Relationship between abnormal P-wave axis, chronic obstructive pulmonary disease and mortality in the general population.

BACKGROUND: It is unclear whether the presence of a vertical P-wave axis on electrocardiogram modifies the association of COPD with mortality. OBJECTIVE: To examine the association and interaction of abnormal P-wave axis and COPD with mortality. STUDY DESIGN AND METHODS: The analysis included 7359 with ECG data from the Third National Health and Nutrition Examination Survey (NHANES-III) who were free of cardiovascular disease (CVD) at enrollment. Abnormal P-wave axis (aPWA) was defined as values above 75°. COPD was self-reported as either a diagnosis of emphysema or chronic bronchitis. National Death Index was used to identify the date of death and cause of death. Using multivariable Cox proportional hazard analysis, we examined the association of COPD with all-cause mortality by aPWA status. RESULTS: Over a median follow-up of 14 years, 2435 deaths occurred. Participants with concomitant presence of aPWA and COPD experienced higher death rates (73.9 per 1000 person-years (PY)) compared to either COPD or aPWA alone (36.4 per 1000 PY and 31.1 per 1000 PY), respectively. In multivariable-adjusted models, a stronger association between COPD and mortality was noted in the presence compared to the absence of aPWA (HR 95% CI): 1.71 (1.37-2.13) vs. 1.22(1.00-1.49), respectively (interaction P-value = 0.02). Similarly, a stronger association between aPWA and mortality was observed in the presence compared to the absence of COPD (HR 95% CI): 1.66(1.26-2.19) vs. 1.18(1.06-1.31), respectively (interaction P-value = 0.02). Similar higher death rates and mortality risk was observed when spirometry-confirmed COPD and aPWA were present together than in isolation. CONCLUSION: The concomitant presence of aPWA and COPD leads to a significantly higher mortality rate compared to the presence either COPD or aPWA alone as a clinical variable. P-wave axis, reported routinely on ECG printout, can potentially identify patients with COPD who need intensive control of risk factors and disease management.

Saliva vs. plasma bioequivalence of metformin in humans: validation of class II drugs of the salivary excretion classification system.

To study saliva and plasma bioequivalence of metformin in humans, and to investigate the robustness of using saliva instead of plasma as surrogate for bioequivalence of class II drugs according to the salivary excretion classification system (SECS).Plasma and saliva samples were collected for 12 h after 500 mg oral dosing of metformin to 16 healthy humans. Plasma and saliva pharmacokinetic parameters, 90% confidence intervals and intra-subject variability values were calculated using Kinetica V5. Descriptive statistics and dimensional analysis were calculated by Excel. SimCYP program V13 was used for estimation of effective intestinal permeability.Metformin was subjected to salivary excretion since it falls into class II (Low permeability/High fraction unbound to plasma proteins), with correlation coefficients of 0.95-0.99 between plasma and saliva concentrations. Saliva/plasma concentration ratios were 0.29-0.39. The 90% confidence limits of all parameters failed in both saliva and plasma. Intra-subject variability values in saliva were higher than plasma leading to need for higher number of subjects to be used in saliva.Saliva instead of plasma can be used as surrogate for bioequivalence of class II drugs according to SECS when adequate sample size is used. Future work is planned to demonstrate SECS robustness in drugs that fall into class III.

Saliva vs. plasma bioequivalence of paracetamol in humans: validation of class I drugs of the salivary excretion classification system.

