Chronic high dose transdermal nicotine in Parkinson's disease: an open trial.

Whether nicotine has therapeutic effects on Parkinson's disease (PD) symptoms is controversial, but high doses and chronic treatment have never been tested. We report the results of a pilot, open-label trial to assess the safety and possible efficacy of chronic high doses of nicotine. Six patients with advanced idiopathic PD received increasing daily doses of transdermal nicotine up to 105 mg/day over 17 weeks. All patients but one accepted the target dose. Nausea and vomiting were frequent but moderate, and occurred in most of the patients (four of six) who received over 90 mg/day and 14 weeks of nicotine treatment. During the plateau phase, patients improved their motor scores and dopaminergic treatment was reduced. These results confirm the feasibility of chronic high dose nicotinic treatment in PD but warrant validation of the beneficial effects by a randomized controlled trial.

Simultaneous analysis of heart rate variability and myocardial contractility during head-up tilt in patients with vasovagal syncope.

INTRODUCTION: The aim of this study was to evaluate simultaneously cardiac autonomic activity, through heart rate variability (HRV) analysis, and cardiac inotropic changes during head-up tilt (HUT) in patients with recurrent vasovagal syncope. METHODS AND RESULTS: Twelve subjects implanted with a permanent dual-chamber pacemaker for recurrent vasovagal syncope characterized by marked bradycardia were studied. The tip of the right ventricular electrode was equipped with a sensor that measured peak endocardial acceleration (PEA) as an index of myocardial contractility. RR interval and PEA signals were acquired simultaneously and processed in the time and frequency (low frequencies [LF] and high frequencies [HF] of RR signal) domain during early HUT (T1), late HUT, or before syncope (T2). In the six subjects with positive HUT: (1) Abnormal heart rate oscillations were evidenced at T1 and discriminated this group from the negative group (LF/HF decreased by 46% from supine to T1, but increased by 55% in the negative group; P < 0.01 positive vs negative HUT). (2) Gradual diminution of the HF component was associated with an increase in PEA index during HUT with a correlation between PEA/RR interval (R = -0.8, P < 0.001), PEA/HF components (R = -0.6, P < 0.05). (3) Sympathetic stimulation responsible for changes in both HRV and PEA parameters occurred immediately before the faint (LF/LF+HF: 0.6 +/- 0.2 to 0.8 +/- 0.09; P < 0.05 T2 vs T1; PEA: 0.62 +/- 0.10G to 0.83 +/- 0.22G; P < 0.01 T2 vs T1). CONCLUSION: Our findings showed that a homogeneous subgroup of patients with recurrent vasovagal syncope and positive HUT exhibited abnormal cardiac autonomic and inotropic responses to an orthostatic stimulus. Continuous changes over time of HRV and PEA parameters highlight the dynamic behavior of the mechanisms leading to syncope.

[Effects of 17beta-estradiol on peripheral and coronary vasomotor function in postmenopausal women]. / Effets du 17 beta-estradiol sur la vasomotricité périphérique et coronaire chez la femme ménopausée.

Women appear to be protected, until the menopause, from the development of coronary artery syndromes. This protective effect seems to be due to the beneficial effect of ovarian hormones, in particular oestrogens. A number of potential mechanisms for the protective effect of oestrogens have been proposed. An important postulated mechanism could be by improving the function of vascular endothelium. In this review, we present the currently published studies that have evaluated the effects of 17 beta-estradiol, the only oestrogen used in France for hormone replacement therapy, on peripheral and coronary vasomotor function in postmenopausal women.

Glucocorticoids inhibit sulfur mustard-induced airway muscle hyperresponsiveness to substance P.

