Continuous octreotide infusion for the treatment of secretory diarrhea caused by acute intestinal graft-versus-host disease in a child.

This report describes the use of octreotide, a synthetic somatostatin analogue, for severe diarrhea caused by acute intestinal graft-versus-host disease (GVHD) after bone marrow transplantation. A 22-month-old boy suffered grade 4 intestinal GVHD, with profuse diarrhea, intestinal inflammation, and grossly bloody stools after matched, unrelated donor transplant for biphenotypic leukemia. He required intensive blood product support. In addition to aggressive anti-GVHD therapy, octreotide acetate was initiated at 30 microg (2 microg/kg) intravenously 3 times per day and escalated to continuous infusion at 15 microg/hr (1 microg/kg per hour). The diarrhea did not improve with anti-GVHD treatment. However, moderate dose octreotide therapy resulted in prompt control of the bloody diarrhea, which rebounded on cessation of octreotide therapy. Rebound diarrhea responded promptly when the dose of octreotide was escalated. Octreotide was associated with an exacerbation of preexisting hypertension, but it appeared to be effective for control of severe, bloody diarrhea caused by acute GVHD in a child, with manageable side effects. Further studies of this application in infants and children are warranted.

Amifostine for protection from antineoplastic drug toxicity.

The mechanism of action, pharmacokinetics, clinical efficacy, adverse effects, and dosage and administration of amifostine are reviewed. Amifostine is a prodrug converted by alkaline phosphatase to the active sulfhydryl compound WR-1065. WR-1065 protects normal cells by scavenging free radicals, donating hydrogen ions to free radicals, depleting oxygen, and binding to active derivatives of antineoplastic agents. The immediate conversion of amifostine to WR-1065, its small volume of distribution, and the limited amount of drug and metabolite recovered in the urine suggest that amifostine is rapidly dephosphorylated and enters cells as its active metabolite. The selectivity of amifostine for normal tissue is hypothesized to be a results of the decreased vascularity of tumors, decreased activity of alkaline phosphatase in tumor cells, and pH dependence of WR-1065 uptake. In clinical studies, amifostine decreased the frequency of cisplatin-induced nephrotoxicity, ototoxicity, neurotoxicity, and myelosuppression. Amifostine has demonstrated an ability to decrease the hematologic toxicity of cyclophosphamide, carboplatin, mitomycin, and antineoplastic drug combinations. Amifostine has FDA-approved labeling for use in reducing cumulative renal toxicity in patients receiving repeat doses of cisplatin for advanced ovarian cancer and non-small-cell lung cancer. The recommended dose in adults is 910 mg/m2 administered as a 15-minute infusion 30 minutes before the start of chemotherapy. The major adverse effects of amifostine include hypotension and emesis. The benefits of amifostine must be weighted against its potential adverse effects, and the drug's impact on the efficacy of antineoplastics should be further investigated. Amifostine has shown promise in protecting non-malignant cells from the toxic effects of antineoplastics, apparently without compromising toxicity against cancer cells.

Epicardial controlled-release verapamil prevents ventricular tachycardia episodes induced by acute ischemia in a canine model.

Sustained-release preparations composed of verapamil-polymeric controlled-release matrices were characterized in vitro and utilized as epicardial implants in dogs with ischemic ventricular arrhythmias. Anesthetized open-chest dogs were subjected to 5 hourly, 10-min complete occlusions of the left anterior descending coronary artery followed by reperfusion. A controlled-release matrix preparation (20% verapamil, 80% polyurethane), placed on the left ventricular epicardium prior to the third occlusion, resulted in successful inhibition of ventricular tachycardia (VT) during acute ischemia in a dose-dependent manner. The largest matrix size used, 300 mg (20% verapamil), provided a net systemic dose of 0.52 +/- 0.18 mg/kg over 140 min and significantly reduced VT episodes during acute ischemia (fifth occlusion) compared to untreated controls (0.16 +/- 0.04 vs. 1.01 +/- 0.35 episodes/min, respectively; t = 2.62, p = 0.01). In controls, by the fifth occlusion ventricular fibrillation (VF) occurred after 5.41 +/- 0.78 min in 89% of animals. However, after a 300-mg verapamil matrix was placed on the left ventricular ischemic zone, VF occurred in only 45% (chi-squared = 4.1, p = 0.04, vs. controls) of the animals after 7.87 +/- 0.92 min (fifth occlusion). Systemic venous plasma verapamil levels during the 2 h following the 300-mg matrix ischemic zone implantation ranged from 8.4-22.0 ng/ml, while simultaneous regional coronary venous levels were 125.0-387.0 ng/ml. Sonomicrometry studies of left ventricular wall thickening carried out with a series of 300-mg verapamil matrix cardiac implants did not demonstrate any significant myocardial dysfunction. It is concluded that controlled-release verapamil, administered directly to the heart, was effective for preventing VT and VF associated with acute coronary ischemia, and that this route of administration was not associated with any significant deterioration of cardiac function.

Epicardial propranolol administration for ventricular arrhythmias in dogs: matrix formulation and characterization.

