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Circadian rhythms have been documented throughout the plant and animal kingdom at every level of eukariotic organization. Circadian rhythms are endogenous in nature, driven by oscillators or clocks, and persist under free-running (e.g. constant darkness) conditions. The genes expressing the biological clock have been identified in various species. The important feature of endogeneous biological rhythms is their anticipatory character. Rhythmicity inherent to all living systems, allows them to adapt more easily and to better survive under changing environmental conditions during the 24 hours of a day as well as during changing seasons. Having this in mind it is easy to conceive that not only must the right amount of the right substance be at the right place, but also this must occur at the right time. Also in man nearly all functions of the body including those influencing pharmacokinetic parameters such as drug absorption and distribution, drug metabolism and renal elimination display significant daily variations. Also the onset and symptoms of diseases such as coronary infarction, angina pectoris, stroke, ventricular tachycardia are circadian phase dependent. Myocardial infarction and angina attacks as well as silent ischemias (ST-segment depression) in stable angina pectoris have an early morning peak between 8-12 h. In contrast, ECG abnormalities and angina attacks in variant angina mainly occur at night. Blood pressure and heart rate in normotensives and essential (primary) hypertensive patients display highest values during daytime followed by a nightly drop and an early morning rise. In about 70% of forms of secondary hypertension (e.g. renal disease, hyperthyroidisms, hormonal diseases, gestational hypertension), however, this rhythmic pattern is abolished or even reversed exhibiting nightly peaks in blood pressure. This form of hypertension is accompanied by increased end organ damages. Thus, different subtypes of a disease (angina pectoris, hypertension) can display different circadian patterns in symptoms. These observations are a challenge for basic and clinical research to get a better understanding on the underlying mechanisms of regulation. Moreover, they call for a circadian time-specified drug treatment. From above it is evident that pharmacokinetics may also not be constant within a day. Chronopharmacokinetics have been shown for several cardiovascular active drugs (propranolol, nifedipine, verapamil, enalapril, isosorbide-5-mononitrate, digoxin, etc.). Far more drugs were shown to display significant daily variations in their effects (chronopharmacodynamics, chronotoxicology) even after chronic application or constant infusion. In conclusion, there is clear evidence that the dose/concentration-response relationship of drugs can be significantly dependent on the time of day. Thus, circadian time has to be taken into account as an important variable influencing a drug's pharmacokinetics and/or its effects or side effects.
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PMID:Chronopharmacology and its impact on antihypertensive treatment. 1073 10

Nearly all functions of the body, including those influencing pharmacokinetic parameters, such as drug absorption and distribution, drug metabolism, and renal elimination display significant daily variations. Also, the onset and symptoms of diseases such as asthma attacks, coronary infarction, angina pectoris, stroke, and ventricular tachycardia are circadian-phase dependent. Asthma attacks predominantly occur around 4 o'clock at night. Blood pressure and heart rate in normotensives and essential (primary) hypertensive patients display highest values during daytime followed by a nightly drop and an early morning rise. In about 70% of forms of secondary hypertension, however, this rhythmic pattern is abolished or even reversed exhibiting nightly peaks in blood pressure. Similar findings were obtained in children. This form of hypertension is accompanied by increased end organ damages. These observations call for a circadian time-specified drug treatment. In nocturnal asthma unequal dosing of antiasthmatic drugs with a higher/single evening dose is recommended. In secondary hypertension not only the elevated blood pressure must be reduced but the disturbed blood pressure profile should be normalized, too, possibly best achieved by evening dosing. Pharmacokinetics may also not be constant within 24 hours of a day as shown for cardiovascular active drugs, antiasthmatics, anticancer drugs, psychotropics, analgesics and local anesthetics, antibiotics to mention but a few. Far more drugs were shown to display significant daily variations in their effects even after chronic application or constant infusion. Because circadian rhythms undergo maturation with development, drug therapy in children can/may also be modified by circadian time of drug dosing as shown for anticancer drugs. In conclusion, there is clear evidence that the dose/concentration-response relationship of drugs can be significantly dependent on the time of day. Thus, circadian time has to be taken into account as an important variable influencing a drug's pharmacokinetics and/or its effects or side effects.
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PMID:Relevance for chronopharmacology in practical medicine. 1097 34

