Phase 1 Rising Multiple-Dose Study of Talabostat (PT-100) in Healthy Subjects.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4215-4215 ◽  
Author(s):  
Margaret J. Uprichard ◽  
Barry Jones
Keyword(s):  
Adverse Events ◽  
Healthy Subjects ◽  
Significant Inhibition ◽  
Average Increase ◽  
Healthy Male ◽  
Post Dose ◽  
Peripheral Edema ◽  
Dpp Iv ◽  
Limit Of Quantitation ◽  
Male Subjects

Abstract Background: Talabostat (PT-100) is an orally available small molecule that competitively inhibits dipeptidyl peptidases such as DPP-IV/CD26 and fibroblast activation protein (FAP). In vitro, talabostat promotes proliferation of hematopoietic progenitor cells. In vivo it stimulates expansion of progenitors in both white and red cell lineages and causes tumor regression in mouse models. Talabostat has also been shown to accelerate neutrophil recovery in patients and mice receiving myelosuppressive chemotherapy. Its activity appears to be mediated via rapid upregulation of cytokine and chemokine (e.g., G-CSF, IL-6, IL-8) production. Methods: This randomized, placebo-controlled, sequential, dose-escalation study was conducted to evaluate the pharmacodynamics and safety of talabostat in healthy male subjects. 48 healthy male subjects aged 19 to 44 years were randomized to receive daily doses of either 25-, 100-, 300-, 600-, 1200-, 1800μg talabostat or placebo for 7 days. Subjects were randomized in cohorts of 8 subjects each in a 6:2 (talabostat: placebo) scheme. Pharmacodynamics were assessed by measurement of plasma DPP-IV activity, plasma G-CSF, IL-6 and IL-11, and white blood cell (WBC), and absolute neutrophil counts (ANC) at specified timepoints intervals during the study. Clinical examinations, laboratories, vitals, ECG, and adverse events (AEs) were evaluated at specified intervals. Results: At 30 minutes post-dose, talabostat doses ≥ 100μg showed a dose-related, sustained, significant inhibition of DPP-IV activity to 75% to 95% of baseline (p<0.001) in healthy subjects. On Day 1, there was a significant increase in IL-6 at 6 and 12 hours post-dose across all dose cohorts (p<0.01). At 6 and 12 hours, respectively, an average increase in IL-6 of 1426% and 2130% relative to baseline was observed (p<0.05). There was a dose-related increase in G-CSF, with significant increases at doses ≥600μg noted pre-dose on Day 4 (p<0.05). Across all groups on Day 1, an average increase in G-CSF of 132% was noted at 6 hours. Only modest changes in WBC and ANC were noted in these healthy subjects. IL-11 remained unchanged or below the limit of quantitation. The most frequent AEs across all cohorts were (talabostat vs placebo): headache 19/36 (53%) vs 4/12 (33%), myalgia 9/36 (25%) vs 1/12 (8%), nausea 6/36 (17%) vs 0, vomiting 5/36 (14%) vs 1/12 (8%), peripheral edema 5/36 (14%) vs 0, rigors 5/36 (14%) vs 0, sore throat 4/36 (11%) vs 1 (8%)., and arthralgia 4/36 (11%) vs 0. Peripheral edema, myalgia, arthralgia, and rigors were dose-related with all but one event of peripheral edema occurring at talabostat single doses ≥1200μg. There were no serious AEs. The talabostat 1800μg dose cohort was terminated after 2 doses due to adverse events of edema, and talabostat 1200μg was considered the maximum tolerated dose. Conclusion: Talabostat doses ≥100μg showed significant inhibition of DPP-IV activity. Significant dose-related increases in IL-6 and G-CSF were observed. ANC and WBC counts did not change significantly in healthy subjects over the 7-day study. Multiple doses of talabostat were well-tolerated. These results support conducting additional clinical studies in patients to further evaluate the hematopoietic effects of talabostat.

