Relief of pain induced by varicella-zoster virus in a rat model of post-herpetic neuralgia using a herpes simplex virus vector expressing enkephalin.

Acute and chronic pain (post-herpetic neuralgia or PHN) are encountered in patients with herpes zoster that is caused by reactivation of varicella-zoster virus (VZV) from a state of neuronal latency. PHN is often refractory to current treatments, and additional strategies for pain relief are needed. Here we exploited a rat footpad model of PHN to show that herpes simplex virus (HSV) vector-mediated gene delivery of human preproenkephalin (vHPPE) effectively reduced chronic VZV-induced nocifensive indicators of pain. VZV inoculated at the footpad induced prolonged mechanical allodynia and thermal hyperalgesia that did not develop in controls or with ultraviolet light-inactivated VZV. Subsequent footpad administration of vHPPE relieved VZV-induced pain behaviors in a dose-dependent manner for extended periods, and prophylactic vector administration prevented VZV-induced pain from developing. Short-term pain relief following low-dose vHPPE administration could be effectively prolonged by vector re-administration. HPPE transcripts were increased three- to fivefold in ipsilateral ganglia, but not in the contralateral dorsal root ganglia. VZV hypersensitivity and its relief by vHPPE were not affected by peripheral delivery of opioid receptor agonist or antagonist, suggesting that the efficacy was mediated at the ganglion and/or spinal cord level. These results support further development of ganglionic expression of enkephalin as a novel treatment for the pain associated with Zoster.

Oral load of tyrosine or L-dopa and plasma levels of free and sulfoconjugated catecholamines in healthy men.

The levels of free and sulfoconjugated catecholamines were measured in the plasma of fasting, recumbent normal subjects before and after an oral load of the catecholamine precursors tyrosine or L-dopa. Basal values of sulfoconjugated catecholamines, measured in plasma samples diluted 1:100 were 7998 +/- 540 pg/ml for dopamine sulfate, 2938 +/- 281 pg/ml for norepinephrine sulfate, and 2958 +/- 288 pg/ml for epinephrine sulfate (n = 37 tests in 15 men); these basal values are higher than those reported previously. Neither free nor sulfoconjugated catecholamine concentrations were changed by a tyrosine load (100 mg/kg) that induced a doubling of the plasma tyrosine level or by a meal low in phenylalanine and tyrosine (but otherwise supplying constituents of normal nourishment) that induced a greater than 50% reduction in the plasma tyrosine concentration. After an oral load of L-dopa (125 mg) the following were observed. (1) An extremely large increase (greater than 100-fold) in dopamine sulfate levels was noted, an increase that was less marked in the same subjects given L-dopa (125 mg) plus the peripheral dopa-decarboxylase inhibitor carbidopa (12.5 mg); as expected, free dopamine concentration also was increased. (2) Neither free nor sulfoconjugated norepinephrine concentrations were altered. (3) Epinephrine sulfate but not free epinephrine concentration was increased (more than ten-fold) after L-dopa ingestion alone; this result was unexpected and has to be confirmed before considering its physiological meaning, if any.

Activity of cyclic GMP-dependent protein kinase in aortae from spontaneously hypertensive rats.

It has been suggested that various agents induce relaxation of vascular smooth muscles through guanosine 3',5'-cyclic monophosphate (cGMP) and cGMP-dependent protein kinase (cGMP-PK). In this work, the activity of cGMP-PK was studied in the 30,000 g supernatant from aortae of 4, 6, 8 and 12-week-old spontaneously hypertensive (SHR) and age-matched normotensive Wistar-Kyoto (WKY) rats and also of 4 and 12-week-old normotensive Wistar (W) and Sprague Dawley (SD) rats. At 4 weeks of age, both basal and cGMP-stimulated activity were not different in SHR and WKY rats. Nevertheless, a greater basal activity was measured in W (+50%) and SD (+20%) rats than in SHR, while no difference was observed between stimulated activities. In contrast with observations in the three normotensive rat strains, cGMP-PK activity did not decrease in the aortae supernatant of SHR rats aged 4-12 weeks. This resulted in mean increases of 45 and 30% in the basal and the cGMP-stimulated activity, respectively, in the 12-week-old SHR rats. The abnormal evolution of cGMP-PK activity in the hypertensive strain was already detectable at 4-6 weeks of age. In apparent agreement with observations on protein kinase activity, cGMP binding activity attributable to cGMP-PK was 25% greater in 12-week-old hypertensive rats compared with age-matched WKY rats. These results indicate that in aortae of SHR rats, control of cGMP-PK activity is abnormal early in life.

