Oral octreotide absorption in human subjects: comparable pharmacokinetics to parenteral octreotide and effective growth hormone suppression.

CONTEXT: Oral administration of a novel octreotide formulation enabled its absorption to the systemic circulation, exhibiting blood concentrations comparable to those observed with injected octreotide and maintaining its biological activity. OBJECTIVES: The aim of the study was to determine oral octreotide absorption and effects on pituitary GH secretion compared to sc octreotide injection. DESIGN: Four single-dose studies were conducted in 75 healthy volunteers. INTERVENTION: Oral doses of 3, 10, or 20 mg octreotide and a single sc injection of 100 µg octreotide were administered. MAIN OUTCOME MEASURE: We measured the pharmacokinetic profile of orally administrated octreotide and the effect of octreotide on basal and stimulated GH secretion. RESULTS: Both oral and sc treatments were well tolerated. Oral octreotide absorption to the circulation was apparent within 1 h after dose administration. Escalating oral octreotide doses resulted in dose-dependent increased plasma octreotide concentrations, with an observed rate of plasma decay similar to parenteral administration. Both 20 mg oral octreotide and injection of 0.1 mg sc octreotide resulted in equivalent pharmacokinetic parameters [mean peak plasma concentration, 3.77 ± 0.25 vs. 3.97 ± 0.19 ng/ml; mean area under the curve, 16.2 ± 1.25 vs. 12.1 ± 0.45 h × ng/ml); and median time ≥ 0.5 ng/ml, 7.67 vs. 5.88 h, respectively). A single dose of 20 mg oral octreotide resulted in basal (P < 0.05) and GHRH-stimulated (P < 0.001) mean GH levels suppressed by 49 and 80%, respectively. CONCLUSIONS: The results support an oral octreotide alternative to parenteral octreotide treatment for patients with acromegaly.

Nasopharyngeal carcinoma: repeat treatment with conformal proton therapy--dose-volume histogram analysis.

PURPOSE: To analyze control, survival, and complication rates of conformal proton radiation for recurrent nasopharyngeal carcinoma. MATERIALS AND METHODS: Sixteen patients with nasopharyngeal carcinoma initially treated with 50.0-88.2 Gy photons were re-treated with protons to additional doses of 59.4-70.2 CGE. Local-regional control and survival were correlated with extent of relapse, recurrence versus persistence, and prescribed dose and were subjected to dose-volume histogram analysis. Mean follow-up was 23.7 months (range, 4-47 months). RESULTS: Twenty-four-month actuarial overall and local-regional progression-free survival rates were both 50%. The 24-month actuarial overall survival rates for patients with "optimal" dose-volume histogram coverage versus "suboptimal" coverage were 83% and 17%, respectively (P = .006). Doses to critical structures were low (0-22.0 Gy); no central nervous system side effects supervened. CONCLUSION: Adequate tumor coverage, as evaluated by using dose-volume histogram analysis, was found to be the most important variable influencing local-regional control and survival. No central nervous system complications were observed; increases in the dose to adjacent critical structures are being evaluated.

Conformal proton therapy for early-stage prostate cancer.

OBJECTIVES: To assess the effect of proton radiation on clinical and biochemical outcomes for early prostate cancer. METHODS: Three hundred nineteen patients with T1-T2b prostate cancer and initial prostate-specific antigen (PSA) levels 15.0 ng/mL or less received conformal radiation doses of 74 to 75 cobalt gray equivalent with protons alone or combined with photons. No patient had pre- or post-treatment hormonal therapy until disease progression was documented. Patients were evaluated for biochemical disease-free survival, PSA nadir, and toxicity; the mean and median follow-up period was 43 months. RESULTS: Overall 5-year clinical and biochemical disease-free survival rates were 97% and 88%, respectively. Initial PSA level, stage, and post-treatment PSA nadir were independent prognostic variables for biochemical disease-free survival: a PSA nadir 0.5 ng/mL or less was associated with a 5-year biochemical disease-free survival rate of 98%, versus 88% and 42% for nadirs 0.51 to 1.0 and greater than 1.0 ng/mL, respectively. No severe treatment-related morbidity was seen. CONCLUSIONS: It appears that patients treated with conformal protons have 5-year biochemical disease-free survival rates comparable to those who undergo radical prostatectomy, and display no significant toxicity. A Phase III randomized dose-escalation trial is underway to define the optimum radiation dose for early-stage prostate cancer.

