The safety, pharmacokinetic, and pharmacodynamic effects of LY2584702, a selective inhibitor for ... more The safety, pharmacokinetic, and pharmacodynamic effects of LY2584702, a selective inhibitor for p70 S6 serine/threonine protein kinase‐1, were evaluated in healthy dyslipidemic volunteers. LY2584702 was tolerated well as a monotherapy and dose‐dependently reduced low‐density lipoprotein cholesterol and triglycerides by up to 60% and 50%, respectively, without significantly changing high‐density lipoprotein cholesterol levels in plasma. LY2584702 also dose‐dependently decreased factor V activity. Alanine aminotransferase elevations were noted in 2 subjects when LY2584702 was given with atorvastatin. We suspect that the formation of 4‐aminopyrazolo[3,4‐d]pyrimidine (4‐APP) during metabolism may have contributed to some of the adverse effects of LY2584702, and the contribution of 4‐APP to the pharmacology merits further investigation. Although clinical investigation of LY2584702 has been terminated because of hepatotoxicity risk, we suggest that a selective inhibitor of p70 S6 serine/...
Introduction: Many commercially available glucagon products for treatment of severe hypoglycaemia... more Introduction: Many commercially available glucagon products for treatment of severe hypoglycaemia require cumbersome reconstitution and potentially intimidating injection during an emergency. Nasal glucagon (NG) is a novel drug-device combination product consisting of a single-use dosing device that delivers glucagon dry powder through nasal administration. The present study assessed whether 3 mg NG was non-inferior to 1 mg intramuscular glucagon (IMG) in adults with type 1 diabetes. Methods: This randomised, open-label, twoperiod, crossover trial was conducted at two clinical sites. Hypoglycaemia (plasma glucose [PG] target of \3.3 mmol/l (60 mg/dl) was induced by an intravenous insulin infusion. Glucagon preparations were given by study staff. Treatment success was defined as an increase in PG to C 3.9 mmol/l (70 mg/dl) or an increase of C 1.1 mmol/l (20 mg/dl) from the PG nadir within 30 min of receiving glucagon. Results: Of the 66 participants included in the primary efficacy analysis who received both NG and IMG, 100% achieved treatment success, thus demonstrating non-inferiority of NG to IMG. All participants achieved treatment success within 25 min with the mean time to treatment success of 11.4 min (NG) and 9.9 min (IMG). No serious adverse events occurred. Forty-eight treatment-emergent adverse events (TEAEs) occurred after NG and 51 after IMG. Most TEAEs were mild and transient. Conclusion: Nasal glucagon was as efficacious and well tolerated as IMG for the treatment of insulin-induced hypoglycaemia in adults and will be as useful as IMG as a rescue treatment for severe hypoglycaemia. Trial Registration: NCT03339453, ClinicalTrials. gov Digital Features To view enhanced digital features for this article go to https://doi.org/10.6084/m9.figshare. 12319730.
Background: LY3039478 is an oral Notch inhibitor that prevents release of the Notch Intracellular... more Background: LY3039478 is an oral Notch inhibitor that prevents release of the Notch Intracellular Domain (NICD) by inhibiting proteolytic activity of the gamma (γ)-secretase complex. LY3039478 also inhibits production of plasma amyloid-beta (Aβ), which can be used as a biomarker to determine pharmacodynamic (PD) effects of LY3039478. Covariates affecting the pharmacokinetics (PK) of LY3039478, and also PK-PD relationships, are explored in the current analysis. The analysis included PK and PD data from advanced cancer patients from the first human dose trial and healthy volunteers (HV) from the single ascending dose and pilot relative bioavailability trial. Methods: A summary of the study design elements can be found in Table 1. Population PK and PK/PD models were developed using non-linear mixed effects approaches using NONMEM Version 7.3. A sequential modelling approach was used. Table 1.Study Design Elements of the First Human Dose and Healthy Volunteer TrialsStudy ParametersFirst...
Background: LY3039478 is an oral, potent small-molecule Notch inhibitor being investigated for th... more Background: LY3039478 is an oral, potent small-molecule Notch inhibitor being investigated for the treatment of advanced cancers. The effect of single doses on corrected QT interval, absolute and relative bioavailability were explored in three studies (Table 1). These studies were conducted in healthy subjects to mitigate the confounding effects of disease state and concomitant medication, while avoiding nonbeneficial drug exposures in cancer patients. Table 1. Designs for three clinical studies of LY3039478 in healthy subjects Study ParametersNCT02659865 Eudra CT No. 2016-001073-33 Study 1Study 2Study 3Completed subjects (N)141312Overall designSingle ascending dose; investigator-subject blinded, placebo-controlled, randomized 3 period cross-over; 25, 50 and 75 mgPilot relative bioavailability; randomized 2 period cross-over open-label; 50 mgAbsolute bioavailability; single-period open label; 75mg oral and 350µg IV infusionFormulationFormulated capsuleFormulated capsule, drug in cap...
