[The treatment of arterial hypertension in elderly men in Iceland].

The choice of antihypertensive therapy in elderly Icelanders is unknown. In the database of the Icelandic Heart Association 1145 men, aged 70-84 were alive in 1994. Eight hundred thirty-four came to the Heart Association Clinic, 429 of whom either had hypertension or were found to be hypertensive on examination. The prevalence of hypertension in elderly Icelandic men was therefore about 50%. One hundred fifty-seven men took drugs for hypertension. Ninety-five of them were treated with a single drug, 49 with two drugs and five with three drugs. The type of drugs was unknown concerning eight men. Diuretics and ß-blockers were dominant. Although the comparison between those two classes of drugs was uncontrolled the blood pressure was significantly lower in systole on diuretics. The most common combination was ß-blockers and diuretics, then angiotensin converting enzyme inhibitors and diuretics, finally ß-blockers and calcium blockers. It is suggested that the use of diuretics should be increased in this age group.

Impact of hypertension on the outcome of patients admitted with acute coronary syndrome

OBJECTIVE The role of hypertension and its impact on outcome in patients with acute coronary syndrome (ACS) is still debated. This study aimed to compare the outcomes of hypertensive and nonhypertensive ACS patients. METHODS Using data of ACS patients enrolled in the Acute Myocardial Infarction in Switzerland Plus Registry from 1997 to 2013, characteristics at presentation and outcomes in hospital and after 1 year were analyzed. Hypertension was defined as previously diagnosed and treated by a physician. The primary endpoint was mortality. Data were analyzed using multiple logistic regressions. RESULTS Among 41 771 ACS patients, 16 855 (40.4%) were without and 24 916 (59.6%) with preexisting hypertension. Patients with preexisting hypertension had a more favorable in-hospital outcome [odds ratio (OR) in-hospital mortality 0.82, 95% confidence interval (CI) 0.73-0.93; P = 0.022]. The independent predictors of in-hospital mortality for patients with preexisting hypertension were age, Killip class greater than 2, Charlson Comorbidity Index greater than 1, no pretreatment with statins and lower admission systemic blood pressure. Preexisting hypertension was not an independent predictor of 1-year mortality in the subgroup of patients (n = 7801) followed: OR 1.07, 95% CI 0.78-1.47; P = 0.68. Independent predictors of mortality 1 year after discharge for the 4796 patients with preexisting hypertension were age, male sex and comorbidities. Angiotensin-converting enzyme inhibitors or angiotensin II receptor antagonists and statins prescribed at discharge improved the outcomes. CONCLUSION Outcome of ACS patients with preexisting hypertension was associated with an improved in-hospital prognosis after adjustment for their higher baseline risk. However, this effect was not long-lasting and does not necessarily mean a causal relationship exists. Short-term and long-term management of patients with hypertension admitted with ACS could be further improved.

Thyroid disruption in zebrafish (Danio rerio) larvae: Different molecular response patterns lead to impaired eye development and visual functions

The vertebrate thyroid system is important for multiple developmental processes, including eye development. Thus, its environmentally induced disruption may impact important fitness-related parameters like visual capacities and behaviour. The present study investigated the relation between molecular effects of thyroid disruption and morphological and physiological changes of eye development in zebrafish (Danio rerio). Two test compounds representing different molecular modes of thyroid disruption were used: propylthiouracil (PTU), which is an enzyme-inhibitor of thyroid hormone synthesis, and tetrabromobisphenol A (TBBPA), which interacts with the thyroid hormone receptors. Both chemicals significantly altered transcript levels of thyroid system-related genes (TRα, TRβ, TPO, TSH, DIO1, DIO2 and DIO3) in a compound-specific way. Despite these different molecular response patterns, both treatments resulted in similar pathological alterations of the eyes such as reduced size, RPE cell diameter and pigmentation, which were concentration-dependent. The morphological changes translated into impaired visual performance of the larvae: the optokinetic response was significantly and concentration-dependently decreased in both treatments, together with a significant increase of light preference of PTU-treated larvae. In addition, swimming activity was impacted. This study provides first evidence that different modes of molecular action of the thyroid disruptors can be associated with uniform apical responses. Furthermore, this study is the first to show that pathological eye development, as it can be induced by exposure to thyroid disruptors, indeed translates into impaired visual capacities of zebrafish early life stages.

A novel mode of action of the putative sphingosine kinase inhibitor 2-(p-hydroxyanilino)-4-(p-chlorophenyl) thiazole (SKI II): induction of lysosomal sphingosine kinase 1 degradation

Sphingosine kinase 1 (SK1) is a key enzyme in the generation of sphingosine 1-phosphate (S1P) which critically regulates a variety of important cell responses such as proliferation and migration. Therefore, inhibition of SK-1 has been suggested to be an attractive approach to treat tumor growth and metastasis formation.

