Burkhard Weisser

The use of self-measured blood pressure determinations in assessing dynamics of drug compliance in a study with amlodipine once a day, morning versus evening.

Objective: To test whether the time of administration influences the therapeutic response to a calcium antagonist taken once a day. Also, the dynamics of drug compliance and its impact on blood pressure control were investigated Design: Twenty outpatients with mild-to-moderate hypertension were included in a randomized, placebo-controlled open study. In a crossover design, all of the patients received 5 mg amlodipine, either in the morning or in the evening, during two consecutive 4-week treatment periods Methods: Blood pressure was taken by casual measurement, ambulatory 24-h monitoring (SpaceLabs 90202) and self-measurement at home, performed with a semi-automatic oscillometric device during the whole study period. Compliance was assessed using the Medication-Event-Monitoring System (MEMS) Results: Neither casual nor ambulatory day- or night-time readings detected a significant difference between morning and evening administration. However, self-measurement documented significantly greater blood pressure reductions for morning than for evening administration. The MEMS showed different compliance on the days of ambulatory monitoring (100% with both drug regimens) compared with the whole treatment period. The number of days with missed medication was thus significantly higher for the evening dosing regimen. The difference in self-measured blood pressure between the two regimens was lost if the days with missed medication were removed from the statistical analysis Conclusions: Time of once-a-day amlodipine administration does not influence its efficacy for 24-h blood pressure control. Furthermore, the use of self-measurement and the MEMS may provide useful additional information on the pharmacodynamic impact of different dosing patterns in hypertensive patients

Oxidation of low density lipoprotein enhances its potential to increase intracellular free calcium concentration in vascular smooth muscle cells.

There have been suggestions that oxidation of low density lipoproteins (LDL) might increase their atherogenic potential. Because changes in intracellular free calcium concentration [Ca2+]i have been linked to atherogenesis, we compared the influence of oxidized LDL (Ox-LDL) and native LDL (N-LDL) on [Ca2+]i in vascular smooth muscle cells cultured from rat aortas. For determination of [Ca2+]i, fura-2 fluorescence was used. LDL was isolated by ultracentrifugation from the sera of human donors (n = 17). In N-LDL, oxidation was prevented by addition of antioxidants, whereas Ox-LDL was obtained by auto-oxidation. The extent of oxidation was assessed by measurement of thiobarbituric acid-reactive substances. Addition of Ox-LDL (20 micrograms protein/ml) to the vascular smooth muscle cells induced a mean increase of 129 +/- 13% in [Ca2+]i compared with 81 +/- 7% with N-LDL (p less than 0.01). Dose-response curves from 1 to 20 micrograms/ml (six experiments) confirmed this difference within the entire dose range. These results indicate that a more pronounced increase in [Ca2+]i induced by Ox-LDL might be one of the cellular mechanisms responsible for the higher atherogenic potential of Ox-LDL compared with N-LDL, as [Ca2+]i is an important second-messenger system involved in many atherogenic processes such as hypertrophy, cell migration, and cell damage.

A Comparative Review of the Adverse Effects of Treatments for Hyperlipidaemia

SummaryVarious lipid-lowering drugs have been shown to reduce serum cholesterol and serum triglycerides effectively. In view of trials indicating that lipid-lowering drugs may reduce cardiac morbidity and mortality but not the overall mortality in the study group, increased attention must be focused on potential harmful side effects during treatment with these agents.The adverse effects of many of the principal drugs in this category are discussed. Gastrointestinal symptoms, usually self-limited and reversible, are the most common side effects. Potential harmful adverse effects include drug interactions (cholestyramine), myopathy and hepatic injury (HMG-CoA reductase inhibitors), and increased gallstone formation and ventricular arrhythmias (clofibrate).Not all lipid-lowering drugs have been studied adequately on a long term basis, so that medications given for an indefinite period must be reevaluated frequently. However, there are several agents that lower serum lipid levels effectively and that have been used for more than 20 years without serious side effects.

Lysolecithin actions on vascular smooth muscle cells.

Oxidation of low density lipoprotein increases its atherogenic potential. During oxidation there is an extensive conversion of lecithin to lysolecithin. In rat aortic smooth muscle cells, 2-25 micrograms/ml lysolecithin elevated cytosolic calcium concentration up to 560%. Lysolecithin (10-20 micrograms/ml) increased [3H]thymidine incorporation from 15 cpm/mg cell protein (controls) up to 189 cpm/mg cell protein. Lysolecithin (10 micrograms/ml) potentiated the PDGF-induced (50 ng/ml) [3H]thymidine incorporation up to 6.3 times. The results indicate that lysolecithin could induce mechanisms, by which oxidized low density lipoproteins could promote cell growth and thus contribute to atherosclerosis.

Oxidized Low-density Lipoproteins in Atherogenesis: Possible Mechanisms of Action

The increased atherogenic potential of oxidized low-density lipoprotein (ox-LDL) is well documented. In the present study, we investigated possible mechanisms of action of the difference to native LDL. In vitro oxidation of LDL was determined by measurement of thiobarbituric acid-reacting substances and absorption at 234 nm. Copper (5 mumol/L) induced significant (p less than 0.01) oxidation in vitro. Furthermore, LDL isolated from atherosclerotic patients was slightly but significantly (p less than 0.05) more oxidized than LDL from normal controls (2.81 +/- 0.08 vs. 3.21 +/- 0.16 nmol of TBARS/mg of LDL protein). Ox-LDL caused significantly (p less than 0.01) more pronounced contractions of rat aortic rings in vitro compared to nonoxidized LDL expressed as a percentage of maximal contractions induced by 40 mmol/L of KCl (29.0 +/- 5.4% vs. 61.1 +/- 7.2%). Lysolecithin, which is a principal component of ox-LDL formed during oxidation, induced a dose-dependent increase in intracellular free calcium in vascular smooth muscle cells cultured from rat aorta. Doses from 2-25 micrograms/ml were tested and caused a maximum increase of more than 500% (25 micrograms/ml). In conclusion, this study provides further evidence for a higher biological activity of ox-LDL. Lysolecithin might be one of the active components formed during oxidation of LDL.

Ambulatory 24-hour blood pressure versus self-measured blood pressure in pharmacologic trials.

In recent years, indirect ambulatory 24-h blood pressure monitoring and self-measurement at home have gained increasing importance in pharmacologic studies. Both methods have important advantages over conventional casual blood pressure determinations in the clinic. The better reproducibility of blood pressure recordings by either ambulatory monitoring or home readings suggests that both techniques are superior to office readings for evaluating the effect of antihypertensive therapy. The multiple readings obtained during ambulatory 24-h monitoring or by self-measurement at home reduce the variability of blood pressure estimates and substantially decrease the number of patients needed to detect clinically relevant blood pressure differences. Furthermore, dose-response relationships of new and established antihypertensive drugs are improved, as the random effect of blood pressure measurements falls below the expected treatment effect. Although there is some overlap between the information obtained with home and ambulatory monitoring, there are also important differences. Ambulatory monitoring provides information about the diurnal profile of blood pressure and has great advantages for trials investigating the time course of a particular drug. Self-measurement can provide repeated measurements in the same situation over prolonged periods of time, and therefore is ideally suited for monitoring changes in blood pressure induced by treatment or progression of the disease. In pharmacologic studies both techniques are thus complementary.