Analysis of Factors Related to Variation in Dissolution Profiles Estimated from Continuously Conducted Dissolution Tests of Generic Products.

The development of generic pharmaceuticals involves a bioequivalence study to ensure the therapeutic equivalence of the test formulation to the original innovative product. The formulation characteristics of generic products are expected to be maintained in the long term after approval. This study analyzed the factors contributing to the changes in the dissolution profiles of approved products during their life cycles. Cumulative data on the dissolution similarity of 1675 products of 127 ingredients tested by official laboratories in Japan were assessed according to Japanese bioequivalence guidelines with slight modifications. The products showing dissimilarities in dissolution profiles were analyzed for reporting year, therapeutic category, co-development, physical properties of the active pharmaceutical ingredient (API), and suspected reasons for dissolution change. The increase in the number of dissimilar products is related to the co-development of generic products. Although the solubility of the API was not associated with the dissolution change in the analysis of the total dissolution data, control of the API particle size is suggested to be important for drugs with poorly soluble APIs. Additionally, a risk factor for dissolution changes in the test solutions at a certain pH was the presence of acidic or basic residues. These results indicate the importance of proper development through a thorough evaluation of the formulation and process factors affecting the dissolution properties throughout the product lifecycle.

Blood Pressure Phenotypes Defined by Ambulatory Blood Pressure Monitoring and Carotid Artery Changes in Community-Dwelling Older Japanese Adults: The Ohasama Study.

White coat hypertension is defined as elevated blood pressure in the office, but a normal blood pressure out-of-office, whereas masked hypertension is defined as elevated blood pressure in the office, but normal out-of-office blood pressure. The objective was to investigate the associations between these blood pressure phenotypes and carotid artery changes. Conventional blood pressure, ambulatory blood pressure, and carotid ultrasonography were evaluated in 851 Ohasama residents (31.8% men; mean age 66.3 years). The blood pressure phenotypes were defined by the ordinary thresholds (140/90 mmHg for conventional blood pressure, 135/85 mmHg for daytime blood pressure) and then by the 2017 American College of Cardiology/American Heart Association (ACC/AHA) thresholds for hypertension (130/80 mmHg for both conventional and daytime blood pressure), irrespective of antihypertensive medication treatment status. Blood pressure phenotypes were linearly associated with the mean intima-media thickness of the carotid artery in ascending order for sustained normal blood pressure, white coat hypertension, masked hypertension, and sustained hypertension according to the ordinary thresholds and the 2017 ACC/AHA thresholds (both linear trends P < 0.0001) after adjustments for possible confounding factors. The odds ratios for the presence of carotid plaques showed similar linear trends with the blood pressure phenotypes according to the 2017 ACC/AHA thresholds (linear trend P < 0.0191). In conclusion, there was a close relationship between blood pressure phenotypes and carotid artery changes, suggesting that blood pressure phenotypes as defined by ambulatory blood pressure are potentially useful for risk stratification of carotid artery changes in the Japanese general population.

Association of microalbuminuria with brachial-ankle pulse wave velocity: the Ohasama study.

BACKGROUND: Microalbuminuria is recognized as a marker of generalized vascular dysfunction. However, the associations between microalbuminuria and pulse wave velocity (PWV), carotid intima-media thickness (IMT), and ambulatory blood pressure (ABP), respectively, have not been investigated. METHODS: Brachial-ankle PWV (baPWV), IMT, and ABP were determined in 328 individuals (mean age, 65.7 +/- 6.4 years) from the general population of Ohasama, a rural Japanese community. The participants were assigned to groups with microalbuminuria and with normoalbuminuria, and their characteristics were compared. We also examined the association between microalbuminuria and baPWV, IMT, and ABP, respectively, using multivariate analyses. RESULTS: Seventy-nine participants (24%) with microalbuminuria had significantly higher baPWV (P < 0.001) and 24-h systolic BP (SBP) (P = 0.006) than those with normoalbuminuria, although 24-h pulse pressure and mean IMT did not significantly differ between the groups. Multiple logistic regression analyses showed that baPWV, but not 24-h ABP, was independently associated with microalbuminuria (P = 0.002) when adjusted for various confounding factors. After further adjustment for 24-h SBP, the association between baPWV and microalbuminuria remained significant (P = 0.012). The trend was significant even when daytime or nighttime SBP was used instead of 24-hour SBP in this model. CONCLUSIONS: Microalbuminuria appears to be associated with baPWV more closely than with IMT and ABP, and its association with baPWV is independent of ABP and other cardiovascular risk factors.

Plasma fibrinogen, ambulatory blood pressure, and silent cerebrovascular lesions: the Ohasama study.

OBJECTIVE: Twenty-four-hour ambulatory blood pressure (24-hour ABP) values are considered a powerful predictor of stroke. Silent cerebrovascular lesions are associated with an increased risk of stroke. Because fibrinogen is a major determinant of plasma viscosity, an elevated fibrinogen level might also be associated with stroke risk. We evaluated the association of 24-hour ABP and plasma fibrinogen levels with the risk of silent cerebrovascular lesions (white matter hyperintensity and lacunar infarct) detected by MRI. METHODS AND RESULTS: The study cohort comprised 958 individuals from the general population of Ohasama, a rural Japanese community. Multiple logistic regression analysis adjusted for age, sex, smoking and drinking status, use of antihypertensive medication, body mass index, 24-hour ABP, and a history of hypercholesterolemia, diabetes mellitus, and atrial fibrillation demonstrated that each 1-SD increase in fibrinogen level was associated with a significantly increased risk of silent cerebrovascular lesions (odds ratio, 1.26; P=0.001). The 24-hour ABP was also significantly and independently associated with the risk of silent cerebrovascular lesions. Even when 24-hour ABP values were within normal range (<135/80 mm Hg), elevated fibrinogen levels were associated with an increased risk of silent cerebrovascular lesions. Fibrinogen and 24-hour BP had additive effects on silent cerebrovascular lesions. CONCLUSION: The 24-hour ABP and plasma fibrinogen levels were closely and independently associated with the risk of silent cerebrovascular lesions including white matter hyperintensity and lacunar infarct.