Pharmacokinetics of cibenzoline in patients with renal impairment.

Pharmacokinetic values of cibenzoline, a new, investigational, antiarrhythmic drug, were determined in 13 patients with varying degree of renal impairment, creatinine clearance range between 5 and 53 mL/min. Cibenzoline plasma levels were measured after direct intravenous injection of one single 1 mg/kg dose. The apparent volume of distribution of the drug (276 1) was similar to that reported in healthy subjects. Total body clearance decreased with creatinine clearance, and there was a close correlation between cibenzoline renal clearance and creatinine clearance (r = 0.956; P less than 0.001). Plasma elimination half-life was prolonged, with values ranging from 7:4 to 23.6 hours. This study showed that cibenzoline total body clearance correlated with the degree of renal impairment, and it is suggested that in patients with chronic renal failure dosage should be adjusted according to creatinine clearance values.

Bandlimited and Haar filtered back-projection reconstructions.

A new way to discretize the filtered back-projection (FBP) algorithm is presented. The function basis is the Haar system (2D product of rectangular windows). This scheme allows one to derive the optimal shape of the apodisation window, which is angle varying, and the oversampling ratio between the pixel and the projection cell size. The discrete equivalent filter is also derived. The comparison of standard radial band-limited and separable Haar reconstructions shows that improvements, in terms of linearity, shift-invariance and aliasing, can be obtained even for the case of a limited number of views. Considerations of projection degradations are then analyzed according to a specific imaging device to derive the optimum oversampling ratio.

Late streptokinase therapy in thrombotic microangiopathy: a case study.

A 42 year woman presented with malignant hypertension, anuria and hemolytic anemia with schistocytosis. The diagnosis of thrombotic microangiopathy was confirmed by early renal biopsy. Purely symptomatic treatment (peritoneal dialysis and hypotensive drugs) was supplemented by administration of heparin and Dipyridamole. Gastro-intestinal bleeding prevented early thrombolytic therapy. Microangiopathic anemia rapidly disappeared but anuria persisted. Three months later a second renal biopsy showed persistence of active lesions and absence of irreversible parenchymal damage. Streptokinase treatment was then instituted and followed by a rapid return of urinary output. Hemodialysis was stopped and renal function continued to improve over the following months. Two years later the patient remains well despite persistence of hypertension difficult to control. Creatinine clearance is stable at 20 ml/min. This observation suggests that late thrombolytic therapy may be effective in patients with thrombotic microangiopathy when histological findings do not indicate extensive irreversible lesions.

[Borderline essential hypertension and the adrenergic nervous system. Identification assay]. / Hypertension essentielle limite et système nerveux adrénergique. Essai d'identification.

The physiopathological participation of the sympathetic nervous system in borderline hypertension may be assessed on the following criteria: I) A quantitative rather than qualitative classification of hypertensive patients shows a group of patients with diastolic pressures between 75 and 95 mm Hg, in whom increases in cardiac output are closely related to increases in heart rate; 2) Clinical examination, which should include an assessment of personality, shows a higher incidence of signs in favour of an increase (absolute or relative) in sympathetic activity; 3) Plasma catecholamine levels are not helpful: the absence of raised concentrations could be related to increased excretion, especially by the kidney; 4) Urinary excretion of catecholamines is slightly raised: this is very evident when homovanillic acid levels are assessed.

[Acute hemodynamic study of intravenous nicardipine in arterial hypertension]. / Etude hémodynamique aiguë de la nicardipine intraveineuse dans l'hypertension artérielle.

