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Die Atherosklerose wird heute zunehmend als inflammatorische Erkrankung betrachtet, bei der die Inflammation sowohl in der Anfangszeit bis hin zu möglichen Folgekomplikationen als eine Hauptursache gilt. Die Migration CD4- (cluster of differentiation 4-) positiver Lymphozyten in die Gefäßwand mit anschließender Aktivierung anderer Gefäßzellen stellt dabei einen wichtigen Schritt in der frühen Atherogenese dar. In verschiedenen experimentellen Untersuchungen konnte gezeigt werden, dass eine Verringerung der Rekrutierung CD4-positiver Lymphozyten die Entwicklung atherosklerotischer Läsionen und Plaques eindämmt. Im Rahmen der vorliegenden Arbeit wurde die Wirkung des Calciumantagonisten Amlodipin auf die SDF-1α (stromal cell derived factor-1) induzierte Migration humaner CD4-positiver Lymphozyten untersucht. Amlodipin ist ein Calciumkanalblocker vom Nifedipin-Typ und hemmt den Einstrom von Calcium-Ionen durch L-Typ-Calciumkanäle, die hauptsächlich in vaskulären glatten Muskelzellen vorkommen, was zu einer verringerten Kontraktilität dieser Muskelzellen und damit zu einer Vasodilatation führt. Es findet daher breite Anwendung in der Behandlung der Hypertonie. Neben der blutdrucksenkenden Funktion wurden aber auch eine entzündungshemmende Wirkung bei der Atherosklerose und eine Verringerung der Größe atherosklerotischer Läsionen durch die Gabe von Amlodipin nachgewiesen. Der Einfluss von Amlodipin auf das Migrationsverhalten CD4-positiver Lymphozyten wurde durch Migrationsversuche in einer so genannten Boyden-Kammer untersucht. Hierbei konnte nachgewiesen werden, dass Amlodipin die SDF-1α induzierte Migration der Lymphozyten hemmt. Mit steigender Zugabe von Amlodipin nahm das Migrationsverhalten der Lymphozyten ab und erreichte seinen Tiefpunkt bei einer Amlodipinkonzentration von 10 µM. Die Vitalität der Lymphozyten blieb bei den Versuchen unbeeinflusst. Mit Hilfe eines PI3- (Phosphatidylinositol-3-) Kinase-Assays konnte gezeigt werden, dass Amlodipin die PI3-Kinase in humanen CD4-positiven Lymphozyten inhibiert. Dafür wurden humane CD4-positive Lymphozyten mit steigenden Amlodipinkonzentrationen und mit dem chemotaktisch wirkenden Zytokin SDF-1α versetzt. SDF-1α steuert die Zellmigration und spielt unter anderem eine Schlüsselrolle bei der Progression von Entzündungsprozessen im Körper. Es konnte nachgewiesen werden, dass die PI3-Kinase-Aktivität mit ansteigender Amlodipinkonzentration stetig abnahm und ihr Minimum bei einer Amlodipinkonzentration von 5 bis 10 µM hatte. Mittels Western Blot Versuchen wurde die konzentrationsabhängige, inhibierende Wirkung von Amlodipin auf die SDF-1α induzierte Aktivierung von p-ERK (phospho-extracellular signal-regulated Kinase), p-AKT (phospho-aktivierte Proteinkinase B), p-MLC (phospho-Myosin light-chain) und p-SRC (sarcoma/proto-oncogenic tyrosine Kinase) in humanen CD4-positiven Lymphozyten nachgewiesen. Es wurde festgestellt, dass die Aktivierung mit steigender Amlodipinkonzentration kontinuierlich abnahm und ihren maximalen Effekt bei 10 µM Amlodipin erreicht hatte. Bei einer Konzentration von 10 µM kam es also zu einer signifikanten Inhibierung der Phosphorylierung von ERK, AKT, MLC bzw. SRC gegenüber SDF-1α stimulierten CD4-positiven Lymphozyten. Bei nicht mit SDF-1α stimulierten CD4-positiven Lymphozyten, die zusätzlich mit 10 µM Amlodipin versetzt wurden, zeigte sich kein Effekt auf die basale Aktivierung. Im Rahmen dieser Dissertation konnte der hemmende Effekt von Amlodipin auf die SDF-1α induzierte Migration humaner CD4-positiver Lymphozyten in vitro nachgewiesen werden. Dieser Effekt sollte nun auch in vivo in Tiermodellen, wie auch klinisch in weiteren Studien untersucht werden.

