No change in developmental outcome with incubator covers and nesting for very preterm infants in a randomised controlled trial.

OBJECTIVE: To investigate in a randomised controlled trial the effect of basic elements of developmental care (incubator covers and positioning aids) on growth and neurodevelopment in infants born at < 32 weeks. METHOD: Infants were randomised within 48 h of birth to a developmental care (DC) or standard care (C) group. Outcome measures at 1 and 2 years corrected age were growth, standardised neurological examinations, and mental (MDI) and psychomotor (PDI) development (Dutch version of the Bayley Scales of Infant Development II). RESULTS: 192 infants were recruited (DC = 98; C = 94). Thirteen infants (DC = 7, C = 6) were excluded because they were admitted for <5 days or died within the first 5 days. In total, 179 infants met the inclusion criteria. In-hospital mortality was 12/91 (13.2%) in the DC group and 8/88 (9.1%) in the C group. Assessments were carried out on 147 children (DC = 74, C = 73) at 1 year and 142 children (DC = 72, C = 70) at 2 years. No significant difference in growth, neurological outcomes or MDI was found. A positive trend in PDI at 1 year (p = 0.05) did not continue once the children reached 2 years. There was no difference found when neurological and developmental scores were combined. CONCLUSIONS: Basic developmental care has no positive effect on neurological and mental development or growth at 1 and 2 years of age in infants born at <32 weeks. A positive effect on psychomotor development at 1 year did not continue at 2 years of age.

ESH-ESC guidelines for the management of hypertension.

The following is a brief statement of the 2003 European Society of Hypertension (ESH)-European Society of Cardiology (ESC) guidelines for the management of arterial hypertension. The continuous relationship between the level of blood pressure and cardiovascular risk makes the definition of hypertension arbitrary. Since risk factors cluster in hypertensive individuals, risk stratification should be made and decision about the management should not be based on blood pressure alone, but also according to the presence or absence of other risk factors, target organ damage, diabetes, and cardiovascular or renal damage, as well as on other aspects of the patient's personal, medical and social situation. Blood pressure values measured in the doctor's office or the clinic should commonly be used as reference. Ambulatory blood pressure monitoring may have clinical value, when considerable variability of office blood pressure is found over the same or different visits, high office blood pressure is measured in subjects otherwise at low global cardiovascular risk, there is marked discrepancy between blood pressure values measured in the office and at home, resistance to drug treatment is suspected, or research is involved. Secondary hypertension should always be investigated. The primary goal of treatment of patient with high blood pressure is to achieve the maximum reduction in long-term total risk of cardiovascular morbidity and mortality. This requires treatment of all the reversible factors identified, including smoking, dislipidemia, or diabetes, and the appropriate management of associated clinical conditions, as well as treatment of the raised blood pressure per se. On the basis of current evidence from trials, it can be recommended that blood pressure, both systolic and diastolic, be intensively lowered at least below 140/90 mmHg and to definitely lower values, if tolerated, in all hypertensive patients, and below 130/80 mmHg in diabetics. Lifestyle measures should be instituted whenever appropriate in all patients, including subjects with high normal blood pressure and patients who require drug treatment. The purpose is to lower blood pressure and to control other risk factors and clinical conditions present. In most, if not all, hypertensive patients, therapy should be started gradually, and target blood pressure achieved progressively through several weeks. To reach target blood pressure, it is likely that a large proportion of patients will require combination therapy with more than one agent. The main benefits of antihypertensive therapy are due to lowering of blood pressure per se. There is also evidence that specific drug classes may differ in some effect or in special groups of patients. The choice of drugs will be influenced by many factors, including previous experience of the patient with antihypertensive agents, cost of drugs, risk profile, presence or absence of target organ damage, clinical cardiovascular or renal disease or diabetes, patient's preference.

Vasopressin receptor antagonists: pharmacological tools and potential therapeutic agents.

