Disparities in long-term cardiovascular disease risk by sexual identity: The National Longitudinal Study of Adolescent to Adult Health.

OBJECTIVE: To examine long-term cardiovascular disease (CVD) risk disparities by sexual identity using a nationally representative sample of young adults in the United States. METHODS: Data include participants in wave 4 (2008/09; ages 24-34years) of the National Longitudinal Study of Adolescent to Adult Health (7087 females; 6340 males). Sexual identity was self-reported (heterosexual, mostly heterosexual, bisexual, mostly homosexual, homosexual) and a Framingham-based prediction model was used to estimate participants' risk of a CVD event over 30years. Differences in CVD risk by sexual identity, relative to heterosexuals, were calculated with linear regression models adjusted for age, race/ethnicity, education, and financial distress. RESULTS: Average 30-year CVD risk was 17.2% (95% CI: 16.7, 17.7) in males and 9.0% (95% CI: 8.6, 9.3) in females. Compared to heterosexual females, mostly heterosexual (0.8%; 95% CI: 0.2, 1.4) and mostly homosexual females (2.8%; 95% CI: 0.8, 4.9) had higher CVD risk. Bisexual and homosexual females had higher but not statistically significant CVD risk compared to heterosexuals. Among males, differences in CVD risk by sexual identity were not statistically significant. CONCLUSION: Sexual identity was associated with CVD risk in sexual minority subgroups. Population- and clinic-based prevention strategies are needed to minimize disparities in subsequent disease.

Application of quantitative 19F and 1H NMR for reaction monitoring and in situ yield determinations for an early stage pharmaceutical candidate.

Quantitative NMR spectrometry (qNMR) is an attractive, viable alternative to traditional chromatographic techniques. It is a fast, easy, accurate, and nondestructive technique which allows an analyst to gain quantitative information about a component mixture without the necessity of authentic reference materials, as is the case with most other analytical techniques. This is ideal for the synthesis of active pharmaceutical ingredients (API) that are in the early stages of development where authentic standards of the analytes may not be available. In this paper, the application of (19)F and (1)H qNMR for reaction monitoring and in situ potency determinations will be discussed for an early stage pharmaceutical candidate with several analytical challenges. These challenges include low UV absorption, low ionization, thermal instability, and lack of authentic reference standards. Quantitative NMR provided quick, fit-for-purpose solutions for process development where conventional separation techniques were limited.

Fused-core particles: a practical alternative to sub-2 micron particles.

The benefits of sub-2 micron particle size columns have been widely researched and published. The use of these columns on ultrahigh-pressure liquid chromatography (UHPLC) instrumentation may lead to increased efficiencies and higher throughput. However, these instruments may not be readily available to the pharmaceutical chemist. Within the past year, a practical alternative has been introduced which offers increased efficiencies, but at conventional HPLC pressure limitations. These particles are called fused-core particles and are comprised of a 1.7-micron solid core encompassed by a 0.5-micron porous silica layer (dp = 2.7 micron). The goal for this research was to test these columns for efficiency and robustness utilizing a mixture of Torcetrapib and its relative impurities. Our results indicate that excellent theoretical plates (approximately 14000) were achievable for run times less than 5 min. Compared to the Waters Acquity particles, the fused-core particles achieved approximately 80% of the efficiency but with half the observed backpressure. Our robustness results concluded that these separations were reproducible for at least 500 injections while the % RSD for retention time, theoretical plates, peak asymmetry, and resolution was found to be less than 1%.

Enantioselective analysis for L-pidolic acid in ertugliflozin drug substance and drug product by chiral gas chromatography with derivatization.

L-pidolic acid is being used as a coformer for ertugliflozin, a sodium-glucose cotransport 2 inhibitor. A sensitive and rapid two-step achiral derivatization combined with gas chromatography with flame ionization detection or gas chromatography with mass spectroscopic detection was developed and validated for the enantiomeric purity determination of L-pidolic acid in the drug substance and drug product, respectively. The method was used to analyze ertugliflozin drug substance forced degradation samples and showed no racemization of pidolic acid in any of the solid or solution stress samples. Analysis of ertugliflozin drug product stability samples showed no significant levels of D-pidolic acid in the drug product indicating that no significant racemization of pidolic acid occurs in the drug product under normal storage conditions. Based on the data generated, a chiral control for pidolic acid is not necessary for drug substance or drug product, but rather can be controlled in the purchase of L-pidolic acid.

Rapid screening test for sleep apnea using a nonlinear and nonstationary signal processing technique.

