Phase I trial of trimetrexate glucuronate on a five-day bolus schedule: clinical pharmacology and pharmacodynamics.

Trimetrexate glucuronate (TMTX), a nonclassical folate antagonist, has been evaluated clinically on several schedules. We have studied TMTX administered as an iv bolus for 5 consecutive days every 3 weeks in 35 patients with advanced solid tumors. Drug was given at doses ranging from 7.6 to 18.8 mg/m2. The maximal tolerated dose was 13.1 mg/m2 per day x 5 for patients without prior myelotoxic treatment and 7.6 mg/m2 per day x 5 for previously treated patients. Because of wide individual differences in drug tolerance, dose escalation in 25% increments is recommended for patients not experiencing toxic effects. The dose-limiting toxicity was neutropenia. Rash and mucositis were also significant. TMTX concentrations were measured 1 and 24 hours after each dose, and the data were fit by use of a one-compartment pharmacokinetic model. With this simplified sampling and modeling scheme, the mean total body clearance (+/- SD) of trimetrexate was 31 +/- 20 mL/min per m2 and the volume of distribution was 13 +/- 7 L/m2. Mean plasma concentrations 1 hour after a dose were 1.12, 2.43, 3.33, and 3.25 mumol/L at 7.6, 9.1, 10.9, and 13.1 mg/m2, respectively. The mean TMTX concentration (+/- SD) 24 hours after a dose was 114 +/- 87 nmol/L. The mean area under the concentration-versus-time curve at 13.1 mg/m2 was 2,266 mumol.min/L. The drug concentration 1 hour after the first dose and the area under the concentration-versus-time curve were highly correlated with leukopenia and thrombocytopenia (r = .6 and .65 and P = .0007 and .0001, respectively). The maximal tolerated dose on the daily x 5 schedule was 30% of the dose tolerated on an iv bolus schedule. The choice of drug schedule for clinical trials when murine and human pharmacokinetics differ is discussed. Phase II trials are under way with both the iv bolus and the daily x 5 schedules.

Effect of calcium-binding additives on ventricular fibrillation and repolarization changes during coronary angiography.

Ventricular fibrillation during coronary angiography with Renografin-76 (meglumine sodium diatrizoate) has been attributed to the calcium-binding additives sodium citrate and sodium ethylenediaminetetraacetic acid (EDTA), which may produce repolarization changes manifested as prolongation of the QT interval. Angiovist-370 is a newer form of meglumine sodium diatrizoate that contains calcium EDTA as its additive and thus has a decreased calcium-binding effect. Eight hundred sixteen patients were prospectively randomized to receive either Renografin-76 or Angiovist-370. Ventricular fibrillation occurred in 10 of 410 patients receiving Renografin-76 and in 0 of 406 patients given Angiovist-370 (p less than 0.0005). Clinical data were analyzed without knowledge of other data in the 10 patients treated with Renografin-76 who had ventricular fibrillation (Group I), 103 randomly selected patients who also received Renografin-76 but had no ventricular fibrillation (Group II) and 108 randomly selected patients given Angiovist-370 (Group III). Of several variables examined, only the QT interval differentiated patients receiving Renografin-76 and Angiovist-370. The mean corrected QT interval (QTc interval) before coronary angiography was slightly but not significantly (p = 0.7) higher in Group I than in Groups II and III. Ten seconds after the first left coronary artery injection it was more prolonged in Groups I and II (0.552 and 0.561 second, respectively) than in Group III (0.448 second) (p less than 0.00005). Similarly, 10 seconds after the first right coronary artery injection it was significantly longer in Groups I and II (0.545 and 0.544 second) than in Group III (0.477 second) (p less than 0.00005).(ABSTRACT TRUNCATED AT 250 WORDS)

Myocardial contrast echocardiography in humans: I. Safety--a comparison with routine coronary arteriography.

