[A descriptive epidemiological study on canine babesiosis in the Lake Geneva region]. / Etude épidémiologique descriptive de la Babésiose canine dans la Région Lémanique.

A descriptive study was carried out in the district of the Lake Geneva between March 1, 2005 and August 31,2006 to assess the incidence and prevalence of canine babesiosis, to genotype the Babesia species occurring, to assess the most frequently clinical signs found and to address the potential of autochthonous transmission. This included a data assessment on the different tick-populations occurring in the area and on the prevalence of Babesia-DNA in these ticks. A total of 56 veterinary practices participated in the study. By blood smear and PCR, Babesia canis canis was found in 12 out of 21 cases with suspected babesiosis. In an additional 13th case, the parasite could only be detected by PCR. All autochthonous cases originated from the Western part of the Lake Geneva region. Clinical signs in affected dogs included inappetence, apathy, anemia, fever, hemoglobinuria and thrombocytopenia. There were no risk factors with regard to age, sex and breed. Most cases were diagnosed during the spring periods of 2005 and 2006 (11 cases) and two cases in autumn 2005, coinciding with the main activity period of Dermacentor reticulatus, the main vector of B. canis canis. A total of 495 ticks were collected on patients by the veterinarians, 473 were identified as Ixodes sp., 7 as Rhipicephalus sanguineus and 15 as Dermacentor reticulatus. While Ixodes sp. was found in the whole study area, D. reticulatus and R. sanguineus occurred only in the Western part till Lausanne. PCR and sequencing yielded B. canis canis positivity in 3 D. reticulatus specimen, these three ticks were collected from two different dogs both suffering from babesiosis. All R. sanguineus were negative by Babesia-PCR. Global warming, ecological changes in the potential habitat of ticks, increasing host- and vector-populations and increasing mobility of dog owners may be responsible for an emergence situation of infection risk for Babesia spp. by time. E.g., Dermacentor reticulatus has become autochtonously prevalent already till Lausanne in the Lake Geneva region, and further surveillance is suggested to tackle this problem.

[Blood pressure recording in outpatient service: experience with the Sandoz Pressure System]. / Enregistrement tensionnel en ambulatoire: expérience avec le Sandoz Pressure System.

The Sandoz Pressure System (SPS) is a widely used device for ambulatory blood pressure recording. The accuracy of blood pressure profiles recorded in daily routine with this device has been demonstrated. In 34 untreated hypertensive patients the blood pressure values were in good agreement with measurements taken by auscultation. The variability of recordings was less or equal to 5 mmHg in 10% of patients for the systolic and in 94% of patients for the diastolic value. During daily activity 100 +/- 6% (mean +/- standard deviation) of the values expected by programming were available for analysis. These results confirm that arterial pressure under ambulatory conditions cannot be reliably predicted based on blood pressure measurements in the doctor's office.

Effects of SCH 34826, an orally active inhibitor of atrial natriuretic peptide degradation, in healthy volunteers.

Atrial natriuretic peptide is cleared from plasma by clearance receptors and by enzymatic degradation by way of a neutral metalloendopeptidase. Inhibition of neutral metalloendopeptidase activity appears to provide an interesting approach to interfere with metabolism of atrial natriuretic peptide to enhance the renal and haemodynamic effects of endogenous atrial natriuretic peptide. In this study, the effects of SCH 34826, a new orally active neutral metalloendopeptidase inhibitor, have been evaluated in a single-blind, placebo-controlled study involving eight healthy volunteers who had maintained a high sodium intake for 5 days. SCH 34826 had no effect on blood pressure or heart rate in these normotensive subjects. SCH 34826 promoted significant increases in excretion of urinary sodium, phosphate, and calcium. The cumulative 5-hour urinary sodium excretion was 15.7 +/- 7.3 mmol for the placebo and 22.9 +/- 5, 26.7 +/- 6 (p less than 0.05), and 30.9 +/- 6.8 mmol (p less than 0.01) for the 400, 800, and 1600 mg SCH 34826 doses, respectively. During the same time interval, the cumulative urinary phosphate excretion increased by 0.3 +/- 0.4 mmol after placebo and by 1.5 +/- 0.3 (p less than 0.01), 1.95 +/- 0.3 (p less than 0.01), and 2.4 +/- 0.4 mmol (p less than 0.001) after 400, 800, and 1600 mg SCH 34826, respectively. There was no change in diuresis or excretion of urinary potassium and uric acid. The natriuretic response to SCH 34826 occurred in the absence of any change in plasma atrial natriuretic peptide levels but was associated with a dose-dependent elevation of urinary atrial natriuretic peptide and cyclic guanosine monophosphate.(ABSTRACT TRUNCATED AT 250 WORDS)