Many laboratories use electronic message standards to transmit results to their clients. If all l... more Many laboratories use electronic message standards to transmit results to their clients. If all laboratories used the same "universal" set of test identifiers, electronic transmission of results would be greatly simplified. The Logical Observation Identifier Names and Codes (LOINC) database aims to be such a code system, covering at least 98% of the average laboratory's tests. The LOINC database should be of interest to hospitals, clinical laboratories, doctors' offices, state health departments, governmental healthcare providers, third-party payors, organizations involved in clinical trials, and quality assurance and utilization reviewers. The fifth release of the LOINC database, containing codes, names, and synonyms for approximately 6300 test observations, is now available on the Internet for public use. Here we describe the LOINC database, the methods used to produce it, and how it may be obtained.
Adults with diabetes at risk for hypoglycemia were surveyed in Canada's largest population-based ... more Adults with diabetes at risk for hypoglycemia were surveyed in Canada's largest population-based study on hypoglycemia (InHypo-DM). Respondents rated how often they report their SH events to their HCPs, on a scale from Never to Always. Univariable analyses (p<0.2) followed by a zero-inflated negative binomial analysis determined the independent association of SH disclosure and the retrospective incidence of self-reported SH. In total, 552 respondents (17% type 1 diabetes, 83% type 2 diabetes) completed the InHypo-DM questionnaire. Forty percent of respondents experienced ≥1 SH event within the past year. The incidence rate of SH was 2.45 events/person-year. Notwithstanding, only 34% of respondents indicated that they always report SH events. Although disclosure behaviour was not associated with the odds of experiencing SH (p=0.86), the rate of SH almost doubled (1.9, 95% CI: 1.2 to 3.0, p=0.004) among individuals who underreported events compared to those who did not. Results persisted after adjusting for age, medication class, income, HbA1C, and presence of comorbidities. Results revealed nearly 2-fold higher rates of SH among those who underreport events to HCPs. Providers should endeavor to elicit accurate information on SH frequency from patients, particularly those at risk for repeated SH.
Purpose Crenigacestat (LY3039478) is a Notch inhibitor currently being investigated in advanced c... more Purpose Crenigacestat (LY3039478) is a Notch inhibitor currently being investigated in advanced cancer patients. Conducting clinical pharmacology studies in healthy subjects avoids nonbeneficial drug exposures in cancer patients and mitigates confounding effects of disease state and concomitant medications. Methods Three studies were conducted in healthy subjects, assessing safety, pharmacokinetics, effect on QT interval, and relative and absolute bioavailability of crenigacestat. Crenigacestat was administered as single 25, 50, or 75 mg oral doses or as an intravenous dose of 350 µg 13 C 15 N 2 H-crenigacestat. Electrocardiogram measurements, and plasma and urine samples were collected up to 48 h postdose, and safety assessments were conducted up to 14 days postdose. Results and conclusions Exposures were dose proportional in the 25 to 75 mg dose range and mean elimination half-life was approximately 5-6 h. The exposure achieved from the new formulated capsule was approximately 30% and 20% higher for area under the plasma concentration time curve from time zero to infinity [AUC(0-∞)] and maximum plasma concentration (C max), respectively, compared to the reference drug in capsule formulation. The geometric least-squares mean [90% confidence interval (CI)] absolute bioavailability of crenigacestat was 0.572 (0.532, 0.615). The regression slope (90% CI) of placebo-adjusted QTcF against crenigacestat plasma concentration was − 0.001 (− 0.006, 0.003), suggesting no significant linear association. Thirty-nine subjects completed the studies and the majority of adverse events were mild. Single oral doses of 25 to 75 mg crenigacestat and an IV dose of 350 µg 13 C 15 N 2 H-crenigacestat were well tolerated in healthy subjects.
To examine the effect of increased gastric pH on exposure to evacetrapib, a cholesteryl ester tra... more To examine the effect of increased gastric pH on exposure to evacetrapib, a cholesteryl ester transfer protein inhibitor evaluated for the treatment of atherosclerotic heart disease. Open-label, two-treatment, two-period, fixed-sequence, crossover study. Clinical research unit. Thirty-four healthy subjects. In period 1, subjects received a single oral dose of evacetrapib 130 mg on day 1, followed by 7 days of analysis for evacetrapib plasma concentrations. In period 2, subjects received a once-daily oral dose of omeprazole 40 mg on days 8-20, with a single oral dose of evacetrapib 130 mg administered 2 hours after the omeprazole dose on day 14, followed by 7 days of pharmacokinetic sampling. Subjects were discharged on day 21 and returned for a follow-up visit at least 14 days after the last dose of evacetrapib in period 2. Gastric pH was measured before subjects received each evacetrapib dose. Noncompartmental pharmacokinetic parameters were estimated from plasma concentration-time...