Refractory hypertension is common in patients non-compliant with antihypertensive therapy, in obese and stroke patients, and due to drug interactions with nonsteroidal anti-inflammatory drugs or excessive alcohol intake. The evaluation and management of these pitfalls as well as the causes of secondary hypertension are discussed.
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PMID:[Refractory hypertension: evaluation and treatment]. 1197 34

Resistant hypertension, secondary hypertension, and hypertensive crises are uncommon but potentially dangerous forms of hypertension that are associated with an increased risk of complications such as myocardial infarction, heart failure, stroke, and renal failure. Appropriate diagnostic screening and selective drug or surgical management can reduce the risk of these complications dramatically. In compliant patients, resistant hypertension occurs most often in obese patients receiving inadequate diuretic therapy. In patients with clinical clues to the diagnosis, the best current screening test for renovascular hypertension is probably the ACE-inhibitor renal scintiscan. Angioplasty is considerably more successful in younger patients with fibrous dysplasia than in older patients with the atherosclerotic variety. Hypertensive crises are divided into BP urgencies and emergencies. In both settings, the reduction in BP should generally be gradual rather than abrupt, with no intent to acutely normalize the BP.
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PMID:Resistant hypertension, secondary hypertension, and hypertensive crises. 1211 1

Since 1959 the investigations on prevalence of hypertension and studies on the prevention and treatment of this disease have been carried out. The vascular mechanism of hypertension and the depressor effect of Chinese traditional herbs were also studied in Chinese Academy of Medical Sciences. The results revealed that: (1) The prevalence of hypertension in Chinese adults increased from 7.73% in 1979 to 11.26% in 1991, both much higher than that in 1959 (5.11%). The rate of awareness, treatment and control was only 26.3%, 12.1%, and 2.8% respectively. The risk factors of hypertension included overweight and alcohol drinking. High sodium, low potassium, low calcium, and low animal protein diet were also very important risk for elevation of blood pressure. Hypertension was the most important causal risk factor of coronary heart disease and stroke. (2) Hypertension diagnosis and staging criteria were established in 1959. Secondary hypertension was found to constitute 1.1% among community hypertensive patients. The new concept of aortitis was formed and found to be the most common cause of renal vascular hypertension. Patient education together with low dose compounds of antihypertensive drugs was implicated widely. Randomized clinical trials Syst-China, Post-stroke Antihypertensive Treatment Study, Chinese Acute Stroke Trial, and Chinese Cardiac Study 1 demonstrated benefits of treatment for hypertensive, stroke or acute myocardial infarction affordable by Chinese population at large. (3) A series of functional changes and abnormalities with evident hereditary characteristics were found in the processes of cellular Ca2+ transportation, utilization, metabolism and their modulation of the vascular smooth muscle in SHR, and SHRsp, which seem to be the principal cause of the increase in peripheral vascular resistance in hypertension. (4) Alkaloid of Rauwolfia verticilata and Ligustrazine had marked depressor effect. Flavones of Radix Pueraricae could reduce the cardiac and cerebral ischemic damage and symptoms in hypertensive patients.
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PMID:[A forty-year study on hypertension]. 1290 63

