Can an amino acid-based oral rehydration solution be effective in managing immune therapy-induced diarrhea?

Immune checkpoint inhibitor (ICPi) therapy has transformed the way we treat cancer. However, its immune related adverse events (irAEs) can be debilitating and life threatening. Immune therapy-induced diarrhea (ITID) is one of the most commonly encountered irAEs and can lead to expensive and prolonged hospitalizations. The current standard of care for grade 3 or 4 ITID involves ICPi discontinuation, the initiation of steroids, and infliximab for refractory disease. This treatment regimen reverses the desired anti-tumor effect of ICPis, can lead to side effects, and is cost-ineffective. We report the first case of the successful treatment of grade 3 ITID with steroids and an amino acid-based oral rehydration solution (AA-ORS), enterade. Research suggests that AA-ORS may be used to reduce diarrhea and adequately hydrate patients, in contrast to glucose-based oral rehydration solutions, which have been implicated as a contributing factor to diarrhea in cancer patients. We hypothesize that an AA-ORS may mitigate ITID via safer and more economically viable means than the current standard of care, but more controlled trials are needed to test this hypothesis.

Prevention and management of chemotherapy-induced diarrhea in patients with colorectal cancer: a consensus statement by the Canadian Working Group on Chemotherapy-Induced Diarrhea.

Chemotherapy-induced diarrhea (cid) is a common side effect of cancer treatment and can cause significant morbidity and mortality. Diarrhea is frequently severe enough to require a dose reduction of, a delay in, or a discontinuation of chemotherapy. Diarrhea-associated mortality has been reported to be as high as 3.5% in clinical trials of irinotecan and bolus 5-fluorouracil in colorectal cancer. The frequency of cid and its impact on patient management are frequently under-recognized in clinical practice.A Canadian working group, consisting of medical oncologists and an oncology pharmacist, was formed in 2001 to review the optimal approach to managing cid and to identify and implement new areas of research. The recommendations that follow are the result of the group's work.Acute medical management of cid includes loperamide or diphenoxylate as first-line agents. Subcutaneous octreotide is recommended for intractable grade 2 diarrhea and may be considered for grade 1 cid that does not resolve with high-dose loperamide. Hospitalization is recommended for patients with grades 3 and 4 cid; in-hospital care includes rehydration, antibiotic therapy, and octreotide.A chemotherapy dose reduction is generally advised for patients who have experienced grade 3 or 4 diarrhea in a previous chemotherapy cycle. If a dose reduction is not desired, prophylaxis with intramuscular long-acting release octreotide may be considered.The foregoing recommendations are based on expert opinion and require validation in prospective clinical trials.

High-dose indium 111In pentetreotide radiotherapy for metastatic atypical carcinoid tumor.

Indium In 111 pentetreotide imaging of neuroendocrine tumors that overexpress somatostatin receptors has become standard for localization of these tumors. This radioligand is internalized into the cell and can induce receptor-specific cytotoxicity by emission of Auger electrons. We hypothesized that high-dose 111In-pentetreotide could be therapeutic in patients with somatostatin receptor-expressing tumors. Our 35-year-old patient had atypical carcinoid tumor metastatic to cervical, supraclavicular, mediastinal, and mesenteric lymph nodes and to the liver and bone. Chemotherapy had stabilized the disease but with severe gastrointestinal side effects. After a diagnostic 111In-pentetreotide scan, the patient was given eight courses (180 mCi each) of 111In-pentetreotide therapy to selectively target somatostatin receptor-expressing tumor cells. The disease was stable for approximately 14 months. The patient had two additional courses of 111In-pentetreotide therapy (360 mCi each). She died of the disease approximately 18 months after initiation of 111In-pentetreotide therapy.

In situ radiotherapy with 111In-pentetreotide. State of the art and perspectives.

111In-pentetreotide (Octreoscan) and other radiolabeled somatostatin analogs are useful in the management of well differentiated neuroendocrine malignancies such as carcinoid or islet cell neoplasms. These radiopeptides bind to membrane bound somatostatin receptors (sst 1-5) which are over-expressed in a wide variety of neoplasms, especially those arising from the neuroectoderm. Imaging advances allow for the noninvasive determination of the presence of sst receptors by combining radioactivity [111Indium with a somatostatin analog, DTPA-D-phe1-octreotide (pentetreotide)]. Radiolabeled somatostatin analogs bind to membrane receptors and internalization of the complex occurs. Auger emitting somatostatin analogs offer a novel and significantly less toxic approach to controlling neoplastic diseases by delivering targeted radiation specifically to receptor bearing cells while sparing receptor negative cells. Responses of 62-69% in 85 patients with metastatic neuroendocrine tumors treated with high dose (6-19.6 GBq) 111In-pentetreotide, specifically targeting tumor somatostatin receptors, have been reported. Objective responses observed included biochemical and radiographic responses with prolonged survival. This article will discuss and review the multi-center data available to date, the mechanisms of action of radiolabeled somatostatin analogs, dosimetry, clinical response parameters, and toxicity.