Journal of labelled compounds & radiopharmaceuticals, May 7, 2015
This open-label, single-period study in healthy subjects estimated evacetrapib absolute bioavaila... more This open-label, single-period study in healthy subjects estimated evacetrapib absolute bioavailability following simultaneous administration of a 130-mg evacetrapib oral dose and 4-h intravenous (IV) infusion of 175 µg [(13) C8 ]-evacetrapib as a tracer. Plasma samples collected through 168 h were analyzed for evacetrapib and [(13) C8 ]-evacetrapib using high-performance liquid chromatography/tandem mass spectrometry. Pharmacokinetic parameter estimates following oral and IV doses, including area under the concentration-time curve (AUC) from zero to infinity (AUC[0-∞]) and to the last measureable concentration (AUC[0-tlast ]), were calculated. Bioavailability was calculated as the ratio of least-squares geometric mean of dose-normalized AUC (oral : IV) and corresponding 90% confidence interval (CI). Bioavailability of evacetrapib was 44.8% (90% CI: 42.2-47.6%) for AUC(0-∞) and 44.3% (90% CI: 41.8-46.9%) for AUC(0-tlast ). Evacetrapib was well tolerated with no reports of clinically...
Evacetrapib is an investigational cholesteryl ester transfer protein inhibitor (CETPi) for reduct... more Evacetrapib is an investigational cholesteryl ester transfer protein inhibitor (CETPi) for reduction of risk of major adverse cardiovascular events in patients with high-risk vascular disease. Understanding evacetrapib disposition, metabolism, and the potential for drug-drug interactions (DDI) may help guide prescribing recommendations. In vitro, evacetrapib metabolism was investigated with a panel of human recombinant cytochromes P450 (CYP). The disposition, metabolism, and excretion of evacetrapib following a single 100-mg oral dose of (14)C-evacetrapib were determined in healthy subjects, and the pharmacokinetics of evacetrapib were evaluated in the presence of strong CYP3A or CYP2C8 inhibitors. In vitro, CYP3A was responsible for about 90% of evacetrapib's CYP-associated clearance, while CYP2C8 accounted for about 10%. In the clinical disposition study, only evacetrapib and two minor metabolites circulated in plasma. Evacetrapib metabolism was extensive. A mean of 93.1% and ...
British journal of clinical pharmacology, Jan 12, 2015
Evacetrapib is a cholesteryl ester transfer protein (CETP) inhibitor under development for reduci... more Evacetrapib is a cholesteryl ester transfer protein (CETP) inhibitor under development for reducing cardiovascular events in patients with high-risk vascular disease. CETP inhibitors are likely to be utilised as "add-on" therapy to statins in patients receiving concomitant medications, so the potential for evacetrapib to cause clinically important drug-drug interactions (DDI) with cytochromes P450 (CYP) was evaluated. The DDI potential of evacetrapib was investigated in vitro, followed by predictions to determine clinical relevance. Potential DDI with possible clinical implications were then investigated in the clinic. In vitro, evacetrapib inhibited all of the major CYPs, with inhibition constants (Ki ) ranging from 0.57 μM (CYP2C9) to 7.6 μM (CYP2C19). Evacetrapib was a time-dependent inhibitor and inducer of CYP3A. The effects of evacetrapib on CYP3A and CYP2C9 were assessed in a Phase 1 study using midazolam and tolbutamide as probe substrates, respectively. After 14 d...
The Regenstrief Medical Record System (RMRS) continues to grow in breadth and depth. As we expand... more The Regenstrief Medical Record System (RMRS) continues to grow in breadth and depth. As we expand its breadth -- the system links 5 health care systems, 11 acute care hospitals, 13 homeless care sites, nearly 100 clinics/offices and the county and state health departments -- we have had to overcome critical problems inherent to creating a community wide electronic medical record (EMR). Data for more than 2 million patients consisting of 300 million coded observations, 5.8 million text reports, 300,000 electrocardiogram tracings and 700,000 images. We are now processing almost 8 million observations monthly. In order to accommodate this expansion, significant we have made extended the system architecture over the last several years. These improvements include enhanced message routing, extended message processing, a multiple entity database, a master patient index, master provider index, and methods for displaying and attributing data from multiple entities.
The international journal of neuropsychopharmacology / official scientific journal of the Collegium Internationale Neuropsychopharmacologicum (CINP), Jan 31, 2014
Selective kappa opioid receptor antagonism is a promising experimental strategy for the treatment... more Selective kappa opioid receptor antagonism is a promising experimental strategy for the treatment of depression. The kappa opioid receptor antagonist, LY2456302, exhibits ~30-fold higher affinity for kappa opioid receptors over mu opioid receptors, which is the next closest identified pharmacology. Here, we determined kappa opioid receptor pharmacological selectivity of LY2456302 by assessing mu opioid receptor antagonism using translational pupillometry in rats and humans. In rats, morphine-induced mydriasis was completely blocked by the nonselective opioid receptor antagonist naloxone (3mg/kg, which produced 90% mu opioid receptor occupancy), while 100 and 300mg/kg LY2456302 (which produced 56% and 87% mu opioid receptor occupancy, respectively) only partially blocked morphine-induced mydriasis. In humans, fentanyl-induced miosis was completely blocked by 50mg naltrexone, and LY2456302 dose-dependently blocked miosis at 25 and 60mg (minimal-to-no blockade at 4-10mg). We demonstrat...