It is hypothesized that obstructive sleep apnea (OSA) can be detected from a short-time, daytime recording of the nasal airway pressure, resulting in a screening tool to identify adult patients at risk for OSA. A nonlinear and nonstationary signal analysis technique based on the Hilbert-Huang transform was used to extract signals intrinsic to OSA, using the first two intrinsic mode functions from the empirical mode decomposition. The Hilbert spectrum was centered around 1.5Hz for normal subjects and shifted upward in frequency scale with increased likelihood of OSA. The histogram of the 1.5Hz signal from the Hilbert spectrum was used to compute the apnea percentage for assessing OSA. The proposed method was tested with two data sets. Data set 1 consisted of 18 human subjects with 3 OSA cases from retrospective diagnosis. Data set 2 consisted of 16 subjects who went through a prospective study of the all-night polysomnographic test and the 5-min nasal airway pressure test. The proposed OSA detection method achieved 100% sensitivity and 100% specificity for data set 1, 85.7% sensitivity and 100% specificity for data set 2. While further tests will be needed to insure robustness and standardize the instrumentation, the study has demonstrated the feasibility of a rapid screening test for obstructive sleep apnea.

Validation of an enantioselective analysis for (l)-pidolic acid by chiral gas chromatography with derivatization.

A sensitive and rapid analytical method has been validated for the enantiomeric purity determination of l-pidolic acid, a biological lactam and metabolite of glutamic acid commonly found in urine, skin, bones, brain and is available commercially as a food supplement. An efficient, two-step achiral derivatization was implemented which consisted of an alkylation step (using HCl-IPA) followed by an acylation step (using TFAA) of the carboxy and amide functional groups. This allowed detection with high sensitivity using gas chromatography with flame ionization detection. The described procedure employs a CP-Chiralsil-L Val column (25m×0.25mm) at a constant flow rate of 1.5mLmin(-1), a gradient temperature program from 80°C to 160°C and an injector and detector temperature of 250°C. The proposed method was validated according to ICH Q2 standards and included such parameters as specificity, system precision, analyst repeatability, intermediate precision, accuracy, linearity, LOD/LOQ and solution stability.

Method development and validation of arene substituted regioisomers in a pharmaceutical candidate by high temperature GC-FID.

This paper describes the development and validation of a high temperature gas chromatography flame ionization detection (HTGC-FID) method for the purity evaluation of arene substituted regioisomers in a key starting material of a pharmaceutical candidate in Phase 3 studies. The chromatographic conditions of the method employ a (5%-phenyl)-methylpolysiloxane packed column (30m×0.25mm) at a constant flow of 1.0mLmin(-1) with a gradient temperature program from 150°C to 400°C with injector and detector temperatures of 300°C and 340°C, respectively. The calibration curve for the desired product (r=0.9999) was assessed for five points in the range from approximately 1.0µgmL(-1) to 40µgmL(-1). The precision (% RSD) of the method was calculated for six replicate injections and found to be 0.81%. The limits of detection and quantitation were determined to be 0.06 and 0.20µgmL(-1), respectively.

The role of UHPLC in pharmaceutical development.

Pharmaceutical separations can be divided into three categories: high throughput, high productivity, and high resolution. These categories contain specific pharmaceutical applications, each of which has distinct separation goals. Traditionally, these goals have been achieved utilizing conventional HPLC with typical column dimensions and particle sizes. The recent introduction of ultra-HPLC (UHPLC) has provided a new potential for method development and analysis. Pharmaceutical chemists must determine the impact of this emerging technology. UHPLC is achieved by using sub-2 microm particle size column packing at increased linear velocities. In order to utilize this technology, mobile phase viscosity must be minimized or the chromatography system must be redesigned to withstand an increased backpressure. Today, there are many commercially available UHPLC systems capable of exceeding conventional pressure limits of 400 bar. The advantage of UHPLC over conventional HPLC is the capability to increase the speed without sacrificing efficiency. In comparison to traditional HPLC, our research showed that UHPLC can decrease run times up to 7 x. In addition, for high resolution applications, UHPLC achieved significant efficiency advantages over traditional HPLC. This paper will evaluate the potential roles for utilizing UHPLC in the pharmaceutical industry.

Assessment of chaotic parameters in nonstationary electrocardiograms by use of empirical mode decomposition.

This study addressed the issue of assessing chaotic parameters from nonstationary electrocardiogram (ECG) signals. The empirical mode decomposition (EMD) was proposed as a method to extract intrinsic mode functions (IMFs) from ECG signals. Chaos analysis methods were then applied to the stationary IMFs without violating the underlying assumption of stationarity. Eight ECG data sets representing normal and various abnormal rhythms were obtained from the American Heart Associate Ventricular Arrhythmia database. The chaotic parameters including Lyapunov exponent, entropy, and correlation dimension were computed. The results consistently showed that the 10th IMF (IMF-10) was stationary and preserved sufficient nonlinearity of the ECG signals. Each IMF-10 from the data sets (n = 8) gave a positive dominate Lyapunov exponent (0.29-0.64, p < 0.0001), a positive entropy (0.039-0.061, p < 0.0001), and a noninteger correlation dimension (1.1-1.9). These were evidences of a chaotic dynamic system. We therefore concluded that the original ECG signals must also have chaotic properties. The chaotic parameters did not show significant differences among the eight data sets representing normal sinus rhythm and various abnormalities. This study has demonstrated an effective way to characterize nonlinearities in nonstationary ECG signals by combining the empirical mode decomposition and the chaos analysis methods.