The clinical relevance of the drug-drug interaction simvastatin and amlodipine is appraised controversially by german simvastatin Summary of Product Characteristics (SPCs) and different drug interaction databases. Results of clinical trials have shown that simultaneous administration of simvastatin and amlodipine can increase simvastatin bioavailability. However, it is unclear whether this increase is associated with a higher risk for adverse drug events. So far there is no evidence that the combination might increase cases of myopathy or rhabdomyolysis. Therefore combined treatment with amlodipine and up to 40 mg simvastatin daily seems clinically justifiable if the patient does not report adverse events. If myopathy or muscle weakness occur, simvastatin dose should be reduced to 20 mg daily or the patient should be switched to pravastatin, fluvastatin or rosuvastatin. The highest approved dose of simvastatin (80 mg) is generally not recommended in new patients because of increased risk of muscle damage.

A 67-year old patient underwent a kidney biopsy because of newly diagnosed hypertension, haemolytic anemia with fragmentocytes and acute kidney failure requiring dialysis therapy. The biopsy showed thrombotic microangiopathy. Since last winter Raynaud's phenomenon and changes of hands and lips were recognised.Initial immunological tests revealed anti-nuclear antibodies (ANA) but neither anti-centromere nor anti-Scl70 antibodies. The positive analysis of anti-RNA polymerase III antibodies confirmed the clinical suspicion of scleroderma renal crisis in the setting of first diagnosis of systemic sclerosis.After diagnosis therapy with lisinopril, candesartan and amlodipin was established. Four months after discharge dialysis dependency persisted.Scleroderma renal crisis is an important differential diagnosis in the setting of acute kidney failure. Medical history, clinical examination and immunological test confirm the diagnosis. The mainstay of therapy is aggressive blood pressure control with ACE-inhibitors (or angiotensin receptor blocking agents).

We report on a 41-year-old patient admitted for refractory arterial hypertension that had developed after a curative chemotherapy regimen due to seminoma stadium IIb four years ago. After exclusion of secondary forms of arterial hypertension (actually unsuccessfully treated with 5 different antihypertensive drugs) we performed a controlled medication intake-trial in our outpatient clinic. 90 minutes after taking the pills the patient complained of dizziness and perspiration while hypotension and bradycardia were measured simultaneously. Due to the difficult psychosocial situation (conflicts with the insurance and in the family, financial problems) and the suspected narcisstic personality disorder the issue of the proven malcompliance was not openly discussed in order to preserve the patient-doctor alliance. The antihypertensive regimen was then reduced to a double regimen. In the second part of the article the most common reasons for refractory arterial hypertension, especially the problem of treatment malcompliance, are summarized.

Raynaud's syndrome has a prevalence of 3-5% in the general population. Despite its high frequency, the majority of available therapies have not been validated in randomized controlled trials. Effective therapies with a high level of evidence include the calcium channel blocker nifedipine. As analyzed by meta-analyses, nifedipine showed improvement of the peripheral circulation, as well as reduction of both the intensity and frequency of attacks in patients with primary and secondary Raynaud's syndrome as compared to placebo. Similar results in a metaanalysis were obtained for intravenous infusions of iloprost in patients with secondary Raynaud's phenomenon associated with systemic sclerosis. In addition, intravenous infusions of iloprost improved healing of fingertip ulcers in patients with systemic sclerosis. Therapies with significant effects in single randomized controlled trials include angiotensin II-receptor type 1 antagonists (losartan), the calcium channel blockers felodipine und amlodipine, serotonin-reuptake-inhibitors (fluoxetine) und phosphodiesterase-V-inhibitors (sildenafil, vardenafil). However, the results for these promising substances have to be confirmed in long-term trials with larger patient numbers.

The irbesartan in Diabetic Nephropathy Trial (IDNT) demonstrated that treatment of patients with type 2 diabetes, hypertension and nephropathy with irbesartan resulted in a 20% relative reduction of the composite endpoint of doubling serum creatinine, end-stage renal disease or death as compared with amlodipine and placebo (antihypertensive standard therapy). The objective of this study was to investigate the long-term health economic consequences of this treatment strategy in a Swiss health care setting. This analysis used a Markov model to simulate the progression of nephropathy, life-years and treatment costs over ten years for each of the three treatment options. In additon, sensitivity analyses were performed. Treatment with irbesartan will save CHF 22681/patient as compared with amlodipine and CHF 13847 as compared with standard therapy.

Some of the reported findings of numerous studies on the treatment of hypertension are still giving rise to heated discussions. The result is conflicting recommendations and uncertainty among care-providing physicians. Today, the substances from the group of more recent hypertensive agents (calcium antagonists, ACE-inhibitors and angiotensin 1 receptor blockers) together with the classical agents (diuretics and beta blockers) are recognized as equally justifiable as the five agents of first choice in the treatment of uncomplicated hypertension. If, however, accompanying diseases are present, the choice of primary medication depends on the respective risk (diabetes, etc.) of the individual patient. In many cases, combination treatment should be considered from the very beginning.