Journal of cardiovascular pharmacology and therapeutics, Jan 3, 2015
To determine the effect of a high-fat meal on evacetrapib exposure at steady state in healthy par... more To determine the effect of a high-fat meal on evacetrapib exposure at steady state in healthy participants. This was a randomized, 2-period, 2-sequence, open-label, crossover study. Patients were randomly assigned to 1 of the 2 treatment sequences in which they received evacetrapib 130 mg/d for 10 days following a 10-hour fast each day or following a high-fat breakfast each day. Plasma samples collected through 24 hours were analyzed for evacetrapib concentrations and pharmacokinetic parameter estimates including area under the concentration-time curve during a dosing interval (AUCτ), maximum observed concentration (Cmax), and time of Cmax (tmax) were calculated. Pharmacodynamic parameters, including cholesteryl ester transfer protein (CETP) activity, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), total cholesterol, and triglycerides, were also assessed. A total of 34 males and 6 females, mean age 41.5 years and mean body mass index 26.6 k...
Journal of Cardiovascular Pharmacology and Therapeutics, 2013
Purpose: To evaluate whether evacetrapib prolongs QT intervals in healthy participants. Methods: ... more Purpose: To evaluate whether evacetrapib prolongs QT intervals in healthy participants. Methods: This was a single-center, randomized, active and placebo-controlled, 3-period, 6-sequence, and crossover study. Participants were randomized to 1 of 6 treatment sequences in which they received 1 of 3 treatments: evacetrapib 1200 mg daily for 10 days (supratherapeutic dose), moxifloxacin 400 mg for 1 day (positive control), or placebo for 10 days in each of the 3 separate treatment periods. Electrocardiographic parameters were recorded at time points specified in the protocol. The primary end point was the comparison of evacetrapib effect on the population-corrected QT interval (QTcP) to that of placebo at 7 time points following dosing on day 10. An upper limit of the 2-sided 90% confidence interval (CI) <10 milliseconds confirmed the absence of significant effect. Pharmacokinetic parameters were also calculated. Results: Subjects were predominantly male (73.2%) with a mean age of 43...
Journal of the American Medical Informatics Association, 1999
The authors surveyed existing standard codes for units of measures, such as ISO 2955, ANSI X3.50,... more The authors surveyed existing standard codes for units of measures, such as ISO 2955, ANSI X3.50, and Health Level 7's ISOϩ. Because these standards specify only the character representation of units, the authors developed a semantic model for units based on dimensional analysis. Through this model, conversion between units and calculations with dimensioned quantities become as simple as calculating with numbers. All atomic symbols for prefixes and units are defined in one small table. Huge permutated conversion tables are not required. This method is also simple enough to be widely implementable in today's information systems. To promote the application of the method the authors provide an open-source implementation of this method in JAVA. All existing code standards for units, however, are incomplete for practical use and require substantial changes to correct their many ambiguities. The authors therefore developed a code for units that is much more complete and free from ambiguities.
The rain forest canopy is a seamless web through which arboreal creatures efficiently move to rea... more The rain forest canopy is a seamless web through which arboreal creatures efficiently move to reach the edible fruits without any attention to the individual trees. Individual health care computer systems are rich with patient data, but rather than a canopy linking all the trees in the forest, the data "fruit" come from a diverse forest of individual computer "trees"-laboratory systems, word processing systems, pharmacy systems, and the like. These different sources of patient information are difficult or impossible to reach by individual physicians, especially from their offices. The World Wide Web and other standardization technology provide physicians and their institutions the tools needed for seamless and secure access to their patients' data and to medical information, when and where they need it. We and others have adopted these tools to combine independent sources of clinical data. Physicians who assist in the purchase of clinical information systems should demand products in their practice settings that are Web enabled, use standard coding systems, and communicate with other computer systems via broadly accepted protocols.
Two studies were conducted in subjects with mild or moderate hepatic or renal impairment and subj... more Two studies were conducted in subjects with mild or moderate hepatic or renal impairment and subjects with normal organ function to evaluate the pharmacokinetics of casopitant and to assess its safety in these populations. A total of 26 subjects were enrolled in the hepatic impairment study and 18 subjects in the renal impairment study. All subjects received oral casopitant 100 mg once-daily for 5 days. Casopitant area under the concentration-time curve (AUC) increased 11% and 24% in subjects with mild or moderate hepatic impairment, respectively, on Day 1, compared with subjects with normal hepatic function; a similar increase was observed on Day 5. The AUC of the active major metabolite, GSK525060, was reduced 29% and 19% on Days 1 and 5, respectively, in subjects with moderate hepatic impairment, but not altered by mild hepatic impairment. Casopitant AUC increased 34% and 22% on Day 1 in subjects with mild or moderate renal impairment, respectively, and 28% and 11% on Day 5, respectively, compared with subjects with normal renal function. GSK525060 AUC was increased 17% and 24% on Days 1 and 5, respectively, in subjects with mild renal impairment; but did not significantly change in subjects with moderate renal impairment. Further age-adjusted analysis showed no meaningful effect of renal impairment on casopitant or GSK525060 AUC. Plasma protein binding of casopitant and GSK525060 was similar in all subjects. The pharmacokinetics of casopitant is not altered to a clinically significant extent in subjects with mild or moderate, hepatic or renal impairment. The impact of severe hepatic or renal impairment was not evaluated.
