Intraventricular administration of gabapentin in the rat increases flurothyl seizure threshold.

INTRODUCTION: We investigated efficacy of prolonged intraventricular gabapentin (GBP) infusion in the rat flurothyl epilepsy model. METHODS: Sprague-Dawley rats, under anesthesia, were implanted with bilateral Alzet model 2001 osmotic pumps. The pumps infused GBP 80 microg/microL (3.8 mg/day) or isotonic saline control at 1.0 microL/h into each ventricle for 5 days. After 5 days of GBP infusion, seizures were induced by flurothyl dripped onto filter paper. Time to first myoclonic jerk, first partial seizure and first tonic-clonic seizure was recorded by an observer unaware of the treatment group. Determination of seizures was behavioral. RESULTS: Data were obtained from 54 rats. First tonic-clonic seizure was at 295.8+/-58.8s (n=28) for control rats, versus 338.0+/-89.9 s (n=26) for rats with GBP in the pump (p=0.049). First myoclonic jerk occurred at 158.7+/-20.8 versus 164.6+/-33.5 s (p=0.44, n.s.). Regression of time to seizure versus weight was not significant. No animal had measurable serum levels (<1 microg/ml) of GBP. The distribution of GBP in brain was not studied, but qualitative observations of methylene blue dye installed in the pumps showed dye in periventricular white matter and also over cortex, especially ipsilaterally. DISCUSSION: GBP instilled into the lateral ventricles by pump for 5 days delays onset of generalized tonic-clonic seizures produced by flurothyl in the rat. Time to first myoclonic or partial seizure was not influenced. Effects were not due to systemic absorption of GBP. This study provides a proof-in-principle for intraventricular therapy with AEDs.

Long-term prognostic impact of repeated measurements over 1 year of pulse pressure and systolic blood pressure in the elderly.

Systolic blood pressure (SBP) and pulse pressure (PP) have been identified in western industrialized countries as major predictors of cardiovascular events in the elderly on the basis of measurements taken at a single visit. Considering the wide variability of blood pressure (BP) in older people, this study set out to assess the prognostic significance of measurements of SBP and PP taken over several months according to a monitoring scheme mimicking routine care. A total of 444 Italian general practitioners enrolled a cohort of 3858 unselected elderly outpatients and followed them up for 10 years. BP was recorded at recruitment, 1 week later and at quarterly visits during the first year. The average BP of these six visits was used to define the patient's BP status. During the 10-year follow-up, 1561 participants died, 709 from cardiovascular diseases. Proportional hazard regression analysis, adjusted for all main prognostic factors including antihypertensive treatment, showed that for each 10-mmHg increment in SBP and PP there were, respectively, 5 and 9% increases in risk for total mortality (TM) and 9 and 13% increases in risk for cardiovascular mortality (CVM) (all P < 0.01). However, including both SBP and PP in the model, only PP showed an independent, significant relationship with TM and CVM. In conclusion, prognostic information based on repeated measurements of PP is stronger than that given by SBP and consequently should be recommended in the definition of cardiovascular risk in the elderly.

Focally injected adenosine prevents seizures in the rat.

Prophylactic drug injection directly onto a seizure focus has the potential to improve seizure control with fewer side effects than is produced by systemic therapy. Using a dose-response model, we evaluated the effectiveness of adenosine application for focal seizure prophylaxis in 12 rats. Total spikes and electroencephalographic ictal events were reduced significantly by treatment with adenosine compared to control (P < 0.0001). This study demonstrates effectiveness and feasibility in a model system using intracranial injection of adenosine to prevent epileptiform events.

Effects of low-dose aspirin on clinic and ambulatory blood pressure in treated hypertensive patients. Collaborative Group of the Primary Prevention Project (PPP)--Hypertension study.