To explore the mechanisms of airway hyperreactivity to aerosolized substance P observed in guinea pigs 14 days after intratracheal injection of sulfur mustard (SM), we studied the effects of epithelium removal and inhibition of neutral endopeptidase (NEP) activity on airway muscle responsiveness. Tracheal rings from SM-intoxicated guinea pigs expressed a greater contractile response to substance P than rings from nonintoxicated guinea pigs. After epithelium removal or incubation with the NEP inhibitor phosphoramidon, the contractile responses of tracheal rings to substance P did not differ in guinea pigs injected with SM or ethanol (SM solvent). Treatment of the guinea pigs with betamethasone for 7 days before measurement abolished the airway muscle hyperresponsiveness observed in untreated SM-intoxicated guinea pigs and partially restored tracheal epithelium NEP activity. In addition, the tracheal epithelium height and cell density of SM-intoxicated guinea pigs treated with betamethasone were significantly greater than in those without betamethasone. These results demonstrate that SM intoxication induces airway muscle hyperresponsiveness to substance P by reducing tracheal epithelial NEP activity and that glucocorticoids might inhibit this hyperresponsiveness by increasing this activity.

Acute and chronic respiratory effects of sulfur mustard intoxication in guinea pig.

Sulfur mustard (SM) has been used as a vesicant chemical warfare agent. To investigate the respiratory damages it causes, we studied the effects on guinea pigs of an intratracheal injection of 0.3 mg/kg of SM 5 h and 14 days after injection. Five hours after SM intoxication, respiratory system resistance and microvascular permeability were increased. These alterations were not prevented by pretreatment with 50 mg/kg sc of capsaicin 2 wk before SM intoxication. Histological studies showed columnar cell shedding all along the tracheal epithelium, bronchoconstriction, and peribronchial edema. Fourteen days after SM intoxication, guinea pigs demonstrated airway hyperreactivity to aerosolized substance P and histamine. Pretreatment with phosphoramidon caused a further increase in airway responsiveness to substance P. Neutral endopeptidase activity in the tracheal epithelium was decreased by twofold in SM-intoxicated guinea pigs. At this stage, the tracheal epithelium was disorganized and atrophic. These results demonstrate that in guinea pigs SM intoxication induces severe lesions to the tracheal epithelium, which might account for the airway hyperresponsiveness observed 14 days after intoxication.

Effects of capsaicin on the airway responses to inhaled endotoxin in the guinea pig.

Inhalation of lipopolysaccharide (LPS) has been associated with increased airway responsiveness and inflammation both in humans and in animals. To investigate the contribution of capsaicin-sensitive nerves to these changes, we compared airway responsiveness and inflammation after intratracheal administration of 10 micrograms/kg LPS (Escherichia coli O55:B5 lipopolysaccharide) or saline in guinea pigs treated 10 days previously with 50 mg/kg capsaicin and in those pretreated with the capsaicin vehicle. Four hours after LPS, airway responsiveness and cell counts in the bronchoalveolar lavage were assessed. To determine airway responsiveness, guinea pigs were anesthetized, tracheotomized, and mechanically ventilated before exposure to increasing concentrations of aerosolized histamine (10(-4) to 10(-3) M). Capsaicin pretreatment prevented the LPS-induced increase in airway responsiveness in response to aerosolized histamine. It significantly reduced total cell recovery in the bronchoalveolar lavage after LPS (1,167 +/- 167 10(3) cells/ml in capsaicin-treated guinea pigs versus 2,171 +/- 184 10(3) in vehicle-treated guinea pigs) by reducing the LPS-induced influx of neutrophils and macrophages. Additional experiments demonstrated that the activity of neutral endopeptidase (NEP) in the tracheal epithelium was not significantly different in guinea pigs injected with LPS from that in the saline-treated control animals, and that the pretreatment with the NEP inhibitor phosphoramidon did not increase the LPS-induced influx of neutrophils into the bronchoalveolar lavage. These results demonstrate that in the guinea pig, capsaicin-sensitive nerves are involved in LPS-induced airway hyperresponsiveness and inflammation.

Involvement of tachykinins in pentamidine-induced airway constriction and microvascular leakage in the guinea pig.