Myocardial contrast echocardiography is a new diagnostic cardiovascular imaging technique capable of defining perfusion zones of coronary vessels in vivo; ultimately, it may be used to measure absolute regional myocardial blood flow. However, before it can be used in humans, its safety must be clearly established. Accordingly, the electrocardiographic and hemodynamic effects of intracoronary injections of 2 cc of sonicated Renografin-76 were compared with 5 to 10 cc of non-sonicated Renografin-76 in 10 subjects with normal coronary arteries. Two cubic centimeters of sonicated Renografin provides optimal myocardial opacification during echocardiography, while 5 to 10 cc of Renografin is required for an adequate coronary arteriogram. During coronary arteriography, heart rate decreased while PR and QT intervals and QRS duration increased as compared with baseline and myocardial contrast echocardiography (p less than 0.01). Similarly, the decrease in aortic pressure and first derivative of left ventricular pressure (dP/dt) was significantly (p less than 0.01) greater during routine coronary arteriography than during myocardial contrast echocardiography. Changes in left ventricular end-diastolic or pulmonary capillary wedge pressure were similar during myocardial contrast echocardiography and coronary angiography. There were no significant differences in the duration of electrocardiographic and hemodynamic changes between myocardial contrast echocardiography and coronary arteriography. It is concluded that intracoronary injection of 2 cc of sonicated Renografin-76 provides optimal myocardial opacification. It is safe in humans, producing transient electrocardiographic and hemodynamic alterations that are less pronounced than those seen during routine coronary angiography.

Clinical superiority of a new nonionic contrast agent (iopamidol) for cardiac angiography.

The hemodynamic and electrophysiologic alterations induced by ionic contrast agents during cardiac angiography are well described. Recently nonionic contrast agents have become available for cardiac angiography. To evaluate the safety of these new agents, a double-blind randomized study was performed comparing a new nonionic agent (iopamidol) with a commonly used ionic contrast agent (Renografin-76). Eighty-one patients undergoing left ventriculography and coronary angiography were included; 41 received iopamidol and 40 received sodium meglumine diatrizoate (Renografin-76). After left ventriculography, there was a decrease in the arterial pressure with both contrast agents. However, the severity and the duration of hypotension were both significantly greater with Renografin-76 compared with the new nonionic agent (p less than 0.001). After selective injections of the coronary arteries, electrocardiographic analysis demonstrated that the increase in the QT interval (p less than 0.0002) and the changes in both the ST segment and T wave amplitude (p less than 0.001) were significantly greater in the Renografin-76 group compared with the iopamidol group. During coronary angiography, 8 of the 40 patients receiving Renografin-76 required temporary pacing for sinus pauses of 2.5 seconds or more, and 2 of the 40 also developed ventricular fibrillation. None of the 41 patients receiving iopamidol had these complications. This report demonstrates that the electrocardiographic changes, the severity and duration of hypotension and the incidence of serious arrhythmias are significantly greater with Renografin-76 than with iopamidol. Thus, this new nonionic agent appears to enhance the safety of cardiac angiography.

Anti-infective drug use in relation to the risk of agranulocytosis and aplastic anemia. A report from the International Agranulocytosis and Aplastic Anemia Study.

The risks of agranulocytosis and aplastic anemia in relation to the use of anti-infective drugs were estimated in a population-based case-control study conducted in Europe and Israel. Anti-infective drug use in the 2-week period before the onset of illness was compared between 251 patients admitted to hospital with agranulocytosis and 1271 controls hospitalized for reasons judged to be unrelated to previous use of anti-infective drugs. Anti-infectives significantly associated with agranulocytosis when used for at least 3 consecutive days were trimethoprim/sulfamethoxazole (relative risk, 12; 95% confidence interval, 3.9 to 40) and macrolides (infinity). The relative risk estimate for any use of sulfonamides without trimethoprim was elevated, but not statistically significant (3.6; 0.7 to 18). These estimates took confounding by various factors, in particular the use of other drugs, into account. The estimated excess risks of agranulocytosis attributable to the use of trimethoprim/sulfamethoxazole and macrolides in a 2-week period were 1.6 and 7.1 per million, respectively. Anti-infective use during the 29- through 180-day period before hospital admission was compared between 135 patients with aplastic anemia and 1410 controls. Although relative risk point estimates were elevated for trimethoprim/sulfonamides (2.1), other sulfonamides (2.9), and beta-lactams (1.5), none was statistically significant.

Hyperkalemia in diabetes mellitus. Effect of a triamterene-hydrochlorothiazide combination.