The acute hemodynamic effects of intravenous Nicardipine (N), a new calcium antagonist, were studied in 8 patients with moderate essential hypertension. The forearm arterial blood flow (ABF) was measured using plethysmography before and after N infusion: 1st step was obtained after infusion of 1 mg during 5 min then 1 mg during 25 min; a second step was obtained after the infusion of the same dose during the same time; thus a cumulative dosage of 4 mg was infused over a total duration of 60 mn. Systolic (SBP), diastolic (DBP) mean (MBP) blood pressure and heart rate (HR) were measured every minute using a non invasive device (Dinamap). Systemic vascular resistances (SVR) were calculated. Plasma concentration of N was determined at the beginning, in the middle and at the end of each step. Results are as follows: (table; see text) A 33% decrease in SVR was observed at the 2nd step whereas MBP decreased by 15% only. The date confirm the potent vasodilatory effect of intravenous N at low dosage; the BP alteration was moderate in relation to an increase in local blood flow. These results indicate that Nicardipine could be useful as part of the treatment of chronic arteriopathy and Raynaud disease.

[Hemodynamic and hormonologic basis of the treatment of arterial hypertension]. / Bases hémodynamiques et hormonologiques du traitement de l'hypertension artérielle

The efficiency and the variety of drugs used in the treatment of arterial hypertension demand that the various disorders responsible for the blood pressure increase be well individualized. The study of the haemodynamic and hormonal factors and of their interelations in the patients provides interesting informations which make it possible to classify the hypertensive subjects according to physiopathological criteria. Starting from these data, it is possible to consider a rational treatment by selecting the drugs acting specifically on the anomalies to be corrected.

[The effects of inhibition of converting enzyme by perindopril on renal hemodynamics and natriuresis in essential arterial hypertension]. / Etude de l'inhibition de l'enzyme de conversion par le périndopril sur l'hémodynamique rénale et la natriurèse dans l'hypertension artérielle essentielle.

Renal hemodynamics and natriuresis have been studied before and 6 hours after oral intake of perindopril (8 mg) in 8 hypertensive patients without renal failure. Then, the patients were treated with perindopril (8 mg per day) and renal hemodynamics was repeated on the fifth day, 6 hours after the morning intake of the substance. Sodium diet was controlled during the study (100 mmol sodium per day). Renal blood flow (RBF) and glomerular filtration rate (GFR) were measured by the clearance method using 131I-hippuran and 125I-iothalamate respectively. The results are as follows: (table; see text) Perindopril produced a potent renal vasodilatation after the first intake and the following days without any change in GFR. A significant decrease in FF was observed indicating that efferent as well as afferent arteriolar vasodilatation was induced. Perindopril produced an increase in natriuresis after the first intake and at D5; this natriuretic effect may be related to the changes in renal hemodynamics inducing a decreased sodium reabsorption in the proximal tubule.

[Acute effects of metoprolol on blood pressure and heart rate. Value of the nitroglycerin test]. / Effets aigus du métoprolol sur la pression artérielle et la fréquence cardiaque. Intérêt du test à la trinitrine.

The acute effects of Metoprolol on blood pressure and heart rate were studied with reference to the plasma level of the betablocker in 10 patients (6 male and 4 female) with permanent moderate uncomplicated hypertension. Each patient was given a single oral dose of 200 mg Metoprolol: blood samples were taken over a 12 hour period at given times for Metoprolol estimation. The blood pressure was measured with a mercury manometer; heart rate was measured lying and during a stress test (glyceryl trinitrate). The antihypertensive effect of Metoprolol was significant from the 4th hour; at the 8th hour the systolic pressure was reduced by 15% and the diastolic pressure by 17% (p less than 0.001). The blood pressure then rose progressively. The heart rate in the recumbent position fell 10 to 15% during the study. The heart rate during the trinitrin test varied linearly with time (r = 0.991, p less than 0.001). The variation in systolic and diastolic blood pressure did not correlate with the plasma Metoprolol level (r = 0.03, and 0.19); no correlation was found between the fall in lying heart rate and the plasma betablocker level. On the other hand, the trinitrin heart rate (at the end of the test) correlated negatively with the logarithm of the plasma Metoprolol (n = 56, r = 0.688, p less than 0.001). These results confirm that the antihypertensive effect of Metoprolol is not directly related to the plasma level of the betablocker. On the other hand, the betablocker effect assessed by the trinitrin test, correlated with the plasma Metoprolol level. This relationship is similar to those previously observed with other betablockers; atenolol and oxprenolol.

