of the radiolabelled compound is excreted in the urine.

Antithrombotic agents from salivary glands of hematophagous animals.

The introduction of thrombolytic agents and adjunctive anticoagulant therapy in acute myocardial infarction and heparin-aspirin combinations in unstable angina have resulted in major gains in the acute management of these disorders; however, it is widely believed that available therapeutic agents, such as streptokinase and tissue plasminogen activator (t-PA), anticoagulants, such as heparin, and antiplatelet agents, such as aspirin, may not possess the optimal efficacy and safety profile. A major surge was initiated to identify alternative thrombolytic and antithrombotic drugs, and as a part of these efforts the isolation and characterization of protein salivary anticoagulants from hematophagous animal species has assumed importance. In the following, we briefly review these proteins and the development of peptides and peptidomimetic compounds based on their structures and discuss the potential utility of these compounds in cardiovascular disease therapy.

Quantification and mechanism of the fluoxetine and tricyclic antidepressant interaction.

Clinical reports of concurrent use of fluoxetine and tricyclic antidepressant agents suggest that tricyclic concentrations increase upon coadministration with fluoxetine. This study was conducted to confirm the clinical reports, to quantify the degree of change in tricyclic kinetics, and to establish the mechanism of interaction. Twelve male subjects were given 50 mg desipramine (six subjects) or 50 mg imipramine (six subjects) on three occasions: alone, after a 60 mg dose of fluoxetine, and after eight daily 60 mg doses of fluoxetine.

Single-dose pharmacokinetics and antibacterial activity of daptomycin, a new lipopeptide antibiotic, in healthy volunteers.

Three separate single-dose studies were performed to define the disposition and pharmacokinetics of daptomycin in healthy volunteers. Daptomycin was administered as a single 14C-labeled dose (1.0 mg/kg of body weight) and as single doses between 0.

In vivo evaluation of an electroenzymatic glucose sensor implanted in subcutaneous tissue.

Cleanroom processing techniques have been used to mass-produce flexible, electroenzymatic glucose sensors designed for implantation in subcutaneous tissue. In vitro characterization studies have shown the sensor's performance to be acceptable. Initial in vivo studies were conducted with the sensor implanted in the subcutaneous tissue of rabbits.

The stereospecific determination of fluoxetine and norfluoxetine enantiomers in human plasma by high-pressure liquid chromatography (HPLC) with fluorescence detection.

A quantitative method for the simultaneous HPLC resolution and detection of the enantiomers of (R,S) fluoxetine (F) and their metabolites (R,S) norfluoxetine (N) in human plasma has been developed. F is a serotonin uptake inhibitor used in the treatment of depression and is administered as a racemate. After liquid-liquid extraction and derivatization with (R) napthyl ethyl isocyanate (NEI), the separation and detection of the resultant diasteriomers were achieved using normal phase HPLC and fluorescence.

Isomazole disposition in man as a function of dose and route of administration.

The disposition of a new cardiotonic agent (isomazole (ISO] was evaluated in healthy volunteers after various single oral (p.o.), intravenous (i.

14C-isomazole disposition in man after oral administration.

A 50-mg dose containing 50 microCi 14C-isomazole was administered orally to five healthy male volunteers. Blood, plasma, urine, feces, and saliva were collected and measured for total 14C; in addition, all collections except feces were measured for parent drug (ISO) and three metabolites: hydroxyisomazole (OHISO) and sulfone (SULF) and hydroxysulfone (OHSULF) analogues. Urine and fecal recoveries accounted for 97.

Measurement of insulin-like growth factor-II in physiological fluids and tissues. I. An improved extraction procedure and radioimmunoassay for human and rat fluids.

The measurement of serum insulin-like growth factors (IGFs) in serum is complicated by the presence of high affinity IGF-binding proteins. The accurate measurement of IGFs by radioligand binding assays requires that the interference from binding proteins be eliminated. Acid-gel chromatography, the standard method for removing binding proteins, is laborious and time consuming.

Radioenzymatic assay for histamine: development and validation.

Radioenzymatic assays are sensitive analytic tools that use an enzyme to quantify a substrate for that enzyme. Purified histamine N-methyltransferase has been used as the basis for an assay for histamine. The sensitivity of the procedure is less than 10 fmol.