Conformal proton therapy for prostate carcinoma.

BACKGROUND: The role and optimum dose of radiation to eradicate prostate cancer continues to be evaluated. Protons offer an opportunity to increase the radiation dose to the prostate while minimizing treatment toxicity. METHODS: Six hundred forty-three patients with localized prostate cancer were treated with protons, with or without photons. Treatments were planned with a 3D planning system; patients received 74-75 CGE (Cobalt Gray Equivalent) at 1.8-2.0 CGE per fraction. Patients were evaluated for response to therapy and treatment-related toxicity. RESULTS: The overall clinical disease-free survival rate was 89% at 5 years. When post-treatment prostate-specific antigen (PSA) was used as an endpoint for disease control, the 4.5-year disease-free survival rate was 100% for patients with an initial PSA of < 4.0 ng/ml, and 89%, 72%, and 53% for patients with initial PSA levels of 4.1-10.0, 10.1-20.0, and > 20.0, respectively. Patients in whom the post-treatment PSA nadir was below 0.5 ng/ml did significantly better than those whose nadir values were between 0.51-1.0 or > 1.0 ng/ml: the corresponding 5-year disease-free survival rates were 91%, 79%, and 40%, respectively. Minimal radiation proctitis was seen in 21% of patients; toxicity of greater severity was seen in less than 1%. CONCLUSION: Proton therapy to 74-75 CGE produced minimal treatment-related toxicity and excellent PSA normalization and disease-free survival in patients with low initial PSA levels. A prospective randomized dose-escalation trial is now underway to help define the optimum dose of radiation for patients with early stage prostate cancer.

Combined proton and photon conformal radiation therapy for locally advanced carcinoma of the prostate: preliminary results of a phase I/II study.

PURPOSE: A study was developed to evaluate the use of combined photons and protons for the treatment of locally advanced carcinoma of the prostate. This report is a preliminary assessment of treatment-related morbidity and tumor response. METHODS AND MATERIALS: One hundred and six patients in stages T2b (B2), T2c (B2), and T3 (C) were treated with 45 Gy photon-beam irradiation to the pelvis and an additional 30 Cobalt Gray Equivalent (CGE) to the prostate with 250-MeV protons, yielding a total prostate dose of 75 CGE in 40 fractions. Median follow-up time was 20.2 months (range: 10-30 months). Toxicity was scored according to the Radiation Therapy Oncology Group (RTOG) grading system; local control was evaluated by serial digital rectal examination (DRE) and prostate specific antigen (PSA) measurements. RESULTS: Morbidity evaluation was available on 104 patients. The actuarial 2-year rate of Grade 1 or 2 late morbidity was 12% (8% rectal, 4% urinary). No patients demonstrated Grade 3 or 4 late morbidity. Treatment response was evaluated on 100 patients with elevated pretreatment serum PSA levels. The actuarial 2-year rate of PSA normalization was 96%, 97%, and 63% for pretreatment PSAs of > 4-10, > 10-20, and > 20, respectively. The 13 patients with rising PSA demonstrated local recurrence (3 patients), distant metastasis (8 patients), or no evidence of disease except increasing PSA (2 patients). CONCLUSIONS: The low incidence of side effects, despite the tumor dose of 75 CGE, demonstrates that conformal protons can deliver higher doses of radiation to target tissues without increasing complications to surrounding normal tissues. The initial tumor response, as assessed by the high actuarial rate of normalization with pretreatment PSA < or = 20, and the low rate of recurrences within the treatment field (2.8%), are encouraging.

