Action of Cinnarizine on the Hyperviscosity of Blood in Patients With Peripheral Obliterative Arterial Disease Tullio Di Perri, M.D., F.I.C.A., Sandro Forconi, M.D., F.I.C.A., Maurizio Guerrini, M.D., Franco Laghi Pasini, M.D., Roberto Del Cippola, M.D., Carlo Rossi, M.D., and Donato Angnusdei, M.D.
SIENA,
ITALY
Abstract a drug capable of improving blood flow, was studied for its blood viscosity and its main components in patients affected by peripheral obliterative arterial diseases (POAD). Both acute and chronic administration of the drug diminished the increased whole-blood viscosity in patients, without affecting plasma and serum viscosity, hematocrit, plasma fibrinogen concentration, and plasma osmolality. Since cinnarizine also led to a significant increase of peripheral muscular blood flow, it was hypothesized that this action may be due to an increased deformability of the red cells, and may play a considerable role in the therapeutic approach to POAD.
Cinnarizine,
action
on
Introduction The therapeutic effects of cinnarizine in patients with circulatory disorders have been repeatedly described. Many controlled clinical trials have confirmed the usefulness of the drug both in cerebrovascularl-5 and peripheral obliterative arterial diseases.6-11 In a previous paper we demonstrated that in either short-or long-term therapy, cinnarizine increased blood flow in the lower limbs of both patients with obliterative arterial diseases and normal subjects.12 This property of the drug was also noted by Verhaegen et aI.,13 Ellis et aI.,14 and Schuermans et al .,15 and it was attributed to the inhibition of the calcium-induced contraction of the vascular smooth muscIe,16,17 probably because it reduced calcium transfer to the muscular fibrocell.l8 Recently the relationships between blood flow and blood viscosity was studied once again. This profound investigation led to the hypothesis of the existence of a reciprocal control at the microcirculatory level. Therefore such aspects as the viscosity of blood and the factors influencing it, i.e., plasma and serum viscosity, fibrinogen concentration, hematocrit, and possibly red cell aggregation or deformability, have been seriously considered.19-25 -
From the Institute of Medical Semeiotics, School of Medicine,
13
---~
University
.
of Siena,
Italy.
14
The blood-flow-increasing activity of the pharmacologic agents could be due either to a direct action on the vessel wall followed by a reduction of the circulatory resistance, or to an effect on the blood viscosity. Since cinnarizine undoubtedly influences the peripheral circulation, thus increasing the muscular blood flow, the possibility of a specific effect on blood viscosity can be postulated. The aim of this research was to test this working hypothesis in man. Materials and Methods
experiment was designed to study the action of cinnarizine on the blood viscosity after both a single dose and a week of treatment. Twenty-five subjects affected with peripheral obliterative arterial disease (POAD) of the lower legs and suffering from intermittent claudication were included in the study. They were divided into two groups. The first group, composed of 14 patients, 10 men and 4 women with a mean age of 59 =b 3 SE and a mean weight of 68 ~ 4 SE constituted the single-dose study. The second group, composed of 11 patients, 9 men and 2 women with a mean age 65 ~ 2 and a mean weight of 67 ~ 3, was included in the one-week study. The diagnosis of POAD was confirmed in all our patients by the significant reduction of postischemic first flow measured with venous occlusion &dquo;strain gauge&dquo; plethysmography.26,27 In the first group of patients, POAD was associated with diabetes in 2 cases, with hypothyroidism in 1 case, with angina pectoris in 1 case, with essential hypertension in 1 case, and with essential hypertension, angina pectoris, and cerebral stroke in 1 case. In the second group there were 2 diabetics and 1 hypertensive patient; 1 of the diabetic patients had The
°
had a stroke. 75 mg 25 Cinnarizine was supplied in an 7.5% alcoholic solution (1 ml In the each received 300 of cinnarizine drops). single-dose study subject mg a plastic syril:ge in the with Blood were taken orally early morning. samples from an antecubital vein before the administration of the drug, after 90 minutes, and after 180 minutes. In the 1-week study each subject received 75 mg of cinnarizine three times daily for 7 days. Blood samples were taken before the first administration and in the early morning of the eighth day, 8 hours after the last administration of the drug. Blood samples were treated with the following anticoagulants: 10% EDTA (0.1 ml in 8 ml of blood) for whole blood and plasma viscosity measurements, 3.8% sodium citrate (0.5 ml in 4.5 ml of blood) for fibrinogen determination, and a minimal amount of heparin sodium for osmolality determination. In each sample we estimated the following parameters: 1. Blood, plasma, and serum viscosity were determined by a WellsBrookfield cone/plate 1/4 RVT viscometer at 37°C at selected shear rates of 750, 375, 150, 75, 37.5, 18.75, 7.50, and 3.75 s-1. For plasma and serum determinations, readings were made at a shear rate of 750 s-1, since plasma and =
=
15
considered Newtonian fluids, which do not vary their viscosity with changing shear rates. 2. Hematocrit was calculated as a percentage. 3. Plasma fibrinogen concentration was determined by nephelometry, measuring the formation of antigen-antibody complexes by the fluornephelometer of an Autoanalyzer Technicon II, continuous flow, AIP system. 4. Plasma osmolality was calculated by a Knauer osmometer.
serum are
Results The mean SE results are reported in Table 1 for the single-dose study and in Table 2 for the 1-week study. Statistical analysis was performed by using student’s t test for paired variables (the mean values after treatment were compared with mean pretreatment values). All the subjects affected by POAD had higher blood viscosity values before treatment than the group of 45 normal subjects whom we studied in our laboratory.28 This finding is in keeping with our previous report28 and with the papers of the other authors29-36 who studied blood viscosity in POAD. In the single-dose study, blood viscosity decreased significantly, 90 minutes, and even more 180 minutes after the administration of the drug. At the 180th minute the percentage of decrease was almost the same at all the shear rates
TABLE 1
Results
Statistical
analysis
was
treatment values. *
P
SIENA,
ITALY
Abstract a drug capable of improving blood flow, was studied for its blood viscosity and its main components in patients affected by peripheral obliterative arterial diseases (POAD). Both acute and chronic administration of the drug diminished the increased whole-blood viscosity in patients, without affecting plasma and serum viscosity, hematocrit, plasma fibrinogen concentration, and plasma osmolality. Since cinnarizine also led to a significant increase of peripheral muscular blood flow, it was hypothesized that this action may be due to an increased deformability of the red cells, and may play a considerable role in the therapeutic approach to POAD.