The effect of propranolol on the prevention of ventricular tachycardia/fibrillation (VT/VF) due to acute coronary ischaemia was studied in dogs. A series of propranolol-polymer controlled release matrices in slab configuration using various polyurethanes and a polyurethane-silicone rubber copolymer were formulated and characterized. In general, drug release in vitro occurred with an initial burst phase followed by an exponentially declining delivery rate; the silicone rubber containing copolymer preparation had more sustained release properties than did pure polyurethane matrices. In the animal studies, dogs underwent 5-hourly 10 min complete occlusions of the left anterior descending coronary artery (LAD), followed by 50 min normal perfusion. During non-drug occlusions VT occurred at a frequency of 1.22 +/- 0.12 episodes/min. A propranolol-polyurethane matrix (30% w/w, 28-42 mg) was placed on the ischaemic zone of the left ventricular epicardium immediately after the fifth occlusion. After an hour of drug delivery a sixth occlusion took place. The number of arrhythmia episodes both before and after drug were quantified and compared. The time to ventricular fibrillation (when present) and the mean blood pressure were also assessed. The drug patch delivered propranolol at a dose of 140 +/- 45 micrograms/kg by the conclusion of the 1 h study period. Therapeutic drug levels were achieved in the peripheral blood samples (8.7-43.7 ng/ml) and were enhanced in coronary venous samples (360.9-556.2 ng/ml). Reduction of blood pressure and proarrhythmic events following epicardial controlled release propranolol administration were noted but were not statistically significant. Arrhythmia episodes before and after propranolol were not found to be significantly different (VT/min 1.02 +/- 0.31 and 1.22 +/- 0.12).(ABSTRACT TRUNCATED AT 250 WORDS)

Efficacy of epicardial controlled-release lidocaine for ventricular tachycardia induced by rapid ventricular pacing in dogs.

The effects of epicardial lidocaine on ventricular tachycardia (VT) induced by rapid ventricular pacing (50 Hz) were studied in dogs. Lidocaine-polyurethane (28% wt/wt) matrixes (40-50 mg, 5 x 5 mm) were placed proximal to bipolar left ventricular epicardial electrodes in open-chest anesthetized dogs (n = 9) after VT was established by rapid ventricular pacing. In the first set of experiments, matrices were removed immediately after VT had converted to sinus rhythm. Control animals underwent VT induction protocol with a nondrug-containing matrix positioned next to the epicardial electrode. In the lidocaine-treated animals, VT conversion was noted in all animals and occurred after 51.7 +/- 8.9 s (mean +/- SE), with a VT threshold current elevation of 73.5 +/- 11.2% above baseline at the time of conversion which progressed to 259 +/- 44% of the initial value by 5.4 +/- 0.5 min post-matrix placement. Lidocaine 1.4 +/- 0.1 mg was delivered to the myocardium at the time of VT conversion (0.11 +/- 0.01 mg/kg). In comparison, accelerated VT persisted for 5 min in three of five control animals, and progressed to ventricular fibrillation (VF) in the other two animals. In a separate series of eight dogs, the lidocaine-polyurethane matrixes were left in palce for 4 h so that we could study the sustained antiarrhythmic action of controlled-release lidocaine on VT induction. The results of these experiments demonstrated a maintenance of the VT threshold elevation at a level of 53.9 +/- 10.8% after 4 h, with a net lidocaine dose of 0.52 +/- 0.06 mg/kg after 4 h of controlled release.(ABSTRACT TRUNCATED AT 250 WORDS)

Sustained behavioral recovery from unilateral nigrostriatal damage produced by the controlled release of dopamine from a silicone polymer pellet placed into the denervated striatum.

This study was conducted to determine if the behavioral asymmetry associated with unilateral nigrostriatal dopamine (DA) depletion could be alleviated by placing a small DA-releasing silicone polymer matrix pellet into the denervated striatum of rats. Animals that received DA-releasing pellets showed a 50% reduction in apomorphine-induced rotational behavior, and this effect persisted for the 2-month duration of the experiment. The results suggest that the controlled release of DA from an intrastriatal polymer matrix can produce a long-lasting reduction in some of the symptoms associated with DA depletion.

Sensitive high-performance liquid chromatographic assay using 9-fluorenylmethylchloroformate for monitoring controlled-release lidocaine in plasma.

A sensitive high-performance liquid chromatographic (HPLC) assay using fluorescence detection for quantifying lidocaine levels in plasma (in the ng/ml range) was developed. This novel HPLC assay has made possible the simultaneous monitoring of lidocaine levels in coronary and peripheral plasma obtained after myocardial controlled-release matrix administration (0.92 mg/kg during 4 h) in the arrhythmic dog. The method employed extracts the drug from plasma using 1-chlorobutane and a subsequent derivatization with 9-fluorenylmethylchloroformate in acetonitrile at 110 degrees C. The derivative was chromatographed on a C18 reversed-phase column and measured with fluorescence detection (excitation 254 nm, emission 313 nm). N-Methylephedrine was found to be suitable as an internal standard, post-derivatization. The derivatization product of lidocaine was identified and characterized by mass spectral analysis. It was found to have a unique and reproducible dicarbamate structure, which was stable for at least three days at room temperature. The method was tested with human plasma as well as on dog plasma. Analytical recoveries were 88.6 +/- 3.6 and 77.4 +/- 3.0% (mean +/- S.E.), respectively, at levels ranging from 25 to 200 ng/ml. The lower detection limit was 1 ng/ml lidocaine. In conclusion, this rapid and convenient analysis was found to be suitable for the bioavailability pharmacokinetic assessment of lidocaine following low-dose regional drug administration.