Randomized angiographic trial of recombinant tissue-type plasminogen activator (alteplase) in myocardial infarction. RAAMI Study Investigators.

Clot dissolution with restoration of infarct-related artery blood flow is the likely mechanism for the improved prognosis and mortality reduction seen after thrombolytic therapy of acute myocardial infarction. A pilot study has suggested that 100 mg of recombinant tissue-type plasminogen activator (rt-PA) infused over 90 min may lead to higher patency rates than the current standard of 100 mg over 3 h. In this multicenter, randomized, open label trial, 281 patients with acute myocardial infarction receive 100 mg of rt-PA according to either the standard 3-h infusion regimen (an initial 10-mg bolus followed by 50 mg for the 1st h, then 20 mg/h for 2 h) or an accelerated 90-min regimen (15-mg bolus followed by 50 mg over 30 min, then 35 mg over 60 min). All patients also received intravenous heparin and oral aspirin during and after rt-PA infusion. At 60 min after initiation of the rt-PA infusion, the observed angiographic patency rates were 76% (95% confidence intervals 65% to 84%) in the accelerated regimen group and 63% in the control group (52% to 73%, p = 0.03). At 90 min these rates were 81% (73% to 87%) and 77% (68% to 84%), respectively (p = 0.21). Both randomized groups experienced similar rates of recurrent ischemia, reinfarction, angiographic reocclusion, other complications of myocardial infarction (including stroke and death) and bleeding complications.(ABSTRACT TRUNCATED AT 250 WORDS)

Use of rapid serial sampling of creatine kinase MB for very early detection of myocardial infarction in patients with acute chest pain.

To determine how early myocardial infarction can be detected, serial creatine kinase MB concentrations were sampled in 313 patients during triage of acute (less than 12 hours) chest pain. Serum was sampled on hospital arrival (baseline) and hourly for 3 hours (total of four samples). Creatine kinase MB concentrations were subsequently analyzed for their ability to detect infarction. Infarction was present in 70 patients (22%) and was diagnosable from the index electrocardiograms in 27 of these (39%). Sensitivity and specificity for detection of infarction were 76% and 72%, respectively, as determined from baseline MB values only and increased with each additional sample to a maximum of 92% and 96%, respectively, in all four samples. Analysis of two serum samples taken 2 hours apart showed a sensitivity of 94% and a specificity of 91%. If these results are confirmed, improved initial diagnostic accuracy with this rapid assay technique in acute chest pain may (1) conserve resources when initial suspicion of infarction is low, (2) identify patients with infarction appropriate for early intervention, and (3) avoid premature hospital discharge of patients with infarction.

A prospective evaluation of prehospital 12-lead ECG application in chest pain patients.

The objective of this study was to prospectively determine the utility, efficiency, and reliability of early prehospital 12-lead electrocardiogram (ECG) application, the improvement in prehospital diagnostic accuracy, and paramedic and base physician opinions regarding early application of prehospital 12-lead ECGs in a broad range of stable chest pain patients. The patient population consisted of cooperative, stable adult prehospital patients with a chief complaint of nontraumatic chest pain of presumed ischemic origin. From July 17, 1989 through January 1, 1990 paramedics acquired prehospital 12-lead ECGs on 680 stable adult chest pain patients. Factors affecting prehospital 12-lead ECG application were evaluated. Paramedic application of prehospital 12-lead ECGs was found to be efficient and reliable, and it can be applied to most cooperative stable adult prehospital chest pain patients. Prehospital 12-lead ECGs significantly improve base physicians' diagnostic accuracy in myocardial infarction, angina, and nonischemic chest pain patients. Paramedic and base physicians' opinions regarding early application of prehospital 12-lead ECGs during patient evaluation were favorable.