Long-acting formulations of somatostatin analogues.

Somatostatin has represented a significant breakthrough in the treatment of patients with hormonally-acting, neuroendocrine gastroenteropancreatic neoplasms, even if its short half-life made it impractical in the clinic. In recent years, new long-acting formulations have been developed from the native peptide. The long-lasting formulation of the somatostatin analogue octreotide (octreotide-LAR) can be administered once-monthly and has been shown to provide similar efficacy to subcutaneous octreotide administered three times a day in the control of flushing and diarrhoea associated with the carcinoid syndrome. Another-long acting somatostatin analogue, lanreotide, is available in a slow-release form, lanreotide-SR. In a multicentre 6-month trial on carcinoid tumour patients, 30 mg lanreotide-SR were administered intramuscularly every 14 days, obtaining the control of symptoms in the majority of subjects. Thus, both octreotide-LAR administered monthly, and lanreotide-SR administered every 10-14 days, have been shown to be an effective tool in the treatment of carcinoid tumours, providing, in addition, a substantial improvement in patient compliance.

Experiences with high dose radiopeptide therapy: the health physics perspective.

One of the new, promising areas of nuclear medicine involves radiolabeled low-molecular-weight peptides for the diagnosis and management of cancer. Somatostatin analogous peptides bind to membrane receptors on tumors with high specificity. These analogues, when radiolabeled with 123I, 131I, 99mTc, or (111)In, allow for external scintigraphic imaging or radioguided surgical resection of tumors. Somatostatin analogues with high tumor binding affinity have also been used for high-dose radiotherapy at the Medical Center of Louisiana since 1994. Although we had extensive prior experience with relatively high-dose 131I administration for thyroid ablation, our personnel protection, contamination control, and other safety techniques required significant modification to ensure effective contamination and radiation exposure control. As therapy with radiolabeled peptides becomes more widely utilized, the controls developed at our institution may be implemented by others to maintain exposures ALARA.

Echocardiographic and biochemical evaluation of the development and progression of carcinoid heart disease.

OBJECTIVES: To study the applicability of a newly developed echocardiographic scoring system in the assessment of carcinoid valvular heart disease. BACKGROUND: We investigated prospectively the development, progression and regression of carcinoid valvular heart disease in patients with carcinoid syndrome by serial echocardiography, correlating these features with urinary 5-HIAA levels and clinical data collected during therapy with somatostatin analog. METHODS: Twenty-three patients with carcinoid syndrome underwent serial echocardiographic examinations. An echocardiographic carcinoid valvular heart disease (CVHD) % score was determined from points assigned for tricuspid and pulmonary valve structure and function. RESULTS: Fifteen patients had no CVHD at study entry (group 1), while 8 patients had findings of CVHD (group 2). Five patients in group q developed new CVHD (1B), while one demonstrated progression of CVHD (2B). The remaining patients did not develop (1A) or had no progression of CVHD (2B). Despite major declines in 5-HIAA levels during therapy in most patients, CVHD did not regress. There were significantly lower levels of median baseline 5-HIAA (98.8 vs. 256 mg/24 h), posttreatment 5-HIAA (50.3 vs. 324 mg/24 h) and posttreatment 5-HIAA time integral (37.3 vs. 192 g/24 h* days) in group A vs. B (p < 0.05). However, only posttreatment 5-HIAA levels independently predicted the development or progression of CVHD by multiple step-wise regression analysis (p < 0.005), with a threshold observed in the 100 mg/24 h range. CONCLUSIONS: We designed a new echocardiographic scoring system to evaluate CVHD. Correlating echocardiographic scores with biochemical and clinical markers showed that only posttreatment 5-HIAA levels independently predicted the development or progression of CVHD. This study strengthens the association between serotonin secretion and CVHD, as well as introducing a new technique for serial follow-up of these patients.

Hepatic artery chemoembolization for management of patients with advanced metastatic carcinoid tumors.