This observational study investigated prescription behavior and the efficacy and safety of Amlodipine besylate in hypertensive patients.9,672 hypertensive patients were treated with Amlodipine besylate 5-10 mg/day for 12 weeks. At the end of the observation period, the participating physicians were asked to give their subjective evaluation of the efficacy and safety of treatment with Amlodipine besylate as well as their therapeutic considerations regarding the use of Amlodipine besylate.55.2% of the patients received Amlodipine besylate in combination with other antihypertensive agents. The mean baseline blood pressure was 168.0/96.7 mmHg and the mean blood pressure reduction achieved at the end of the observation period was -28.5/-14.5 mmHg. In 80.3% of the total population, a reduction to diastolic blood pressure values of90 mmHg was achieved. A reduction to systolic blood pressure values of140 mmHg was obtained in 41.6% of the patients. Adverse events were reported by only 1.2% of the patients. For the vast majority of the patients, efficacy (96.6%) and safety (98.9%) were rated "very good" or "good" by their physicians. 24-hour efficacy with once daily dosing was given as the most important argument for using Amlodipine besylate.The observation study confirmsthat Amlodipine besylate is an effective and safe antihypertensive drug both in mono and combination therapy.

The "Irbesartan in Diabetic Nephropathy Trial" (IDNT), demonstrated a reduction in the combined endpoint of doubling of serum creatinine, end-stage renal disease (ESRD) or death compared to control or amlodipine arms in patients with hypertension, type 2 diabetes and overt nephropathy when treated with irbesartan. Aim of this study is to compare long-term consequences in costs and outcomes of IDNT treatment alternatives from the German health care system's perspective.A Markov model simulated progression from overt nephropathy to doubling of serum creatinine, end-stage renal disease, and death in patients with hypertension, type 2 diabetes and overt nephropathy for the three treatment arms. Treatment-specific probabilities were derived from IDNT. German-specific ESRD-related data were retrieved from published sources to reflect local management practices, ESRD outcomes and costs. A time horizon of 10 years was used. Delay in onset of ESRD and mean costs per patient were calculated. Future costs were discounted at 5 % per annum.The cumulative incidence of ESRD after 10 years with irbesartan (36 %) is lower compared to amlodipine (49 %) or control (45 %). Irbesartan leads to cost savings of 14 424 EUR and 8 720 EUR per patient versus amlodipine or control respectively.Treating patients with hypertension, type 2 diabetes and nephropathy using irbesartan lowers the cumulative incidence of ESRD and is cost-saving compared to amlodipine or control.

A 78-year-old woman was admitted to the intensive care unit 9 hours after ingestion of 2 g of isosorbitmononitrate, 430 mg of amlodipine, 250 mg of benazepril and 600 mg of mirtazapin in suicidal intent.Clinical findings and invasive monitoring showed signs of a hyperdynamic hemodynamic cardiovascular failure caused by toxic vasodilatation.Despite of primary detoxication, intravenous volume infusion with calcium gluconate, glucagon and naloxone and administration (norepinephrine up to 2 micro g/kg/min) no hemodynamic stabilization was achieved. Only when the vasopressin-analogue argipressin was given peripheral vasodilatation was overcome and hemodynamic stabilization resulted. 10 hours after discontinuing argipressin and norepinephrine the patient developed a mesenteric ischemia, and she finally died on the third day after admission.In circulatory shock due to toxic vasodilatation the use of vasopressin analogue argipressin can be helpful as an ultima therapeutic measure in catecholamine refractory shock caused by vasodilatation. Attention must be paid to overwhelming vasoconstrictor effects resulting in mesenteric ischemia.

Antihypertensive therapy improves the prognosis of essential hypertension. Therapy reduces mortality and decreases the incidence of myocardial infarction, sudden cardiac death and stroke. Target blood pressure in patients with essential hypertension are levelsor = 140/90 mmHg. In patients with essential hypertension and concomitant diabetes mellitus type 2, blood pressure should be lowered toor = 130/80 mmHg. Diuretics, beta-blockers, calcium antagonists, angiotensin-converting enyzme (ACE) inhibitors, and angiotensin I (AT(1)) antagonists may nowadays be regarded as drugs of first choice in the treatment of essential hypertension. The Joint National Committee in the USA recommends to start treatment with a thiazide diuretic. A Guidelines Committee of European Society of Hypertension-European Society of Cardiology considers the Endgroups of drugs mentioned above to be equally suitable for the initiation and maintenance of antihypertensive therapy. Both groups of experts agree that in the majority of patients with essential hypertension, a combination of two or more drugs is required to reach target blood pressure. Both groups of experts emphasize that the main benefits of antihypertensive therapy are due to decreasing blood pressure per se.

