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The authors propose a promising new therapy for the treatment of Raynaud's phenomenon, with parenteral prostacyclin (carbaprostacyclin) and a serotonergic S2-receptor antagonist (ketanserin) given orally. They studied 31 patients, 22 treated with ketanserin and carbaprostacyclin, 9 with carbaprostacyclin alone. Both groups demonstrated successful results and a significant improvement in measurements performed by photoplethysmography and transcutaneous pulse oximetry.

The authors report the results of a study of 25 patients with Raynaud's phenomenon (primary, posttraumatic, and secondary to diffuse connective tissue diseases) treated with regional intravenous injections of guanethidine or ketanserin. These two drugs were chosen because of the different etiopathologic profiles of the conditions. All the patients showed a substantial clinical improvement with a remission of trophic lesions. Conditions secondary to connective tissue disorders did not demonstrate much improvement based on instrumental data alone, possibly because of the intrinsic limitations of the techniques used for evaluating peripheral blood flow. This specific type of pharmaceutical treatment appeared to be especially suitable for this disease owing to a combination of therapeutic efficacy and a substantial reduction in the total dosage for each patient.

After a two-week washout (WO) period with placebo 1 capsule/bid, 12 patients suffering from stable Raynaud's phenomenon were treated with ketanserin (K) 40 mg/bid for fifteen days. Blood pressure, heart rate, and laboratory parameters were evaluated at the end of each period. Patients used diary cards to record the number, duration, and intensity of attacks. Computerized thermometry of the fingers was evaluated at basal temperature after acclimatization, 23 degrees C for thirty minutes; after cold test, 10 degrees C for five minutes; and after thermal recovery, 23 degrees C for eighteen minutes. Results were analyzed statistically by use of Student's t-test for paired data (p less than 0.05). No marked changes were observed in the symptoms of the attacks, but K proved effective in significantly reducing the number and duration of daily attacks and in promoting their spontaneous regression. Thermometry revealed a parallel increase in temperatures, particularly basal and recovery values. The data suggest increased flow and decreased vasospasm following 5-HT2 receptor blockade.

The efficacy of buflomedil in reducing the mean daily frequency and severity of winter ischemic attacks has been shown in a randomized, double-blind, placebo-controlled trial including 31 patients (16 in the buflomedil group, 15 in the placebo group) suffering from idiopathic Raynaud's phenomenon and followed up for six months. The efficacy was confirmed by nail fold capillaroscopy, which showed a significant alleviation of hemodymanic disturbances and background pallor in comparison with the placebo. Results in terms of clinical and laboratory safety parameters assessed over a six-month period were satisfactory, thus demonstrating the possibility of a long-term treatment.

In a randomized, placebo-controlled, crossover study, 15 ambulatory patients with Raynaud's phenomenon, treated for three weeks with ketanserin 80 mg/day and pentoxiphylline 1,200 mg/day, were evaluated by subjective symptom scores, daily frequency and duration of attacks, and photoplethysmography, at room temperature and after cold test. Reduced subjective symptoms and duration of attacks, together with improved cold test plethysmography, were significant only after ketanserin. All subjective symptom scores also improved after ketanserin but only for cyanosis and paresthesia after pentoxiphylline. Excellent results were obtained in 4 cases after ketanserin and in 1 case with pentoxiphylline. The authors discuss the greater importance of antivasospastic action over antiaggregating and hemorheologic effects in Raynaud's phenomenon therapy, as well as the pathogenetic role of serotonin.

The efficacy of the calcium-channel blocker nicardipine in the treatment of Raynaud's phenomenon was assessed in a prospective, double-blind, randomized, crossover trial in 20 patients. Each patient received nicardipine 20 mg or placebo three times a day for two weeks and then was crossed over for two weeks. Nicardipine significantly decreased the frequency and severity of Raynaud's phenomenon as compared with placebo. The authors conclude that nicardipine is effective in the treatment of Raynaud's phenomenon.

Twenty-eight patients suffering from either primary or secondary Raynaud's phenomenon were treated with nifedipine and ketanserin. Each patient was treated with one of the two drugs administered after an adequate washout period. Furthermore each patient was submitted before and after treatment with each drug to computerized digital thermometry to evaluate the therapeutic response. The data obtained during the intake of the two drugs at zero, five, and twenty-three minutes were compared with thermometry-relevant baseline data at the same periods. Ketanserin proved to be useful in the treatment of Raynaud's phenomenon and statistically significantly superior (alpha less than 0.05) with respect to nifedipine in the thermometric controls and also in the subjective evaluation of the patients (p less than 0.02). In this study nifedipine did not show particular efficacy. Furthermore only 2 patients had to discontinue treatment with ketanserin, whereas 8 had to discontinue treatment with nifedipine (p less than 0.001).