Absorption, Metabolism and Excretion of GBT440, a Novel Hemoglobin S (HbS) Polymerization Inhibitor for the Treatment of Sickle Cell Disease (SCD), in Healthy Male Subjects

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2487-2487 ◽  
Author(s):  
Peter Rademacher ◽  
Athiwat Hutchaleelaha ◽  
Carla Washington ◽  
Josh Lehrer ◽  
Eleanor Ramos
Keyword(s):  
Steady State ◽  
Adverse Events ◽  
Phase Ii ◽  
Whole Blood ◽  
Healthy Subjects ◽  
Total Radioactivity ◽  
Healthy Male ◽  
Employment Equity ◽  
Equity Ownership ◽  
Male Subjects

Abstract Background: SCD is caused by a point mutation in the β-globin gene producing hemoglobin S (HbS) that polymerizes upon deoxygenation with subsequent formation of sickled red blood cells (RBCs). GBT440 is a novel, orally bioavailable small molecule that inhibits HbS polymerization by increasing the affinity of O2 to hemoglobin (Hb). Methods: The pharmacokinetics, mass balance, and metabolite profile of [14C]-GBT440 were evaluated in 7 healthy male subjects in this open-label study. In order to evaluate the disposition kinetics of GBT440 at steady-state concentrations, a loading/maintenance dose schema was employed. Each subject received an oral loading dose of 2000 mg GBT440 on Day 1 followed by oral maintenance doses of 400 mg once daily on Day 2 to Day 4. Once the target steady-state was achieved, a single [14C]-GBT440 400 mg dose (approximately 100 μCi) was administered orally on Day 5. Blood, plasma, urine and feces were collected serially up to 26 days postdose. Results: There were no serious adverse events or discontinuations due to adverse events for any of the healthy subjects participating in this study. GBT440 reached Cmax in plasma and whole blood with median time to maximum concentration (Tmax) values of 2.00 hours in plasma and whole blood and in 6.00 hours in RBCs. After reaching Cmax, GBT440 concentrations appeared to decline in a monophasic manner, with the terminal elimination phase for GBT440 in plasma, whole blood, and RBCs appearing to decline in a parallel manner, with geometric mean T1/2 values of 98.0 hours in plasma, 66.3 hours in whole blood, and 65.8 hours in RBCs. This study achieved 98.0% average recovery of total radioactivity in urine and feces over the course of the study. Most of the administered radioactivity (88.2%) was recovered by 144 hours postdose (Day 7). GBT440 was eliminated primarily in feces (62.6% of the total radioactive dose) with urinary excretion accounting for 35.4% of the total radioactive dose. In whole blood, the majority of the total radioactivity (TRA) was unchanged GBT440 (97.5%) while three metabolites accounted for the remaining TRA (2.5%). In plasma, unchanged GBT440 was the prominent circulating radioactive component, accounting for 48.8% of the TRA. Eleven circulating metabolites with corresponding radioactive peaks were identified. There was one major Phase II metabolite (GBT440 O-dealkylation-sulfation), accounting for 16.8% of the TRA. Two potential active metabolites were identified but only accounted for 2.5% of the dose in whole blood. GBT440 was eliminated predominately in feces. Unchanged GBT440 was the most abundant radioactive component, accounting for 33.3% of the administered dose. Four metabolites were identified, each accounting for 5.62%, 2.66%, 1.66% and less than 6% of the dose in the 0-216-hr human feces. Urine was a relatively minor excretion route for GBT440 in humans. An average of 34.3% of the dose was recovered in the urine samples. Unchanged GBT440 accounted for 0.08% of the administered dose and the rest were metabolites. GBT440 glucuronidation and reduction-glucuronidation products, which are Phase II metabolites, were the most abundant metabolites in urine, accounting for a combined 9.22% of dose. Because GBT440 does not undergo renal elimination, patients with renal disorders should not experience changes in pharmacokinetics of GBT440. Conclusions: Although GBT440 has high specific binding to hemoglobin, it was completely excreted from the body with a half-life of approximately three days in healthy subjects. Since the half-life of GBT440 was much shorter than RBC lifespan (~ 120 days), this supports the hypothesis that the binding between GBT440 to hemoglobin is a reversible process. Following an oral administration, approximately one-third of the dose was excreted as the unchanged drug into the feces (unabsorbed and/or via biliary excretion). Two-thirds of the administered dose was metabolized and excreted into urine and feces. The major metabolic pathway was via Phase I and Phase II metabolism. Because GBT440 was not excreted directly into the urine, the pharmacokinetics are unlikely to be affected in patients with renal disorders. Disclosures Rademacher: Global Blood Therapeutics: Employment, Equity Ownership. Hutchaleelaha:Global Blood Therapeutics: Employment, Equity Ownership. Washington:Global Blood Therapeutics: Employment, Equity Ownership. Lehrer:Global Blood Therapeutics: Employment, Equity Ownership. Ramos:Global Blood Therapeutics: Employment, Equity Ownership.