The safety, pharmacokinetic, and pharmacodynamic effects of LY2584702, a selective inhibitor for ... more The safety, pharmacokinetic, and pharmacodynamic effects of LY2584702, a selective inhibitor for p70 S6 serine/threonine protein kinase‐1, were evaluated in healthy dyslipidemic volunteers. LY2584702 was tolerated well as a monotherapy and dose‐dependently reduced low‐density lipoprotein cholesterol and triglycerides by up to 60% and 50%, respectively, without significantly changing high‐density lipoprotein cholesterol levels in plasma. LY2584702 also dose‐dependently decreased factor V activity. Alanine aminotransferase elevations were noted in 2 subjects when LY2584702 was given with atorvastatin. We suspect that the formation of 4‐aminopyrazolo[3,4‐d]pyrimidine (4‐APP) during metabolism may have contributed to some of the adverse effects of LY2584702, and the contribution of 4‐APP to the pharmacology merits further investigation. Although clinical investigation of LY2584702 has been terminated because of hepatotoxicity risk, we suggest that a selective inhibitor of p70 S6 serine/...
Introduction: Many commercially available glucagon products for treatment of severe hypoglycaemia... more Introduction: Many commercially available glucagon products for treatment of severe hypoglycaemia require cumbersome reconstitution and potentially intimidating injection during an emergency. Nasal glucagon (NG) is a novel drug-device combination product consisting of a single-use dosing device that delivers glucagon dry powder through nasal administration. The present study assessed whether 3 mg NG was non-inferior to 1 mg intramuscular glucagon (IMG) in adults with type 1 diabetes. Methods: This randomised, open-label, twoperiod, crossover trial was conducted at two clinical sites. Hypoglycaemia (plasma glucose [PG] target of \3.3 mmol/l (60 mg/dl) was induced by an intravenous insulin infusion. Glucagon preparations were given by study staff. Treatment success was defined as an increase in PG to C 3.9 mmol/l (70 mg/dl) or an increase of C 1.1 mmol/l (20 mg/dl) from the PG nadir within 30 min of receiving glucagon. Results: Of the 66 participants included in the primary efficacy analysis who received both NG and IMG, 100% achieved treatment success, thus demonstrating non-inferiority of NG to IMG. All participants achieved treatment success within 25 min with the mean time to treatment success of 11.4 min (NG) and 9.9 min (IMG). No serious adverse events occurred. Forty-eight treatment-emergent adverse events (TEAEs) occurred after NG and 51 after IMG. Most TEAEs were mild and transient. Conclusion: Nasal glucagon was as efficacious and well tolerated as IMG for the treatment of insulin-induced hypoglycaemia in adults and will be as useful as IMG as a rescue treatment for severe hypoglycaemia. Trial Registration: NCT03339453, ClinicalTrials. gov Digital Features To view enhanced digital features for this article go to https://doi.org/10.6084/m9.figshare. 12319730.
Background: LY3039478 is an oral Notch inhibitor that prevents release of the Notch Intracellular... more Background: LY3039478 is an oral Notch inhibitor that prevents release of the Notch Intracellular Domain (NICD) by inhibiting proteolytic activity of the gamma (γ)-secretase complex. LY3039478 also inhibits production of plasma amyloid-beta (Aβ), which can be used as a biomarker to determine pharmacodynamic (PD) effects of LY3039478. Covariates affecting the pharmacokinetics (PK) of LY3039478, and also PK-PD relationships, are explored in the current analysis. The analysis included PK and PD data from advanced cancer patients from the first human dose trial and healthy volunteers (HV) from the single ascending dose and pilot relative bioavailability trial. Methods: A summary of the study design elements can be found in Table 1. Population PK and PK/PD models were developed using non-linear mixed effects approaches using NONMEM Version 7.3. A sequential modelling approach was used. Table 1.Study Design Elements of the First Human Dose and Healthy Volunteer TrialsStudy ParametersFirst...
Background: LY3039478 is an oral, potent small-molecule Notch inhibitor being investigated for th... more Background: LY3039478 is an oral, potent small-molecule Notch inhibitor being investigated for the treatment of advanced cancers. The effect of single doses on corrected QT interval, absolute and relative bioavailability were explored in three studies (Table 1). These studies were conducted in healthy subjects to mitigate the confounding effects of disease state and concomitant medication, while avoiding nonbeneficial drug exposures in cancer patients. Table 1. Designs for three clinical studies of LY3039478 in healthy subjects Study ParametersNCT02659865 Eudra CT No. 2016-001073-33 Study 1Study 2Study 3Completed subjects (N)141312Overall designSingle ascending dose; investigator-subject blinded, placebo-controlled, randomized 3 period cross-over; 25, 50 and 75 mgPilot relative bioavailability; randomized 2 period cross-over open-label; 50 mgAbsolute bioavailability; single-period open label; 75mg oral and 350µg IV infusionFormulationFormulated capsuleFormulated capsule, drug in cap...