BACKGROUND: Patients with advanced metastatic carcinoid tumors who have disease progression despite conventional therapy are left with few therapeutic options. Hepatic artery chemoembolization (HACE) may play a role in palliating these patients' symptoms. METHODS: Fifteen patients with biopsy-proven advanced bilobar hepatic carcinoid metastases who demonstrated progression of symptoms and/or tumor size despite treatment with somatostatin analogues were treated with intra-arterial chemotherapy and HACE to determine efficacy and safety. Five days of intra-arterial 5-fluorouracil (1 g/m2) were followed by HACE with adriamycin (60 mg), cisplatin (100 mg), mitomycin C (30 mg), and polyvinyl alcohol (Ivalon); 200 micron to 710 micron). Patients were continued on octreotide at the same dose (150 to 2000 microg subcutaneous q 8 hours) before, during, and after the procedure. RESULTS: Efficacy of treatment was assessed by comparing pretreatment and 3-month clinical, laboratory, radiographic, and quality of life parameters. Symptoms were improved in 8 of 12 patients who had diarrhea, 7 of 12 who had flushing, 9 of 12 who had abdominal pain, and in 4 of 7 who had malaise. Elevated tumor markers decreased in all patients. Biochemical markers (mean +/- SE) at 3 months decreased by 60% +/- 6% for 5-HIAA, 75% +/- 10% for chromogranin A and 50% +/- 7% for neuron-specific enolase. Tomographic assessment revealed tumor liquefaction in 10 of 13 patients. The Karnofsky performance status improved from a mean of 66 +/- 2 to 84 +/- 2 (P <0.001). Median follow-up was 16 months, with 13 deaths occurring from 1 week to 71 months after treatment. CONCLUSIONS: Hepatic artery chemoembolization improves symptoms of carcinoid syndrome, has a high tumor response rate, and improves short-term quality of life in this group of patients with advanced hepatic carcinoid disease.

In situ radiotherapy with 111In-pentetreotide: initial observations and future directions.

PURPOSE: Somatostatin and its analogues, such as octreotide and lanreotide, are used to treat neuroendocrine malignancies. Somatostatin analogues bind to somatostatin receptors (sst 1-5), which are differentially expressed in a wide variety of neoplasms. Following ligand receptor binding, a fraction of these complexes internalize. Internalization of radiolabeled somatostatin analogues, especially those that emit Auger electrons, may allow treatment of somatostatin-receptor-positive tumors by delivering a radioactive isotope to the cancer cell in a targeted fashion. 111In-pentetreotide, an sst-2-preferring somatostatin analogue, has been used for scintigraphic evaluation and management of neuroendocrine cancer patients. We hypothesized that binding and internalization of 111In-pentetreotide, an Auger electron emitter, may induce receptor-specific cytotoxicity and could be a useful therapeutic agent in somatostatin-receptor-expressing malignancies. METHODS: To test this hypothesis, subjects who had failed conventional therapy and had somatostatin-receptor-positive malignancies, as determined by positive uptake on a 6.0 mCi 111In-pentetreotide scan, were treated with two monthly 180 mCi intravenous injections of 111In-pentetreotide. CT scans were obtained before therapy and within 30 days following the completion of the second 111In-pentetreotide dose. Toxicity was evaluated using standard criteria. RESULTS: Fourteen patients were studied from February 1997 to August 1997. Clinical benefit occurred in six of 10 gastroenteropancreatic tumor patients. Objective partial radiographic responses occurred in two of 14 patients, and significant tumor necrosis (defined by changes in Hounsfield units) developed in six of the 10 gastroenteropancreatic tumor patients. Possible treatment-related toxicity included two patients experiencing grade 3/4 myelosuppression, and two patients had no measurable toxicity. The most common toxicity was grade 1/2 hemoglobin (N = 6). CONCLUSION: One hundred eighty millicurie (180-mCi) doses of 111In-pentetreotide are well tolerated and are an effective therapy in some subjects with somatostatin receptor-expressing tumors. The maximal tolerated dose of 111In-pentetreotide and the optimal dosing schedules remain to be determined.

Pharmacokinetics of an intravenous-oral versus intravenous-mesna regimen in lung cancer patients receiving ifosfamide.