[Renal effects of intravenous tertatolol in essential arterial hypertension]. / Effets rénaux du tertatolol intraveineux dans l'hypertension artérielle essentielle.

The acute renal effects of intravenous tertatolol were studied in eight patients with moderate essential hypertension: the study included a 100 mmol/day sodium intake during 3 days. Then, tertatolol was infused after a water load during 2 consecutive periods of 30 min (priming dose followed by constant infusion) in order to obtain plasma concentrations of tertatolol at 2 different levels: 10 ng/ml, then 40 ng/ml successively; the measurements were obtained at 15, 30, 45 and 60 min. The renal plasma flow (RPF) and the glomerular filtration rate (GFR) were calculated from the 131I-Hippuran clearance and the 125I-Iothalamate clearance respectively; a bladder catheter allowed a precise urine collection. The results indicate that intravenous tertatolol, at low dose, induced a marked and early renal vasodilatation; higher dose of tertatolol attenuated the vasodilator response, probably because of a decrease in cardiac output (suggested by the decrease in heart rate); thus, the systemic effects would hide the direct renal hemodynamic effects of tertatolol. Natriuresis and kaliuresis were unchanged by intravenous tertatolol.

[Effect of renal insufficiency on the pharmacokinetics of captopril and converting enzyme inhibition in the hypertensive patient]. / Influence de l'insuffisance rénale sur la pharmacocinétique du captopril et le blocage de l'enzyme de conversion chez l'hypertendu.

The influence of renal insufficiency (RI) on the pharmacokinetics of captopril (1 mg/kg, orally) and on the kinetics of the induced converting enzyme inhibition (CEI) was investigated in three groups of hypertensive patients: without RI (n = 10, plasma creatinine less than 100 mumol/l), with moderate RI (MRI) (n = 10,200 less than creatinine less than 400 mumol/l) and with severe RI (SRI) (n = 8, creatinine greater than 500 mumol/l). Captopril pharmacokinetic parameters were not modified by RI, with the exception of elimination half-life which was lengthened, but relative bioavailability of the drug was not modified. In contrast, captopril-induced CEI was strongly potentiated in patients with RI, an effect correlated with plasma creatinine values. This apparent discrepancy between the lack of modification in captopril plasma bioavailability and the prolongation of its biological effects can probably be accounted for by a decreased elimination and/or an increased formation of captopril metabolites during RI.

[Renovascular hypertension and beta blockers. Theoretical and practical implications]. / Hypertension réno-vasculaire et bêta-bloquants. Implications théoriques et pratiques.

Beta blockade was instituted in 10 patients with renovascular hypertension due to renal artery stenosis or thrombosis. The treatment was very effective in unilateral stenosis with a normal contralateral kidney (2 kidney Goldblatt) and in fibromuscular dystrophy of the renal artery. On the other hand many failures were observed in hypertension with a single kidney (1 kidney Goldblatt) and in renovascular hypertension with complex lesions or associated renal failure. Although a clear relationship was often observed between the increased plasma renin activity and the antihypertensive effect of beta blockade, this association was sometimes completely erroneous. Beta blockade, which is easy to perform, should be tried out systematically in renovascular hypertension, but, when no result is observed, this therapeutic test should not exclude surgical management thereafter.

[Clinical pharmacology of enalapril in hypertension with chronic renal failure]. / Pharmacologie clinique de l'énalapril dans l'hypertension artérielle avec insuffisance rénale chronique.