AIMS: To study saliva and plasma bioequivalence of paracetamol in healthy human volunteers, and to investigate the robustness of using saliva instead of plasma as surrogate for bioequivalence of class I drugs according to the salivary excretion classification system (SECS). METHODS: Saliva and plasma pharmacokinetic parameters were calculated by non compartmental analysis. Analysis of variance, 90% confidence intervals, intra-subject and inter-subject variability values of pharmacokinetic parameters were calculated after logarithmic transformation. Calculations were done using Kinetica program V5. Descriptive and comparative statistics were also calculated by Excel. RESULTS AND DISCUSSION: Paracetamol falls into class I (High permeability/High fraction unbound to plasma proteins) and was subjected to salivary excretion, with correlation coefficient of 0.99 between saliva and plasma concentrations and saliva/plasma concentrations ratios of 1.45-1.50. The 90% confidence limits of areas under curve (AUC(last) and AUC(∞)) showed similar trend and passed the 80-125% acceptance criteria in both saliva and plasma. On the other hand for maximum concentration (C(max)), the 90% confidence limits passed the acceptance criteria in plasma and failed in saliva. Inter and intra subject variability values in saliva were higher than plasma leading to need for higher number of subjects to be used in saliva. Saliva and plasma parameter ratios were not significantly different (P>0.05). CONCLUSIONS: Saliva instead of plasma can be used as surrogate for bioequivalence of class I drugs according to SECS when adequate sample size is used. Future work is planned to demonstrate SECS robustness in drugs that fall into classes II or III.

Population pharmacokinetic analysis of clopidogrel in healthy Jordanian subjects with emphasis optimal sampling strategy.

AIM: Clopidogrel is metabolized primarily into an inactive carboxyl metabolite (clopidogrel-IM) or to a lesser extent an active thiol metabolite. A population pharmacokinetic (PK) model was developed using NONMEM(®) to describe the time course of clopidogrel-IM in plasma and to design a sparse-sampling strategy to predict clopidogrel-IM exposures for use in characterizing anti-platelet activity. METHODS: Serial blood samples from 76 healthy Jordanian subjects administered a single 75 mg oral dose of clopidogrel were collected and assayed for clopidogrel-IM using reverse phase high performance liquid chromatography. A two-compartment (2-CMT) PK model with first-order absorption and elimination plus an absorption lag-time was evaluated, as well as a variation of this model designed to mimic enterohepatic recycling (EHC). Optimal PK sampling strategies (OSS) were determined using WinPOPT based upon collection of 3-12 post-dose samples. RESULTS: A two-compartment model with EHC provided the best fit and reduced bias in C(max) (median prediction error (PE%) of 9.58% versus 12.2%) relative to the basic two-compartment model, AUC(0-24) was similar for both models (median PE% = 1.39%). The OSS for fitting the two-compartment model with EHC required the collection of seven samples (0.25, 1, 2, 4, 5, 6 and 12 h). Reasonably unbiased and precise exposures were obtained when re-fitting this model to a reduced dataset considering only these sampling times. CONCLUSIONS: A two-compartment model considering EHC best characterized the time course of clopidogrel-IM in plasma. Use of the suggested OSS will allow for the collection of fewer PK samples when assessing clopidogrel-IM exposures.

Smoking behaviour modulates pharmacokinetics of orally administered clopidogrel.

BACKGROUND AND OBJECTIVES: Clopidogrel is an important antiplatelet drug that is effective in preventing thrombotic events, especially for patients undergoing percutaneous coronary intervention. The therapeutic usefulness of clopidogrel has been limited by documented inter-individual heterogeneity in platelet inhibition, which may be attributable to known clopidogrel pharmacokinetic variability. The objective of this study was to assess the influence of smoking cigarettes and abnormal body weight on the pharmacokinetics of clopidogrel. METHODS: Seventy-six healthy adult male volunteers were selected randomly. Each subject received a single 75 mg oral dose of clopidogrel after overnight fast. Clopidogrel carboxylate plasma levels were measured and non-compartmental analysis was used to determine peak plasma concentration (C(max)), time to peak plasma concentration (T(max)), elimination half-life (t(1/2e)), and area under the curve (AUC(0-->infinity)). RESULTS: One-third of volunteers were smokers (n = 27) and one-half had abnormal body weight (n = 39). Smokers had lower AUC(0-->infinity) (smokers: 6.24 +/- 2.32 microg/h/mL vs. non-smokers: 8.93 +/- 3.80 microg/h/mL, P < 0.001) and shorter half-life (smokers: 5.46 +/- 2.99 vs. non-smokers: 8.43 +/- 4.26, P = 0.001). Smoking behaviour had no influence on C(max) (P = 0.3) and T(max) (P = 0.7). There was no statistically significant difference in C(max), AUC(0-->infinity), T(max) and t(1/2e) between volunteers with abnormal body weight and normal body weight. However the difference in body weight of the two groups was relatively narrow (mean +/- SE; 26.93 +/- 0.16 vs. 23.11 +/- 0.27). In general, the pharmacokinetic parameters were characterized by considerable inter-individual differences (C(max) = 3.09 +/- 0.99 microg/mL, CV = 32%), (T(max) =0.76 +/- 0.24 h, CV = 31.6%), (AUC(0-->infinity) = 7.98 +/- 3.58 microg/h/mL, CV = 44.8%), and (t(1/2e) = 7.38 +/- 4.10 h, CV = 55.6%). CONCLUSION: Smoking is a significant factor affecting the pharmacokinetics of clopidogrel, following administration of a single 75 mg dose in healthy young volunteers. The study supports smoking-cessation recommendations. Further studies are required to evaluate the influence of smoking and body weight on the pharmacokinetics of the active metabolite of clopidogrel and on the clinical effects of any differences observed.