We investigated the effects of aerosolized pentamidine isethionate on airway constriction and microvascular leakage in the guinea pig, and the role of tachykinins in these abnormalities. The bronchoconstrictor response to pentamidine was determined in anesthetized, tracheotomized and mechanically ventilated guinea pigs by exposing them to increasing concentrations of aerosolized pentamidine (5 to 30 mg/ml; 60 breaths). Respiratory system resistance was measured by the occlusion method. Airway microvascular permeability was evaluated by measuring the Evans blue dye concentration in the trachea and main bronchi. Aerosolized pentamidine caused a concentration-related increase in respiratory system resistance that was prevented by pretreatment with 50 mg/kg capsaicin given subcutaneously 2 wk before pentamidine and was significantly reduced by pretreatment with 1 mg/kg morphine given intravenously. Pretreatment with 10(-4) M aerosolized phosphoramidon (90 breaths) significantly enhanced the bronchoconstrictor response to pentamidine. Aerosolized pentamidine (50 mg/ml; 90 breaths) increased airway microvascular permeability, as the Evans blue dye concentration was 72.6 +/- 3.7 ng/mg tissue in guinea pigs aerosolized with pentamidine versus 34.2 +/- 3.5 ng/mg tissue in the controls. Capsaicin pretreatment inhibited the increase in microvascular leakage induced by pentamidine. Pretreatment with 5 mg/ml aerosolized albuterol (90 breaths) prevented the bronchoconstrictor response to pentamidine but failed to prevent the pentamidine-induced increase in microvascular permeability. Atropine did not modify the bronchoconstrictor response to pentamidine. These results indicate that in the guinea pig, pentamidine isethionate induces bronchoconstriction and airway microvascular leakage, which are mediated by tachykinins released from sensory nerves. Albuterol, which is used in humans to prevent bronchoconstriction, does not seem able to prevent airway edema.

Effect of thoracic epidural anesthesia combined with general anesthesia on segmental wall motion assessed by transesophageal echocardiography.

Patients scheduled for vascular surgery are considered at risk for perioperative cardiac complications. Choice of anesthetic in such patients is guided by a desire not to adversely affect myocardial function. On the basis of data from laboratory studies, thoracic epidural anesthesia (TEA) has been advocated to prevent myocardial ischemia. The aim of this study was to assess whether TEA combined with general anesthesia has any effect on segmental wall motion (SWM) monitored by transesophageal echocardiography in these patients. Patients received alfentanil, midazolam, vecuronium, and 50% N2O in oxygen, and ventilation was controlled after orotracheal intubation; 12.5 mL of 2% lidocaine HCl was injected through an epidural catheter placed at T6-7 or T7-8. Hemodynamic measurements and transesophageal echocardiographic recordings were obtained before and 10, 20, 30, 40, and 60 min after lidocaine injection. Segmental wall motion was graded a posteriori by two independent experts on a predetermined scale (from 1 = normal to 5 = dyskinesia). A decrease greater than or equal to 2 grades was considered an SWM abnormality indicative of ischemia. Thoracic epidural anesthesia induced a decrease in systemic arterial blood pressure, heart rate, and cardiac index. The SWM score decreased slightly from 1.34 +/- 0.68 to 1.27 +/- 0.64 (mean +/- SD) (at 10 and 20 min, respectively) (P less than 0.05). Patients were a posteriori analyzed according to whether they had documented coronary artery disease or not. The SWM score before TEA was significantly higher in patients with documented coronary artery disease (1.51 +/- 0.88 vs 1.17 +/- 0.51, respectively; P less than 0.05) and did not change significantly after TEA.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of neuraminidase on airway reactivity in the guinea pig.

