Clinical and laboratory effects of nifedipine in Raynaud's phenomenon

Summary The calcium channel blocking drug nifedipine was shown to be more effective than placebo as a treatment for Raynaud's phenomenon. Given in a dose of 10 mg four times a day it was well tolerated and reduced both the frequency and the severity of vasospastic attacks. There was, however, a large individual variation in response and while approximately half the patients showed marked improvement others showed no improvement at all. Patients with idiopathic Raynaud's phenomenon responded more favourably than those with systemic sclerosis. Nifedipine was shown to inhibit mitogen-induced lymphocyte proliferation but only in patients who responded to the drug clinically. Calcium channel blocking drugs may therefore have potential as immunoregulatory agents.     

Prognostic significance of nailfold capillary microscopy in patients with Raynaud's phenomenon and scleroderma-pattern abnormalities a six-year follow-up study

Summary The aim of this study was to assess the prognostic significance of scleroderma capillary pattern (SD-pattern) in patients with Raynaud's phenomenon. Thirty patients with a capillaroscopy examination suggestive of scleroderma (megacapillaries and/or avascularity) but without clinical criteria of scleroderma (ARA criteria) were reevaluated 6 years after the initial clinical and capillaroscopy examinations. SD-pattern abnormalities were classified according to a semiquantitative method. Eight out of the 28 evaluated patients (28%) developed a scleroderma spectrum disorder (SDS). The presence of avascularity and/or a mean of more than two megacapillaries digit greatly enhanced the percentage of evolution toward SDS (70% / 88% respectively). Most of the patients with few enlarged capillaries and no capillary rarefaction at entry had primary acrocyanosis (11/15). None of them developed SDS. The microangiopathy disappeared during the follow-up period in most of these patients (14/15). These results confirm the prognostic value of SD-pattern capillary abnormalities for SDS. Primary acrocyanosis, a benign clinical entity should be considered in presence of few megacapillaries and without capillary rarefaction.     

A randomized double blind cross-over trial of nifedipine in the treatment of primary Raynaud's phenomenon

During three winter months, 23 women participated in a doubleblind placebo controlled cross-over clinical trial of nifedipinein the treatment of Raynaud's phenomenon. Nifedipine and placebowere given in random order for two consecutive four-week periods.The dose of nifedipine was increased from 5 mg three times daily(ids) to 15 mg tds. During the final two weeks, the median numberof attacks of Raynaud's phenomenon on nifedipine was 2–3per week compared to 5.0 on placebo (P < 0.01). Fifteen patientsgave nifedipine a higher drug evaluation score than placebo(P < 0.01). Side-effects were experienced by 14 patients(61%) on nifedipine and by two on placebo (P = 0.005). Fingersystolic pressure after digit cooling did not differ significantlyat the end of each treatment period. Nifedipine is effectivein primary Raynaud's phenomenon in most patients but side effectsare common.     

Pathogenesis and treatment of Raynaud's phenomenon

Summary The pathogenetic theories and treatment of Raynaud's phenomenon are reviewed. In primary Raynaud's disease, most evidence supports a local defect at the digital artery level, with vasoconstriction or vasospasm of the digital arteries inducing the color changes. Normal sympathetic activity, low transmural arterial distending forces, and serotonin may be associated factors in the production of vasospastic attacks. In Raynaud's phenomenon, persistent vasoconstriction, thickened vessel walls, increased blood viscosity, and low digital artery blood pressure distal to obstructions may lead to vasospastic attacks with normal sympathetic nerve stimuli. Since the underlying cause of primary Raynaud's disease is unknown, treatment involves the use of agents to reduce sympathetic nerve activity or to prevent vascular smooth muscle contraction. Most patients will respond to conservative measures, but if they fail nifedipine is the drug of choice and alleviates the syndrome in about two thirds of patients. Reserpine and guanethidine may be as effective, but well-controlled studies have not been performed. The beneficial response to prazosin is moderate and dissipates with time. Side effects with these drugs prevent their use in many patients. Diltiazem and nitroglycerin ointments are of questionable value. Ketanserin, a serotonergic S₂-receptor antagonist, which has been shown to decrease the frequency of vasospastic attacks, and parenteral prostacyclin are among the new promising therapies.Part of this work was supported by grants from Janssen Pharmaceutica and the National Heart, Lung and Blood Institute, grant HL-26320.     