Oral administration of DuP 753, a specific angiotensin II receptor antagonist, to normal male volunteers. Inhibition of pressor response to exogenous angiotensin I and II.

BACKGROUND: The purpose of the present study was to assess the inhibitory effect of DuP 753, an orally active angiotensin II receptor antagonist, on the pressor action of exogenous angiotensin I and II in healthy male volunteers. METHODS AND RESULTS: In the first study (single-dose study), eight volunteers were included in a 2-day protocol repeated four times at 1-week intervals. In each phase, a different dose of drug (2.5, 5, 10, 20, or 40 mg) or placebo was given. The peak systolic blood pressure response to a test-dose of angiotensin I was determined serially before and after oral administration of DuP 753 by continuously monitoring finger blood pressure using a photoplethysmographic method. DuP 753 reduced the systolic blood pressure response to angiotensin I in a dose-dependent fashion. Three, 6, and 13 hours after the 40-mg dose, blood pressure response decreased to 31 +/- 5%, 37 +/- 6%, and 45 +/- 3% of the control values (mean +/- SEM, n = 7), respectively. In the second study, 29 volunteers were treated for 8 days with either a placebo or DuP 753 (5, 10, 20, or 40 mg p.o. q.d.) and challenged on the first, fourth, and eighth days with bolus injections of angiotensin II. Again, the inhibitory effect on the systolic blood pressure response to angiotensin II was clearly dose dependent. Six hours after 40 mg DuP 753, the systolic blood pressure response to the test-dose of angiotensin II was reduced to 37 +/- 7%, 40 +/- 4%, and 38 +/- 6% of baseline values (mean +/- SEM, n = 6) on days 1, 4, and 8, respectively. With this latter dose, there was still a blocking effect detectable 24 hours after the drug. Similar to angiotensin converting enzyme and renin inhibitors, DuP 753 induced a dose-dependent increase in plasma renin that was more pronounced on the eighth than on the first day of drug administration. In these normal volunteers, no consistent clinically significant side effects were observed. There was no evidence for an agonist effect. CONCLUSIONS: DuP 753 appears to be a well-tolerated, orally active, potent, and long-lasting antagonist of angiotensin II in men.

Precursors of neuropeptides in the marine worm Nereis diversicolor. In vitro translation of a precursor related to human prepro-cholecystokinin and immunolocalization of this precursor in the nervous system.

Total mRNA extracted from the brain of a marine worm, Nereis diversicolor, were in vitro translated using 2 cell-free systems: rabbit reticulocyte lysate and wheat germ extract. Among numerous products newly translated in both systems, only one class of 70 kDa polypeptides immunoprecipitated when we used a mixture of 3 well defined antibodies raised against known sequences of the human prepro-CCK. At the cellular level, using immunocytochemistry techniques, strong and moderate immunoreactivities were seen in perikarya located in various ganglionic nuclei of the worm brain. Immunoreactive nerve fibres were visible in the neuropile but not in the infracerebral region, a neurohemal area. Immunoreactions also appeared on perikarya located in the anterior and medial groups of the ventral nerve cord. Furthermore, immunolabeled cells were observed in the midgut. Interestingly, several co-localizations of materials immunologically related to human prepro-CCK and CCK/gastrin were observed in the brain and the ventral nerve cord both in perikarya and in nerve fibres. We propose that, in Nereis a polypeptide (molecular mass 70 kDa) is the large precursor of molecules related to those of the CCK/gastrin peptide family.