Effect of Valine on 5-HT-mediated Prolactin Release in Healthy Volunteers, and on Mood in Remitted Depressed Patients

1995 ◽  
Vol 167 (2) ◽  
pp. 238-242 ◽  
Author(s):  
D. J. Williamson ◽  
S. F. B. McTavish ◽  
S. B. G. Park ◽  
P. J. Cowen
Keyword(s):  
Depressive Symptoms ◽  
Healthy Subjects ◽  
Antidepressant Drug ◽  
Experimental Studies ◽  
Healthy Male ◽  
Prolactin Release ◽  
Depressed Patients ◽  
Symptomatic Relapse ◽  
Male Subjects ◽  
Antidepressant Drug Treatment

BackgroundAnimal experimental studies suggest that the amino acid valine may decrease brain serotonin (5-HT) function by inhibiting the transport of the 5-HT precursor, L-tryptophan, across the blood barrier. The aim of the present study was to assess whether valine could decrease brain 5-HT function in healthy subjects and provoke symptomatic relapse in recently remitted depressed patients taking antidepressant drug treatment.MethodWe studied the effect of valine (30 g) on the prolactin (PRL) response to the 5-HT releasing agent, d-fenfluramine, in healthy male subjects and on the mood of 12 remitted depressed patients taking either selective serotonin re-uptake inhibitors (n = 10) or lithium and amitriptyline (n = 2).ResultsValine significantly lowered the PRL response to d-fenfluramine in healthy subjects. In the remitted depressives, valine caused a mild but detectable lowering of mood on a number of measures but only one patient experienced a significant relapse in mood.ConclusionsValine administration may decrease brain 5-HT neurotransmission in humans. This effect could explain the mild increase in depressive symptoms in patients taking 5-HT-potentiating drugs.

Single and Multiple Oral Doses of LGD-4665, a Small Molecule Thrombopoietin Receptor Agonist, Increase Platelet Counts in Healthy Male Subjects

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1298-1298 ◽  
Author(s):  
Zofia E. Dziewanowska ◽  
Richard M. Matsumoto ◽  
J.K. Zhang ◽  
Kristine Schindler ◽  
Gordon Loewen ◽  
...  
Keyword(s):  
Platelet Count ◽  
Single Dose ◽  
Multiple Dose ◽  
Receptor Agonist ◽  
Healthy Male ◽  
Post Dose ◽  
Dose Administration ◽  
Platelet Counts ◽  
Multiple Dose Administration ◽  
Male Subjects

Abstract LGD-4665, an oral thromobopoietin receptor agonist, is being developed as a new generation small molecule thrombopoietin (TPO) mimetic. LGD-4665 is a highly selective and potent agonist of the TPO receptor and induces differentiation and proliferation of megakaryocytes. A single-center, randomized, placebo-controlled, double-blind, escalating dose group study was conducted to assess the pharmacodynamics, pharmacokinetics (PK), and safety of LGD-4665 in healthy male subjects after single and multiple doses. In the single dose phase of the study, 5 dose cohorts of 6 subjects each were randomized at a ratio of 2:1 (LGD-4665: Placebo). LGD-4665 doses of 1, 5, 10, 20, and 40 mg were escalated sequentially. In the multiple dose phase, 8 subjects received 5 mg of study drug or placebo at a ratio of 3:1, respectively, once daily for 14 days. Clinical assessments were conducted for 21 and 35 days following treatment initiation in the single and multiple dose phases, respectively. Platelet count increases were determined as the maximal observed increase in post-dose platelet value relative to baseline, expressed both as absolute value and percent increase. Following single dose administration, a statistically-significant (p=0.011) platelet count increase compared to placebo was observed following a 40 mg LGD-4665 dose. In subjects receiving this dose, individual maximum increases in platelet counts ranged between 53 and 83 x1000/μL (mean = 65 x1000/μL; 29% increase from baseline). Following multiple dose administration of 5 mg daily for 14 days, increases in platelet counts over baseline were observed in all drug-treated subjects (n=6) with a mean maximal increase from baseline of 43%. From PK measurements, a dose-proportional increase in systemic exposure after single doses of LGD-4665 was observed among the dose groups. Mean area-under-the-curve from time zero to infinity (AUC0-inf) increased from 2.88 to 155 μg·h/mL following single doses of 1 to 40 mg, respectively, with AUC0–24h values of 0.43 – 25.3 μg·h/mL. Maximum LGD-4665 concentrations (Cmax) increased from 0.029 to 1.56 μg/mL following administration of 1 to 40 mg single doses, respectively. In the multiple phase, 5 mg daily doses for 14 days resulted in a mean Cmax of 0.83 μg/mL and the Cmax were reached at 4 hours post dose. The mean steady-state AUC0 to 24h was 17.4 μg·h/mL. Overall, LGD-4665 was safe and well tolerated at all dose levels tested during both phases of the study. All AEs were appraised as mild to moderate. The majority of AEs were not related to LGD-4665 and no apparent dose-relationship was observed. No serious AEs were reported. No subjects discontinued the study due to AEs. No clinically significant laboratory abnormalities, effects on electrocardiograms and vital signs were observed. In summary, LGD-4665 increase platelet counts following single and multiple dose administration and was well tolerated.