The effects of a single oral dose of enalapril (20 mg) on blood pressure (BP), heart rate (HR) plasma renin activity (PRA) aldosterone (PA), converting enzyme inhibition (CEI) and enalaprilat (E, active metabolite) were investigated during 96 h in 3 groups of 5 hypertensive patients with (1) normal renal function (creatinine clearance: Clcr greater than 80 ml.min-1); (2) moderate chronic renal failure: 80 greater than or equal to Clcr greater than 30 ml.min-1; (3) severe chronic renal failure: 30 greater than or equal to Clcr greater than 10 ml.min-1. Results are as follows (mean +/- SEM): (Table: see text) CEmax: maximal plasma concentration; TEmax: delay corresponding to CEmax; TE 1/2: plasma elimination half-life; AUCE: area under plasma level versus time curve. a: p less than 0.01; b: p less than 0.001; versus (1). In the 3 groups, CEI reached 87-94% as early as the 3rd h; however, at 96 h, CE1 was higher in (3) than in (1) and (2): 77.6 +/- 3.3% versus 6.0 +/- 1.6 and 17.7 +/- 4.8 (p less than 0.001 respectively). In (3). PRA increased at the 1st h and remained elevated: at 96 h, delta PRA was + 3.0 +/- 2.9 ng.ml-1 -.h-1 in (3) versus + 0.10 +/- 0.06 and + 0.25 +/- 0.17 ng.ml-1.h-1 .n (1) and (2) [(3) versus (1): p less than 0.01]; delta PA was lower in (3): -4.56 +/- 2.01 ng. 100 ml-1 versus -0.54 +/- 0.31 and -2.50 +/- 0.38 ng. 100 ml-1 [(3) versus (1): p less than 0.05].(ABSTRACT TRUNCATED AT 250 WORDS)

[Comparative effects of nifedipine and indapamide in the treatment of arterial hypertension]. / Effets comparés de la nifédipine et de l'indapamide dans le traitement de l'hypertension artérielle.

A controlled multicentre trial was organised to compare the effects of 20 mg Nifedipine tablets (N) and 2,5 mg Indapamide tablets (I) during a 4 months' treatment period after a placebo period, in 59 patients with moderate essential hypertension (n = 59). The results of blood pressure measurements of 18 patients treated by nifedipine (1 tablet twice daily) and 22 patients treated by indapamide (1 tablet every morning) were compared. The systolic blood pressure, after 10 minutes recumbency, fell from 165 +/- 10 mmHg to 148 +/- 13 mmHg (p less than 0.01), and the diastolic pressure from 104 +/- 6 mmHg to 86 +/- 7 mmHg (p less than 0.01) in the patients treated with nifedipine. In the indapamide group, the SBP fell from 164 +/- 13 mmHg to 152 +/- 15 mmHg (p less than 0.01) and the DBP from 100 +/- 4 mmHg to 87 +/- 6 mmHg (p less than 0.01). There were no significant changes of heart rate with either drug; plasma creatinine, potassium and uric acid concentrations were also unchanged. There was a higher incidence of headaches and tiredness in the nifedipine group, whilst patients treated with indapamide complained more often of muscular cramps. Flushing was observed in nearly a quarter of the patients in both groups. These results confirm that both nifedipine and indapamide induce significant and persistant falls in systolic and diastolic blood pressure. Although the fall was greater with nifedipine than with indapamide, the difference was not statistically significant. The tolerance was satisfactory in both groups of patients.(ABSTRACT TRUNCATED AT 250 WORDS)

[Acute and chronic effects of a new calcium blocker, nicardipine, on renal hemodynamics in arterial hypertension]. / Effets aigus et chroniques d'un nouvel inhibiteur calcique, la nicardipine, sur l'hémodynamique rénale dans l'hypertension artérielle.

Renal hemodynamics and natriuresis were studied in 9 hypertensive patients without renal failure, 2 hours and 4 hours after oral intake of Nicardipine 30 mg; sodium intake was kept constant during the study (100 mmol per day). Then, Nicardipine was given at a dose of 30 mg three times a day and the hemodynamic study was repeated on the 6th day (2 hours after the morning dose). Renal blood flow (RBF) and glomerular filtration rate (GFR) were measured by the clearance methods using 131I-hippuran and 125I-iothalamate respectively. Results are as follows: (Table: see text). These results confirm the potent renal vasodilatory effect of Nicardipine; GFR was not significantly altered while RBF and FF returned to normal levels. An early and transient natriuretic effect was observed after the first dose of Nicardipine and body weight showed a significant decrease during the study indicating that no sodium retention was induced by Nicardipine.

[Acute hemodynamic effects of prostacyclin in severe or malignant hypertension]. / Effets hémodynamiques aigus de la prostacycline dans les hypertensions sévères ou malignes.