A 61-year-old male patient complained about diffuse upper abdominal pain and a progressive dyspnoe on exertion. Of clinical relevance were signs of congestive heart failure and a distinct kyphoscoliosis.A cardiac catheter examination proved a pulmonary hypertension without cardiac genesis. Both, pulmonary function test and computed tomography of the thorax rule out obstructive bronchial asthma and embolism of the lung. As the sole cause of pulmonary hypertension, kyphoscoliosis was diagnosed. Since the patient refused noninvasive positive pressure ventilation, a medication with calcium entry blocker and ACE blocker was induced, followed by oxygen breathing. This successfully helped to reduce pulmonary resistance (746 vs. 332 dyn*s*cm(-5)).Kyphoscoliosis can create a considerable increase of pulmonary resistance. Medical treatment and oxygen breathing have proven to be an efficient method to lower that significantly.

This double-blind study compared the efficacy and safety of once daily amlodipine (5-10 mg/day) vs twice daily nifedipine (40-80 mg/day) in 244 patients with chronic stable angina pectoris. Efficacy was assessed after 4 and 24 weeks by bicycle exercise test.No statistically significant differences were found between the two treatment groups at the end of treatment with regard to the ergometry parameters determined (maximum ST segment deviation, maximum workload in watts, maximum exercise duration and time to 0.1 mV ST segment depression). Furthermore, the two treatment groups were comparable with regard to the effected reduction in anginal attacks and short acting nitrate consumption. The incidence of adverse events was lower in the amlodipine relative to the nifedipine group (11.5% vs 19.1%).The results of this study show that once daily amlodipine offers comparable antianginal and antiischemic efficacy as twice daily sustained release nifedipine in the monotreatment of chronic stable angina pectoris. Given the lower incidence of adverse events with amlodipine and its convenient once daily dosing regimen, however, amlodipine may help to enhance patient compliance.

The effect of amlodipine, a recently developed calciumantagonist on 21 uterine strips was investigated. Uterine activity, expressed by the area under the curve was depressed from 504 (51 to 1056) mm2 to 0 (0 to 130) 10 min after the application of amlodipine. After 20 and 60 min, the values were 0 (0 to 1310) and 0 (0 to 317) (median, 10th and 90th percentile). The decrease of uterine activity was highly significant (p0.0001). In summary, amlodipine exhibits a prompt and excellent relaxation on the spontaneous contractions of uterine strips.

A double-blind multicenter study involving 89 patients with mild-to-moderate essential hypertension was performed to compare the efficacy and tolerability of amlodipine and enalapril. Following a placebo-controlled run-in phase, treatment was initiated with a daily dose 5 mg amlodipine or enalapril. In the second week of treatment, the daily dose of enalapril was increased to 10 mg. After two weeks of treatment, the amlodipine dose was increased from 5 to 10 mg, the enalapril dose from 10 to 20 mg if the diastolic seated blood pressure exceeded 90 mmHg.Mean systolic and diastolic blood pressures decreased in the amlodipine group from, respectively, 158 +/- 17/101 +/- 6 mmHg to 142 +/- 14/87 +/- 11 mmHg, and in the enalapril group from 157 +/- 15/102 +/- 5 mmHg to 140 +/- 16/88 +/- 12 mmHg. The reduction in blood pressure was statistically significant in both groups (p0.0001), but the difference in blood pressure lowering effect of the two treatments was not statistically significant. The target blood pressure (diastolic BP seated90 mmHg) was achieved in 24 patients (75%) in the amlodipine group, and 23 patients (68%) in the enalapril group. Neither group experienced any severe adverse reactions. Side effects were seen in 3 patients of the amlodipine group and in 6 of the enalapril group.

The efficacy and safety of amlodipine in the long term treatment of outpatients with mild to moderate hypertension were examined in an open, non-comparative study. 87 patients were enrolled in the study, 62 (71%) of whom were observed for 27 months under controlled conditions. Daily doses of 5-10 mg amlodipine led to a statistically significant decrease in systolic and diastolic blood pressure (-30.5/-20.7 mmHg, p less than 0.01) while there was no substantial influence on heart rate or decrease in efficacy. Amlodipine was tolerated very well; only 17% of the patients reported side effects, most of which were either mild or moderate and were tolerated or disappeared with continued treatment. No clinically significant changes were noted in clinical laboratory or ECG examinations. Based on its special pharmacological and pharmacokinetic properties, amlodipine is a novel calcium antagonist from the dihydropyridine class which has proved to be effective in the treatment of hypertension. The antihypertensive effect, which is sustained for more than 24 hours, parallels the circadian variations in blood pressure and thus induces beneficial pharmacodynamic effects. Due to the low incidence of side effects and the once-daily dosage regimen, an improvement in patient compliance can be expected.