Hemodynamic and humoral effects of the new renin inhibitor enalkiren in normal humans.

The effect of the renin inhibitor enalkiren (Abbott-64662) was evaluated in eight normal volunteer subjects on a standardized sodium diet (100 mmol/day) by measurement of various components of the renin-angiotensin system and drug levels in plasma. On day 1, vehicle and doses of 0.001, 0.003, and 0.01 mg/kg i.v. were administered within 2 minutes at 90-minute intervals. On day 2, vehicle and doses of 0.01, 0.03, and 0.1 mg/kg i.v. were given. With the higher doses, blood pressure tended to decrease slightly with no change in heart rate. Plasma renin activity and plasma angiotensin-(1-8)octapeptide (angiotensin II) fell markedly in a dose-dependent manner. Inhibition of plasma renin activity was maximal 5 minutes after administration of the drug and persisted 90 minutes after the doses of 0.03 and 0.1 mg/kg. Not surprisingly, there was a close correlation between plasma renin activity and plasma angiotensin II levels (r = 0.81, n = 28, p less than 0.001). In contrast, active and total renin measured directly by monoclonal antibodies rose in dose-related fashion in response to renin inhibition. Pharmacokinetic parameters were calculated using the plasma drug concentrations obtained up to 6 hours after the 0.1 mg/kg dose. By means of a two-compartment model, plasma mean half-life of the drug was estimated at 1.60 +/- 0.43 hours.

Effects of intranasal administration of synthetic (4-28)human atrial natriuretic peptide to normal volunteers.

The effects of intranasal administration of increasing doses of synthetic human natriuretic peptide (4-28 hANP) were studied in six healthy volunteers. The peptide was administered as a nasal spray at doses of 50, 100, 200, and 500 micrograms in ascending order at 48-h intervals. Vehicle was administered by the same route randomly between any two of the doses. Intranasal hANP administration had no effect on either blood pressure, heart rate (HR), or hematocrit. Diuresis did not change consistently, whereas natriuresis tended to rise with vehicle as well as with hANP administration. This was attributed to the infusion of isotonic saline during the experiment. There was no significant increase in plasma ANP levels after intranasal administration of any of the different doses. Thus, no evidence that the atrial natriuretic peptide tested (4-28 hANP) can cross the nasal mucosal barrier was found.

Effects of prolonged administration of the angiotensin converting enzyme inhibitor CGS 16617 in normotensive volunteers.

A new, orally active angiotensin converting enzyme (ACE) inhibitor, CGS 16617, has been evaluated in normotensive subjects during acute and prolonged administration. Single ascending doses of CGS 16617 20 to 100 mg were given to 9 normotensive volunteers at one week intervals and the changes in blood pressure, plasma ACE and renin activity were examined up to 72 h after drug intake. Also, CGS 16617 50 mg/day or placebo were given for 30 days to 8 and 6 normotensive subjects, respectively, maintained on an unrestricted salt diet. Blood pressure was measured daily in the office and ambulatory blood pressure profiles were also obtained before, during and after therapy, using the Remler M 2000 blood pressure recording system. CGS 16617 was an effective and long lasting ACE inhibitor. It did not induce a consistent change in blood pressure, but, the individual responses were very variable and several subjects experienced a clear decrease in the average of the blood pressures recorded during the daytime.

Individual responses to converting enzyme inhibitors and calcium antagonists.

This study was designed to assess whether the acute blood pressure response of an individual hypertensive patient to a calcium antagonist or an angiotensin converting enzyme (ACE) inhibitor is a good predictor of the long-term efficacy of these drug classes in this particular patient. The concept that good responses to ACE inhibitors and calcium antagonists may be mutually exclusive was also tested. Sixteen patients were included in a randomized crossover trial of enalapril, 20 mg daily, and diltiazem, 120 mg daily, for 6 weeks each. Blood pressure was measured by ambulatory blood pressure recording. During the washout phase, the acute effect of nifedipine, 10 mg p.o., and enalaprilat, 5 mg i.v., was evaluated. Nifedipine and enalaprilat reduced blood pressure equally well. The long-term blood pressure reduction induced by enalapril and diltiazem was similar. The acute blood pressure response to a given drug was not a good predictor of the result obtained with long-term therapy. No age dependency of the antihypertensive effect of either drug class was apparent. There was no evidence that a good response to one drug excluded a similarly good response to the other.