We investigated the effects of neuraminidase, a viral enzyme that cleaves alpha ketosidic cell-bound sialic acids, to see if it accounts for parainfluenza and influenza virus-induced airway hyperreactivity. Accordingly, Vibrio cholerae neuraminidase was administered intratracheally in guinea pigs, and airway reactivity was assessed 3 h later. Removal of sialic acid residues was evaluated by histologic studies. Airway responsiveness was determined in anesthetized, tracheotomized, and mechanically ventilated guinea pigs by exposing them to increasing concentrations of aerosolized bronchoconstrictor agents. Respiratory system conductance was measured by the occlusion method. Neuraminidase injected intratracheally did not change airway reactivity to 10(-4) to 10(-2) M acetylcholine or 10(-4) to 2.5 x 10(-3) M histamine; nor did it prevent aerosolized albuterol from inhibiting histamine-induced bronchoconstriction. Substance P (10(-6) to 5 x 10(-5) M) had no significant bronchoconstrictor effect on guinea pigs pretreated with saline or neuraminidase. In guinea pigs pretreated with aerosols of the neutral endopeptidase inhibitor phosphoramidon (10(-4) M) before the concentration curve to aerosolized substance P was recorded, neuraminidase significantly reduced substance P-induced bronchoconstriction. When bronchoconstriction was induced by the 4-11 fragment of substance P (10(-5) to 10(-2) M), which is devoid of positive charges, it did not differ significantly in guinea pigs pretreated with saline and those pretreated with neuraminidase. These results indicate that in the guinea pig, neuraminidase injected intratracheally does not induce non-specific airway hyperreactivity and may alter the binding of substance P to its receptors.

Effects of clonidine on variation of arterial blood pressure and heart rate during carotid artery surgery.

The effect of oral premedication with 300 micrograms of clonidine on systemic arterial pressure, heart rate, and plasma norepinephrine levels was assessed in a double-blinded, placebo-controlled study conducted in 29 patients subjected to carotid artery surgery (CAS). Anesthesia was induced with thiopental, 6 mg/kg, and alfentanil, 0.05 mg/kg, and maintained with alfentanil and 0.6% isoflurane in 50% N20/O2. The study was divided into five periods as follows: (1) anesthesia to start of surgery; (2) surgery to carotid artery clamping; (3) carotid artery clamping to unclamping; (4) carotid artery unclamping to the end of surgery; and (5) the first 4 postoperative hours in the recovery room. In the clonidine group (n = 14), plasma norepinephrine concentrations were significantly lower before induction of anesthesia and during the operative period. Heart rate and systemic arterial pressure were lower (P less than 0.01) in the clonidine group at 3 different time intervals (control, carotid clamping, carotid unclamping). However, during each of the previously defined periods, the variability of heart rate and systemic arterial pressure, assessed by the coefficient of variation, was not different between the two groups. The lability of these hemodynamic parameters, expressed as the percentage of values, which increased or decreased more than 20% of control values during the corresponding period, was also comparable between the two groups. The number of patients who experienced at least one episode of hypertension (systolic arterial pressure greater than 180 mm Hg), hypotension (systolic arterial pressure less than 100 mm Hg), or bradycardia less than 45 beats/min was not different between the two groups.(ABSTRACT TRUNCATED AT 250 WORDS)

[Cutaneous microvascular flow studied by laser-Doppler. A study of 100 healthy volunteers]. / Flux microcirculatoire cutané étudié par laser-doppler. Etude sur une population de 100 sujets volontaires sains.

Cutaneous capillary flow (tip of the 3rd right finger) was measured with a laser Doppler (Periflux, Perimed), in 100 healthy volunteers without any history of hypertensive or vasospatic diseases, 15 females smoke and were taking contraceptive drugs. Smokers (n = 16 M, 25 F) stopped smoking 3 hours before the study. Basal laser Doppler flux (BLDF), amplitude of vasomotion waves (AV), post-occlusive reactive hyperthermia peakflow (F Max), difference between BLDF and F Max (delta F Max), time to reach 50 percent of the initial value (t1/2 r) and total recovery (tr), t Max (peak of over-shoot) and t/2 over shoot were measured. F Max after heating stimulus (40 degrees) (f Max H), delta F Max H (difference between BLDF and F Max H) and t Max H time (mn) to reach F Max H were measured before a cold stimulus was applied. Results were expressed in arbitrary units (cvolts), BLDF showed inter-individual variation but was reproducible over months in the same subject. The basal flux was statistically different between males (352.7 +/- 21.7) and females (249.6 +/- 22.4). Spontaneous vasomotion waves and different times (in sec.) to reach the peak after three minutes of arterial occlusion could be measured with this technique. These normal range of values can allow comparison and assessment of variations in pathological conditions, mainly Raynaud's phenomenon, high blood pressure, diabetes, smokers, sickle-cell anemia. Acute pharmacological tests can be carried out with drugs showing specific action on microcirculation and spontaneous vasomotion.