Despite the frequency of Raynaud's disease in cold climates, the etiology of the condition remains uncertain. This report reviews the literature since Raynaud's original description and Lewis and Pickering's addition to the concept, and several recent observations which add to our understanding of the disease are discussed. We investigated the effect of posture and a vasodilator drug on the digital capillary circulation; digital blood flow increases as the body moves from a recumbent, through a sitting, ti an upright position. Bradilan, a vasodilator drug, increases the circulation in the recumbent and sitting positions, but has no effect in standing patients, despite symptomatic relief.

A group of 11 female patients (mean age 33.7 +/- 8 years) with a clearly proven primary Raynaud's syndrome of up to five years' duration were subjected to a two-month oral treatment with 3 X 400 mg pentoxifylline per day. The following parameters were studied without and with exposure to cold conditions: hemodynamics (finger photoplethysmography), red cell deformability (filtration test), various clotting variables (prothrombin activity, antithrombin III, plasma fibrinogen, partial thromboplastin time, thrombin time, thrombelastogram), and clinical symptomatology. After treatment 7 of the 11 patients showed a distinct improvement of peripheral blood flow and of symptoms (decrease or removal of asphyxia attacks, pain, color change) under basal conditions, as well as after exposure to cold. Red cell filtration was significantly (p less than 0.05) improved, increasing by 35% under normal conditions and by 30% after exposure to cold. Positive changes were also found in respect to antithrombin III (increase) and plasma fibrinogen (decrease). The thrombelastogram was unchanged. Clinical and instrumental improvements were probably ascribable to better microcirculatory flow due to increased red cell deformability, reduced viscosity, and decreased fibrinogen, all capable of influencing in various degrees the blood flow at the microcirculatory level.

Fourteen ambulatory and hospitalized patients with primary and secondary Raynaud's phenomenon have been examined before and after a thirty-one-day therapeutic trial. The treatment was conducted in two cycles. The first one lasted ten days, during which placebo was administered. The second cycle lasted three weeks, during which ketanserin, a selective antagonist of 5-hydroxytryptamine (5-HT2) receptors, was administered. The therapeutic effect consisted of the complete healing of digital ulcers in 4 of 5 patients and a considerable decrease in the number, length, and severity of daily attacks. To evaluate the digital blood flow, each patient was submitted to a medical dynamic telethermographic test. This, after the cooling test, demonstrated an average decrease of twenty minutes in the time necessary to reestablish basal thermal conditions (T') at the end of an adequate period of therapy using optimal doses of the drug. The authors affirm that orally administered ketanserin has a beneficial effect and can be well tolerated in subjects with Raynaud's phenomenon.

The clinical response to two doses of sustained-release nifedipine was assessed during a double-blind, randomized, placebo-controlled trial in 22 patients with primary Raynaud's phenomenon. Nifedipine at doses of 20 mg and 40 mg daily reduced the mean number of attacks by 40% compared with placebo with no significant differences between the two doses in the number of attacks or their severity. Unwanted effects were more common and more persistent with the higher dose of nifedipine. Fingertip vibrotactile thresholds measured at 31.5 and 125 Hz were unchanged by treatment with nifedipine. There was, however, a correlation between the pretreatment threshold at 125 Hz and the response to treatment with nifedipine, the most favorable responses occurring in patients with the lowest thresholds.

We examined in a double blind fashion and placebo controlled the effects of some alpha and beta adrenergic receptor agonists and antagonists on the recovery of finger skin temperature 12 min after finger cooling (5 min waterbath for both hands) in twelve patients with Raynaud's syndrome. A favourable effect was established on phenoxybenzamine 20 mg as compared to placebo. A significant but rather small effect on orciprenaline 10 mg. The beta-agonists prenalterol (10 mg) and terbutaline (5 mg) did not influence the recovery of finger skin temperature. The beneficial effect of phenoxybenzamine 20 mg was not influenced by the addition of beta-agonists (prenalterol 10 mg or terbutaline 5 mg) or a beta-blocker (propranolol 40 mg). The beta-agonists terbutaline and orciprenaline caused a fall in diastolic pressure and an increase in heart rate. These effects presumably were connected with one collapse and three near-collapses. On alpha- and beta-blocker (phenoxybenzamine and propranolol) a decrease in systolic pressure appeared, whereas diastolic pressure did not significantly differ from the placebo value. While physical exercise is considered to exacerbate the hypotensive effect of alpha-blockers, a fall in blood pressure during physical exercise could not be established in our experiments after the addition of propranolol to the alpha-blocker phenoxybenzamine. Our results suggest that an alpha-blocker is a good choice in Raynaud's syndrome, whereas the addition of a beta-blocker may have some advantages.