The present survey deals with the development and applications of non-peptidergic vasopressin receptor antagonists. The existence of at least three vasopressin receptors (V(1), V(2) and V(3) respectively) is firmly established. V(1)-receptors play a relevant role in the regulation of vascular tone, whereas V(2)-receptors are known to mediate the antidiuretic activity of vasopressin at the level of the renal collecting ducts. The V(3)-receptor appears to be involved in the release of the adreno-corticotropic hormone. Vasopressin receptor antagonists which are peptides have been known for several decades, more recently, both V(1)- and V(2)-receptor blockers which are non-peptidergic have been introduced, as well as agents with affinity for both V(1)- and V(2)-receptor subtypes. A survey of these non-peptidergic antagonists is presented here. Such compounds are useful as pharmacological tools, and they can also be thought of as therapeutic agents as therapeutic agents in cardiovascular and renal diseases. Selective V(1)- and V(2)-receptor antagonists were used to study the interaction between vasopressin receptors and sympathetic neurones. Depending on the experimental model used this interaction can occur at either the pre- or postsynaptic sites. In both cases predominantly V(1)-receptors are involved. A brief survey is given of the potential use of V-receptor antagonists in the drug therapy of syndrome of inappropriate antidiuretic hormone secretion and other water retaining disorders, congestive heart failure and certain forms of hypertension (in particular in the Negroid hypertensive patients).

Significant food interactions observed with a nifedipine modified-release formulation marketed in the European Union.

The objective of this study was to compare the rate and extent of nifedipine bioavailability after single dose administration of Adalat OROS 30 (Reference) and Nifedipine Sandoz retard 30 tablets (Test). Both modified release formulations are marketed in Member States of the European Union. Prior to the clinical study the in vitro dissolution characteristics were investigated. There was a significant pH dependency observed with the Test product but drug release with the Reference product was almost independent of the experimental conditions used. In the subsequent open, randomized, controlled, 4-way crossover study both pharmaceutical products were administered to 28 healthy male volunteers, either after fasting overnight or immediately after a high-fat American breakfast. Blood sampling was performed over 48 hours post-dose for the determination of pharmacokinetic profiles of nifedipine. Considerable differences were observed between the two formulations when administered to fasted subjects where maximum nifedipine plasma concentration (C(max)) were higher in the case of the Test formulation. Differences were even more pronounced after a high-fat American breakfast. Under these conditions a significant food interaction was detected in the case of Nifedipine Sandoz retard 30 with a three-fold increase in the mean C(max) when compared to values obtained in fasting subjects. In contrast, food intake had no clinically relevant effect on bioavailability of nifedipine (rate and extent) in the case of Adalat OROS 30. The pharmacokinetic findings in this study were reflected in the adverse event pattern which indicated a potential tolerability problem in the case of Nifedipine Sandoz retard 30. The results confirm the relationship between the in vitro dissolution profile results and the effects of the drug in vivo. Dose dumping after intake of a high-fat meal could be shown. Nifedipine Sandoz retard 30 is not bioequivalent to Adalat OROS 30 and produced highly variable and poorly predictable nifedipine plasma concentrations. The differences observed between the two products investigated may have direct therapeutic relevance when switching from one formulation to the other and, in particular, when administration conditions change i.e. administration in the fasting state and administration with a meal, since the pharmacological and therapeutic actions of nifedipine are closely associated with the concentration.

Angiotensin II receptor antagonists (AT1-blockers, ARBs, sartans): similarities and differences.

A survey is presented of the registered non-peptidergic angiotensin II receptor antagonists (AT1 blockers, ARBs, sartans) and their general properties and similarities. Accordingly, their receptor profile, pharmacokinetic and therapeutic applications are discussed. In addition, attention is paid to the individual characteristics of the AT1 blockers now available. A few components of this category offer additional potentially beneficial properties, owing to their pharmacological or metabolic characteristics. Such additional properties are critically discussed for eprosartan, losartan, telmisartan and valsartan.

The metabolic syndrome - background and treatment.

The metabolic syndrome (MBS) is characterised by a clustering of cardiovascular and metabolic risk factors. This syndrome is now widely recognised as a distinct pathological entity, and it is receiving a great deal of attention in the medical literature but also in the lay press. Globally speaking, persons with MBS have a clustering of the following risk factors: [List: see text] MBS is associated with important cardio/cerebrovascular and metabolic risks. Prevention and treatment are therefore of great importance. Preventive measures involving lifestyle are mandatory. In addition, MBS patients require pharmacological treatment, usually for the rest of their lives. Complex patterns of drug treatment will be required, since all the different, heterogenous pathophysiological problems will require appropriate treatment. After an introduction to MBS, this article provides an extensive and critical review of the drug treatment of this complex pathological entity.

[Recently published European and American guidelines for the diagnosis and treatment of hypertension]. / Onlangs gepubliceerde Europese en Amerikaanse richtlijnen voor hypertensiediagnostiek en -behandeling.