Pulmonary vascular response to endothelin in rats.

This study investigated the pulmonary vascular response to endothelin (ET) in rats. In conscious rats, an incremental intravenous bolus of ET-1 (100-1,000 pM) caused, after an initial drop in systemic arterial pressure (Psa), a secondary dose-dependent increase of Psa concomitant with a decrease of cardiac output (CO) and heart rate (HR). Pulmonary arterial pressure (Ppa) remained unchanged, and pulmonary vascular resistance (PVR) increased significantly only after 1,000 pM (+ 40.0 +/- 10.4 at 15 min). Meclofenamate (6 mg/kg iv) did not alter hemodynamic response to ET (300 pM). After autonomic blockade with hexamethonium (6 mg/kg iv) plus atropine (0.75 mg/kg iv), bradycardia response to ET (300 pM) was blocked, but CO decreased, systemic vascular resistance increased, and PVR remained unchanged as in controls. In anesthetized ventilated rats, bolus injections of ET (10-1,000 pM) induced a transient dose-related decrease in compliance (-10.9 +/- 1.8% after 1,000 pM) but no change of conductance. In isolated lungs, Ppa increased at doses greater than 100 pM, and edema developed in response to 1,000 pM ET. The rise of Ppa in response to 300 pM was not altered by meclofenamate (3.2 x 10(-6) M) but was potentiated by inhibitors of endothelium-derived relaxing factor(s) (EDRF), methylene blue (10(-4) M), pyrogallol (3 x 10(-5) M), and NG-monomethyl-L-arginine (6 x 10(-4) M) (3.9 +/- 0.3, 4.6 +/- 0.5, and 5.9 +/- 0.3 mmHg, respectively, compared with 1.5 +/- 0.5 mmHg in control lungs). These results suggest that circulating ET is a more potent constrictor of the systemic circulation than of the pulmonary vascular bed.(ABSTRACT TRUNCATED AT 250 WORDS)

Mechanisms of endothelin-mediated bronchoconstriction in the guinea pig.

Intravenous injection of anesthetized ventilated guinea pigs with doses of endothelin ranging from 0.25 to 2.50 micrograms/kg caused dose-dependent decreases in respiratory system conductance and compliance. These effects were maximal 1 min after injection and had disappeared 15 min thereafter. When guinea pigs were pretreated with 3 mg/kg of propranolol or 5 mg/kg of hexamethonium, endothelin-induced bronchoconstriction rose significantly, but when they were pretreated with 3 mg/kg of propranolol plus 3 mg/kg of atropine it remained unchanged. The bronchoconstrictor effects of endothelin were suppressed in guinea pigs pretreated with 0.5 or 2 mg/kg of meclofenamate but remained unchanged in those pretreated with 30 micrograms/kg of nicardipine. Endothelin did not increase either lung permeability, as assessed by 99m technetium diethylenetriamine pentaacetic acid clearance, or airway responsiveness to histamine or 5-hydroxy-tryptamine. Histological studies showed that endothelin induced reversible contraction of airway and pulmonary artery smooth muscles but no inflammatory reactions. These results demonstrate that, in guinea pigs, endothelin 1) induces airway smooth muscle contraction mediated by cyclooxygenase metabolites and modulated by the autonomic nervous system and 2) does not induce airway hyperreactivity or inflammation.

Abnormalities in myocardial segmental wall motion during lumbar epidural anesthesia.

