T. Di Perri

Peripheral Neuropathy Associated with Ischemic Vascular Disease of the Lower Limbs

This paper deals with the possible identification of somatic and autonomic nerve damage in patients with peripheral obliterative arterial disease (POAD) at different stages of the disease, with a well-reproducible technique like electroneurographic evaluation of nerve conduction. In 64 patients with intermittent claudication, 19 patients with pain at rest, and 7 patients with trophic ulcers, electroneurographic evaluation of motor (tibial and peroneal) and sensory (superficial peroneal and sural) nerve conduction was performed. The median nerve (motor and sensory) was used as control. A severe impairment of sural and superficial peroneal nerve velocities was evident in many claudicant patients and in all patients with pain at rest and trophic ulcers, with a progression in the conduction abnormalities in advanced stages of the disease. Motor nerve conduction showed only minor reductions in patients with claudica tion and pain at rest, although some of them did show very poor velocity values. In 21 patients with intermittent claudication and sensory nerve abnormalities, the autonomic fibers activity, evaluated by the skin sympathetic response (SSR) test, was significantly depressed, thus suggesting an involvement of the local autonomic system in the ischemic disease. A correlation exists between the severity of the somatic nerve damage and the stage of the vascular insufficiency. However, in the group of claudicant patients, the evidence of similar ischemic threshold (claudication distance) may be associated with a marked difference in the amount of somatic nerve damage. The somatic and autonomic nerve alterations may play a relevant role in the progression of the disease toward critical limb ischemia.

Pharmacodynamics of ticlopidine in man in relation to plasma and blood cell concentration

SummaryIn 6 normal volunteers given single oral doses of 250, 500 and 1000 mg ticlopidine (T), the peak plasma level of unchanged drug was reached after about 2 h. There was no correlation between the plasma T level and its inhibitory effect on platelet function, expressed as % inhibition of ADP-induced aggregation. By means of HPLC and GC/MS significant concentrations of T were demonstrated in washed red cells, platelets and neutrophils, with a marked difference in the time course of the appearance of cell-associated drug. The time course of platelet-associated T very accurately fitted that of the antiaggregatory activity.After subacute oral administration (250 mg b. d. for 7 days), the maximum effect on platelet function was observed after 3 to 4 days, when a significant concentration of platelet-associated T had been reached. The pharmacological effect persisted as long as drug was detectable in platelet.An in vitro study strongly suggested that the antiaggregating effect was retained by treated washed platelets but not by treated plasma. It is suggested that the platelet compartment represents the pharmacological target of T via a specific uptake system.

Nitroprusside in vitro inhibits platelet aggregation and intracellular calcium translocation. Effect of haemoglobin

The biologically final active compound of nitrovasodilators is now supposed to be nitric oxide (NO), a labile substance identical to EDRF. The effects of nitroprusside on platelet functions were studied in vitro. Platelet aggregation induced by several stimuli (ADP, collagen, arachidonic acid and PAF) was inhibited by increasing concentrations of the drug (1-50 uM); interestingly, the potency of nitroprusside is higher when PAF is employed as stimulating agent in comparison with the other agonists (ED50 = 2 uM for ADP, 2.5 uM for A.A., 4.5 uM for collagen and 0.3 uM for PAF-induced aggregations). The concomitant addition of haemoglobin is able to reverse the inhibitory effect of nitroprusside, according to the view that haemoglobin possesses a high affinity for NO, thus antagonizing the effect of this compound. Nitroprusside was also able to inhibit intracellular calcium translocation, as studied with the Quin 2 technique, induced by PAF and arachidonic acid. Fron these observations the hypothesis may be suggested that nitroprusside inhibits platelet functions by mimicking the endogenous NO, and that the intracellular calcium metabolism is involved in the inhibitory activity of the drug.

Plasma lipid lowering activity of acipimox in patients with type II and type IV hyperlipoproteinemia: Results of a multicenter trial

A multicenter study was carried out in 130 out-patients to assess the plasma lipid lowering activity of acipimox in type IIa, IIb and IV hyperlipoproteinemia. The study consisted of two periods, an 8-week randomized, double-blind comparison of active drug versus placebo and a 16-week open follow-up with acipimox (400 mg and 250 mg t.i.d., respectively, in type II and IV patients). During the double-blind phase acipimox, compared to placebo, showed a highly significant triglyceride lowering effect in type IV patients (-43% vs. +4%, P less than 0.01), while reducing plasma cholesterol significantly in type II patients (-7% vs. -3%, P less than 0.05). Further reductions in plasma lipids were obtained in both types of hyperlipoproteinemia after the 16-week follow-up. In type II patients, total cholesterol fell by 9% in the former acipimox group and 17% in the former placebo group, whereas a 34% reduction in triglycerides was found in type IV patients previously treated with placebo. Treatment had to be discontinued in 4 patients during the double-blind phase and in 5 patients during follow-up, because of adverse events such as skin reactions and gastric disturbances. Statistical analysis of hematological and biochemical variables expressing safety did not show any significant change during treatment.