scholarly journals Co-Administration of Vonoprazan, Not Tegoprazan, Affects the Pharmacokinetics of Atorvastatin in Healthy Male Subjects

2021 ◽  
Vol 12 ◽  
Author(s):  
Sejung Hwang ◽  
Jae-Wook Ko ◽  
Heechan Lee ◽  
Seokuee Kim ◽  
Bongtae Kim ◽  
...  
Keyword(s):  
Healthy Subjects ◽  
Clinical Laboratory ◽  
Systemic Exposure ◽  
Cytochrome P450 3A4 ◽  
Healthy Male ◽  
Open Label ◽  
Once Daily ◽  
New Class ◽  
Inhibitory Activities ◽  
Male Subjects

Potassium-competitive acid blocker is a new class of drugs inhibiting gastric acid. It is controversial that vonoprazan showed the inhibitory activities of cytochrome P450 3A4. This study aimed to evaluate the pharmacokinetics (PK) of atorvastatin and safety when atorvastatin was administered alone and co-administered with vonoprazan or tegoprazan. An open-label, multiple-dose, 3-intervention, 4-sequence, 4-period, partial replicate crossover study was conducted, and three interventions were; one is orally administered atorvastatin 40 mg alone once daily for 7 days, another is atorvastatin co-administered with vonoprazan 20 mg, and the other is atorvastatin co-administered with tegoprazan 50 mg. PK blood samples were collected up to 24 h after the last dose, and PK parameters for atorvastatin, 2-hydroxyatorvastatin and atorvastatin lactone were estimated by a non-compartmental method. Safety was evaluated, including adverse events and clinical laboratory tests. A total of 28 subjects completed the study. When atorvastatin was co-administered with vonoprazan, the systemic exposures of atorvastatin and atorvastatin lactone significantly increased, and the metabolic ratio of 2-hydroxyatorvastatin significantly decreased. Hypergastrinemia only occurred when atorvastatin was co-administered with vonoprazan. However, the plasma concentration profiles of atorvastatin, 2-hydroxyatorvastatin and atorvastatin lactone were similar when atorvastatin was administered alone or co-administered with tegoprazan. In conclusion, after multiple doses of atorvastatin co-administered with vonoprazan in healthy subjects, the systemic exposure of atorvastatin and the incidence of hypergastrinemia increased. With tegoprazan, however, those interactions were not observed.

scholarly journals A Phase 1, Randomized, Double-blind, Placebo-controlled, Crossover Study to Evaluate the Pharmacodynamic Effects of VX-150, a highly selective NaV1.8 inhibitor, in Healthy Male Adults

Pain Medicine ◽  
2021 ◽  
Author(s):  
H J (Hemme) Hijma ◽  
P S (Pieter) Siebenga ◽  
M L (Marieke) de Kam ◽  
G J (Geert Jan) Groeneveld
Keyword(s):  
Crossover Study ◽  
Repeated Measures ◽  
Healthy Subjects ◽  
Cold Pressor ◽  
Pain Tolerance ◽  
Healthy Male ◽  
Post Dose ◽  
Double Blind ◽  
Double Blind Placebo ◽  
Pain Tests