Effect of heparin on coronary arterial patency after thrombolysis with tissue plasminogen activator in acute myocardial infarction.

Infarct artery patency rates at 90 minutes after coronary thrombolysis using recombinant tissue-type plasminogen activator (rt-PA) with and without concurrent heparin anticoagulation have been shown to be comparable. The contribution of heparin to efficacy and safety after thrombolysis with rt-PA is unknown. In this pilot study, 84 patients were treated within 6 hours of onset of acute myocardial infarction (mean of 2.7 hours) with the standard dose of 100 mg of rt-PA over 3 hours. Forty-two patients were randomized to receive additionally immediate intravenous heparin anticoagulation (5,000 U of intravenous bolus followed by 1,000 U/hour titrated to a partial thromboplastin time of 1.5 to 2.0 times control) while 42 patients received rt-PA alone. Coronary angiography performed on day 3 (48 to 72 hours, mean 57) after rt-PA therapy revealed infarct artery patency rates of 71 and 43% in anticoagulated and control patients, respectively (p = 0.015). Recurrent ischemia or infarction, or both, occurred in 3 (7.1%) anticoagulated patients and 5 (11.9%) control patients (difference not significant). Mild, moderate and severe bleeding occurred in 52, 10 and 2% of the group receiving anticoagulation, respectively, and 34, 2 and 0% of patients in the control group, respectively (p = 0.006). These data indicate that after rt-PA therapy of acute myocardial infarction, heparin therapy is associated with substantially higher coronary patency rates 3 days after thrombolysis but is accompanied by an increased incidence of minor bleeding complications.

Thrombolytic therapy in acute myocardial infarction: Part II--rt-PA.

Thrombolysis with pharmacologic agents is a valuable modality for treatment of acute myocardial infarction. The results of several clinical studies indicate that early recanalization can be elicited with intravenous agents and that it is associated with substantial reductions of infarct size, improvement of ventricular function, and reduction in mortality. The recently introduced fibrin-selective agent, rt-PA, appears to represent a significant pharmacologic advance. Its use intravenously elicits high recanalization rates without marked derangements of the coagulation system, reflecting its relative fibrin selectivity. The efficacy of thrombolysis with any drug given by any route, unfortunately, is not 100 per cent. Bleeding remains an important risk. The optimal approach to management of residual stenosis after thrombolysis has not yet been delineated. Currently available information appears to justify the following conclusions: 1. Transmural myocardial infarction usually is caused by an acute obstructing coronary thrombus superimposed on a chronic atherosclerotic lesion. Myocardial necrosis following interruption of blood flow generally is complete within several hours. 2. The thrombus can be lysed and blood flow can be restored with intravenous agents that activate plasminogen. Intravenous rt-PA, a relatively fibrin-specific agent, elicits recanalization in 70 to 75 per cent of infarct-related arteries. 3. Recombinant t-PA evokes only modest depletion of fibrinogen (16 to 36 per cent reduction from baseline). 4. Early reperfusion preserves myocardium and ventricular function and reduces mortality. 5. The extent of benefit after pharmacologic reperfusion is correlated strongly with the brevity of myocardial ischemia prior to initiation of therapy. The greatest benefit is realized in patients treated within the first few hours of onset of acute myocardial infarction. 6. The incidence and optimal means of prevention of reocclusion and reinfarction following successful pharmacologic reperfusion are not yet entirely clear. Mechanical recanalization with PTCA in conjunction with thrombolysis is promising, but its routine immediate use on an emergency basis does not appear to be beneficial. Vigorous educational efforts are needed to heighten the awareness of prospective patients and all members of the health care team to the value of prompt diagnosis of incipient or evolving infarction so that prompt implementation of thrombolysis in appropriate candidates can be facilitated.

Thrombolytic therapy in acute myocardial infarction: Part I.