Pharmacokinetics and pharmacodynamics profiles of enalapril maleate in healthy volunteers following determination of enalapril and enalaprilat by two specific enzyme immunoassays.

BACKGROUND AND OBJECTIVES: Most of the pharmacokinetic (PK) parameters for enalapril and enalaprilat were established following determination of the drug and its metabolite, using angiotensin converting enzyme (ACE) inhibition assays. In these methods, enalapril has to be hydrolysed to enalaprilat first and then assayed. The purpose of this study was to re-estimate the PK parameters of enalapril and enalaprilat in healthy volunteers using two specific enzyme immunoassays for enalapril and enalaprilat. METHODS: The rate and extent of absorption of enalapril and enalaprilat from a 10-mg dose of two enalapril maleate commercial brands (Renetic and Enalapril) were estimated using a two-way-cross over design with 1-week washout period. Blood pressure was also measured at specified time intervals and correlated to enalaprilat plasma concentrations. RESULTS: For enalapril, the AUC(o-->infinity) values (Mean+/-SD) were 450.0+/-199.5 and 479.6+/-215.6 ng h/mL, Cmax values were 313.5+/-139.6 and 310.1+/-186.6 ng/mL, Tmax values were 1.06+/-0.30 h and 1.13+/-0.22 h, and t1/2 ranged between 0.3 to 6.1 h (1.6+/-1.5) and 0.40 to 5.05 h (1.3+/-1.0), for the two brands. For enalaprilat, the AUC(o-->infinity) values were 266.9+/-122.7 and 255.9+/-121.8 ng h/ml, Cmax values were 54.8+/-29.5 and 57.2+/-29.0 ng/mL, Tmax values were 4.6+/-1.6 h and 4.3+/-1.45 h, and t1/2 ranged between 1.1 to 10.5 h (4.5+/-2.9) and 0.6 to 9.4 h (3.5+/-2.5) for the two brands. CONCLUSIONS: Cmax values for enalapril are about 10 times those published in the literature and the rate and extent of absorption of the two brands of enalapril and their deesterification to enalaprilat following the administration of either brand were bioequivalent. Secondly, enalaprilat concentrations at 12-24 h following a single oral dose of enalapril in healthy volunteers were lower than those reported in the literature. The values reported here correlated with the return of blood pressure to predose level. Thirdly, enzyme immunoassays for enalapril and enalaprilat are better than ACE inhibition assays and can be used in bioequivalence assessment of enalapril and enalaprilat and for therapeutic drug monitoring in a clinical laboratory setting.

Enzyme linked immunosorbent assay for determination of amlodipine in plasma.