The cardiovascular system is highly organised in time; blood pressure (BP), heart rate (HR), peripheral resistance, pressure and the release/activity of vasodilating hormones all display pronounced circadian variations. Pathophysiological events within the cardiovascular system are also not random, as shown for instance by sudden cardiac death (SCD), stroke, ventricular arrhythmias (VA), arterial embolism, and symptoms of coronary heart disease (CHD) such as myocardial infarction (MI) and ischemia, angina attacks (AA) in stable angina (stA) or variant angina (varA) or silent ischemia. In hypertensive patients various anti-hypertensive drugs were investigated in crossover studies (morning vs. evening dosing); however consistent data were only obtained for angiotensin-converting enzyme (ACE) inhibitors and calcium channel blockers. Whereas in dippers ACE inhibitors had a super-dipping effect when dosed at night, no consistent difference in BP lowering effect on the 24-hr BP profile was found with calcium channel blockers after morning and evening dosing. In non-dippers the calcium channel blockers isradipine and amlodipine consistently transformed non-dippers into dippers, after evening dosing. Diuretics are also able to normalize a non-dipping behaviour. Moreover, a circadian phase-dependency in pharmacokinetics has been demonstrated for various cardiovascular active drugs such as beta-blockers, calcium channel blockers, oral nitrates and ACE inhibitors, modified by the pharmaceutical formulation. There is evidence that in hypertensive dippers anti-hypertensive drugs should be given in the early morning, whereas in non-dippers it may be necessary to add an evening dose or even to use a single evening dose in order to not only reduce high BP but also to normalize a disturbed non-dipping 24 hr BP profile. In CHD, calcium channel blockers-mainly short acting and non-retarded preparations-seem to be less effective than beta-adrenoceptor antagonists in reducing ischemic events during the night and early morning. However, the role of formulation and/or subclasses of the calcium channel blockers remains to be elucidated. In order to get more insight into the circadian regulation of the cardiovascular system animal models of primary and secondary hypertension have been studied in various strains of normotensive and hypertensive rats and mice. At least in rodents there is ample evidence that the 24-hr rhythms in BP and HR are under the control of biological clock(s) as they persist under constant darkness (i.e. in free-run conditions) with a period deviating from 24 hr; these rhythms are abolished by lesioning of the "master clock" located in the suprachiasmatic nuclei (SCN). In conclusion, chronobiological and chronopharmacological studies are important experimental and clinical approaches to get a better insight into the physiological and pathophysiological regulation of the cardiovascular system including their rhythmic organisation. Circadian time-dependent clinical studies also have implications for drug therapy in hypertension and CHD.
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PMID:The importance of circadian rhythms on drug response in hypertension and coronary heart disease--from mice and man. 1648 Jul 70

The global epidemic of childhood and adolescent obesity in developing and developed countries has become a major public health concern. Given the relation between obesity and hypertension as documented in several landmark studies, it is no surprise that as the prevalence of obesity has increased in the pediatric population, the rates of hypertension have also increased substantially. Hypertension is one of the most important risk factors for cardiovascular diseases and stroke; therefore, evaluation and initiation of appropriate treatment are extremely important in the pediatric population. Evaluation for secondary causes of hypertension, including renovascular, renoparenchymal, and endocrine disease is the approach most commonly used in healthcare settings, with the goal to detect abnormalities that already have or might, if left unrecognized, affect the physical health of the child in the future. Children and adolescents are commonly evaluated for organic disease even in situations in which secondary hypertension is unlikely and overweight or obesity is most likely the primary factor contributing to hypertension. Psychological and psychosocial factors, which may play an important role in the etiology of obesity and related blood pressure elevation, are often addressed inadequately or completely ignored, potentially reducing long-term therapy success and increasing the incidence of avoidable complications. It is proposed that a comprehensive evaluation by a behavioral health provider will improve outcomes and potentially reduce long-term morbidity and hypertension-related end organ disease. A framework for mental health evaluation is provided.
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PMID:Obesity, hypertension, and mental health evaluation in adolescents: a comprehensive approach. 1854 Feb 79