Hyperkalemia is known to occur with increased frequency in the patient with diabetes mellitus and in the elderly when agents that interfere with renal potassium excretion are employed, but the precise frequency has not been established. We employed data from a post-marketing surveillance trial following the introduction of a triamterene-hydrochlorothiazide (Maxzide) combination to estimate the frequency. In patients normokalemic at baseline, hyperkalemia developed with a frequency of 0.59% in 20,809 nondiabetics and in 1.08% of 922 diabetics. Hyperkalemia was threefold to fivefold more likely in those more than 60 years of age, and all of the excess hyperkalemia in diabetics occurred in the elderly. The severity of hyperkalemia was not influenced by the diabetes mellitus. Hypokalemia occurred with a frequency of about 5% and was not influenced by either age or diabetes. In patients who were hypokalemic prior to treatment, hypokalemia was corrected in more than two thirds and hyperkalemia occurred less frequently. Although hyperkalemia indeed occurs with increased frequency in the elderly diabetic when a potassium-sparing combination is employed, the frequency is not so great that such agents should be avoided routinely when their use could be beneficial. Renal function and serum potassium concentration should be assessed prior to instituting treatment and repeated within a few days and a few weeks thereafter in the patient at risk, especially when renal function is suspected, and in the elderly.

Fatal toxic epidermal necrolysis during prophylaxis with pyrimethamine and sulfadoxine in a human immunodeficiency virus-infected person.

The combination of pyrimethamine and sulfadoxine (Fansidar) has been reported to cause severe skin reactions including erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis. Recently, this drug combination has been used for prophylaxis of Pneumocystis carinii pneumonia in patients with the acquired immunodeficiency syndrome. After two months of weekly prophylaxis with pyrimethamine and sulfadoxine, a 48-year-old homosexual man who was antibody positive for human immunodeficiency virus developed severe widespread erythema, blisters, and loss of skin in sheets, and subsequently died. To our knowledge, this is the first reported case of fatal toxic epidermal necrolysis occurring in a patient with acquired immunodeficiency syndrome-related complex. The lack of absolute safety of prophylaxis with pyrimethamine and sulfadoxine is emphasized in our case, and mandates cautious use and the consideration of less toxic prophylactic measures such as therapy with the recently introduced aerosolized pentamidine.

Sulfamethoxazole-trimethoprim therapy for Wegener's granulomatosis.

Cyclophosphamide has proved to be the most effective therapy for Wegener's granulomatosis, but mortality remains high at many medical centers, and the necessity for giving this toxic agent for many years to prevent relapses remains a major problem. Successful treatment of this disease with sulfamethoxazole-trimethoprim has been reported by DeRemee et al, and experience in a series of ten patients at Thomas Jefferson University Hospital, Philadelphia, confirms its effectiveness. Nine patients are in remission, and the condition of one patient improved. Relapses occurred in four patients after intervals of remission ranging from four to 30 months, but responded to increased doses of trimethoprim in two patients, while two patients required resumption of therapy with cytotoxic agents. Although the effects of sulfamethoxazole-trimethoprim are suppressive rather than curative, its use represents a major advance in treatment of Wegener's granulomatosis, permitting successful treatment of many patients without high toxic doses of cyclophosphamide and prednisone.

Trimethoprim-sulfamethoxazole-induced cholestatic hepatitis. Inadvertent rechallenge.

Trimethoprim-sulfamethoxazole is known to produce hepatitis. We report a case involving the inadvertent rechallenge with trimethoprim-sulfamethoxazole (Bactrim) in a patient with a previous episode of drug-induced hepatitis. A liver biopsy specimen showed both cholestatic and cytotoxic changes consistent with drug-induced damage. Comparison with existing cases is presented and an immunologic cause is considered.

Angiographic contrast agent-induced acute hemolysis in a patient with hemoglobin SC disease.

Radiographic contrast media used for angiographic procedures are hyperosmolar and induce sickling in vitro of erythrocytes from patients with sickle cell disorders. We treated a 51-year-old black woman with hemoglobin SC disease, but without a history of painful crises, who developed severe intravascular hemolysis and pulmonary infiltrates following administration of a contrast agent for coronary angiography and ventriculography. This case emphasizes the potential for severe complications following administration of the currently available contrast agents to patients with sickle cell disease. We suggest that newer contrast agents with lower osmolality than the commonly used ones need to be carefully evaluated for radiologic studies in patients with sickle cell disease.