Pharmacokinetics of exogenous adenosine in man after infusion

SummaryThe plasma kinetics of adenosine was investigated in healthy volunteers after a 1 minute infusion of 2.5, 5 and 10 mg (38, 79 and 148 μg·kg−1 respectively) and after infusion of 200 μg·kg−1 in 10 min followed by 400 μg·kg−1 in 10 min.As the dose in the 1 min infusion study was increased the mean CL of adenosine decreased (10.7, 4.70 and 4.14 l·min−1, respectively), its mean half-life increased (0.91, 1.24 and 1.86 min, respectively), and the mean volume of distribution did not show any clear trend (8–13 l).After the 20 minute infusion the plasma level of adenosine reached a peak value comparable to that observed after infusion of 5 mg in 1 min (about 0.5 μg·ml−1), but the mean clearance and half-life were significantly different (12.1 l·min−1 and 0.63 min respectively).In all the subjects the plasma concentration of adenosine had returned to the baseline value in 5–15 min after the end of the infusion.

Adenosine inhibits polymorphonuclear leukocyte in vitro activation: a possible role as an endogenous calcium entry blocker.

Adenosine is able to in vitro inhibit FMLP-dependent activation of polymorphonuclear leukocytes as evaluated by enzyme release, superoxide anion generation and chemiluminescence production. The inhibiting effect is more relevant when A23187 is employed as stimulating agent. In this case the effect is significantly reversed by increasing concentrations of extracellular calcium. Since A23187-dependent activation is strictly dependent on Ca++ influx into the cell, the hypothesis is suggested that adenosine could act by regulatory mechanisms involving membrane calcium transport.

Immunokinetics of a single dose of thymopoietin pentapeptide.

14 patients with classical or definite rheumatoid arthritis and a low number of E-rosette forming cells were given single doses of 5 mg and 50 mg of thymopoietin intravenously. Thymopoietin pentapeptide produced a dose-related sustained increase in E-rosette forming lymphocytes as shown by the decrease of thymopoietin dependent rosetting ratio. A single dose of 50 mg restored the number of E-rosette forming cells to normal after 12 h and this effect lasted 60 to 7 days. With the administration of 5 E-rosette forming cells markedly increased after 12 h and returned to the pretreatment level on the 2nd day. These immunokinetic data clarify some aspects of the clinical pharmacology of thymopoietin pentapeptide and must be considered for a rational schedule of treatment with the drug.

Adenosine system and cell calcium translocation: interference of calcium channel blockers.

Adenosine is able to inhibit in vitro neutrophil functions induced by formyl-methionyl-leucyl-phenylalanine (FMLP) and A23187, but not phorbol 12-myristate 13-acetate (PMA). The inhibiting activity on A23187 is reversed by increasing extracellular Ca2++ concentration. The calcium entry blocker flunarizine shows an activity very similar to that of adenosine. Both adenosine and flunarizine prevent Ca++ influx into activated neutrophils as detected by the fluorescent Ca++ chelator Quin-2. Finally, flunarizine binds to the neutrophil membrane and adenosine competitively inhibits flunarizine binding as assessed by 1H-Nuclear Magnetic Resonance (1H-NMR) technique, thus indicating that the two agents share a common binding site on the cell membrane.

Adenosine and chronic ischemia of the lower limbs

Adenosine is an endogenous nucleoside with multiple biological properties which plays a central role in the pathophysiology of tissue ischemia. Adenosine signals an imbalance between oxygen demand and supply, and it initiates responses to redress such a discrepancy. Besides its vasodilating properties, adenosine possesses anti-platelet and anti-neutrophil activities and provides cytoprotection. Adenosine is presumably the main mediator of the preconditioning phenomenon. During ischemia of the lower limbs, adenosine plays a physiological role by inducing vasodilatation and by preventing microcirculatory failure. Exercise training prolongs claudication distance possibly by inducing pulse increases of adenosine and consequently skeletal muscle preconditioning. Moreover, the adenosine increase which follows the administration of some drugs, such as buflomedil and propionylcarnitine, opens new perspectives in the management of leg ischemia. In fact, the concept arises of an ischemic (exercise-dependent) or pharmacologic preconditioning in the treatment of patients with claudication.

Pharmacodynamic Effects of Sulodexide on Profibrinolytic and Haemorrheological Patterns

SummaryTwenty-four patients with vascular disorders, randomly divided into 3 dosage groups of 8 patients, were treated with a single oral dose of sulodexide (50, 100 or 200mg) and placebo. Tissue plasminogen activator (t-PA), plasminogen activator inhibitor (PAI-1) activity and antigen, euglobulin lysis time, α2-antiplasmin, plasminogen, fibrinogen, blood and plasma viscosity, and whole blood filtration rate were determined before administration and over the following 24 hours. Sulodexide significantly increased t-PA activity linearly with the dose over the range of 50 to 200mg. At the same time, it also significantly decreased the concentration of PAI-1 linearly and proportionally with the dose. No clear effects were observed on the other monitored parameters, although euglobulin lysis time and plasma viscosity showed a tendency to decrease after the administration of sulodexide. These results justify the clinical activity of sulodexide. Indeed, the concomitant increase of t-PA and decrease of PAI-1 activity and antigen might increase the natural fibrinolytic activity with a physiological potentiation, without other adverse effects. The known activity of sulodexide in decreasing plasma viscosity during long term treatment is, however, not immediately explicable by the single-dose effects.