Disposition in humans of racemic picenadol, an opioid analgesic.

Racemic picenadol is being tested clinically as an analgesic. The (+)-enantiomer of picenadol is an opioid agonist and the (-)-enantiomer is a weak agonist/antagonist. The disposition of racemic [14C] picenadol was studied in healthy men after a single dose was administered im (N = 3) and orally (N = 5).

Functional properties of the recombinant kringle-2 domain of tissue plasminogen activator produced in Escherichia coli.

The kringle-2 domain (residues 176-262) of tissue-type plasminogen activator (t-PA) was cloned and expressed in Escherichia coli. The recombinant peptide, which concentrated in cytoplasmic inclusion bodies, was isolated, solubilized, chemically refolded, and purified by affinity chromatography on lysine-Sepharose to apparent homogeneity. [35S]Cysteine-methionine-labeled polypeptide was used to study the interactions of kringle-2 with lysine, fibrin, and plasminogen activator inhibitor-1.

Determination of a potential antiasthmatic compound, tibenelast, and its application to phase I clinical trials.

A sensitive and selective high-performance liquid chromatographic (HPLC) assay was developed for the determination of tibenelast, 5,6-diethoxybenzo[b]thiophene-2- carboxylic acid, in plasma and urine. The plasma assay involves protein precipitation with 4% trichloroacetic acid, while the urine assay is an automated solid-phase extraction procedure that utilizes the Waters Millilab workstation. The analysis was achieved by reversed-phase HPLC with ultraviolet detection at 313 nm.

Cross-reactivity of monomeric and dimeric biosynthetic human growth hormone in commercial immunoassays.

Commercial kits give different measurements for concentrations of growth hormone (GH, somatotropin) in serum. Most notably, a two-site monoclonal-antibody-based immunoradiometric assay (IRMA) from Hybritech routinely yields lower values than do conventional RIAs in which polyclonal antibodies are used. We used purified dimeric biosynthetic human GH as a model compound to investigate the specificity of five commercial immunoassays for size variants of GH.

In vivo behavior of detergent-solubilized purified rabbit thrombomodulin on intravenous injection into rabbits.

Thrombomodulin is a thrombin endothelial cell membrane receptor. The thrombomodulin-thrombin complex rapidly activates protein C resulting in anticoagulant activity. We investigated the anticoagulant effects and pharmacokinetic behavior of detergent-solubilized purified rabbit thrombomodulin labeled with iodine 125 when intravenously injected into rabbits.

Beneficial effects of pinacidil on blood lipids: comparisons with prazosin and placebo in patients with hypertension. Pinacidil-Prazosin and Pinacidil-Placebo Research Groups, Lilly Research Laboratories.

In two randomized, double-blind clinical trials comparing pinacidil with prazosin and with placebo in patients with hypertension, a number of statistically significant and potentially beneficial effects on blood lipids were detected in the patients taking pinacidil. Patients treated with pinacidil exhibited significant average decrements from baseline in concentrations of total and low-density lipoprotein cholesterol and triglycerides and a significant average increment in high-density lipoprotein cholesterol. The mean effects seen in the pinacidil group were significantly greater than those in the placebo group for both total cholesterol (-9.

After coronary thrombolysis and reperfusion, what next?

Thrombolytic therapy for the removal of intravascular thrombi was introduced when streptokinase was first given to humans 40 years ago, the same year the American College of Cardiology was founded. Streptokinase was first administered to patients with acute myocardial infarction in 1959. Today, thrombolytic therapy has been established to offer significant benefits to patients with acute myocardial infarction provided they are brought to medical attention early enough after the onset of symptoms.

A sensitive immunoradiometric assay for the quantification of murine monoclonal antibodies in human serum.

The clinical investigation of murine monoclonal antibodies (MoAbs) as potential immunotherapeutic agents necessitates their quantification in human serum. The present paper reports the development of a sensitive, non-competitive "sandwich" immunoradiometric assay specifically optimized for measurement of murine IgG in human serum. Affinity-purified goat anti-mouse IgG antibody covalently bound to acrylic microspheres serves as the solid-phase antibody and 125I-labelled goat anti-mouse IgG antibody functions as tracer.