Calcium entry blockade attenuates the acute blood pressure rise induced by cigarette smoking.

The purpose of this study was to assess whether the administration of a calcium entry blocker can prevent the acute blood pressure rise induced by cigarette smoking. Seven male habitual smokers were included. After 45 min of equilibration, they took in randomized single-blind fashion at a 1 week interval either a placebo or nifedipine, 10 mg p.o. Thirty minutes thereafter, the subjects smoked within 10 min two cigarettes containing 1.4 mg of nicotine each. In addition to heart rate and skin blood flow (laser Doppler method), blood pressure of the median left finger was monitored continuously for 100 min using a noninvasive device (Finapres). Nifedipine induced an increase in skin blood flow that was not influenced by smoking. This skin blood flow response was observed although nifedipine had by itself no effect on systemic blood pressure. The calcium antagonist markedly attenuated the blood pressure rise induced by cigarette smoking. However, it tended to accentuate the heart rate acceleration resulting from inhalation of nicotine-containing smoke.

Hemodynamic, renal, and endocrine effects of 4-h infusions of human atrial natriuretic peptide in normal volunteers.

A synthetic human atrial natriuretic peptide of 26 aminoacids [human (3-28)ANP or hANP] was infused into normal male volunteers. Six subjects were infused for 4 h at 1-wk intervals with either hANP at the rate of 0.5 or 1.0 microgram/min or its vehicle in a single-blind randomized order. Human (3-28)ANP at the dose of 0.5 microgram/min raised immunoreactive plasma ANP levels from 104 +/- 17 to 221 +/- 24 pg/ml (mean +/- SEM), but it induced no significant change in blood pressure, heart rate, effective renal plasma flow, glomerular filtration rate, or renal electrolyte excretion. At the rate of 1.0 microgram/min, human (3-28)ANP increased immunoreactive plasma ANP levels from 89 +/- 12 to 454 +/- 30 pg/ml. It reduced effective renal plasma flow from 523 +/- 40 to 453 +/- 38 ml/min (P less than 0.05 vs. vehicle), but left glomerular filtration rate unchanged. Natriuresis rose from 207 +/- 52 to 501 +/- 69 mumol/min (P less than 0.05 vs. vehicle) and urinary magnesium excretion from 3.6 +/- 0.5 to 5.6 +/- 0.5 mumol/min (P less than 0.01 vs. vehicle). The excretion rate of the other electrolytes, blood pressure, and heart rate were not significantly modified. At both doses, human (3-28)ANP tended to suppress the activity of the renin-angiotensin-aldosterone system. In 3 additional volunteers, the skin blood flow response to human (3-28)ANP, infused for 4 h at the rate of 1.0 microgram/min, was studied by means of a laser-doppler flowmeter. The skin blood flow rose during the first 2 h of peptide administration, then fell progressively to values below baseline. After the infusion was discontinued, it remained depressed for more than 2 h. Thus, in normal volunteers, human (3-28)ANP at the dose of 1.0 microgram/min produced results similar to those obtained previously with rat (3-28)ANP. It enhanced natriuresis without changing the glomerular filtration rate while effective renal plasma flow fell. It also induced a transient vasodilation of the skin vascular bed.

[Effect of atrial natriuretic factor on the hematocrit of patients in chronic hemodialysis]. / Effet du facteur natriurétique auriculaire sur l'hématocrite de patients en hémodialyse chronique.