The beneficial effects of intra-arterial or intravenous infusion of the prostanoid products of anachridonic acid, PGE and prostacyclin (PGI2) are well documented. More recently an analogue of PGE2, (CL 115,347, American Cynamid Co.) has become available. This substance is absorbed transdermally from a patch placed on the skin. In a placebo-controlled trial the vasodilatory effect of single incremental dosage, 500 mcg, 1000 mcg and 1500 mcg, was measured in a temperature-/humidity controlled laboratory in normal subjects and in patients with primary and secondary Raynaud's phenomenon. The optimal dosage proved to be 1000 mcg; the effect may last for 84 hours; higher dosage may be associated with a "steal" phenomenon.

Fifty-eight patients with Raynaud's phenomenon were randomly allocated in a six week double-blind clinical trial in parallel groups to compare the efficacy of a pure antiplatelet agent, ticlopidine (250 mg b.i.d.) with that of a placebo. There was no significant difference between the two treatments in percent reduction of weekly number of attacks and in subjective improvement assessed by both patient and investigator. It is unlikely that platelets are involved in the mechanisms of Raynaud's crisis.

In a double blind placebo-controlled cross-over trial of 24 weeks 31 patients with Raynaud's syndrome were treated with the alpha-blocker phenoxybenzamine (10-20 mg daily) and with the combination of the alpha-blocker phenoxybenzamine (10-20 mg daily) and the beta-blocker sotalol (40-80 mg daily). A favourable effect on recovery of finger temperature after finger cooling was demonstrated after alpha-blockade as compared to the before treatment situation. This favourable effect was not different when the group received the combined alpha- and beta-blockade. The blood pressure was not influenced by either of the 2 medications. Fluid retention appeared with alpha-blockade and was absent with combined alpha- and beta-blockade. Decrease of heart rate occurred with alpha- plus beta-blockade and was absent with alpha-blockade alone. Clinical symptoms of Raynaud's syndrome equally were alleviated by the two medications. Common, and equally frequent side effects of the two medications were nasal congestion, disturbed ejaculation and potency, dry mouth, exercise-induced and orthostatic dizziness. We conclude that alpha-blockade is beneficial in Raynaud's syndrome and that additional beta-blockade counteracts the alpha-blocker side-effect fluid retention, reduces the heart rate and thus may prevent alpha-blocker induced tachycardia, and that it does not cause hypotension.

Twenty-eight patients with spastic and obstructive vascular disease were treated with intravenous regional guanethidine (IRG). The drug was injected into the affected hand or foot in doses of 10 or 20 mg, respectively. Temperature and strain-gauge plethysmography curves of the extremity were recorded before treatment, and three to four times during the subsequent 10 days. The effects of IRG, as observed by clinical laboratory examinations, were good in 8 of 12 patients. But in patients suffering from Bürger's disease or from major vessel obstructive disease, the results were not as good. However, in most patients IRG proved beneficial in relieving pain, an effect which sometimes outlasted objective improvements. IRG treatment is a simple and safe method for prolonged chemical sympathectomy.

Now progressive systemic sclerosis (PSS) is considered a disease of small vessels with which many immunologic alterations are associated. The presence in the blood of large amounts of serotonin can be considered a very important aggravating factor able to cause the sclerodermic alterations. The authors have treated 10 PSS patients with ketanserin, a selective antagonist of the S2 serotonin receptors, which are found in small vessels and platelets. Their results show that ketanserin represents an efficacious and very well tolerated therapy for treatment of the initial vascular symptoms of PSS.

An open trial on the therapeutic effect of diltiazem, a calcium antagonist, was conducted on occupational Raynaud's syndrome (vibration disease). Seventeen men with vibration disease were studied. The mean age was 54 years. No patient had cardiovascular disease. Primary and secondary cases of Raynaud's phenomenon were excluded. Diltiazem, 30mg orally 3 times daily, was given to the patients for 6 weeks. Before and after this treatment period, we evaluated the subjective symptoms (11 items including Raynaud's phenomenon, numbness of hands and arms, stiffness of shoulder and neck, and others) and peripheral function (by cold water immersion test, vibration and pain sensations for fingers, tapping test, and momentary grasp strength test), and did laboratory blood tests (12 variables). The "effective" rates of subjective symptoms evaluating by the method of 5 steps and the peripheral function was 69.6% and 52.9%, respectively. The overall effectiveness of diltiazem therapy was assessed by collectively evaluating the changes in subjective symptoms, peripheral functions, and the occurrence of side effects. No side effects occurred during the treatment period. Thus, the collective effectiveness of diltiazem was 64.7%. In conclusion, diltiazem, a calcium antagonist, can be effective in long-term treatment of patients with vibration disease.

Twenty patients with primary and 11 with secondary Raynaud's syndrome were treated with the alpha-adrenoceptor blocker phenoxybenzamine (10-20 mg daily). In the secondary group mean age and mean duration of symptoms as well as presence of positive ANA and positive Clq binding test were significantly higher than in the primary group. In both groups a beneficial effect of the medication on finger temperature 12 min after finger cooling and on clinical symptoms was established. Secondary Raynaud's syndrome reacted at least as well as primary syndrome.