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The bioequivalence of two sustained-release preparations of quinidine bisulphate from Teva (Israel) and from Astra (Sweden) was assessed in an acute, single-dose randomized cross-over study in seven healthy subjects. There was no significant difference in time to peak, peak serum concentration, area under the concentration time curve from 0 to infinity, and the fraction absorbed between quinidine bisulphate 500 mg from Teva and from Astra. In addition, quinidine bisulphate 250 mg from Teva was compared with the short-acting quinidine sulphate 200 mg. The quinidine bisulphate from Teva had a significantly P less than 0.025) decreased peak serum concentration and an increased time to peak compared with the short-acting quinidine sulphate, although these two drugs are similar for the area under the curve from 0 to infinity. Our pharmaceutical records show that 85% of outpatients receiving quinidine are given the sustained-release quinidine bisulphate. However, only 36% of the outpatients prescribed sustained-release quinidine bisulphate are appropriately prescribed for twice-daily treatment. Thus the quinidine bisulphate from Teva is a sustained-release preparation with bioequivalence to the reference sustained-release preparation and can be administered twice daily.

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A double-blind, randomized, crossover chronic study was done to determine the efficacy of colchicine in 10 atopic patients with asthma. A constant dose of sustained-release theophylline and albuterol by inhalation, as needed, was administered. Compared to placebo, colchicine, 0.5 mg twice daily, significantly reduced the mean (+/- SEM) daily clinical score from 2.18 +/- 0.34 to 1.64 +/- 0.32 (p less than 0.05), and the daily number of inhalations of albuterol from 5.89 +/- 1.48 to 4.01 +/- 1.26 (p less than 0.02). Colchicine significantly (p less than 0.05) increased the concanavalin A-induced suppressor cell function from 16.2 +/- 4.6% to 39.0 +/- 10.7%, which was similar to healthy volunteers (41.1 +/- 3.5%). Furthermore, colchicine significantly (p less than 0.05) decreased serum IgE from 248 +/- 63 to 188 +/- 46 IU/ml. Colchicine had no significant effect on pulmonary function tests, the early phase reaction of antigen-induced bronchial inhalation challenge, and immediate skin test responses. Thus, colchicine has immunomodulatory effects that may perhaps have a mild benefit in the treatment of asthma.

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The pharmacokinetic mechanism of the theophylline-terbutaline interaction has been studied. Sustained release theophylline 200-400 mg b.d. was given with placebo or terbutaline 2.5 mg t.d.s. to six adult asthmatic patients. Terbutaline decreased the serum trough theophylline levels from 8.1 to 7.3 micrograms/ml, improved daily the clinical score from 1.51 to 1.26 and increased the peak expiratory flow rate from 316 to 370 l/min. In a single dose study following the chronic therapy, it was shown that there was no change in the peak theophylline concentration or in the timing of the peak, but the t1/2 was reduced from 9.0 to 7.5 h, and the systemic clearance was increased from 20.2 to 24.8 ml.h-1.kg-1. Thus, terbutaline reduced the serum theophylline concentration by increasing its systemic clearance.

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Six asthmatic children participated in an acute crossover randomized study. They received a single dose of aminophylline syrup 6 mg/kg after having received ketotifen syrup 1 mg b.i.d. or placebo for 8 days. Ketotifen did not significantly affect the heart rate, pulse pressure or such pharmacokinetic parameters of theophylline as peak serum level, time to peak, half life and AUC. Thus, ketotifen had no significant effect on the disposition of theophylline.

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Asthmatic patients have a deficiency of concanavalin A-(Con A) induced suppressor cell function. We tested whether oral colchicine 0.5 mg twice daily for 7 days could correct this immunoregulatory abnormality. Peripheral blood mononuclear cells were incubated with Con A and then suppression of proliferation was measured by coculture of these cells with healthy volunteers' mononuclear cells and phytohaemagglutinin. Sixteen asthmatic patients had significantly (P less than 0.002) decreased Con A-induced suppressor cell function (17.0 +/- 17.2%, mean +/- s.d.) as compared to 13 healthy volunteers (37.9 +/- 14.9%). Oral colchicine significantly (P less than 0.05) increased, though only partially corrected, these 16 asthmatic patients' Con A-induced suppressor cell function (28.1 +/- 14.3%). Asthmatic patients had an increased number of monocytes (691 +/- 289 vs 388 +/- 271/mm3 for normals, P less than 0.01) and a normal number of lymphocytes, Leu 4+ total T cells, Leu 3+ helper/inducer T cells, and Leu 2+ suppressor/cytotoxic T cells as well as a normal Leu 3/Leu 2 ratio. Oral colchicine significantly (P less than 0.005) decreased the number of monocytes (451 +/- 255/mm3) without significantly affecting the number of lymphocytes, Leu 4+, Leu 3+, or Leu 2+ T cells, or the Leu 3/Leu 2 ratio. These results are consistent with the hypothesis that the deficiency of Con A-induced suppressor cell function in asthmatic patients may be due, in part, to an increased number and/or abnormal activity of monocytes. If so, then oral colchicine may have partially corrected the deficiency of Con A-induced suppressor cell function by decreasing the number and/or modulating the activity of monocytes.