Abstract Objective To evaluate the analgesic potential, safety, tolerability and pharmacokinetics of VX-150, a pro-drug of a highly selective NaV1.8 inhibitor, in healthy subjects. Design This was a randomized, double-blind, placebo-controlled, crossover study in healthy subjects. Subjects Twenty healthy male subjects with an age of 18-55, inclusive, were enrolled. Eligibility was based on general fitness, absence of current or previous medical conditions that could compromise subject safety and a training assessment of pain tolerance across pain tests, to exclude highly tolerant individuals that could compromise the ability to detect analgesic responses. All dosed subjects completed the study. Methods Subjects were randomized 1:1 to 1 of 2 sequences receiving a single VX-150 dose and subsequently placebo, or vice versa, with at least 7 days between dosing. A battery of pain tests (pressure, electrical stair, (capsaicin-induced) heat and cold pressor) was administered pre-dose and repetitively up to 10 h post-dose, with blood sampling up to 24 h post-dose. Safety was monitored throughout the study. Data were analyzed with a repeated measures mixed-effects model. Results VX-150 induced analgesia in a variety of evoked pain tests, without affecting subject safety. Significant effects were reported for cold pressor and heat pain thresholds. Maximum median concentration for the active moiety was 4.30 ug/mL at 4 h post-dose. Conclusion Results of this proof-of-mechanism study are supportive of the potential of VX-150, a highly selective NaV1.8 channel inhibitor, to treat various pain indications.

scholarly journals The Pharmacokinetics, Pharmacodynamics, and Safety of Intravenous Pegcetacoplan Treatment in Healthy Subjects

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4304-4304
Author(s):  
Federico Grossi ◽  
Michael Yeh ◽  
Raymond Xu ◽  
Pascal Deschatelets
Keyword(s):  
Adverse Events ◽  
Hemolytic Activity ◽  
Healthy Subjects ◽  
Sodium Acetate Solution ◽  
Complement Cascade ◽  
Acetate Solution ◽  
Publicly Traded ◽  
Post Dose ◽  
Complement Activity ◽  
Saline Treatment

Abstract Background: The complement cascade is part of innate immunity and is involved in multiple inflammatory processes and implicated in several diseases. Pegcetacoplan (PEG) is a pegylated, cyclic peptide that binds to complement protein C3 and is a broad inhibitor of the complement cascade. Subcutaneous (SC) dosing of PEG has demonstrated efficacy in the treatment of chronic conditions, such as paroxysmal nocturnal hemoglobinuria (PNH) and was recently approved by the FDA for the treatment of PNH in adults. Intravenous (IV) PEG administration may allow for more rapid and robust reduction of uncontrolled complement activation, especially in an acute setting, such as an acute hemolytic episode in PNH. Aims: To determine the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of IV PEG in acetate-buffered saline treatment in a Phase 1 single ascending dose study (ACTRN12616000700437) in healthy subjects. Methods: On Day 1, four cohorts with PEG doses (200mg, 600mg, 1500mg, 2300mg) received a single bolus of PEG IV (or matching placebo) administered over 30min. Blood samples for PK analyses of PEG concentration and PD analyses of alternative complement pathway hemolytic activity (AH50), total complement hemolytic activity (CH50), C3 and C3a levels were collected at 15, 30, and 60min, 4, 8, 12, and 24hrs, and Days 3, 4, 5, 6, 7, 8, 15, 22, 29, and 43. Subjects were monitored during a safety period from Day 2 to 8 by physical examination, ECG, hematology, serum chemistry, monitoring for injection site reaction and treatment emergent adverse events (TEAEs). Follow-up safety assessments were performed on Days 15, 22, 29, and 43. Results: Twenty subjects were enrolled and allocated 4:1 to PEG or placebo per cohort (PEG-200mg, n=4; PEG-600mg, n=4; PEG-1500mg, n=4; PEG-2300mg, n=4; pooled placebo, n=4). Following a single IV dose, peak concentration (C max) of PEG was observed at 1hr post-dose (infusion start) for most cohorts (mean serum concentration: PEG-200mg, 61μg/mL; PEG-600mg, 193μg/mL; PEG-2300mg, 708μg/mL) except PEG-1500mg (occurred at 4hrs, 542μg/mL). PEG concentration at the end of infusion was similar to the observed C max. PEG concentration declined in a mono-exponential manner, with a terminal elimination half-life ranging from 200 to 285 hrs (Figure). Total body clearance of PEG after IV administration was similar across cohorts. Early, immediate decreases in mean AH50 values were detected within 1hr in all PEG cohorts, with 1500 and 2300mg doses decreasing AH50 to undetectable levels (Figure). Decreases in mean AH50 values were maintained for at least 12, 72, 144 and 168hrs after single doses of 200, 600, 1500 and 2300mg PEG, respectively. All PEG groups had an initial rapid decrease within 1hr in mean C3a levels, with all dose groups having trough mean C3a levels within 24hrs of dosing. Dose related decreases in mean C3a were not observed, all doses recorded a max mean decrease of 47% to 57%. No changes seen with placebo for C3a. C3 and CH50 results will be forthcoming. Of the twenty subjects included in the study, 11 (55.0%) experienced a treatment-related adverse event (TEAE). The most common TEAEs in the PEG group were headache, (n=6, 37.5%); upper respiratory infections attributed to seasonal viral infection (n=2, 12.5%); diarrhea (n=2, 12.5%). No serious adverse events, deaths, or severe TEAEs occurred. One subject (5.0%) in the PEG-2300mg cohort experienced a moderate TEAE (infusion-related reaction, dizziness, clamminess, nausea) that led to study discontinuation. Conclusions: These results suggest that administration of IV PEG in a sodium acetate solution has a favorable safety profile and effectively increases PEG serum concentrations while decreasing complement activity within the first hour post-dose in healthy subjects. Although the safety and efficacy of SC PEG treatment has been demonstrated in patients with PNH, IV PEG administration could serve as a useful therapeutic option for patients with a need for rapid control of complement activity. While this formulation is different than the commercially available PEG (EMPAVELI), which is administered SC and is suspended in sorbitol, the results suggest that IV PEG is well tolerated and provides the grounds for future investigations of IV PEG administration. Figure 1 Figure 1. Disclosures Grossi: Apellis Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Yeh: Apellis Pharmaceuticals, Inc.: Current Employment, Current equity holder in publicly-traded company. Xu: Apellis Pharmaceuticals: Current Employment. Deschatelets: Apellis Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties. OffLabel Disclosure: Pegcetacoplan, a subcutaneously administered C3-inhibitor that was recently approved by the US FDA for the treatment of PNH, controls IVH and prevents EVH. While subcutaneous pegcetacoplan is safe and effective, the aim of this study was to determine the safety, pharmacokinetics, and pharmacodynamics of IV pegcetacoplan in acetate-buffered saline treatment, different from current FDA approved formulation.