Many laboratories use electronic message standards to transmit results to their clients. If all l... more Many laboratories use electronic message standards to transmit results to their clients. If all laboratories used the same "universal" set of test identifiers, electronic transmission of results would be greatly simplified. The Logical Observation Identifier Names and Codes (LOINC) database aims to be such a code system, covering at least 98% of the average laboratory's tests. The LOINC database should be of interest to hospitals, clinical laboratories, doctors' offices, state health departments, governmental healthcare providers, third-party payors, organizations involved in clinical trials, and quality assurance and utilization reviewers. The fifth release of the LOINC database, containing codes, names, and synonyms for approximately 6300 test observations, is now available on the Internet for public use. Here we describe the LOINC database, the methods used to produce it, and how it may be obtained.
Adults with diabetes at risk for hypoglycemia were surveyed in Canada's largest population-based ... more Adults with diabetes at risk for hypoglycemia were surveyed in Canada's largest population-based study on hypoglycemia (InHypo-DM). Respondents rated how often they report their SH events to their HCPs, on a scale from Never to Always. Univariable analyses (p<0.2) followed by a zero-inflated negative binomial analysis determined the independent association of SH disclosure and the retrospective incidence of self-reported SH. In total, 552 respondents (17% type 1 diabetes, 83% type 2 diabetes) completed the InHypo-DM questionnaire. Forty percent of respondents experienced ≥1 SH event within the past year. The incidence rate of SH was 2.45 events/person-year. Notwithstanding, only 34% of respondents indicated that they always report SH events. Although disclosure behaviour was not associated with the odds of experiencing SH (p=0.86), the rate of SH almost doubled (1.9, 95% CI: 1.2 to 3.0, p=0.004) among individuals who underreported events compared to those who did not. Results persisted after adjusting for age, medication class, income, HbA1C, and presence of comorbidities. Results revealed nearly 2-fold higher rates of SH among those who underreport events to HCPs. Providers should endeavor to elicit accurate information on SH frequency from patients, particularly those at risk for repeated SH.
Purpose Crenigacestat (LY3039478) is a Notch inhibitor currently being investigated in advanced c... more Purpose Crenigacestat (LY3039478) is a Notch inhibitor currently being investigated in advanced cancer patients. Conducting clinical pharmacology studies in healthy subjects avoids nonbeneficial drug exposures in cancer patients and mitigates confounding effects of disease state and concomitant medications. Methods Three studies were conducted in healthy subjects, assessing safety, pharmacokinetics, effect on QT interval, and relative and absolute bioavailability of crenigacestat. Crenigacestat was administered as single 25, 50, or 75 mg oral doses or as an intravenous dose of 350 µg 13 C 15 N 2 H-crenigacestat. Electrocardiogram measurements, and plasma and urine samples were collected up to 48 h postdose, and safety assessments were conducted up to 14 days postdose. Results and conclusions Exposures were dose proportional in the 25 to 75 mg dose range and mean elimination half-life was approximately 5-6 h. The exposure achieved from the new formulated capsule was approximately 30% and 20% higher for area under the plasma concentration time curve from time zero to infinity [AUC(0-∞)] and maximum plasma concentration (C max), respectively, compared to the reference drug in capsule formulation. The geometric least-squares mean [90% confidence interval (CI)] absolute bioavailability of crenigacestat was 0.572 (0.532, 0.615). The regression slope (90% CI) of placebo-adjusted QTcF against crenigacestat plasma concentration was − 0.001 (− 0.006, 0.003), suggesting no significant linear association. Thirty-nine subjects completed the studies and the majority of adverse events were mild. Single oral doses of 25 to 75 mg crenigacestat and an IV dose of 350 µg 13 C 15 N 2 H-crenigacestat were well tolerated in healthy subjects.
To examine the effect of increased gastric pH on exposure to evacetrapib, a cholesteryl ester tra... more To examine the effect of increased gastric pH on exposure to evacetrapib, a cholesteryl ester transfer protein inhibitor evaluated for the treatment of atherosclerotic heart disease. Open-label, two-treatment, two-period, fixed-sequence, crossover study. Clinical research unit. Thirty-four healthy subjects. In period 1, subjects received a single oral dose of evacetrapib 130 mg on day 1, followed by 7 days of analysis for evacetrapib plasma concentrations. In period 2, subjects received a once-daily oral dose of omeprazole 40 mg on days 8-20, with a single oral dose of evacetrapib 130 mg administered 2 hours after the omeprazole dose on day 14, followed by 7 days of pharmacokinetic sampling. Subjects were discharged on day 21 and returned for a follow-up visit at least 14 days after the last dose of evacetrapib in period 2. Gastric pH was measured before subjects received each evacetrapib dose. Noncompartmental pharmacokinetic parameters were estimated from plasma concentration-time...