Nonsteroidal antiinflammatory drugs may affect blood pressure (BP) control in hypertensive patients receiving drug treatment, but data on the effects of low-dose aspirin are scanty. This study assessed the effects of chronic treatment with low doses of aspirin (100 mg/day) on clinic and ambulatory systolic (SBP) and diastolic (DBP) BP in hypertensives on chronic, stable antihypertensive therapy. The study was conducted in the framework of the Primary Prevention Project (PPP), a randomized, controlled factorial trial on the preventive effect of aspirin or vitamin E in people with one or more cardiovascular risk factors. Fifteen Italian hypertension units studied 142 hypertensive patients (76 men, 66 women; mean age 59 +/- 5.9 years) treated with different antihypertensive drugs: 71 patients were randomized to aspirin and 71 served as controls. All patients underwent a clinic BP evaluation with an automatic sphygmomanometer and a 24-h ambulatory BP monitoring, at baseline and after 3 months of aspirin treatment. At the end of the study the changes in clinic SBP and DBP were not statistically different in treated and untreated subjects. Ambulatory SBP and DBP after 3 months of aspirin treatment were similar to baseline: deltaSBP -0.5 mmHg (95% confidence intervals [CI] from -1.9 to +2.9 mm Hg) and deltaDBP -1.1 mm Hg (95% CI from -2.5 to +0.3 mm Hg). The pattern was similar in the control group. No interaction was found between aspirin and the most used antihypertensive drug classes (angiotensin converting enzyme inhibitors and calcium antagonists). Despite the relatively small sample size our results seem to exclude any significant influence of low-dose aspirin on BP control in hypertensives under treatment.

Effects of vitamin E on clinic and ambulatory blood pressure in treated hypertensive patients. Collaborative Group of the Primary Prevention Project (PPP)--Hypertension study.

A randomized controlled open trial studied the effect of vitamin E supplementation (300 mg/day) on clinic and 24-h ambulatory blood pressure (BP) in 142 treated hypertensive patients. After 12 weeks, clinic BP decreased whether or not patients were randomized to vitamin E. Ambulatory BP showed no change in systolic BP and a small decrease in diastolic BP (-1.6 mm Hg, 95% confidence intervals from -2.8 to -0.4 mm Hg), approaching statistical significance in comparison to the control group (P = .06). Vitamin E supplementation thus seems to have no clinically relevant effect on BP in hypertensive patients already under controlled treatment.

The long-term prognostic significance of repeated blood pressure measurements in the elderly: SPAA (Studio sulla Pressione Arteriosa nell'Anziano) 10-year follow-up.

BACKGROUND: In young and middle-aged people, both systolic (SBP) and diastolic (DBP) blood pressure have a continuous, strong, and independent relationship with subsequent cardiovascular morbidity and mortality. These relationships are not well documented in older people and, until now, studies in the elderly do not provide homogeneous results on the importance of DBP compared with SBP as a cardiovascular risk factor. OBJECTIVE: To determine whether SBP and DBP are independent indicators of mortality risk in the elderly. DESIGN: An observational prospective cohort study to analyze the long-term prognostic significance of repeated SBP and DBP measurements in the elderly. PATIENTS AND METHODS: A total of 3858 outpatients 65 years or older (mean age [SD], 72.9 [4.9] years, 43.5% men) were selected randomly by 444 Italian National Health Service general practitioners in 1983. The population was followed up for 10 years. Crude and adjusted incidence rates of total and cardiovascular mortality were analyzed for classes of SBP and DBP based on the values recorded at the 2 initial visits 1 week apart and those measured during the first 12 months of follow-up. RESULTS: During the 10-year follow-up, 74 patients (1.9%) were lost to follow-up and 1561 (41.3%) died, 709 (45.4% of all deaths) from cardiovascular causes. A positive continuous, graded, strong, and independent association was observed with both total (P<.001) and cardiovascular (P<.001) mortality for SBP but not for DBP. The pattern was similar in both sexes, in persons younger and older than 75 years, regardless of preexisting cardiovascular diseases, and whether they had been receiving antihypertensive treatment at baseline. There was no J-shaped mortality curve in the subjects with the lowest SBP and DBP. CONCLUSIONS: These findings suggest that SBP, but not DBP, is a strong, positive, continuous, independent indicator of mortality risk in the elderly and should be stressed much more than DBP in the diagnosis and treatment of hypertension in this age group.