The European Society of Hypertension in conjunction with the European Society of Cardiology has published new guidelines on the management of hypertension. At about the same time, the Joint National Committee in the United States updated the American hypertension guidelines. Both guidelines agree on a number of issues, such as the importance of systolic blood pressure, the necessity to take into account additional risk factors and the growing emphasis on combination treatment. As far as pharmacotherapy is concerned, however, there are major differences between the guidelines. Whereas the European report permits a choice from among several classes of drugs for initial treatment, the American guidelines still consider diuretics to be the first choice.

Is hypotension a major risk factor for neurological morbidity at term age in very preterm infants?

OBJECTIVE: To investigate the influence of perinatal risk factors, especially hypotension, on neuromotor status at term in surviving preterm infants born before 32 weeks of gestation. METHODS: This study is part of the Leiden Follow-Up Project on Prematurity: a prospective, regional study of 266 live born infants with a gestational age (GA) < 32 weeks born in 1996-1997. Twenty-eight infants died before term age. Two hundred and eleven infants were examined neurologically at term according to Prechtl. The findings were classified as normal (N), mildly abnormal (MA) or definitely abnormal (DA). Hypotension was defined as a mean arterial blood pressure (MABP) < 30 mm Hg on at least two occasions. RESULTS: One hundred and six (50%) infants were classified as neurologically N, 92 (44%) infants were classified as MA and 13 (6%) infants as DA. Hypotension, bronchopulmonary dysplasia (BPD), flaring and cystic periventricular leucomalacia (PVL) were risk factors for neurological morbidity. Of the 68 infants with hypotension, 33 (49%) were classified as MA and 7 (10%) as DA. Of the 141 infants without hypotension, 58 (41%) were MA, and 5 (4%) were DA. The odds ratio of hypotension for neurological morbidity was 1.9 (95% CI 1.06-3.40), adjusted for gestational age, birth weight, small for gestational age (SGA) and gender, it was 1.96 (95% CI 1.02-3.77). The adjusted odds ratio of PVL was 18.6 (4.4-78.5), of flaring was 2.37 (1.18-4.74) and of BPD was 2.44 (1.08-5.5). CONCLUSIONS: Apart from gestational age, periventricular leucomalacia, and bronchopulmonary dysplasia, hypotension in preterm infants is a major risk factor for neurological morbidity at term.

Vasopressin-induced facilitation of adrenergic responses in the rat mesenteric artery is V1-receptor dependent.

1. The present study was designed to analyse the possible involvement of V1- and V2-receptors in vasopressin (AVP)-induced facilitation of the sympathetic nervous system. Furthermore, we aimed to determine whether the site of facilitation by AVP is located pre- or postsynaptically. 2. Electrical field stimulation (EFS) was applied on the rat mesteric artery to activate the sympathetic nervous system. In addition, we evaluated the direct vascular effects of AVP. The postsynaptic effect of AVP on the sympathetic nervous system was investigated by exposing the vessels to exogenous noradrenaline. These experiments were performed in the absence or presence of selective V1 and V2 receptor antagonists SR 49059 and SR 121463, respectively. Desmopressin was applied as a selective V2 agonist. 3. The direct vasoconstrictor effect of AVP was antagonized by SR 49059 and not by SR 121463. Desmopressin neither showed any direct vasoconstrictor effect nor produced vasodilatation after a precontraction induced by noradrenaline (10 microM). The EFS-induced rise in vascular tone could be increased by a sub-pressor concentration of AVP. This fascilitation could be antagonized by SR 49059, but not by SR 121463. Desmopressin did not influence the increase in vascular tone during EFS. Vasoconstriction induced by exogenous noradrenaline could be facilitated by a sub-pressor concentration of AVP and this selective postsynaptic effect could be antagonized by V1-receptor blockade. 4. In conclusion, the AVP-induced facilitation of the sympathetic nervous system is completely V1-receptor dependent and at least partly postsynaptically mediated.

Behaviour at 2 years of age in very preterm infants (gestational age < 32 weeks).