The treatment of Pneumocystis carinii pneumonia in the acquired immunodeficiency syndrome.

Forty-four episodes of Pneumocystis carinii pneumonia (PCP) occurred in 36 of 70 patients with the acquired immunodeficiency syndrome. Thirty-four patients with 40 episodes of PCP were treated with trimethoprim-sulfamethoxazole. Therapy was successful in 18 episodes (45%), but was unsuccessful in 15 episodes (37.5%). In the latter cases, two patients died within 72 hours; 13, of whom nine died, had therapy changed to pentamidine. In seven additional episodes (17.5%), trimethoprim-sulfamethoxazole was changed to pentamidine due to adverse reactions; all patients survived. Seven patients (26% of survivors) developed recurrent PCP. Twenty-two patients (65%) developed adverse reactions to trimethoprim-sulfamethoxazole, including leukopenia (20), hepatotoxicity (12), fever (eight), rash (six), and immediate reactions (two). Reactions were most common during the second week of therapy. Patients with the acquired immunodeficiency syndrome who have PCP have a high trimethoprim-sulfamethoxazole failure rate, due either to adverse reactions or unresponsive infection. Late recurrence is common.

Propoxyphene and acetaminophen mixture (Darvocet)--related radiation-induced pneumonitis.

In a patient undergoing radiation therapy for recurrent, metastatic breast cancer, a mixture of propoxyphene and acetaminophen (Darvocet) was given for intercurrent viral infection. Discontinuation of therapy with this medication coincided with appearance of pneumonitis, reminiscent of the steroid withdrawal--related radiation pneumonitis.

Effects of ketorolac tromethamine on hemostasis in volunteers.

Ketorolac tromethamine, an analgesic agent with prostaglandin synthetase--inhibiting activity, is more active than aspirin in vitro in inhibiting collagen- or arachidonic acid-induced platelet aggregation. In this randomized, double-blind study, 26 volunteers received ketorolac, 30 mg intramuscularly four times a day for 5 days, and placebo, two capsules orally four times a day for at the last 2 study days. The effects of this treatment were compared with those of intramuscular placebo and oral aspirin, two 325 mg capsules, given on the same schedule to eight volunteers. Aspirin at a mean serum concentration of 84 micrograms/ml did not affect prothrombin time, partial thromboplastin time, platelet count, or bleeding time. Ketorolac produced a modest prolongation of the bleeding time, from 4.9 +/- 1.1 minutes (mean +/- SD) to 7.8 +/- 4.0 minutes (p less than 0.005). Ketorolac did not affect the prothrombin time or partial thromboplastin time but was associated with clinically insignificant change in the platelet count from 303 +/- 57 X 10(3)/m3 to 277 +/- 56 X 10(3)/mm3.

Facilitation of ECT by caffeine pretreatment.

In this study, eight patients participated in a standardized protocol to assess the effects of caffeine on seizures in ECT. Caffeine sodium benzoate (500-2000 mg) was administered intravenously 10 minutes before ECT, and seizure duration was compared with that of a previous treatment unmodified by caffeine. Seizure duration was significantly increased during ECTs preceded by caffeine. Three other patients given caffeine when seizures of adequate duration could no longer be elicited at maximal stimulus levels experienced longer seizures. Administration of caffeine was not associated with significant cardiovascular or other (including cognitive) adverse effects.

Drug-induced alzheimerism.

A 74-year-old man with parkinsonism developed progressive cognitive and behavioral dysfunction suggesting coexistent Alzheimer's disease. The intellectual and behavioral disturbances were reversed following withdrawal of his anticholinergic antiparkinsonian medication. This case demonstrates that anticholinergic drugs used to treat parkinsonism may mimic or exacerbate the clinical signs of Alzheimer's disease and suggests that these medications should be withdrawn for all parkinsonian patients who develop significant impairments of cognition or behavior.

Treatment of chronic Parkinson's disease with controlled-release carbidopa/levodopa.