The antihypertensive effect of Prostacyclin (PGI2) was investigated in 7 patients with severe or malignant hypertension. Cardiac output (dilution method), arterial blood pressure and total blood volume (TBV, radio-albumin dilution method) were measured before and during a PGI2 infusion, the effective dose ranging from 10 to 20 ng/kg/min. Cardiac index(CI) rose from 2.8 to 3.9 1/min/m2 and heart rate (HR) from 75 to 94 beats/min (p less than 0.01) Mean blood pressure decreased from 154 to 120 mmHg (p less than 0.001) and total peripheral resistances from 4650 to 2540 dynes.s.cm-5 (p less than 0.001). The ratio: central blood volume/total blood volume increased from 0.21 to 0.26 (p less than 0.001). The results confirm that PGI2 produces a potent vasodilatation of the systemic compartment with a marked decrease in blood pressure; however the antihypertensive effect is blunted by the increase in CI mainly related to the increase in HR; significant central translocation of blood suggests that PGI2 does not produce dilatation of the capacitance vessels. Sympathetic nervous system is highly stimulated by PGI2 very likely through the baroreceptor system.

[Renal effects of captopril in hypertension with renal artery stenosis. Comparison between Tc-99m-DTPA scintigraphy and clearance method]. / Effets rénaux du captopril dans l'hypertension avec sténose d'artère rénale. Comparaison entre scintigraphie au Tc-99m-DTPA et méthode des clairances.

In eleven hypertensive patients with renal artery stenosis, the acute renal effects of captopril were investigated using two methods: 1) the Tc99m-DTPA renography with determination of an index of renal perfusion (IP), an index of glomerular filtration (IF) and the ratio of these indices (F/P); 2) the renal hemodynamics obtained by the clearance method using a continuous infusion of I131-hippuran and I125-iothalamate for calculation of renal blood flow (RBF), glomerular filtration rate (GFR) and filtration fraction (FF). The studies were performed before and after captopril treatment. Patients were classified according to the acute response to captopril as responders (R; n = 6) and non responders (NR; n = 5). Results are as follows: (B: basal, C = captopril). (table; see text) These data confirm that captopril produced a significant decrease in F/P and FF in R whereas these indices did not change in NR; it was found that IF and GFR decreased in R whereas IF increased and GFR did not change in NR; a significant correlation was observed between delta IF and delta GFR in R (r = 0.834, p less than 0.05). These results indicate that 1) data obtained before and after captopril by renography and by clearance methods are in good correlation either in Ror in NR patients; 2) Captopril test including renography or renal hemodynamic measurements is useful for selection of R patients.

[Clinical pharmacology of prazosin in arterial hypertension with chronic renal insufficiency]. / Pharmacologie clinique de la prazosine dans l'hypertension artérielle avec insuffisance rénale chronique.

The pharmacokinetics of prazosin were studied in 10 patients (7 male and 3 female, Group I) with permanent hypertension and chronic renal failure (serum creatinine 40,5 +/- 5,9 mg/l) and in 10 normal subjects (10 male, Group II). Each patient received a single oral dose of 2 mg of prazosin; serum levels were studied at regular intervals over a ten hour period by spectrofluorometry Clinostatic blood pressure was measured with a mercury manometer in the patients in Group I. The rate of absorption of prazosin was identical in the two groups (t max: I,3 +/- 0,2 h and I,6 +/- 0,4 h). Maximal serum concentrations were significantly higher in Group I (33,5 +/- 3,7 microgram/1 compared to 22,0 +/- 2.5 microgram/l, p less than 0,02) as was the surface under the serum concentration curve plotted against time (206,I +/- 31.I microgram.h.l-1 compared to 99,9 +/- 12,3 microgram.h.l-1, p less than 0,01). Prazosin induced a significant fall in systolic and diastolic blood pressure (-19% and -23% respectively, p less than 0.001) in Group I, 90 minutes after administration, associated with a moderate rise in heart rate (+16%, p less than 0.01). The variation of blood pressure induced by prazosin correlated closely with its serum concentration (p less than 0.001). These results suggest that the bioavailability of prazosin is significantly higher in chronic renal failure and that a reduction of the daily dose should be envisaged in these patients on long-term therapy.