AIM: The objective of this study was to determine behavioural outcome and risk factors for abnormal behaviour at 2 y corrected age in very premature infants in a regionally defined, prospective cohort study. METHODS: The Leiden Follow-Up Project on Prematurity includes all liveborn infants of < 32 wk gestational age, born in 1996/1997 (n = 266). Behaviour was assessed with the Child Behaviour Checklist 2-3. RESULTS: An analysis of 158 questionnaires of 206 survivors (77%) was carried out. Fourteen children (9%) had a total problem score > p90 ("clinical range"). This percentage is comparable with the 10% found in a sample of 2- to 3-y-olds from the Dutch general population. Univariate analysis showed higher syndrome scale scores in one or more of the Child Behaviour Checklist scales in children of lower gestational age, small for gestational age (birthweight < p10), with neurological abnormalities at term or at 2 y and of non-Dutch origin. Lower socioeconomic status and postnatal treatment with dexamethasone were associated with higher scores in the somatic problems scale and lower maternal age at birth with a higher total problem score. After correction for confounding variables, the associations between small for gestational age, neurological abnormalities at 2 y and the anxious/depressed and/or withdrawn scales remained significant. CONCLUSION: The prevalence of behavioural problems at 2 y corrected age in this cohort of very premature infants (gestational age < 32 wk) was comparable with that in a general population sample. Children born small for gestational age or with neurological abnormalities at 2 y of age had higher syndrome scale scores, mainly for anxious/depressed and/or withdrawn behaviour.

Recently completed trials on the drug treatment of hypertension: comments on ALLHAT and ANBP-2.

Recently the results of two important large-scale studies on hypertension management were published and intensely debated: ALLHAT and ANBP-2. In particular the ALLHAT study was discussed and subjected to criticism. The positive and negative aspects of this study are the subject of the present survey. ALLHAT has reemphasised the important role of thiazide diuretics in the treatment of hypertension. However, there should also be an important position for the various other well-known drugs such as ß-blockers, ACE inhibitors, calcium antagonists and AT1-blockers (sartans). The choice of the drug(s) to be prescribed is largely determined by the comorbidity, which occurs frequently in elderly hypertensives. Furthermore, combination therapy is applied more and more frequently.

AT(1)-receptor blockade and sympathetic neurotransmission in cardiovascular disease.

1. The present survey is dealing with the interactions between the renin-angiotensin-aldosterone system (RAAS) and the sympathetic nervous system (SNS) in various organs and tissues, with an emphasis on the angiotensin AT-receptors located at the sympathetic nerve endings. 2. Angiotensin II, the main effector of the RAAS is known to stimulate sympathetic nerve traffic and its sequelae in numerous organs and tissues, such as the central nervous system, the adrenal medulla, the sympathetic ganglia and the sympathetic nerve endings. These stimulatory effects are mediated by AT(1)-receptors and counteracted by AT(1)-receptor antagonists. 3. Sympatho-inhibition at the level of the sympathetic nerve ending appears to be a class effect of the AT(1)-receptor blockers, mediated by presynaptic AT(1)-receptors. With respect to the ratio pre-/postsynaptic AT(1)-receptor antagonism important quantitative differences between the various compounds were found. 4. Both the pre- and postjunctional receptors at the sympathetic nerve endings belong to the AT(1)-receptor population. However, the presynaptic receptors belong to the AT(1B)-subtype, whereas the postjunctional receptors probably belong to a different AT(1)-receptor subpopulation. 5. Sympatho-inhibition is a class effect of the AT(1)-receptor antagonists. In conditions in which the SNS plays a pathophysiological role, such as hypertension and congestive heart failure, this property may well be of therapeutic relevance.

Isolated systolic hypertension as a treatable risk factor.

Isolated systolic hypertension (ISH) is characterised by elevated systolic (SBP) and somewhat lowered diastolic blood pressure (DBP). ISH occurs predominantly in elderly hypertensives as a result of aortic stiffness, which increases with age. Elevated SBP and even more so widened pulse pressure (PP=SBP-DBP) are recognised as important risk factors for stroke and ischaemic heart disease. ISH therefore requires consistent drug therapy, combined with lifestyle advice. It is important to lower SBP without reducing DBP too much, in order to avoid a further widening of the PP. Large-scale intervention studies (SHEP, SYST-EUR, SYST-China, and INSIGHT) have demonstrated that thiazide diuretics and calcium antagonists are the drugs of choice to protect against stroke and MI. ACE inhibitors, AT1-blockers and omapatrilate may be considered because of their haemodynamic effects and their additional benefit in patients with heart failure or diabetes. Nitrates and NO-donors reduce SBP more than DBP because of their effects on the large conduit arteries. Spironolactone is of potential interest since it may reduce aortic stiffness.