Oral voclosporin: novel calcineurin inhibitor for treatment of noninfectious uveitis

Voclosporin, a novel immunomodulatory drug inhibiting the calcineurin enzyme, was developed to prevent organ graft rejection and to treat autoimmune diseases. The chemical structure of voclosporin is similar to that of cyclosporine A, with a difference in one amino acid, leading to superior calcineurin inhibition and less variability in plasma concentration. Compared with placebo, voclosporin may significantly reduce inflammation and prevent recurrences of inflammation in patients with noninfectious uveitis. Future studies have to show if these advantages are accompanied by greater clinical efficacy and fewer side effects compared with the classic calcineurin inhibitors.

Role of calcium-independent phospholipase A2 in cortex striatum thalamus cortex circuitry-enzyme inhibition causes vacuous chewing movements in rats

RATIONALE: High levels of calcium independent phospholipase A2 (iPLA2) are present in certain regions of the brain, including the cerebral cortex, striatum, and cerebellum (Ong et al. 2005). OBJECTIVES: The present study was carried out to elucidate a possible role of the enzyme in the motor system. METHODS: The selective iPLA2 inhibitor bromoenol lactone (BEL), the nonselective PLA2 inhibitor methyl arachidonyl fluorophosphonate (MAFP), and an antisense oligonucleotide were used to interfere with iPLA2 activity in various components of the motor system. Control animals received injections of carrier (phosphate buffered saline, PBS) at the same locations. The number of vacuous chewing movements (VCM) was counted from 1 to 14 days after injection. RESULTS: Rats that received BEL and high-dose MAFP injections in the striatum, thalamus, and motor cortex, but not the cerebellum, showed significant increase in VCM, compared to those injected with PBS at these locations. BEL-induced VCM were blocked by intramuscular injections of the anticholinergic drug, benztropine. Increased VCM was also observed after intrastriatal injection of antisense oligonucleotide to iPLA2. The latter caused a decrease in striatal iPLA2 levels, confirming a role of decreased enzyme activity in the appearance of VCM. CONCLUSIONS: These results suggest an important role for iPLA2 in the cortex-striatum-thalamus-cortex circuitry. It is postulated that VCM induced by iPLA2 inhibition may be a model of human parkinsonian tremor.

The Topoisomerase I Inhibitor Irinotecan and the Tyrosyl-DNA Phosphodiesterase 1 Inhibitor Furamidine Synergistically Suppress Murine Lupus Nephritis

OBJECTIVE The treatment of lupus nephritis is still an unmet medical need requiring new therapeutic approaches. Our group found recently that irinotecan, an inhibitor of topoisomerase I (topo I), reversed proteinuria and prolonged survival in mice with advanced lupus nephritis. While irinotecan is known to stabilize the complex of topo I and DNA, the enzyme tyrosyl-DNA phosphodiesterase 1 (TDP-1) functions in an opposing manner by releasing topo I from DNA. Therefore, we undertook this study to test whether the TDP-1 inhibitor furamidine has an additional effect on lupus nephritis when used in combination with irinotecan. METHODS NZB/NZW mice were treated with low-dose irinotecan and furamidine either alone or in combination beginning at age 26 weeks. DNA relaxation was visualized using gel electrophoresis. Binding of anti-double-stranded DNA (anti-dsDNA) antibodies to DNA modified by topo I, TDP-1, and the topo I inhibitor camptothecin was determined by enzyme-linked immunosorbent assay. RESULTS Compared to treatment with either agent alone, simultaneous treatment with low-dose irinotecan and furamidine significantly improved survival of NZB/NZW mice. Similar to what has been previously shown for irinotecan alone, the combination treatment did not change the levels of anti-dsDNA antibodies. In vitro, recombinant TDP-1 increased topo I-mediated DNA relaxation, resulting in enhanced binding of anti-dsDNA antibodies. In combination with topo I and camptothecin, TDP-1 reversed the inhibitory effects of camptothecin on DNA relaxation and anti-dsDNA binding. CONCLUSION Affecting DNA relaxation by the enzymes topo I and TDP-1 and their inhibitors may be a promising approach for the development of new targeted therapies for systemic lupus erythematosus.

The Fatty Acid Biosynthesis Enzyme FabI Plays a Key Role in the Development of Liver-Stage Malarial Parasites

The fatty acid synthesis type II pathway has received considerable interest as a candidate therapeutic target in Plasmodium falciparum asexual blood-stage infections. This apicoplast-resident pathway, distinct from the mammalian type I process, includes FabI. Here, we report synthetic chemistry and transfection studies concluding that Plasmodium FabI is not the target of the antimalarial activity of triclosan, an inhibitor of bacterial FabI. Disruption of fabI in P. falciparum or the rodent parasite P. berghei does not impede blood-stage growth. In contrast, mosquito-derived, FabI-deficient P. berghei sporozoites are markedly less infective for mice and typically fail to complete liver-stage development in vitro. This defect is characterized by an inability to form intrahepatic merosomes that normally initiate blood-stage infections. These data illuminate key differences between liver- and blood-stage parasites in their requirements for host versus de novo synthesized fatty acids, and create new prospects for stage-specific antimalarial interventions.