A computer-driven approach to PCR-based differential screening, alternative to differential display.

MOTIVATION: Polymerase chain reaction (PCR)-based RNA fingerprinting is a powerful tool for the isolation of differentially expressed genes in studies of neoplasia, differentiation or development. Arbitrarily primed RNA fingerprinting is capable of targeting coding regions of genes, as opposed to differential display techniques, which target 3' non-coding cDNA. In order to be of general use and to permit a systematic survey of differential gene expression, RNA fingerprinting has to be standardized and a number of highly efficient and selective arbitrary primers must be identified. RESULTS: We have applied a rational approach to generate a representative panel of high-efficiency oligonucleotides for RNA fingerprinting studies, which display marked affinity for coding portions of known genes and, as shown by preliminary results, of novel ones. The choice of oligonucleotides was driven by computer simulations of RNA fingerprinting reverse transcriptase (RT)-PCR experiments, performed on two custom-generated, non-redundant nucleotide databases, each containing the complete collection of deposited human or murine cDNAs. The simulation approach and experimental protocol proposed here permit the efficient isolation of coding cDNA fragments from differentially expressed genes. AVAILABILITY: Freely available on request from the authors. CONTACT: fesce.riccardo@hsr.it

Control of hypertension in Italy: results of the "Study on Antihypertensive Treatment in General Practice (STAP)". Physicians Taking Part in STAP.

BACKGROUND: Various epidemiological surveys from different countries have documented the unsatisfactory control of arterial hypertension. The aim of this study was to assess the current status of treatment and control of hypertension in Italy. METHODS: A random sample of general practitioners (GP) working in several Aziende Sanitarie Locali (Local health offices-ASL) throughout Italy were invited to take part in the study. Each doctor had to recruit a random sample of 15-20 hypertensive patients receiving antihypertensive drugs among those attending his/her office for any reason. A standard medical history, specifically oriented to hypertension and its pharmacological treatment, was taken for each patient. Three blood pressure (BP) measurements were made, with the patient seated for at least 5 minutes, using an accurate automatic device (A&D UA-732), and the mean was taken as each patient's BP. RESULTS: A total of 73 GPs (17% of the invited sample), working in 14 Italian ASL (six in the north of the country, four in the center and four in the south and islands), agreed to participate in the study. They recruited an average of 17 patients each, for a total of 1204 hypertensive subjects (663 women and 541 men) 633 of whom were 65 years old or more, mean age 64 +/- 11 years, range 25-94 years. More than half (56%) had been taking antihypertensive drugs for at least five years; 42% were taking one drug, 40% two, 16% three and 2% four drugs. Respectively, 63% and 23% had systolic BP (SBP) > or = 140 and > or = 160 mmHg; 28% and 14% had diastolic BP (DBP) > or = 90 and 95 mmHg. In 71%, BP was < 160/95 mmHg, but only 33% had BP lower than 140/90 mmHg. BP control was similar in males and females, but worse in the elderly. Nine percent of patients complained of symptomatic side effects, usually mild. Only 8% admitted to poor compliance with the antihypertensive therapy, and their BP was significantly less well controlled. CONCLUSIONS: Control of BP in patients receiving antihypertensive drugs is still far from optimal in Italy, just as in other countries. This situation seems more related to the fact that doctors do not tackle the problem aggressively, than to the patients' degree of compliance with therapy.

Long-term effects of angiotensin-converting enzyme inhibitors and calcium antagonists on the right and left ventricles in essential hypertension.