The effects of hypochlorite-induced oxidative stress on presynaptic M2-receptors at sympathetic nerve endings in the rat tail artery.

1 It was shown recently that stimulation of cardiac muscarinic M2-receptors revealed an enhanced negative inotropic response in isolated rat left atria after exposure to hypochlorite-induced oxidative stress. This phenomenon was not observed after stimulation of the cardiac A1-receptor, which like the M2-receptor is coupled to Gi-proteins. Since even the contractile response to M3-receptor stimulation was not amplified in the rat portal vein, we hypothesized a M2-receptor specificity of this hypochlorite-induced enhancement. 2 The present study was performed in order to investigate whether the sympathoinhibitory response to presynaptically located M2-receptor stimulation would also be modified after exposure to hypochlorite in the rat tail artery. We applied electrical field stimulation (EFS) in order to mimic sympathetic neurotransmission. 3 EFS increased the vascular tone frequency-dependently (0.3-4 Hz). EFS-induced vasoconstriction could be attenuated by acetylcholine (30 nM-1 microM) in a concentration-dependent manner. Hypochlorite (10 and 100 microM) did not affect the sympathoinhibitory effect of acetylcholine (100 nM). 4 In conclusion, in contrast to cardiac M2-receptors, hypochlorite did not amplify the sympathoinhibitory effects of presynaptic M2-receptors. The different responsiveness between neuronal and cardiac M2-receptors to hypochlorite may be explained by the different G-protein subunits involved in the activation of the underlying signalling cascade.

Relationship between cardiac metaiodobenzylguanidine uptake and hemodynamic, functional and neurohormonal parameters in patients with heart failure.

BACKGROUND: Sympathetic activation plays a pivotal role in heart failure attributing to the disease process and symptoms of the patient. Myocardial sympathetic activity can be visualized using radioiodinated metaiodobenzylguanidine 123I-MIBG, a structural analogue of norepinephrine (NE). AIM OF THE STUDY: We investigated whether a relation exists between myocardial MIBG uptake and different functional, hemodynamic and neurohormonal parameters in patients with chronic heart failure. METHODS AND RESULTS: The study comprised 52 patients with stable congestive heart failure functional class II or III and left ventricular ejection fractions of <35%. The heart/mediastinum ratio (H/M ratio) was calculated to quantify myocardial MIBG uptake. A significant correlation was found between peak oxygen consumption and maximal exercise duration as exercise parameters and H/M ratio of MIBG (R, respectively, 0.36 and 0.4, P<0.05). From all other measured parameters, only plasma NE showed a significant correlation with the H/M ratio of MIBG. CONCLUSION: Cardiac sympathetic activity, as measured by myocardial MIBG uptake, is correlated with peak exercise parameters.

Effects of calcitonin gene-related peptide and BIBN4096BS on myocardial ischemia in anesthetized rats.

AIM: The cardioprotective effect of calcitonin gene-related peptide (CGRP) was investigated in an ischemia rat model. METHODS: Ischemia-reperfusion injury was provoked by 60 min left main coronary artery occlusion followed by 60 min of reperfusion in anesthetized rats. The transverse slices of ventricles were stained by 2,3,5-triphenyltetrazolium chloride to determine the infarct area. Plasma creatine phosphokinase levels were determined by means of a creatine phosphokinase (CPK) kit. A radioimmunoassay was used to determine plasma CGRP levels. RESULTS: Intravenous infusion of CGRP (1 nmol . kg-1 . h-1) 10 min before occlusion until the end of reperfusion reduced infarct size by 89 %+/- 5 %. The reduction in infarct size was accompanied by a decrease in circulating levels of creatine phosphokinase. Infusion of the same dose of CGRP commencing from the start of reperfusion until its end induced a 40 % +/- 3 % reduction of the infarct size. The cardioprotective effects of CGRP were blocked by the novel CG RP antagonist BIBN4096BS (20 nmol . kg-1 . h-1). Although cardiac ischemia resulted in an almost 50 % increase in plasma CGRP levels in blood sampled from right cardiac ventricle, intravenous infusion of the CGRP antagonist BIBN4096BS before occlusion until the end of reperfusion had no statistically significant effect on the infarct size. CONCLUSION: The present study demonstrates that CGRP is a potent myocardial protective substance.