scholarly journals First-in-Human Study of the Safety, Tolerability, Pharmacokinetics and - Preliminary Dynamics of Neuroprotectant 2-Iminobiotin in Healthy Subjects

2020 ◽  
Vol 15 (2) ◽  
pp. 152-163 ◽  
Author(s):  
Ewoud-Jan van Hoogdalem ◽  
Cacha M.P.C.D. Peeters-Scholte ◽  
Paul W.T.J. Leufkens ◽  
Jan Hartstra ◽  
Jan J. van Lier ◽  
...  
Keyword(s):  
Healthy Subjects ◽  
Cell Injury ◽  
Human Study ◽  
Volume Of Distribution ◽  
Water Volume ◽  
Cerebral Hypoxia ◽  
Healthy Male ◽  
Dose Escalation Study ◽  
Hypoxia Ischemia ◽  
Male Subjects

Background: 2-iminobiotin (2-IB) is an investigational neuroprotective agent in development for the reduction of brain cell injury after cerebral hypoxia-ischemia. Objective: The present first-in-human study evaluated the safety, tolerability, pharmacokinetics (PK) and -dynamics (PD) of 2-IB in healthy male subjects, intravenously infused with or without Captisol® as a solubilizing agent. Methods: This randomized, double-blind, placebo-controlled, dose-escalation study was executed in 2 groups of 9 healthy male subjects. A single dose of 2-IB 0.6 mg/kg or placebo was infused over periods between 15 min and 4 h, and repeated doses escalating from 0.6 mg/kg to 12 mg/kg, or placebo were infused every 4 h for 6 administrations in total. Results: Single and multiple doses of 2-IB up to 6 doses of 6 mg/kg with and without Captisol® were safe and well-tolerated in healthy male subjects. 2-IB proved to be a high-clearance drug with a volume of distribution slightly exceeding total body water volume, and with linear PK that appeared not to be affected by the presence of Captisol®. Conclusion: Sulfobutyletherbeta-cyclodextrin (SBECD) in Captisol® had a low-clearance profile with a small volume of distribution, with time-independent PK. Preliminary PD characterization of repeated iv dosing of 2-IB in an acute peripheral hypoxic ischemia model in healthy subjects did not reveal any notable effects of 2-IB, noting that this model was not selected to guide efficacy in the currently pursued indication of cerebral hypoxia-ischemia.