Clinical diagnosis found in patients with Raynaud's phenomenon: a multicentre study

A multicentre observational study was conducted in order to detect the major clinical diagnosis found in 761 patients with Raynaud's phenomenon (RP) attending 50 Italian centres for rheumatology and internal medicine. Systemic sclerosis was the most frequent condition associated with secondary RP, occurring in 216 (28.4%) patients. The other most frequent clinical diagnoses included systemic lupus erythematosus (52 cases: 6.8%) and rheumatoid arthritis (38 cases: 5%). Other RP-related diseases (hypertension, Sjögren's syndrome, mixed connective tissue disease, undifferentiated connective tissue disease, fibromyalgia, carpal tunnel syndrome, cryoglobulinemia, dermatopolymyositis, vasculitis, thoracic outlet syndrome, hypothyroidism, diabetes mellitus) occurred in less than 5% of cases. A total of 130 (48%) out of 268 patients with primary RP showed one or more clinical features indicating a fairly high risk of evolving into fully established systemic sclerosis. None of these patients fulfilled the ACR criteria for systemic sclerosis. This study shows that over 50% of patients with RP attending 50 Italian centres for rheumatology and internal medicine had a connective tissue disease. The large number of patients with primary RP and isolated clinical features of connective tissue disease indicates that more efforts should be focused on developing new criteria for the classification of RP.     

The effects of peripheral cold exposure on oesophageal motility in patients with autoimmune rheumatic diseases and raynaud's phenomenon

Summary The effects of peripheral cold exposure on oesophageal motility were studied in 14 patients with autoimmune rheumatic diseases. They were divided into two groups: 9 with and 5 without Raynaud's phenomenon. The statistical comparison of these two groups did not reveal any difference in the way they manometrically reacted during and after the cold exposure. We conclude that the oesophageal dysfunction in Raynaud's phenomenon may not be of neurogenic origin.     

Nifedipine-induced fingertip vasodilation in patients with Raynaud's phenomenon

The effect of nifedipine on fingertip hemodynamics was studied in 10 patients with Raynaud's phenomenon. Fingertip blood flow (FBF) was determined in a 20 degrees C environment by venous occlusion air plethysmography and fingertip vascular resistance (FVR) was calculated from the mean blood pressure and the FBF. Nifedipine, administered as a 10 mg sublingual dose, increased FBF in 8 of the 10 patients. FVR for the 10 patients decreased 40% from 40.7 +/- 10.8 to 24.2 +/- 6.1 U (p less than 0.05). Seven of the 10 patients were followed in a crossover placebo-controlled clinical trial. The frequency and severity of Raynaud's phenomenon was less in all seven patients when taking nifedipine as compared to placebo. Nifedipine-induced fingertip vasodilation may contribute to clinical improvement in some patients with Raynaud's phenomenon.     

Acute effects of nifedipine, diltiazem and their combination in patients with chronic stable angina: a double-blind, randomized, cross-over, placebo-controlled study

We evaluated the acute therapeutic effects of the oral administrationof n (10mg) and diltiazem (120 mg) alone and in combinationin 16 patients with effort angina. The 16 patients (13 men andthree women; mean age 59±7 years) performed a symptom-limitedbicycle exercise stress test 3 h after placebo or active substanceadministration. Maximal work load, exercise duration and timeto 1 mm ST segment depression were significantly increased andST depression at peak exercise was significantly decreased bythe combination of drugs. N and diltiazem alone similarly improvedexercise duration as markedly as their combination. One patientstopped the test after all three treatments for angina associatedwith ST depression > 2mm. The combination of drugs yieldedthe best symptomatic effect: only four patients complained ofangina in comparison to eight and seven patients after diltiazemand n respectively. Nifedipine and diltiazem are effective and safe antianginaldrugs. Some patients respond better to one drug than to theother. Patients who remain symptomatic in spite of maximal dosesof a single drug may derive some benefit from combination therapy.     