To compare the effects of chronic antihypertensive treatment on left and right ventricular structure and function, 24 patients with mild to moderate, never-treated hypertension were randomized to receive fosinopril (20 mg daily) or amlodipine (10 mg daily) for 12 months. At baseline and subsequently at the end of third, sixth, and twelfth months, each patient underwent an integrated echocardiographic study and noninvasive ambulatory blood pressure monitoring. Both drugs significantly reduced blood pressure, casual or monitored (p < 0.01), and left ventricular mass index (from 125 +/- 32 to 100 +/- 12 gm/m2 [p < 0.02] with amlodipine and from 106 +/- 18 to 89 +/- 10 gm/m2 [p < 0.02] with fosinopril). The decrease in left ventricular mass was essentially caused by a reduction of ventricular thickness. Free right ventricular wall thickness was also lowered in both groups, more consistently with amlodipine (from 8.0 +/- 2.1 to 6.4 +/- 0.8 mm; p < 0.01), without an increase in plasma natriuretic peptide and insulin concentrations or heart rate. With both treatments, the decrease in ventricular mass was not associated with impairment of systolic function, whereas a trend toward an improvement of Doppler echocardiographic indexes of biventricular diastolic function was observed. In conclusion, both amlodipine and fosinopril induced similar qualitative effects on anatomy and function of both ventricles. The clinical meaning of these observations must be defined further by means of adequately sized prospective trials.

Albuminuria and transferrinuria in essential hypertension. Effects of antihypertensive therapy.

The objectives of this study were to evaluate the effects of an ACE inhibitor (fosinopril) and a calcium antagonist (amlodipine) on the urinary albumin and transferrin excretion and their relationship to the blood pressure in essential hypertension. Twenty-four never-treated patients (mean age, 46.4 +/- 8.9 years) with a diastolic blood pressure between 90 and 114 mm Hg and normal renal function, randomly received amlodipine or fosinopril and, if the diastolic blood pressure was not normalized, doxazosin was added to the therapy. Twenty-four-hour ambulatory blood pressure monitoring and 24-h urine collection for albumin and transferrin measurements were performed before and after 3 and 6 months of therapy. Diastolic blood pressure was normalized in 23 patients (96%). Before treatment, microalbuminuria was present in 50% of patients. In the amlodipine and fosinopril group, antihypertensive therapy significantly decreased blood pressure and, only in the fosinopril group, albuminuria. Transferrinuria did not change significantly in both groups. Fosinopril lowered albuminuria in all patients, whereas amlodipine only in half of patients. Albuminuria, but not transferrinuria, was significantly correlated to the ambulatory blood pressure. This correlation was more pronounced for systolic than for diastolic pressure. In essential hypertensive patients with normal renal function, a high prevalence of microalbuminuria can be observed. Albuminuria appears to correlate with ambulatory blood pressure, particularly with systolic pressure. Intrarenal hemodynamic changes seem to play a more important role than systemic blood pressure decrease in the reduction of albuminuria. Transferrinuria does not seem a useful marker to follow-up nondiabetic hypertensive patients with early signs of glomerular dysfunction.

How informed general practitioners manage mild hypertension: a survey of readers of drug bulletins in 7 countries. International Society of Drug Bulletins (ISDB).