The effect of lumbar epidural anesthesia on myocardial wall motion was compared in two groups of patients using precordial two-dimensional echocardiography (2DE). All patients were scheduled to undergo lower abdominal or peripheral surgery. Group 1 included five healthy ASA PS 1 subjects and group 2 included 10 patients with coronary artery disease (CAD). In all patients 12.5 ml of 2% lidocaine HCl was injected into the lumbar epidural space, and systolic and diastolic blood pressures, and heart rate were continuously monitored. 2DE evaluation was performed before and at 10, 20, 30, and 60 min (T10-T60) after epidural lidocaine injection. The left ventricular wall was divided into 16 segments for parasternal long-axis, short-axis and apical four-chamber views. The wall motion of each segment was graded on a scale from 1 (dyskinesia) to 6 (hyperkinesia), with 5 representing normal motion. A decrease in segmental wall motion greater than or equal to 2 grades was considered indicative of ischemia. Plasma lidocaine and catecholamine levels were measured before and 10, 20, and 60 min after epidural lidocaine injection. Peak plasma lidocaine levels in groups 1 and 2 were 2.79 +/- 1.06 micrograms/ml (mean +/- SD) and 2.58 +/- 1.48 micrograms/ml at 10 min, respectively (NS). Plasma epinephrine and norepinephrine levels were unchanged from baseline. Systolic pressures decreased significantly in group 2 from T10 to T60. Diastolic pressure decreased significantly in the same group from T20 to T60, and in group 1 only at T10. Mean arterial pressure decreased significantly in both groups at T30, without change in heart rate.(ABSTRACT TRUNCATED AT 250 WORDS)

Comparative effects of bisoprolol and acebutolol in smokers with airway obstruction.

1. The effects of single oral doses of 10 mg bisoprolol and 400 mg acebutolol on respiratory function were studied in nine smokers with airway obstruction in a double-blind, placebo-controlled experiment. 2. The effects of the drugs were assessed by measuring specific airway conductance (sGaw) for 3 h after their administration and by studying their interaction with the bronchodilator response to inhaled salbutamol. 3. sGaw did not change for 3 h after bisoprolol or acebutolol administration. The bronchodilator response to inhaled salbutamol was not affected by bisoprolol but significantly reduced by acebutolol (P less than 0.05 vs placebo). 4. Under these conditions, bisoprolol behaves like a selective beta 1-adrenoceptor antagonist but acebutolol exhibits less beta 1-adrenoceptor selectivity.

Impact of surgical stress on the haemodynamic profile of isoflurane-induced hypotension.

It has been suggested that stimulation of adrenoreceptors could be responsible for some of the haemodynamic effects of isoflurane. But there are no solid data demonstrating the role of sympatho-adrenal stimulation induced by pain during isoflurane administration. The impact of surgical stress on the haemodynamic profile of isoflurane-induced hypotension has been investigated in 28 patients (47-76 years), scheduled for total hip arthroplasty. After premedication with morphine hydrochloride (0.1 mg/kg), patients were randomly assigned to receive either no fentanyl (control group) or fentanyl (5 micrograms/kg before tracheal intubation, 5 micrograms/kg before skin incision, and 2 micrograms/kg each 15 min during the 1st hour). Isoflurane was given to maintain mean arterial blood pressure in the range 6.7-8 kPa in both groups. Haemodynamic data and blood samples for determination of plasma renin activity (PRA) and epinephrine (E) and norepinephrine (NE) levels were collected before and during hypotension. The fentanyl group and the control group differed significantly during hypotension: heart rate, cardiac index, oxygen consumption and E, NE and PRA were lower (P less than 0.01) in the fentanyl group than in control group. Fentanyl lowered the required concentration of isoflurane to achieve the same degree of hypotension (end-tidal concentration: 0.8 +/- 0.2% in the fentanyl group and 1.4 +/- 0.15% in the control group; P less than 0.001). Our results demonstrate that the cardiovascular effects of higher isoflurane concentrations in the absence of narcotic analgesia are counterbalanced by adrenergic stress stimulation of released epinephrine and norepinephrine. Among the likely reasons for catecholamine release during isoflurane administration, inadequate analgesia may be considered.