Suppressive effect of saprogrelate hydrochloride on Raynaud's phenomenon and respiratory failure in patients with systemic sclerosis

OBJECTIVE: In seven patients with systemic sclerosis (SS), we evaluated the clinical effectiveness of oral administration of saprogrelate hydrochloride (SH: 300 mg/day) for 2 months on Raynaud's phenomenon (RP) and respiratory failure estimated by Hugh-Jones classification. METHODOLOGY: We evaluated laboratory data (arterial blood gas (pH, PaO2 and PaCO2), pulmonary function tests (%VC, FEV1/FVC and %DL(CO)), mean pulmonary arterial pressure (mPAP), white blood cell count, C-reactive protein and the plasma levels of fibrinopeptide A (FPA), beta-thrombogloblin (beta-TG), platelet factor 4 (PF4) and thrombomodulin (TM)) before and after SH administration. RESULTS: The frequency and duration of RP, as well as the coldness, numbness and pain of RP were significantly decreased after SH administration (P < 0.05, P < 0.01 and P < 0.001). Respiratory failure estimated by Hugh-Jones classification was also significantly decreased after SH administration (P < 0.05), and the %DL(CO) was significantly increased (P < 0.01). The mPAP decreased significantly after SH administration (P < 0.05). Plasma FPA, beta-TG and PF4 significantly decreased after administration (P < 0.05 and P < 0.01). CONCLUSIONS: SH therapy could prevent RP and respiratory failure in patients with SS.     

The effect of isradipine,a new calcium-channel antagonist,in patients with primary Raynaud's phenomenon: A single-blind dose-response study

Summary Isradipine is a new potent calcium-channel blocking agent with highly selective action on peripheral vessels. In this single-blind study, its dose-related effect on cold-induced changes in finger systolic pressure (FSP) was investigated in ten female patients with primary Raynaud's phenomenon, and the side effects of isradipine treatment were evaluated. The patients were studied during 9 weeks of treatment. After 3 weeks of placebo, isradipine was given in doses of 1.25 mg b. i. d. and 2.5 mg b. i. d. for 3 weeks each. FSP was measured on local finger cooling to 10°C. FSP at 10°C expressed in percent of the value of 30°C increased from 21±16% (M±SD) after placebo to 42±28% (p<0.05) and 62±25% (p<0.001) after treatment with isradipine 1.25 mg and 2.5 mg b. i. d., respectively. The subjective efficacy of the treatment was assessed with a visual analogue scale (VAS). The VAS rating increased from 17 (range 0–66) after placebo to 39 (range 12–88) (NS) and 68 (range 25–99) (p<0.001) after isradipine treatment with 1.25 mg and 2.5 mg b.i.d., respectively. Adverse effects of isradipine therapy were few and did not differ from those reported after the placebo period. This single-blind dose-response study showed that isradipine in doses of 1.25 mg and 2.5 mg b.i.d had favorable objective and subjective effects in patients with primary Raynaud's phenomenon and had no serious side effects.     

Increased alpha2-macroglobulin in diabetes: A hyperglycemia related phenomenon associated with reduced antithrombin III activity

Summary Increased α₂-macroglobulin (α₂M) activity and concentration, and decreased antithrombin III (ATIII) plasma concentration are reported in diabetic subjects. In diabetes an inverse correlation between ATIII activity and blood glucose, HbA₁. α₂M activity and α₂M concentration, and a direct correlation between both α₂M concentration with blood glucose and HbA₁ are found. Moreover, a direct correlation between α₂M activity and α₂M concentration fails. In both diabetic and normal subjects induced hyperglycemia increases α₂M activity and α₂M concentration reduces ATIII activity, while ATIII concentration is not affected. These data which show that hyperglycemia may increase α₂M molecule levels while altering only the biological function of ATIII, provide evidence that hyperglycemia may decrease, directly, the biological function of some proteins and may condition the levels of some risk factors for the development of diabetic complications such as α₂M. This study was presented at the 23rd Annual Meeting of the European Association for the Study of Diabetes, Leipzig, GDR, September 1987.     