Journal of labelled compounds & radiopharmaceuticals, May 7, 2015
This open-label, single-period study in healthy subjects estimated evacetrapib absolute bioavaila... more This open-label, single-period study in healthy subjects estimated evacetrapib absolute bioavailability following simultaneous administration of a 130-mg evacetrapib oral dose and 4-h intravenous (IV) infusion of 175 µg [(13) C8 ]-evacetrapib as a tracer. Plasma samples collected through 168 h were analyzed for evacetrapib and [(13) C8 ]-evacetrapib using high-performance liquid chromatography/tandem mass spectrometry. Pharmacokinetic parameter estimates following oral and IV doses, including area under the concentration-time curve (AUC) from zero to infinity (AUC[0-∞]) and to the last measureable concentration (AUC[0-tlast ]), were calculated. Bioavailability was calculated as the ratio of least-squares geometric mean of dose-normalized AUC (oral : IV) and corresponding 90% confidence interval (CI). Bioavailability of evacetrapib was 44.8% (90% CI: 42.2-47.6%) for AUC(0-∞) and 44.3% (90% CI: 41.8-46.9%) for AUC(0-tlast ). Evacetrapib was well tolerated with no reports of clinically...
Evacetrapib is an investigational cholesteryl ester transfer protein inhibitor (CETPi) for reduct... more Evacetrapib is an investigational cholesteryl ester transfer protein inhibitor (CETPi) for reduction of risk of major adverse cardiovascular events in patients with high-risk vascular disease. Understanding evacetrapib disposition, metabolism, and the potential for drug-drug interactions (DDI) may help guide prescribing recommendations. In vitro, evacetrapib metabolism was investigated with a panel of human recombinant cytochromes P450 (CYP). The disposition, metabolism, and excretion of evacetrapib following a single 100-mg oral dose of (14)C-evacetrapib were determined in healthy subjects, and the pharmacokinetics of evacetrapib were evaluated in the presence of strong CYP3A or CYP2C8 inhibitors. In vitro, CYP3A was responsible for about 90% of evacetrapib's CYP-associated clearance, while CYP2C8 accounted for about 10%. In the clinical disposition study, only evacetrapib and two minor metabolites circulated in plasma. Evacetrapib metabolism was extensive. A mean of 93.1% and ...
British journal of clinical pharmacology, Jan 12, 2015
Evacetrapib is a cholesteryl ester transfer protein (CETP) inhibitor under development for reduci... more Evacetrapib is a cholesteryl ester transfer protein (CETP) inhibitor under development for reducing cardiovascular events in patients with high-risk vascular disease. CETP inhibitors are likely to be utilised as "add-on" therapy to statins in patients receiving concomitant medications, so the potential for evacetrapib to cause clinically important drug-drug interactions (DDI) with cytochromes P450 (CYP) was evaluated. The DDI potential of evacetrapib was investigated in vitro, followed by predictions to determine clinical relevance. Potential DDI with possible clinical implications were then investigated in the clinic. In vitro, evacetrapib inhibited all of the major CYPs, with inhibition constants (Ki ) ranging from 0.57 μM (CYP2C9) to 7.6 μM (CYP2C19). Evacetrapib was a time-dependent inhibitor and inducer of CYP3A. The effects of evacetrapib on CYP3A and CYP2C9 were assessed in a Phase 1 study using midazolam and tolbutamide as probe substrates, respectively. After 14 d...
The Regenstrief Medical Record System (RMRS) continues to grow in breadth and depth. As we expand... more The Regenstrief Medical Record System (RMRS) continues to grow in breadth and depth. As we expand its breadth -- the system links 5 health care systems, 11 acute care hospitals, 13 homeless care sites, nearly 100 clinics/offices and the county and state health departments -- we have had to overcome critical problems inherent to creating a community wide electronic medical record (EMR). Data for more than 2 million patients consisting of 300 million coded observations, 5.8 million text reports, 300,000 electrocardiogram tracings and 700,000 images. We are now processing almost 8 million observations monthly. In order to accommodate this expansion, significant we have made extended the system architecture over the last several years. These improvements include enhanced message routing, extended message processing, a multiple entity database, a master patient index, master provider index, and methods for displaying and attributing data from multiple entities.
The international journal of neuropsychopharmacology / official scientific journal of the Collegium Internationale Neuropsychopharmacologicum (CINP), Jan 31, 2014
Selective kappa opioid receptor antagonism is a promising experimental strategy for the treatment... more Selective kappa opioid receptor antagonism is a promising experimental strategy for the treatment of depression. The kappa opioid receptor antagonist, LY2456302, exhibits ~30-fold higher affinity for kappa opioid receptors over mu opioid receptors, which is the next closest identified pharmacology. Here, we determined kappa opioid receptor pharmacological selectivity of LY2456302 by assessing mu opioid receptor antagonism using translational pupillometry in rats and humans. In rats, morphine-induced mydriasis was completely blocked by the nonselective opioid receptor antagonist naloxone (3mg/kg, which produced 90% mu opioid receptor occupancy), while 100 and 300mg/kg LY2456302 (which produced 56% and 87% mu opioid receptor occupancy, respectively) only partially blocked morphine-induced mydriasis. In humans, fentanyl-induced miosis was completely blocked by 50mg naltrexone, and LY2456302 dose-dependently blocked miosis at 25 and 60mg (minimal-to-no blockade at 4-10mg). We demonstrat...