Cinnarizine,
action
on
Introduction The therapeutic effects of cinnarizine in patients with circulatory disorders have been repeatedly described. Many controlled clinical trials have confirmed the usefulness of the drug both in cerebrovascularl-5 and peripheral obliterative arterial diseases.6-11 In a previous paper we demonstrated that in either short-or long-term therapy, cinnarizine increased blood flow in the lower limbs of both patients with obliterative arterial diseases and normal subjects.12 This property of the drug was also noted by Verhaegen et aI.,13 Ellis et aI.,14 and Schuermans et al .,15 and it was attributed to the inhibition of the calcium-induced contraction of the vascular smooth muscIe,16,17 probably because it reduced calcium transfer to the muscular fibrocell.l8 Recently the relationships between blood flow and blood viscosity was studied once again. This profound investigation led to the hypothesis of the existence of a reciprocal control at the microcirculatory level. Therefore such aspects as the viscosity of blood and the factors influencing it, i.e., plasma and serum viscosity, fibrinogen concentration, hematocrit, and possibly red cell aggregation or deformability, have been seriously considered.19-25 -
From the Institute of Medical Semeiotics, School of Medicine,
13
---~
University
.
of Siena,
Italy.
14
The blood-flow-increasing activity of the pharmacologic agents could be due either to a direct action on the vessel wall followed by a reduction of the circulatory resistance, or to an effect on the blood viscosity. Since cinnarizine undoubtedly influences the peripheral circulation, thus increasing the muscular blood flow, the possibility of a specific effect on blood viscosity can be postulated. The aim of this research was to test this working hypothesis in man. Materials and Methods
experiment was designed to study the action of cinnarizine on the blood viscosity after both a single dose and a week of treatment. Twenty-five subjects affected with peripheral obliterative arterial disease (POAD) of the lower legs and suffering from intermittent claudication were included in the study. They were divided into two groups. The first group, composed of 14 patients, 10 men and 4 women with a mean age of 59 =b 3 SE and a mean weight of 68 ~ 4 SE constituted the single-dose study. The second group, composed of 11 patients, 9 men and 2 women with a mean age 65 ~ 2 and a mean weight of 67 ~ 3, was included in the one-week study. The diagnosis of POAD was confirmed in all our patients by the significant reduction of postischemic first flow measured with venous occlusion &dquo;strain gauge&dquo; plethysmography.26,27 In the first group of patients, POAD was associated with diabetes in 2 cases, with hypothyroidism in 1 case, with angina pectoris in 1 case, with essential hypertension in 1 case, and with essential hypertension, angina pectoris, and cerebral stroke in 1 case. In the second group there were 2 diabetics and 1 hypertensive patient; 1 of the diabetic patients had The
°
had a stroke. 75 mg 25 Cinnarizine was supplied in an 7.5% alcoholic solution (1 ml In the each received 300 of cinnarizine drops). single-dose study subject mg a plastic syril:ge in the with Blood were taken orally early morning. samples from an antecubital vein before the administration of the drug, after 90 minutes, and after 180 minutes. In the 1-week study each subject received 75 mg of cinnarizine three times daily for 7 days. Blood samples were taken before the first administration and in the early morning of the eighth day, 8 hours after the last administration of the drug. Blood samples were treated with the following anticoagulants: 10% EDTA (0.1 ml in 8 ml of blood) for whole blood and plasma viscosity measurements, 3.8% sodium citrate (0.5 ml in 4.5 ml of blood) for fibrinogen determination, and a minimal amount of heparin sodium for osmolality determination. In each sample we estimated the following parameters: 1. Blood, plasma, and serum viscosity were determined by a WellsBrookfield cone/plate 1/4 RVT viscometer at 37°C at selected shear rates of 750, 375, 150, 75, 37.5, 18.75, 7.50, and 3.75 s-1. For plasma and serum determinations, readings were made at a shear rate of 750 s-1, since plasma and =
=
15
considered Newtonian fluids, which do not vary their viscosity with changing shear rates. 2. Hematocrit was calculated as a percentage. 3. Plasma fibrinogen concentration was determined by nephelometry, measuring the formation of antigen-antibody complexes by the fluornephelometer of an Autoanalyzer Technicon II, continuous flow, AIP system. 4. Plasma osmolality was calculated by a Knauer osmometer.
serum are
Results The mean SE results are reported in Table 1 for the single-dose study and in Table 2 for the 1-week study. Statistical analysis was performed by using student’s t test for paired variables (the mean values after treatment were compared with mean pretreatment values). All the subjects affected by POAD had higher blood viscosity values before treatment than the group of 45 normal subjects whom we studied in our laboratory.28 This finding is in keeping with our previous report28 and with the papers of the other authors29-36 who studied blood viscosity in POAD. In the single-dose study, blood viscosity decreased significantly, 90 minutes, and even more 180 minutes after the administration of the drug. At the 180th minute the percentage of decrease was almost the same at all the shear rates
TABLE 1
Results
Statistical
analysis
was
treatment values. *
P