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The effect of nifedipine, 10 mg po q.i.d. for 2 weeks, was studied in a randomized, double-blind, crossover trial in nine patients with asthma receiving theophylline. Nifedipine did not significantly affect the mean (+/- SD) morning peak expiratory flow rate (PEFR; 336 +/- 130 L/min for drug vs. 349 +/- 92 L/min for placebo), evening PEFR (393 +/- 69 L/min for drug vs. 367 +/- 66 L/min for placebo), symptom score (27.4% +/- 22.9% for drug vs. 33.8% +/- 26.4% for placebo), or the number of albuterol inhalations per day (5.8 +/- 3.5 for drug vs. 6.2 +/- 4.1 for placebo). Furthermore, there was no change in PEFR 30, 60, or 120 minutes after nifedipine dosing. Nifedipine did not significantly affect the steady-state serum theophylline trough levels (9.1 +/- 2.2 mg/ml for drug vs. 10.2 +/- 1.9 micrograms/ml for placebo) or the theophylline pharmacokinetic parameters, such as the elimination t1/2, peak serum concentration, time to peak, and AUC(0-24). We conclude that nifedipine has little, if any, effect on the clinical status, PEFR, or theophylline serum levels in patients with asthma who receive theophylline.

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Patients with carcinomas have elevated levels of Fc receptors for IgG (Fc gamma R) on their peripheral blood mononuclear cells (PBMC). The purpose of the present study was to determine whether there is a correlation between Fc gamma R levels on PBMC and survival in patients with metastatic breast cancer. Binding assays were performed on PBMC using 125I-labeled fibrinogen complexed with rabbit IgG (or as a control F(ab')2) anti-human fibrinogen. Twenty-two metastatic breast cancer patients had significantly (p less than 0.001) elevated Fc gamma R levels as compared to either 22 breast cancer patients receiving adjuvant chemotherapy following mastectomy without clinical evidence of tumor, or to 34 non-malignant controls. Significantly more metastatic patients with elevated Fc gamma R levels died at 6 months (p less than 0.001) as compared to those with low levels. A direct correlation between Fc gamma R levels and hazard probability was found (correlation coefficient = 0.3321, p less than 0.005). These results raise the possibility that Fc gamma R levels on PBMC from metastatic breast cancer patients may be clinically useful as a prognostic marker of disease activity.

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Cimetidine inhibits the renal tubular secretion of creatinine and digoxin is partly excreted by the same pathway. In order to investigate a possible interaction between the two drugs, a randomized cross-over acute study has been conducted. Six patients with duodenal ulcers were given a single dose of digoxin (Dig) 0.75 mg i.v. with and without oral cimetidine 1200 mg/day. Cimetidine significantly reduced creatinine clearance from 157 to 132 ml/min. There was no significant difference in inulin clearance, 99.2 vs 97.5 ml/min, Dig elimination half life 53.9 vs 56.9 h, apparent volume of distribution 11.3 vs 11.6 l/kg, systemic clearance 2.42 vs 2.35 ml/min/kg, renal clearance 1.48 vs 1.62 ml/min/kg or urinary excretion of digoxin 49.5 vs 51.6% of dose without or with cimetidine. These results suggest that cimetidine does not influence the disposition of digoxin.

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Extrinsic asthmatic patients have been reported to have a deficiency of concanavalin A (Con A)-induced suppressor cell function. We tested whether in vitro colchicine and oral theophylline can correct this immunoregulatory abnormality. Asthmatic patients' mononuclear cells were incubated with Con A and/or colchicine and then suppression of proliferation was measured by coculture of these cells with healthy volunteers' mononuclear cells and phytohaemagglutinin. The Con A induced suppressor cell function of 29 theophylline treated patients (26 +/- 16%, mean +/- s.d.) was significantly (P less than 0.002) increased as compared to 21 untreated patients (12 +/- 10%) but significantly (P less than 0.01) decreased as compared to 45 healthy volunteers (39 +/- 17%). A pharmacological concentration (10(-8) M) of colchicine had no significant effect on Con A-induced suppressor cell function of 19 untreated patients (from 12 +/- 9% to 9 +/- 22%) but significantly (P less than 0.05) increased Con A-induced suppressor cell function of 20 theophylline treated patients (from 26 +/- 17% to 36 +/- 19%). Thus asthmatic patients have decreased Con A-induced suppressor cell function which is partially corrected by oral theophylline and almost completely corrected by oral theophylline plus in vitro colchicine. This synergistic effect raises the possibility that oral colchicine together with theophylline may be useful in treating patients with extrinsic asthma.

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The rapidity by which drug-dependent antiplatelet antibodies can develop is not known, since patients are only studied during or after the episode of thrombocytopenia. This report describes the development of quinidine-induced immune thrombocytopenia in a healthy volunteer during a drug study. The thrombocytopenia developed within two weeks of initiation of quinidine therapy. During the thrombocytopenic episode, but not before receiving the drug, the patient had an IgG antiplatelet antibody that bound to control platelets in the absence of the drug. This antibody was absent when the drug was discontinued and the platelet count rose. The patient's acute serum also induced the release of serotonin from control platelets, and the reaction was enhanced by quinidine. This indicates that drug-dependent antiplatelet antibodies can develop rapidly and supports the hypothesis that quinidine-induced thrombocytopenia is due to a quinidine-dependent platelet-specific IgG.