Estimating energy expenditure from specific activity of urine urea during lengthy subcutaneous NaH14CO3 infusion

1995 ◽  
Vol 269 (1) ◽  
pp. E172-E182 ◽  
Author(s):  
M. Elia ◽  
M. G. Jones ◽  
G. Jennings ◽  
S. D. Poppitt ◽  
N. J. Fuller ◽  
...  
Keyword(s):  
Energy Expenditure ◽  
Healthy Subjects ◽  
Specific Activity ◽  
Daily Variation ◽  
Whole Body ◽  
Co2 Production ◽  
Healthy Male ◽  
Male Subjects ◽  
Urea Method ◽  
Mini Pump

Five healthy male subjects were continuously infused subcutaneously with [14C]bicarbonate (12.3 microCi/day) using a mini pump for 5 days while in a whole body calorimeter. Energy expenditure was varied over a range of 1.35-1.75 times basal metabolic rate. Urine collections were obtained throughout the study and used to measure the specific activity of urea, from which CO2 production was estimated. It was assumed that the recovery of label in gaseous CO2 was 95% of that infused and that the specific activity of urea was 85% that of expired CO2. Continuous daily collections of calorimeter air revealed that 95.6 +/- 1.3% (SD) of infused label was recovered as gaseous CO2, with little daily variation. Another 1.5 +/- 0.4% was recovered as urinary urea. The estimated CO2 production, calculated from the specific activity of urea in 24-h urine samples corrected for the small effects due to changes in the size and specific activity of the urea pool, was found to be 100 +/- 5% of the calorimeter estimate for 1-day periods (20.80 +/- 1.44 mol CO2/day) and 100 +/- 2% for 4-day periods. This study suggests that, in healthy subjects, the labeled [14C]bicarbonate-urea method can provide reasonable estimates of net CO2 production over the range examined.

Measurement of gluconeogenesis by deuterated water: the effect of equilibration time and fasting period

2006 ◽  
Vol 290 (6) ◽  
pp. E1212-E1217 ◽  
Author(s):  
Gideon Allick ◽  
Saskia N. van der Crabben ◽  
Mariette T. Ackermans ◽  
Erik Endert ◽  
Hans P. Sauerwein
Keyword(s):  
Plasma Glucose ◽  
Healthy Subjects ◽  
Hepatic Glycogen ◽  
Equilibration Time ◽  
Deuterated Water ◽  
Healthy Male ◽  
Reliable Measurement ◽  
Fasting Period ◽  
Incubation Periods ◽  
Male Subjects

Fasting gluconeogenesis (GNG) is often quantified using the 2H2O technique, which is based on plasma 2H2O enrichment and ensuing enrichment of plasma glucose at the C5 and C2 positions. Fractional (fr)GNG can be calculated using the ratio of C5 to C2 enrichment or the ratio of C5 to plasma 2H2O enrichment. For the latter, equilibration of 2H2O and C2 is required. The optimal equilibration period of 2H2O and C2 remains to be elucidated. In six healthy male subjects fasted for 18 h, we studied the effects of 3-, 5-, and 15-h 2H2O incubation periods on 1) the equilibration of plasma 2H2O and C2 glucose enrichment, 2) the measurement of frGNG, and 3) C5 labeling of hepatic glycogen after 1 mg of glucagon administration. After 3-h 2H2O incubation, plasma 2H2O and C2 were not equilibrated, frGNG C5/2H2O and C5/C2 were also different as was gluconeogenesis calculated with C5/2H2O and C5/C2. After 5- and 15-h 2H2O incubation, plasma 2H2O and C2 were equilibrated, and frGNG C5/2H2O and C5/C2 were similar, as was GNG calculated with C5/2H2O and C5/C2. After glucagon administration, no difference of C5 enrichment was found between 3, 5, and 15 h of 2H2O incubation. In conclusion, for reliable measurement of GNG in healthy subjects with C5/2H2O incubation periods longer than 3 h are required. After 5- and 15-h 2H2O incubation, GNG can be reliably measured with C5/2H2O. Gluconeogenetic labeling of glycogen did not affect the results after 3, 5, or 15 h of 2H2O incubation.

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