Effect of long-term ketanserin treatment on 5-HT levels, platelet aggregation and peripheral circulation in patients with Raynaud's phenomenon. A double-blind, placebo-controlled cross-over study

The long-term effects of the serotonergic (5-hydroxy-tryptamine, 5-HT) receptor antagonist, ketanserin, on 5-HT levels in whole blood, platelet aggregation and peripheral circulation were investigated in a double-blind placebo-controlled cross-over study. In 13 patients with Raynaud's phenomenon, 5-HT and catecholamine levels in whole blood were determined and platelet aggregation assayed after addition of ADP, collagen and 5-HT. Peripheral circulation was evaluated with fingertip temperatures and finger plethysmography before and after local cooling, with measurements repeated after indirect sympathetic blockade by body warming and after alcohol. Patients' symptoms were continuously registered in an individual diary. All measurements were performed 8 to 12 hours after the last drug intake. Five of seven scleroderma patients reported beneficial effects of ketanserin treatment and all six patients with primary Raynaud's phenomenon reported less severe and shorter cold-induced attacks. 5-HT levels in whole blood were significantly reduced after 5 weeks of ketanserin treatment (p less than 0.001) with a tendency for persistence of this reduction after halting of the medication (a "carry-over" effect). Platelet aggregation velocity induced by ADP, collagen and 5-HT was unaffected after ketanserin treatment. The diastolic blood pressure in these patients was decreased from 77.5 mmHg to 71.0 mmHg (p less than 0.001) after ketanserin, but the finger systolic blood pressure (FSBP) was unchanged. After sympathetic blockade by body warming, patients with ketanserin treatment had a paradoxical reduction in both FSBP and finger-tip temperatures, which makes a supposed alpha-receptor-blocking effect of ketanserin less likely. The reduced 5-HT levels in whole blood may explain the subjective favourable effect on patients with Raynaud's phenomenon.     

Secretion of phospholipase A2 induced by interactions of human platelets with monocytes

Summary Phospholipase A₂ (PLA₂) activity was found and measured in the cell-free supernatants of human mononuclear cells (monocytes and lymphocytes) cultured with platelets for 48 h at 37° C. The relative molecular mass of purified, calcium-dependent PLA₂ was 14 kD. The amount of PLA₂ in the supernatants correlated positively with the number of monocytes and platelets in the cultures. Electron microscopically, direct cell-to-cell interactions of monocytes and platelets were observed. Cultivation of suspensions of human mononuclear cells with platelets in serum-free medium was found to be an efficient way to produce and purify human secretable PLA₂. In the release of secretable PLA₂ in peripheral blood, the interactions between platelets and monocytes may play a considerable role.     

A randomized,double-blind,placebo-controlled clinical study of the histamine H<Subscript>2</Subscript>-receptor antagonist famotidine in Japanese patients with nonerosive reflux disease

BACKGROUND: To investigate whether histamine H2-receptor antagonists are sufficient to treat heartburn in nonerosive reflux disease in Japanese, who produce less gastric acid than Westerners, the efficacy of famotidine in Japanese nonerosive reflux disease patients was studied in a double-blind, placebo-controlled, parallel group-comparative, multicenter study. METHODS: The Los Angeles classification system with Japanese modifications was used to assess the severity of nonerosive reflux disease. Famotidine (10-or 20-mg doses) or placebo was administered to patients twice daily for 8 weeks. Heartburn symptoms were recorded daily by patients. RESULTS: A total of 528 patients participated in the study. The percentage of days without heartburn, the primary end point of the efficacy evaluation, was 62% for 40 mg and 59% for 20 mg of famotidine, and 55% for placebo, with a statistically significant difference between the 40-mg dose and placebo (P = 0.001; significance level, 0.025 one-sided). Famotidine at both doses provided immediate relief from heartburn, and relief persisted throughout the 8-week study with the 40-mg dose. CONCLUSIONS: The results indicate that famotidine relieves heartburn symptoms in Japanese nonerosive reflux disease patients.     