Ambulatory blood pressure, blood pressure variability and the prevalence of carotid artery alteration: the Ohasama study.

OBJECTIVES: To investigate the association between ambulatory blood pressure (BP) variables (level, short-term variability, circadian variation and morning pressor surge) and carotid artery alteration in a general population. METHODS: We measured ambulatory BP every 30 min in 775 participants (mean age 66.2 +/- 6.2 years, 68.8% women) from the Japanese general population. Short-term BP variability during the daytime and night-time were estimated as within-subject standard deviation of daytime and night-time BP, respectively. Circadian BP variation was calculated as the percentage decline in nocturnal BP. Morning pressor surge was defined as morning BP minus pre-waking BP. The extent of carotid artery alteration was evaluated as the average of common carotid intima-media thickness (IMT) and the presence of focal carotid plaque. RESULTS: Daytime and night-time BP values were more closely associated with carotid artery alteration than casual BP. With mutual adjustment for daytime and night-time BP, the latter (P < 0.0001) was more closely associated with IMT, which represents diffuse arterial thickening and arteriosclerosis, than daytime BP (P = 0.2). Night-time systolic BP variability was positively associated with carotid plaque (focal atherosclerotic lesions) independently of possible confounding factors, including night-time systolic BP (P = 0.01). A diminished nocturnal decline in systolic BP was associated with a greater IMT after adjustment for confounding factors (P = 0.03). A morning pressor surge was not associated with carotid artery alteration. CONCLUSION: Ambulatory BP levels and BP variability were closely associated with carotid artery alteration, suggesting that these parameters are independent risk factors or predictors of carotid artery alteration.

Detection of carotid atherosclerosis in individuals with masked hypertension and white-coat hypertension by self-measured blood pressure at home: the Ohasama study.

OBJECTIVE: To investigate carotid atherosclerosis in individuals with masked hypertension (MHT) and white-coat hypertension (WCHT) in a general population. METHODS: Self-measurement of blood pressure at home (HBP) and casual blood pressure (CBP) measurements were recorded in 812 individuals aged at least 55 years (mean 66.4 years) from the general Japanese population. The intima-media thickness (IMT) of the near and far wall of both common carotid arteries was measured and averaged. The relationships between carotid atherosclerosis (IMT and plaque) and the four blood pressure groups (sustained normal blood pressure: HBP < 135/85 mmHg, CBP < 140/90 mmHg; WCHT: HBP < 135/85 mmHg, CBP >or= 140/90 mmHg; MHT: HBP >or= 135/85 mmHg, CBP < 140/90 mmHg; sustained hypertension: HBP >or= 135/85 mmHg, CBP >or= 140/90 mmHg) were examined using multivariate analysis adjusted for possible confounding factors. RESULTS: Adjusted IMT in individuals with sustained hypertension [0.77 mm; 95% confidence interval (CI) 0.75 to 0.79 mm] and MHT (0.77 mm; 95% CI 0.73 to 0.80 mm) was significantly greater than in those with sustained normal blood pressure (0.71 mm; 95% CI 0.69 to 0.72 mm) and WCHT (0.72 mm; 95% CI 0.71 to 0.74 mm) (P < 0.0001). The odds ratios for the presence of plaques in all four groups were similar to the trends in IMT. CONCLUSIONS: Our findings imply that CBP measurements alone are insufficient to distinguish individuals at high risk of carotid atherosclerosis from those at low risk. However, these individuals do have distinct HBP measurements, suggesting that HBP measurement could become a valuable tool for predicting carotid atherosclerosis.

Serum magnesium, ambulatory blood pressure, and carotid artery alteration: the Ohasama study.

BACKGROUND: To investigate the associations of 24-h ambulatory blood pressure (ABP) and serum magnesium level (sMg) with risk of carotid artery alteration in a general population. METHODS: sMg and ABP, monitored every 30 min, were measured in 728 subjects (mean age, 67 years) from the Japanese general population. The extent of carotid artery alteration was evaluated according to mean common carotid intima-media thickness (IMT) and the presence of focal carotid plaque. To determine the association of sMg and carotid artery alteration, analysis of covariance (ANCOVA) (for adjusted mean IMT) or multiple logistic regression analysis (for odds ratio (OR) for the presence of carotid plaques) was used. RESULTS: Lower sMg was significantly associated with mean IMT (P = 0.004) and risk of ≥2 carotid plaques (P = 0.03) after adjusting for possible confounding factors, including 24-h ABP (systolic), creatinine clearance (Ccr) (estimated using the Cockcroft-Gault equation), and serum minerals (sodium, potassium, calcium, and inorganic phosphorus). Even when 24-h ABP values were within normal range (<130/80 mm Hg), lower sMg levels (<2.2 mg/dl) were significantly associated with mean IMT (P = 0.007) and risk of ≥2 carotid plaques (OR, 2.14; 95% confidence interval, 1.18-3.85; P = 0.01). CONCLUSIONS: Both 24-h ABP and lower sMg were closely and independently associated with risk of carotid artery alteration. Further investigations are needed to examine the relationship between sMg levels and the incidence of cardiovascular disease.