A synthetic atrial natriuretic peptide (ANF) has been administered to 7 patients with chronic renal failure to evaluate the role of ANF in the regulation of blood volume. ANF (2 micrograms/min) was infused for 60 minutes before hemodialysis and blood pressure, heart rate, plasma proteins and hematocrit were measured at regular intervals. Although a slight decrease in blood pressure occurred during ANF infusion, no significant changes in hematocrit and plasma proteins were observed. These results suggest that administration of exogenous ANF does not modify the volume distribution in patients with chronic renal failure. ANF's lack of effect is perhaps due to the chronic hypervolemia and the high plasma levels of endogenous ANF commonly found in these patients.

Effect of eight-day converting enzyme inhibition on ambulatory blood pressure recordings in normotensive volunteers.

The three angiotensin converting enzyme (ACE) inhibitors cilazapril, perindopril and CGS 14824A were administered for 8 days to, respectively, 6, 5 and 5 normotensive healthy volunteers maintained on an unrestricted salt intake. Before starting treatment, as well as on the last day of therapy, an ambulatory blood pressure profile was obtained with a semi-automatic blood pressure recorder (Remler M2000). An additional blood pressure recording was performed 1 month after the end of the 8-day course of treatment with cilazapril and CGS 14824A. Eight day ACE inhibition with any of the 3 drugs did not result in a consistent decrease of ambulatory blood pressure recordings. This suggests that in normotensive subjects on a free salt intake the renin-angiotensin system may not be a key determinant of blood pressure.

Repeated administration of the converting enzyme inhibitor cilazapril to normal volunteers.

Cilazapril 1.25 and 5.0 mg p.o. q.d. was administered in double-blind fashion to two groups of six normal volunteers on 8 consecutive days. Blood pressure, heart rate, and plasma converting enzyme activity were measured each day prior to drug administration and up to 72 h after the last dose. Plasma renin activity, blood angiotensin I, plasma angiotensin II, and aldosterone as well as plasma cilazaprilat levels were determined on the first and the last day of active treatment at times 0, 4, and 24 h. The drug was very well tolerated by all volunteers. At 4 h postdrug, plasma converting enzyme activity was reduced in dose-dependent fashion on the first and the eighth day; plasma cilazaprilat levels were also clearly dose dependent. Nevertheless, 24 h postdrug cilazaprilat levels were similar on the first and last day of drug administration, and plasma converting enzyme activity was also stable throughout the 8 days. The various components of the renin-angiotensin system responded in the usual fashion. These results provide strong evidence that cilazapril is a very potent and highly effective converting enzyme inhibitor. Doses well below 5 mg/day will probably suffice for therapeutic efficacy. These data also confirm the hypothesis formulated in the preceding article, i.e., that there is no accumulation of the drug with repeated administration despite its long pharmacological half-life (t1/2).

Effect of prolonged angiotensin converting enzyme inhibition on ambulatory blood pressure of normotensive volunteers.

The blood pressure effect of 8-day angiotensin converting enzyme (ACE) inhibition was studied in normotensive healthy volunteers maintained on an unrestricted salt intake. Six volunteers received cilazapril (5 mg/day), 5 perindopril (8 mg/day) and 5 CGS14824A (10 mg/day). The 3 investigational inhibitors were found to have no consistent effect on blood pressure monitored during day-time outside the clinic using a semi-automatic blood pressure recorder (Remler M2000).

Angiotensin-converting enzyme inhibitor versus calcium antagonist in the treatment of hypertension.

Sixteen patients with essential hypertension were treated for 2 consecutive 6-week periods with either the angiotensin-converting enzyme (ACE) inhibitor enalapril (20 mg once daily) or the calcium antagonist diltiazem (120 mg twice daily). The sequence of the treatment phases was randomly allocated. Blood pressure decreased from 154/102 +/- 5/2 mm Hg (mean +/- SEM) to 135/96 +/- 4/2 and 140/98 +/- 3/2 mm Hg during treatment with enalapril and diltiazem, respectively. It was impossible in the individual hypertensive patient to predict the long-term blood pressure response to one of the agents studied based on the long-term blood pressure response to the other agent.

Acute antihypertensive effect of angiotensin converting enzyme inhibition and calcium entry blockade.