Thrombolytic therapy with pharmacologic agents is an exciting approach to the treatment of myocardial infarction. The results of several clinical studies indicate that perfusion can be restored with intravenous therapy and may be associated with a reduction in infarct size and improved left ventricular function. In a trial involving more than 11,000 patients, thrombolytic therapy reduced acute and long term mortality. Pharmacologic thrombolysis, however, is not without problems. When administered intravenously, the agents currently available, streptokinase and urokinase, are associated with a relatively low recanalization rate as well as a risk of adverse effects, most commonly a systemic lytic state and risk of bleeding complications. Although intracoronary administration is associated with a higher rate of recanalization, the need for cardiac catheterization limits its applicability and results in a delay in the initiation of thrombolytic therapy (which diminishes salvage of myocardium). The trials assessing the existing agents have shown that time is a critical variable in the success of thrombolytic therapy. This had led investigators to focus more attention on intravenous agents that can be administered rapidly. The newer agents now under investigation, acylated streptokinase and single-chain urokinase, may represent improvements of currently available products and may offer potentially increased benefits. A fibrinogen-sparing agent, such as t-PA, in addition to being highly effective, may offer advantages through minimizing the systemic lytic effect. Additional randomized, controlled clinical trials currently are underway to determine the effect on mortality of this "fibrinolytic" therapy as part of a total treatment regimen. The current status of our knowledge concerning thrombolytic therapy in acute myocardial infarction can be summarized as follows: 1. Transmural (that is, Q wave) myocardial infarction usually is caused by an obstructing coronary thrombus. 2. The thrombus can be lysed with intravenous therapy in the majority of cases, particularly with newer, well-tolerated fibrin-specific agents. 3. There is considerable evidence suggesting that reperfusion reduces the acute morbidity and mortality when therapy is administered successfully within the initial 3 to 4 hours (and possibly up to 6 hours) after onset of symptoms. 4. Data on long term prognosis after thrombolysis are very encouraging, although limited. 5. Conventional agents lead to significant fibrinogen depletion and therefore an increased risk of bleeding; the new fibrin-selected agents cause less fibrinogen degradation and may reduce the risk of hemorrhagic complications.(ABSTRACT TRUNCATED AT 400 WORDS)

Disopyramide-pyridostigmine interaction: selective reversal of anticholinergic symptoms with preservation of antiarrhythmic effect.

This double-blind, randomized, placebo crossover study was used to evaluate the effects of a cholinesterase inhibitor--slow-release pyridostigmine (180 mg orally every 12 hours)--on the anticholinergic and antiarrhythmic properties of disopyramide. Quantitative side effects questionnaire scores were used to guide disopyramide administration in 20 men with ventricular tachycardia. Disopyramide was given to each patient both with placebo and with active pyridostigmine. The maximal administered dose for each regimen was used in conjunction with corresponding questionnaire scores to calculate an index or estimate of the maximal tolerable dose of disopyramide. Additional evaluations performed at baseline and at each maximal administered dose regimen included tear and saliva quantitation, 24 hour electrocardiogram (ECG), exercise testing and programmed ventricular stimulation. Results showed that the maximal administered dose of disopyramide was greater with active pyridostigmine than with placebo: 295 +/- 75 versus 245 +/- 100 mg every 6 hours (p less than 0.05). The calculated maximal tolerable dose was substantially greater in the presence of pyridostigmine: 355 +/- 90 versus 260 +/- 115 mg every 6 hours (p less than 0.001). Maximal side effects questionnaire scores also reflected decreased anticholinergic activity in the presence of pyridostigmine compared with placebo: 101.9 +/- 2.2 versus 104.6 +/- 2.8, respectively (p less than 0.005). Baseline tear and saliva production was significantly reduced during disopyramide therapy, but was restored toward normal by the addition of pyridostigmine.(ABSTRACT TRUNCATED AT 250 WORDS)

Antiarrhythmic effects of VVI pacing at physiologic rates: a crossover controlled evaluation.