Controlled-release carbidopa/levodopa 50/200 (SINEMET CR) and standard carbidopa/levodopa (SINEMET 25/100) were compared in a double-blind, six-month, crossover study involving 21 patients with chronic Parkinson's disease and motor response fluctuations. Daily dosage frequency was significantly reduced with SINEMET CR compared with SINEMET 25/100, while the daily amount of levodopa required with SINEMET CR was significantly greater. No significant differences in disability ratings, motor response fluctuations, or safety were detected during double-blind conditions. In the open-label, dose-finding phase of the study, SINEMET CR was superior to standard SINEMET 25/100 in patient ratings of percent "on" time (good motor function), clinical assessments of motor function, and activities of daily living. This finding resulted from a depreciation of the value of the "old drug" rather than an overestimation of the value of the experimental drug. This double-blind study also suggested that elderly male patients with Parkinson's disease derived the greatest benefit from SINEMET CR.

Successful prophylaxis of Pneumocystis carinii pneumonia with trimethoprim-sulfamethoxazole in AIDS patients with previous allergic reactions.

Thirty-four homosexual patients with AIDS were treated for Pneumocystis carinii pneumonia between April 1984 and November 1985. All 31 survivors were treated with oral trimethoprim-sulfamethoxazole (TMP-SMX) prophylaxis immediately upon completion of intravenous therapy, despite the prior occurrence of hypersensitivity reactions to intravenous TMP-SMX in 21 of these patients. Only four patients had subsequent reactions to oral TMP-SMX requiring the drug's discontinuation. None of the patients remaining on prophylaxis developed recurrent Pneumocystis pneumonia. Oral TMP-SMX appears effective at preventing recurrent Pneumocystis pneumonia in patients with AIDS. Hypersensitivity reactions during therapy with TMP-SMX may not be a contraindication to continuation of therapy and subsequent oral prophylaxis.

Controlled-release carbidopa/levodopa (CR4-Sinemet) in Parkinson's disease patients with and without motor fluctuations.

Sixteen patients with advanced Parkinson's disease (PD) and motor fluctuations were evaluated throughout 12 months of open label therapy on CR4-Sinemet. Reduced dosage frequency and significant motor improvement with reduced fluctuation occurred and were maintained with CR4-Sinemet compared with baseline on Sinemet. In a double-blind protocol using CR4-Sinemet in 20 stable PD patients, CR4-Sinemet was given twice daily and compared with Sinemet given four times daily. Patients remained stable without improvement or deterioration when the long-acting drug was substituted at 50% frequency. Plasma levodopa levels with CR4-Sinemet were smoother than with Sinemet. Although some patients receiving CR4-Sinemet found they functioned more slowly in the morning, the easier dosing schedule and improved amount of "on" time in fluctuators suggest that this formulation may become increasingly useful in managing PD.

Treatment of early Parkinson's disease with controlled-release levodopa preparations.

Therapeutic responses to Sinemet CR were studied in 37 patients with early Parkinson's disease previously treated with standard (Madopar) or controlled-release (Madopar HBS) levodopa/benserazide combinations. Patients were followed up for a 3-month period. The optimal therapeutic response of parkinsonian disability to Sinemet CR was equal to that obtained with Madopar or Madopar HBS. The optimal therapeutic dosage of Sinemet CR was equal to that of Madopar HBS but 12% higher than that of standard Madopar. However, with Sinemet CR treatment, the number of daily doses needed was significantly fewer than with both previous treatments. End-of-dose failure, which had developed in 4 patients, and peak-dose dyskinesias present in 6 patients during treatment with standard Madopar, improved significantly with Sinemet CR. Thus, Sinemet CR seems to be beneficial and useful in the treatment of early Parkinson's disease.

Drug-induced asterixis in Parkinson disease.

Asterixis was observed in five parkinsonian patients who were taking levodopa. A prospective study revealed that 4 of 55 consecutive patients had asterixis. Liver and metabolic functions were normal in all patients. Asterixis always occurred as part of a toxic confusional state superimposed on a parkinsonian state associated with some dementia. Insomnia, hallucinosis, and myoclonus were also prominent in the affected patients. Because of this association with other signs of chronic drug toxicity and its reversal with drug withdrawal, the asterixis seemed to be drug-related.