The acute blood pressure response to an angiotensin converting enzyme inhibitor (enalaprilat) was compared in patients with uncomplicated essential hypertension with that obtained under similar conditions with a calcium entry blocker (nifedipine). The patients were studied after a 3 week washout period. At a 48 h interval, each patient received in randomized order either enalaprilat (5 mg i.v.) or nifedipine (10 mg p.o.). Enalaprilat and nifedipine were equally effective in acutely lowering blood pressure. However, good responders to one agent were not necessarily good responders to the other.

[Effects of perfusion of human atrial natriuretic factor in normal volunteers]. / Effets d'une perfusion de facteur natriurétique auriculaire humain chez des volontaires sains.

The renal and systemic effects of a synthetic atrial natriuretic peptide (ANP) corresponding to the sequence of the human hormone was investigated in normal volunteers. Each subject was infused for 4 hours on 3 different days at a one week interval with either ANP (0.5 or 1 microgram/min) or its vehicle. ANP enhanced natriuresis without simultaneously modifying glomerular filtration rate. ANP did, however, reduce effective renal plasma flow. In spite of the increased natriuresis, the activity of the renin-angiotensin-aldosterone system was reduced during ANP infusion. ANP induced a transient increase in skin blood flow. No change in blood pressure and heart rate occurred in the course of the experiment.

Four-hour infusions of synthetic atrial natriuretic peptide in normal volunteers.

Two doses of synthetic atrial natriuretic peptide (0.5 and 5.0 micrograms/min) and its vehicle were infused intravenously for 4 hours in eight salt-loaded normal volunteers, and the effect on blood pressure, heart rate, renal hemodynamics, solute excretion, and secretion of vasoactive hormones was studied. The 0.5 micrograms/min infusion did not alter blood pressure or heart rate, whereas the 5.0 micrograms/min infusion significantly reduced the mean pressure by 20/9 mm Hg after 2.5 to 3 hours and increased the heart rate slightly. Inulin clearance was not significantly changed, but the mean p-aminohippurate clearance fell by 13 and 32% with the lower and higher doses, respectively. Urinary excretion of sodium and chloride increased slightly with the lower dose. With the higher dose, a marked increase in urinary excretion of sodium, chloride, and calcium was observed, reaching a peak during the second hour of the infusion. Potassium and phosphate excretion did not change significantly. A brisk increase in urine flow rate and fractional water excretion was seen only during the first hour of the high-dose infusion. Signs and symptoms of hypotension were observed in two subjects. No change in plasma renin activity, angiotensin II, or aldosterone was observed during either infusion, but a marked increase occurred after discontinuation of the high-dose infusion. In conclusion, the 5 micrograms/min infusion induced a transient diuretic effect, delayed maximal natriuretic activity, and a late fall in blood pressure, with no change in inulin clearance but a dose-related decrease in p-aminohippurate clearance. Despite large amounts of sodium excreted and blood pressure reduction, no counterregulatory changes were observed in the renin-angiotensin-aldosterone system or plasma vasopressin levels during the infusion.

Single and repeated dosing of the converting enzyme inhibitor perindopril to normal subjects.

The new orally active angiotensin converting enzyme (ACE) inhibitor perindopril (S9490-3) was evaluated in 18 normotensive men. In three subjects the pressor response to exogenous angiotensin I was tested. A 8 mg oral dose reduced the pressor response by greater than 80%. Single oral perindopril doses of 2, 4, 8, and 16 mg were given to groups of five subjects each. Eight and 16 mg decreased plasma ACE activity within 4 hours to less than 10% of control; 72 hours later, plasma ACE activity was still reduced by at least 40%. Doses of 4 and 8 mg po once a day were then given for 8 days to two groups of six subjects. Four hours after the first and the last morning doses, plasma angiotensin II, aldosterone, and plasma ACE activity fell significantly, whereas blood angiotensin I and plasma renin activity rose. There was no evidence of drug accumulation. No significant change in blood pressure or heart rate was observed. Thus in normotensive subjects, perindopril seems an effective, orally active, long-lasting ACE inhibitor.