Ventricular pacing can prevent bradycardia-dependent ventricular ectopic activity (VEA) and is helpful in some cases of drug-refractory ventricular tachycardia (VT). This study is a prospective evaluation of VVI pacing for the control of VEA not related to underlying bradycardia, drug side-effects, or prolonged QT interval syndromes. Twenty-nine patients undergoing serial electrophysiologic-pharmacologic testing for VT control were studied. Eighteen of these patients (12 men; mean age = 60.1) both completed the protocol and had sufficient VEA for analysis. Coronary disease was present in 13 patients, cardiomyopathy in two patients, and one patient each had myocarditis, mitral valve prolapse, and no structural heart disease. Ambulatory (Holter) monitor recordings during VVI pacing were compared with control recordings made in the absence of pacing. VVI pacing rates were 10-15 bpm above the mean daily heart rate (mean = 92 bpm; range = 63-110). Hours from paced recordings were paired with hours from control (prior to analysis) according to time of day to reduce the effects of spontaneous variability in VEA frequency. Overall, VVI pacing reduced ventricular premature complexes (VPCs) 26% from 331 to 245/hour (p less than 0.001). During pacing, couplets (pairs, successive VPCs) were reduced from 6.95 to 1.03/hour (p less than 0.000001) and VT (greater than or equal to 3 successive VPCs) from 0.89 to 0.045 episodes/hour (p less than 0.003). Of 13 patients with couplets, 11 had greater than or equal to 50% reduction and five had greater than or equal to 90% reduction. Baseline VT was eliminated in four out of nine patients during pacing. Pacing did not increase VEA significantly in any patient.(ABSTRACT TRUNCATED AT 250 WORDS)

Bethanidine sulfate: efficacy in prevention of ventricular tachyarrhythmias during programmed stimulation. Report of a multicenter study of 56 patients.

Twelve cardiac electrophysiology centers conducted an open label prospective trial of bethanidine sulfate, an oral bretylium analog, for the prevention of ventricular tachyarrhythmias during programmed electrical stimulation. The study group included 56 patients (44 men, 12 women; mean age 60 years; 55 with structural heart disease). Sixteen patients had both ventricular tachycardia and fibrillation, 30 had ventricular tachycardia alone and 10 had ventricular fibrillation alone. Programmed stimulation on no antiarrhythmic drugs induced sustained ventricular tachycardia in 46 patients, nonsustained ventricular tachycardia in 4 patients and ventricular fibrillation in 6 patients. During programmed ventricular stimulation after 59 trials of 20 to 30 mg/kg body weight of oral bethanidine (acute dosing in 40 patients, and divided dosing over 24 hours in 19 patients), no ventricular tachyarrhythmias were inducible in 6 patients (11%), sustained ventricular tachycardia was converted to nonsustained ventricular tachycardia in 3 patients (5%), ventricular tachyarrhythmias remained inducible in 39 patients (70%) and spontaneous ventricular tachyarrhythmias occurred more frequently in 4 patients (7%). Side effects prevented repeat testing in four patients. The 10 patients presenting with only ventricular fibrillation appeared to have a higher response rate: no ventricular tachyarrhythmias were inducible in 2 patients and sustained ventricular tachycardia was converted to nonsustained ventricular tachycardia in 2 patients. Despite protriptyline administration in 54 of 59 bethanidine trials, symptomatic hypotension occurred in 30 trials (51%). In conclusion, the efficacy of bethanidine for preventing ventricular tachyarrhythmias as assessed by programmed stimulation is low. Patients presenting with only ventricular fibrillation may have a more favorable response to bethanidine sulfate. Symptomatic hypotension occurs frequently despite concomitant use of protriptyline.

The value of electrophysiologic studies in syncope of undetermined origin: report of 150 cases.