OBJECTIVE: To determine whether general practitioners (GP) who are readers of independent drug bulletins can be used as an international epidemiological observatory of the criteria adopted by "well informed" doctors in various countries in the management of mild hypertension. DESIGN: Questionnaire study of GPs' diagnostic criteria for mild hypertension, routine investigation and management of patients with this diagnosis. PARTICIPANTS: 206 GPs readers of independent drug bulletins in 7 countries, comprising 95 known systematic readers of a local bulletin and 111 randomly selected regular subscribers. MAIN OUTCOME MEASURES: Response rate to the questionnaire. Diagnostic criteria, routine investigations, and treatment used for patients with mild hypertension. RESULTS: The study required two months for planning and implementation. Four countries out of eleven had a response rate < or = 50% and were excluded; the frequency of responses from other countries was 69%. The average diastolic blood pressure (DBP) considered diagnostic of mild hypertension range from 94 mm Hg (lower threshold) to 106 (upper threshold). A minority (17%) of GPs routinely request the minimum recommended laboratory tests to assess patients. GPs routinely advise non-drug measures before starting a drug. Most would not start drug treatment in patients without other risk factors and a DBP below 100 mmHg. The top first choice drugs were diuretics and beta-adrenoceptor blockers. Half of the doctors were able to quote some published guide to the management of mild hypertension, and 18% cited a relevant trial. Attitudes in diagnosing and treating mild hypertension differed widely between GPs and countries. CONCLUSIONS: GP readers of drug bulletins can be used quickly and inexpensively to assess the extent to which recommended diagnostic and therapeutic practices are accepted by "well informed" doctors. The results suggest that attitudes in managing mild hypertension vary widely among GPs and countries and differ remarkably from the recommendations of published guidelines.

Antihypertensive efficacy and tolerability of different drug regimens in isolated systolic hypertension in the elderly.

The pharmacological treatment, mainly based on diuretics, of isolated systolic hypertension (ISH) has recently been shown to reduce the risk of stroke and coronary heart disease in the elderly. The purpose of this study was to compare the antihypertensive effect and tolerability of different drug regimens in elderly subjects with ISH (systolic blood pressure--SBP-- > or = 160 mmHg and diastolic blood pressure--DBP-- < 90 mmHg). A multicentre, randomized, controlled open trial was planned in the general practice setting. Four widely used treatment schedules were tested: hydrochlorothiazide 25 mg plus amiloride 2.5 mg (H+Am), nifedipine slow release 20 mg (N), atenolol 50 mg (At) and atenolol 25 mg plus chlorthalidone 6.25 mg (At+C). After a baseline evaluation, 308 patients (76.3% female, mean age 75.3 +/- 7.1 years) were randomized and followed up for 6 months. After 3 months the drug dosage was doubled if the systolic blood pressure goal (SBP < 160 mmHg and SBP reduction of at least 20 mmHg) had not been reached. Ninety-four subjects (30.5%) presented contraindications to beta-blockers. At the 3rd- and 6th-month visits all treatment groups, except At, showed a significant reduction in SBP compared to the control group; DBP showed no significant reduction in any group at any time. At the end of the follow-up the percentage of hypertensives who had reached the BP goal was 14.6% in the control group, 52.9% in H+Am, 54.8% in N, 28.6% in At and 52.2% in At+C.(ABSTRACT TRUNCATED AT 250 WORDS)

Feasibility of a long-term low-sodium diet in mild hypertension.

The present study set out to assess the feasibility of long-term moderate dietary sodium restriction in patients with mild hypertension in general practice. After screening and a run-in phase of 6-8 weeks, a total of 77 previously undiagnosed mildly hypertensive patients were identified. Half of them were randomized to receive a few simple dietary instructions from their general practitioners in order to reduce salt usage; the others were randomized to receive no advice. The patients were followed up for 12 months with quarterly visits. A total of 56 patients (72.7%) completed the study, 26 on a low-sodium diet (LD) and 30 on their usual diet (UD). At each visit in the diet phase, patients provided 24h urine, which was analysed for volume and sodium concentration in order to assess their sodium intake. Blood pressure, heart the rate and body weight were recorded. The mean urinary sodium excretion for all diet phase visits overlapped in the two groups (177.0 +/- 32.9 vs. 169.3 +/- 49.4 mEq/24h respectively in the LD and UD groups). Nevertheless the mean systolic and diastolic blood pressures for all diet phase visits were significantly lower in the LD than in UD group (144.2 +/- 11.1/91.6 +/- 6.4 and 148.0 +/- 13.7/95.6 +/- 4.7 mmHg respectively, P less than 0.01). Our data suggest that it is not feasible at present to reduce sodium intake in mild hypertensives with simple and inexpensive dietary instructions, the only ones suitable for widespread application in general practice.