Premedication with orally administered lorazepam in adults undergoing ERCP: a randomized double-blind study

BACKGROUND: Restlessness often complicates ERCP and may be a reason for premature termination of the procedure. OBJECTIVE: Our purpose was to evaluate whether a premedication with orally administered lorazepam could reduce the need for sedatives and improve sedation quality. DESIGN: Randomized double-blind trial. SETTING: Therapeutic ERCP with an intravenous sedation containing midazolam, propofol, and S(+)-ketamine. PATIENTS: 95 inpatients (aged 20-91 years). INTERVENTIONS: 1 mg of lorazepam (n=47) or placebo (n=48) given orally before ERCP. MAIN OUTCOME MEASUREMENT: Total amount of administered propofol. RESULTS: Heart rate, blood pressure, number of oxygen desaturations, and states of restlessness did not differ between the groups. The same amount of midazolam was administered in both groups. There was no significant difference in the total amount of propofol to achieve adequate sedation (lorazepam vs placebo: 71+/-5 vs 63+/-4 microg/kg/min, mean+/-SE). Paradoxically, patients pretreated with lorazepam even needed more propofol in the early phase of sedation (275+/-39 vs 159+/-37 microg/kg in minutes 5-10, P<.05) and the total amount of ketamine administered was higher in this group as well (15.8+/-1.4 vs 11.3+/-1.2 microg/kg/min, P<.05). In both groups there were high rates of satisfaction with the course of the procedure evaluated both by the endoscopists and the patients. CONCLUSION: The trial failed to show an advantage of an oral premedication with lorazepam. The amount of sedatives administered in the lorazepam group even tended to be higher. A premedication with lorazepam may be counterproductive when followed by sedation containing another benzodiazepine.     

The diagnostic value of clinical signs and symptoms in patients with Raynaud's phenomenon. A cross-sectional study

Patients presenting with Raynaud's phenomenon pose differential diagnostic problems. The question is whether the discolorations are a symptom of the benign primary type or a symptom of an underlying disease, mostly a connective tissue disease or an atherosclerotic occlusive disease, both having major prognostic implications. To evaluate whether Raynaud patients can be classified properly in the above-mentioned categories on clinical grounds we evaluated 225 patients using a checklist dealing with signs and symptoms supposed to be specific for primary Raynaud's phenomenon or the two major types of the secondary form. Complaints that started before the age of 20, reactive hyperaemia at the end of an attack and discolorations of the earlobes and the nose have a high predictive value for primary Raynaud's phenomenon. Trophic skin disturbances are rare in the latter but are rather specific for connective tissue diseases. In the case of arterial obstructive disease, the feet are always involved and risk factors associated with atherosclerosis are often present, whereas this type is specifically encountered in men in whom the complaints started over the age of 50 [corrected], and in whom signs of atherosclerotic vessel wall disease were seen elsewhere. In conclusion, in most patients who present with a Raynaud's phenomenon a complete history and physical examination are sufficient for a correct diagnosis. Supplementation with determination of anti-nuclear antibodies, measurements of the capillary perfusion and of the finger skin systolic pressure completes the diagnostic classification.     

A study of zinc distribution in erythrocytes of normal humans

Summary The assignment of zinc bound to carbonic anhydrase isoenzymes (CA-I and CA-II) and Cu₂ Zn₂ superoxide dismutase (SOD₁) was investigated in the hemolysates from 21 normal male subjects.Sufficient care was taken to remove leukocytes and platelets. The following values of zinc distribution were obtained:total zinc, 1113.8±22.7 (mean±S.E.) g · 100 ml^–1; CA-I-derived zinc, 866.6±26.2 g · 100 ml^–1; CA-II-derived zinc, 99.9±3.9 g · 100 m^–1; SOD₁-derived zinc, 60.3±1.9 g · 100 ml^–1; the other zinc, 87.0±12.6 g · 100 ml^–1. Namely, 7.6% of the zinc in human erythrocytes is not bound to the carbonic anhydrases and Cu₂Zn₂ superoxide dismutase, but present in available form or attached to other enzymes.