A prospective study examined the diagnostic yield and therapeutic efficacy of electrophysiologic studies in patients with SUO. We defined SUO as those syncopal or near-syncopal events remaining unexplained after a standardized, noninvasive evaluation that included a history, physical examination, routine laboratory screening, EEG, nuclear brain scan or CAT scan, 12-lead ECG, chest x-ray, orthostatic vital signs, bedside carotid sinus massage, and at least 24 hours of continuous ECG monitoring. The 150 SUO patients included 95 men and 55 women (mean age 62.0 years); 35 had recurrent SUO, 75 (50%) had organic heart disease, and 129 (86%) had abnormal ECGs. There were 162 abnormal electrophysiologic findings that could explain the SUO uncovered in 112 patients, a diagnostic yield of 75%: one finding in 71 patients, two findings in 32, and three findings in nine. These findings were: His-Purkinje disease in 49 patients (30%), inducible ventricular arrhythmias in 36 (22%), AV nodal disease in 20 (12%), sinus node disease in 19 (12%), inducible supraventricular arrhythmias in 18 (11%), carotid sinus hypersensitivity (not elicited by carotid sinus massage prior to electrophysiologic studies) in 15 (9%), and hypervagotonia in five (3%). When electrophysiologic study findings were classified as clearly abnormal or borderline, 54 patients had at least one clearly abnormal finding, a diagnostic yield of 36%. Subgroups of patients presenting with only a single SUO event, no evidence of organic heart disease, or normal baseline ECGs all had substantial diagnostic yields during electrophysiologic studies. Follow-up data in 137 patients (91%) (mean 31 months) showed recurrences in 16 of 34 patients (47%) without and 15 of 103 patients (15%) with electrophysiologic findings despite therapy directed by electrophysiologic testing (p less than 0.0005). This study and a review of the literature indicate that electrophysiologic testing is useful in elucidating the causes of SUO and directing therapy. A significant number of patients benefit from electrophysiologic studies, even when only clearly abnormal findings are considered diagnostic, when only a single syncopal event has occurred, or whether or not organic heart disease or an abnormal ECG is present.

Disopyramide-pyridostigmine: report of a beneficial drug interaction.

A previously unrecognized beneficial drug interaction is described. Without affecting the antiarrhythmic properties of disopyramide, a sustained-release form of pyridostigmine (a cholinesterase inhibitor) was shown to prevent completely anticholinergic side effects in a study population (17 patients), whereas side effects occurred in 26 of 89 patients (29%) in a control group (p less than 0.025). Pyridostigmine also diminished or abolished disopyramide-induced anticholinergic side effects in each of 10 patients in whom they were already present. Pyridostigmine allowed an increase in tolerated disopyramide blood levels (4.53 +/- 1.59 micrograms/ml versus 3.85 +/- 1.78 micrograms/ml) and a significant increase in disopyramide dosages (224 +/- 68 mg versus 188 +/- 68 mg every 6 h) (p less than 0.02). No patients suffered side effects from pyridostigmine. These data suggest that pyridostigmine can be used to prevent as well as to treat the anticholinergic side effects of disopyramide. The usefulness of disopyramide has previously been limited by these anticholinergic side effects. Further investigation is in progress to determine what role pyridostigmine can play in making disopyramide therapy available to patients who otherwise could not benefit from its use.

Cigarette smoking and renovascular hypertension.

A retrospective cohort study to investigate the association between smoking and renal artery stenosis compared 71 patients with documented renovascular hypertension and 308 age-matched control patients with essential hypertension. 94% (30/32) of men and 74% (29/39) of women with renal artery stenosis had smoked cigarettes compared with only 43% (64/150) of men and 41% (65/158) of women in the control group. This striking relation was true for both patients with fibromuscular disease (71% smokers; 15/21) and patients with atherosclerotic lesions (88% smokers; 44/50). All renal artery stenosis groups had significantly higher systolic and diastolic blood pressures than the relevant control group. When the groups were stratified according to blood pressure, there were significantly more smokers in the renal artery stenosis group at every level of blood pressure.