Hypertensive disease is reported to be more severe in black patients than in white patients, but most available data concern African-Americans. We studied blood pressure history and levels, the prevalence of associated risk factors, renal and cardiovascular complications, and secondary forms of hypertension in patients born in sub-Saharan Africa and managed in France, by comparison with up to five control patients born in Europe and matched for age and sex. Compared to European hypertensive women, African hypertensive women had a higher body-mass index (28.8 vs 26.3 kg/m2, p<0.001) and were more often diabetic (12 vs 5%, p<0.001). Hypertensive men and women born in sub-Saharan Africa had higher systolic blood pressure (152 vs 148 mmHg, p<0.001), were more likely to have a history of stroke (11.7 vs 6.7%, p<0.001) and were less likely to have a history of smoking or hyperlipidemia than European controls. Sub-Saharan Africans were more frequently given antihypertensive medication than their paired controls (84 vs 74%, p<0.001), and their antihypertensive regimens were more likely to include a diuretic (54 vs 46%, p=0.001) or a calcium channel antagonist (58 vs 49%, p=0.001). Compared to European controls, patients born in sub-Saharan Africa had more frequent proteinuria (test strip positivity : 32 vs 18%, p<0.001), irrespective of blood pressure and diabetes. The overall prevalence of secondary hypertension was similar in the two populations. However, patients born in sub-Saharan Africa were more likely than their European controls to have primary hyperaldosteronism (12 vs 7%, p=0.001) and less likely to have renovascular disease (1 vs 5%, p=0.001). Thus, the higher prevalence of cardiovascular and renal complications at referral among patients born in sub-Saharan Africa relative to age- and sex-matched European patients does not seem to be explained solely by observed differences in blood pressure or associated risk factors. The difference in the distribution of secondary hypertension warrants further study.
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PMID:[Hypertensive disease in subjects born in sub-Saharan Africa or in Europe referred to a hypertension unit: a cross-sectional study]. 1866 71

Primary aldosteronism is the most common cause of secondary hypertension, accounting for about 10% of all forms of high blood pressure. Life-time pharmacological therapy is the treatment of choice for primary aldosteronism due to idiopathic adrenal hyperplasia (IHA), while adrenalectomy is effective in curing most patients with an aldosterone producing adenoma (APA). Far from being a benign form of hypertension, primary aldosteronism is characterized by the development of cardiovascular renal and metabolic complications, including left ventricular hypertrophy, myocardial infarction, atrial fibrillation and stroke, microalbuminuria, renal cysts as well as metabolic syndrome, glucose impairment and diabetes mellitus. We review recent clinical experience with the above mentioned complications and long-term outcomes of blood pressure normalization and cardiac, renal and gluco-metabolic complications in patients with primary aldosteronism, after medical treatment with mineralocorticoid receptor antagonists and surgical treatment. We conclude that removal of adrenal adenoma results in normalization of the renin-angiotensin-aldosterone system (RAAS) and of kalaemia and improvement of blood pressure levels in all patients. Complete resolution of hypertension is achieved in nearly half of treated patients. Moreover, unilateral adrenalectomy is the best treatment to have the regression of cardiovascular, renal and metabolic complications in patients with APA. On the other hand, targeted medical treatment with aldosterone antagonists improves blood pressure control and appears able to prevent the progression of cardiac and metabolic complications in patients with IHA.
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PMID:Management of primary aldosteronism: its complications and their outcomes after treatment. 1935 5

Hypertension in the elderly is associated with increased occurrence rates of sodium sensitivity, isolated systolic hypertension, and 'white coat effect'. Arterial stiffness and endothelial dysfunction also increase with age. These factors should be considered in selecting antihypertensive therapy. The prime objective of this therapy is to prevent stroke. The findings of controlled trials show that there should be no cut-off age for treatment. A holistic program for controlling cardiovascular risks should be fully discussed with the patient, including evaluation to exclude underlying causes of secondary hypertension, and implementation of lifestyle measures. The choice of antihypertensive drug therapy is influenced by concomitant disease and previous medication history, but will typically include a thiazide diuretic as the first-line agent; to this will be added an angiotensin inhibitor and/or a calcium channel blocker. Beta blockers are not generally recommended, in part because they do not combat the effects of increased arterial stiffness. The hypertension-hypotension syndrome requires case-specific management. Drug-resistant hypertension is important to differentiate from faulty compliance with medication. Patients resistant to third-line drug therapy may benefit from treatment with extended-release isosorbide mononitrate. A trial of spironolactone may also be worthwhile.
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PMID:Management of hypertension in the elderly patient. 1985 13


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