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We studied the effect of oral terbutaline on serum theophylline levels in 12 children with asthma. Sustained-release theophylline (10 mg/kg twice a day) was given with placebo or terbutaline (0.075 mg/kg three times a day) in a chronic, randomized, double-blind, crossover design. The trough serum theophylline concentration fell from 13.8 +/- 4.0 to 10.8 +/- 3.6 micrograms/ml and the peak expiratory flow rate increased from 285 +/- 30 to 310 +/- 29 L/min after terbutaline. Further investigation is needed to clarify the mechanism of action by which terbutaline decreases serum theophylline levels.

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We examined the effect of oral colchicine (1-2 mg/day) on four healthy volunteers' T cell subsets. Colchicine significantly (P less than 0.01) decreased the mean (+/- SD) percent of OKT3+ total T cells (from 70 +/- 16 to 47 +/- 13), OKT4+ helper/inducer T cells (from 44 +/- 9 to 24 +/- 6), and OKT8+ suppressor/cytotoxic T cells (from 27 +/- 7 to 17 +/- 7), but did not significantly affect the OKT4:OKT8 ratio (from 1.64 +/- 0.21 to 1.48 +/- 0.45) or concanavalin A-induced suppressor cell function (from 44 +/- 9% to 47 +/- 13%). Thus, colchicine non-selectively decreased the circulating helper/inducer and suppressor/cytotoxic T cells.

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Patients with primary biliary cirrhosis (PBC) have been previously reported to have immunoregulatory abnormalities. We tested the effect of in vitro colchicine on PBC patients' suppressor cell function in order to determine whether colchicine can correct their suppressor cell deficiency. PBC patients' mononuclear cells were cultured for 44 h with concanavalin A (Con A) as well as with or without colchicine at a pharmacological concentration (10(-8)M) or at a suprapharmacological concentration (10(-5)M) and then tested for their ability to suppress proliferation of phytohaemagglutinin stimulated healthy volunteers' mononuclear cells. Eleven PBC patients had significantly (P less than 0.001) decreased suppressor cell function (12 +/- 15%, mean +/- s.d.) as compared to 37 healthy volunteers (43 +/- 12%). The suprapharmacological concentration of colchicine did not significantly affect the PBC patients' suppressor cell function (16 +/- 15%). In contrast, in the nine PBC patients tested with the pharmacological concentration of colchicine, their suppressor cell function was increased to 40 +/- 20% which was significantly different than without colchicine (P less than 0.01) or with the suprapharmacological concentration of colchicine (P = 0.02) but not significantly different than healthy volunteers. Thus, in vitro colchicine at a pharmacological concentration corrects PBC patients' deficiency of Con A-induced suppressor cell function raising the possibility that oral colchicine might be clinically useful as an immunomodulating drug in PBC.

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The effect of colchicine on immunoregulatory T lymphocytes in children with familial Mediterranean fever (FMF) was studied. Concanavalin A (Con A)-induced suppressor cell function was significantly (P less than 0.0001) decreased in five untreated FMF patients (15 +/- 3%, mean +/- s.e.) as compared to six age matched paediatric controls (46 +/- 3%) and eight healthy adults (49 +/- 4%). When the five untreated FMF patients' mononuclear cells were pre-incubated in vitro with Con A plus 10(-5) M colchicine, their suppressor cell function was significantly increased (52 +/- 10%, P less than 0.01). Similarly, oral colchicine treatment (0.5 mg twice daily) significantly (P = 0.02) increased the five FMF patients' Con A-induced suppressor cell function to levels (34 +/- 6%) that were not significantly (P greater than 0.05) different than the paediatric controls or the healthy adults. The percentage of OKT8+ cells (but not OKT3+ or OKT4+ cells) was significantly (P less than 0.0001) decreased in 10 untreated FMF patients (16.0 +/- 0.9) as compared to 10 paediatric controls (27.6 +/- 2) or 10 healthy adults (25.7 +/- 0.6). The 10 untreated FMF patients had a significant (P less than 0.002) increase in the OKT4/OKT8 ratio (2.41 +/- 0.13) as compared to 10 FMF patients treated with 0.5 mg twice daily of colchicine (1.81 +/- 0.08), 10 pediatric controls (1.47 +/- 0.2), or 10 healthy adults (1.78 +/- 0.11). Colchicine appears to have corrected the FMF patients' elevated OKT4/OKT8 ratio by both decreasing the percentage of OKT4+ cells and increasing (but only partially correcting) the percentage of OKT8+ cells. Thus FMF patients have a suppressor cell deficiency in which colchicine treatment corrects their deficiency of Con A-induced suppressor cell function and their elevated OKT4/OKT8 ratio. This raises the possibility that colchicine might be potentially useful as an immunomodulating drug in treating patients with autoimmune or allergic diseases associated with a suppressor cell deficiency.

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