Amlodipine is a calcium channel antagonist of the dihydropyridine group. It is effective for treating hypertension, chronic stable angina, and vasospastic angina. However, it is difficult clinically to pinpoint the maximum dosage for antihypertensive activity of the drug without having parallel data on the plasma drug concentrations. The methods for assaying amlodipine are either gas chromatography with electron capture detector or liquid chromatography coupled with tandem mass spectrometry (or with an electrochemical detector), which needs tedious derivatization, and is expensive and time consuming. Therefore, in this study we developed an enzyme immunoassay for determining amlodipine in plasma. Anti-amlodipine antibodies were produced following immunization of bovine serum albumin-amlodipine conjugate. These specific antibodies were used in a competitive biotin-avidin-based enzyme-linked immunosorbent assay to measure amlodipine in plasma. Biotin was linked to the antibodies in order to enhance the sensitivity of the assay. The assay was specific for the free form of amlodipine with a detection limit of 0.1 ng/ml and the intra- and interassay coefficient of variation ranged from 1.6-10.2%. This immunoassay provides a sensitive, reliable, rapid, and accurate method for determination of amlodipine in plasma, which can be used in therapeutic drug monitoring pharmacokinetic studies and pharmaceutical analysis.

Determination of captopril in human blood by an enzyme-linked immunosorbent assay.

An immunoassay for the quantitation of the angiotensin-converting enzyme inhibitor, captopril in human plasma is described. Antisera very specific for captopril were produced by immunization with captopril conjugated to bovine serum albumin or porcine thyroglobulin via the drug's thiol group. The antibodies were used to develop an enzyme-linked immunosorbent assay (ELISA) with a detection limit of 0.3 ng mL-1 and intra- and inter-assay coefficients of variation of 7 and 12%, respectively. Apart from stabilizing captopril by the addition of N-ethyl maleimide, the assay was used to detect the drug in human plasma without further extraction or purification. Our immunoassay provides a very sensitive and rapid (four hours) alternative for the study of captopril pharmacokinetics.

A bioequivalence study of two products of furosemide tablets.

Twenty healthy male volunteers participated in a balanced crossover comparison of diusemide versus lasix. Each treatment was given as a single 40 mg tablet following an overnight fast. Furosemide concentration in plasma were determined up to 8 h after treatment. Urine output and urinary sodium excretion was also measured. At the 5% confidence level, no significant difference was found between the area under the plasma concentration-time curves of the two products. The Cmax, tmax, cumulative urine volume, cumulative sodium and potassium electrolytes were found not significantly different for both products. Quality control data including assay, content uniformity, disintegration and dissolution indicated that both products passed the pharmacopoeial requirements, U.S.P. XXII and B.P. 1988. In conclusion, diusemide 40 mg is bioequivalent to the brand name lasix.

Pharmacokinetics and pharmacodynamics of two commercial oral nifedipine products.

Nifedipine, a calcium channel blocker, is widely used in the management of hypertension, angina and cardiac arrhythmias. In this study, the bioequivalence of two pharmaceutical formulations of nifedipine, Nifecard (10 mg capsules) manufactured by Dar Al-Dawa Development and Investment Co, Ltd. and Adalat (10 mg capsules) manufactured by Bayer Pharmaceutical Company, was assessed in twelve healthy male subjects. Nifecard or Adalat was given orally on two occasions separated by one week wash-out interval. Blood samples for the determination of plasma nifedipine concentration were taken for 8 hours following drug administration. Blood pressure and pulse were also measured after each treatment. Plasma nifedipine concentrations were measured by a simple, sensitive and reproducible HPLC method. There were no significant differences in oral absorption, Cmax, tmax, t1/2 and AUC between Nifecard and Adalat. Also, Nifecard and Adalat produced similar hemodynamic profiles (blood pressure and pulse). In conclusion, our results demonstrate that both Adalat and Nifecard are bioequivalent and produced similar pharmacological effects.

A bioequivalence study of two dipyridamole products.

Bioequivalence of Antiplate 75 mg was assessed versus Persantine 75 mg in a two-way crossover study. At the 5% confidence level, no significant difference was found between the area under the plasma concentration-time curves of the two products. The Cmax were comparable for both products. Quality control data including assay, content uniformity, disintegration and dissolution indicated that both products passed the pharmacopoeial requirements, USP XXI and BP 1980, Addendum 1983. It is concluded that Antiplate-75 is bioequivalent to Persantine.