Journal of cardiovascular pharmacology and therapeutics, Jan 3, 2015
To determine the effect of a high-fat meal on evacetrapib exposure at steady state in healthy par... more To determine the effect of a high-fat meal on evacetrapib exposure at steady state in healthy participants. This was a randomized, 2-period, 2-sequence, open-label, crossover study. Patients were randomly assigned to 1 of the 2 treatment sequences in which they received evacetrapib 130 mg/d for 10 days following a 10-hour fast each day or following a high-fat breakfast each day. Plasma samples collected through 24 hours were analyzed for evacetrapib concentrations and pharmacokinetic parameter estimates including area under the concentration-time curve during a dosing interval (AUCτ), maximum observed concentration (Cmax), and time of Cmax (tmax) were calculated. Pharmacodynamic parameters, including cholesteryl ester transfer protein (CETP) activity, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), total cholesterol, and triglycerides, were also assessed. A total of 34 males and 6 females, mean age 41.5 years and mean body mass index 26.6 k...
Journal of Cardiovascular Pharmacology and Therapeutics, 2013
Purpose: To evaluate whether evacetrapib prolongs QT intervals in healthy participants. Methods: ... more Purpose: To evaluate whether evacetrapib prolongs QT intervals in healthy participants. Methods: This was a single-center, randomized, active and placebo-controlled, 3-period, 6-sequence, and crossover study. Participants were randomized to 1 of 6 treatment sequences in which they received 1 of 3 treatments: evacetrapib 1200 mg daily for 10 days (supratherapeutic dose), moxifloxacin 400 mg for 1 day (positive control), or placebo for 10 days in each of the 3 separate treatment periods. Electrocardiographic parameters were recorded at time points specified in the protocol. The primary end point was the comparison of evacetrapib effect on the population-corrected QT interval (QTcP) to that of placebo at 7 time points following dosing on day 10. An upper limit of the 2-sided 90% confidence interval (CI) <10 milliseconds confirmed the absence of significant effect. Pharmacokinetic parameters were also calculated. Results: Subjects were predominantly male (73.2%) with a mean age of 43...
Journal of the American Medical Informatics Association, 1999
The authors surveyed existing standard codes for units of measures, such as ISO 2955, ANSI X3.50,... more The authors surveyed existing standard codes for units of measures, such as ISO 2955, ANSI X3.50, and Health Level 7's ISOϩ. Because these standards specify only the character representation of units, the authors developed a semantic model for units based on dimensional analysis. Through this model, conversion between units and calculations with dimensioned quantities become as simple as calculating with numbers. All atomic symbols for prefixes and units are defined in one small table. Huge permutated conversion tables are not required. This method is also simple enough to be widely implementable in today's information systems. To promote the application of the method the authors provide an open-source implementation of this method in JAVA. All existing code standards for units, however, are incomplete for practical use and require substantial changes to correct their many ambiguities. The authors therefore developed a code for units that is much more complete and free from ambiguities.
The rain forest canopy is a seamless web through which arboreal creatures efficiently move to rea... more The rain forest canopy is a seamless web through which arboreal creatures efficiently move to reach the edible fruits without any attention to the individual trees. Individual health care computer systems are rich with patient data, but rather than a canopy linking all the trees in the forest, the data "fruit" come from a diverse forest of individual computer "trees"-laboratory systems, word processing systems, pharmacy systems, and the like. These different sources of patient information are difficult or impossible to reach by individual physicians, especially from their offices. The World Wide Web and other standardization technology provide physicians and their institutions the tools needed for seamless and secure access to their patients' data and to medical information, when and where they need it. We and others have adopted these tools to combine independent sources of clinical data. Physicians who assist in the purchase of clinical information systems should demand products in their practice settings that are Web enabled, use standard coding systems, and communicate with other computer systems via broadly accepted protocols.
Two studies were conducted in subjects with mild or moderate hepatic or renal impairment and subj... more Two studies were conducted in subjects with mild or moderate hepatic or renal impairment and subjects with normal organ function to evaluate the pharmacokinetics of casopitant and to assess its safety in these populations. A total of 26 subjects were enrolled in the hepatic impairment study and 18 subjects in the renal impairment study. All subjects received oral casopitant 100 mg once-daily for 5 days. Casopitant area under the concentration-time curve (AUC) increased 11% and 24% in subjects with mild or moderate hepatic impairment, respectively, on Day 1, compared with subjects with normal hepatic function; a similar increase was observed on Day 5. The AUC of the active major metabolite, GSK525060, was reduced 29% and 19% on Days 1 and 5, respectively, in subjects with moderate hepatic impairment, but not altered by mild hepatic impairment. Casopitant AUC increased 34% and 22% on Day 1 in subjects with mild or moderate renal impairment, respectively, and 28% and 11% on Day 5, respectively, compared with subjects with normal renal function. GSK525060 AUC was increased 17% and 24% on Days 1 and 5, respectively, in subjects with mild renal impairment; but did not significantly change in subjects with moderate renal impairment. Further age-adjusted analysis showed no meaningful effect of renal impairment on casopitant or GSK525060 AUC. Plasma protein binding of casopitant and GSK525060 was similar in all subjects. The pharmacokinetics of casopitant is not altered to a clinically significant extent in subjects with mild or moderate, hepatic or renal impairment. The impact of severe hepatic or renal impairment was not evaluated.
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Papers by Jeffrey Suico