PURPOSE: To compare the pharmacokinetics of the approved I.V. (intravenous) mesna regimen and an investigational I.V.-oral regimen that could be used in outpatients who receive ifosfamide. PATIENTS AND METHODS: The I.V. regimen consisted of three I.V. mesna doses given at 0, 4, and 8 hours after ifosfamide administration. The investigational regimen included an I.V. mesna dose given concurrently with ifosfamide, followed 2 and 8 hours later by oral administration of mesna tablets. I.V. and oral mesna doses equaled 20% and 40%, respectively, of the ifosfamide dose. The study subjects were 12 lung cancer patients who received ifosfamide 1.2 g/m2 daily for 5 days. The patients were randomized to receive either the I.V.-oral or I.V. mesna regimen on day 1, followed by crossover to the other regimen on days 2 through 5 of ifosfamide treatment. The urinary profiles of mesna and dimesna excretion were determined on days 1, 2, and 5; pharmacokinetic parameters for blood samples were determined only on day 5. RESULTS: During the first 12 hours after ifosfamide administration, the amount of mesna excreted and the profile of urinary mesna excretion was similar for both regimens; however, the I.V.-oral regimen showed less fluctuation in the excretion rate and higher trough values. During hours 12 to 24, about eightfold more mesna was excreted by patients given the I.V.-oral than the I.V. regimen. CONCLUSION: These pharmacokinetic data show that the I.V.-oral regimen should be at least as uroprotective as the I.V. mesna regimen. Patients may also benefit from the I.V.-oral regimen because of the higher trough values during hours 0 through 12 and the sustained urinary mesna excretion during hours 12 through 24.

Somatostatin receptor imaging: predictive and prognostic considerations.

Compared with other imaging modalities and clinical investigation, the 111In-pentetreotide scan identified additional metastatic disease sites in 12 carcinoid patients and 2 occult primaries, and influenced the therapeutic outcome in 36 patients [29 carcinoids, 2 atypical carcinoids, 3 cancers of unknown primaries (CUPs) and 2 medullary thyroid carcinomas (MCTs)]. No adverse reactions were noted. Somatostatin receptors were detected in 59/60 carcinoid patients, 3/4 atypical carcinoid patients, 0/2 MCT patients, and 0/3 cases of CUP. Somatostatin receptor presence is underestimated in some patients using standard hormonal response criteria rather than scintigraphy. 18 patients with metastatic carcinoids who underwent 111In-pentetreotide scanning were all somatostatin receptor positive. Their mean (+/- SE) 5-hydroxyindoleacetic acid (5-HIAA) suppression with octreotide therapy was -53% (+/- 6%). 8 patients had < 50% and 10 had > 50% 5-HIAA suppression (ranges: -4 to -47% and -58 to -94%, respectively). To investigate the effect of somatostatin analogues on survival, 90 consecutive cases of carcinoid syndrome patients treated during the somatostatin analogue era were reviewed. Survival according to primary site was 12.01, 18.29 and 6.05 years (overall median 12.01 years) for patients with foregut, midgut and unknown primaries, respectively. The difference from historical controls is substantial (67 vs. 18% 5-year survival), although our series is neither prospective nor randomised. The heterogeneity in patient and tumour response to somatostatin analogue therapy is discussed.

Consensus statement: octreotide dose titration in secretory diarrhea. Diarrhea Management Consensus Development Panel.

Octreotide is an effective therapeutic option in controlling secretory diarrhea of varied etiology. However, marked patient-to-patient differences in the antidiarrheal effects necessitate titration of octreotide dose in individual patients to achieve optimal symptom control. A consensus development panel established guidelines for octreotide dose titration in patients with secretory diarrhea. Overall, the panel recommended an aggressive approach in selecting the initial octreotide dose and in making subsequent dose escalations in patients with secretory diarrhea due to gastrointestinal tumors (eg, carcinoids, VIPomas), AIDS, dumping syndrome, short bowel syndrome, radiotherapy, or chemotherapy. To avoid hypoglycemia in patients with diabetes mellitus-associated secretory diarrhea, the panel recommended a low initial octreotide dose and a conservative titration regimen with close monitoring a blood glucose levels. The end point of therapy should focus on a reduction in diarrhea (frequency of bowel movements or stool volume) rather than normalization of hormonal profile. Overall, octreotide is well tolerated; principal side effects are transient injection site pain and gastrointestinal discomfort. For many patients with secretory diarrhea, octreotide therapy is expected to improve the overall health and quality of life and in the long run will lessen health care costs.

Case report: lanreotide in the management of hypercalcemia of malignancy.

The management of hypercalcemia of malignancy (HCM) is difficult if the underlying neoplasm cannot be treated successfully. The overexpression of parathyroid hormone-related protein (PTHrP) by various neoplasms is a common mechanism of HCM and usually is a premorbid event. Current pharmacologic measures to control HCM are directed more toward inhibiting the action rather than inhibiting the secretion of PTHrP. The somatostatin congeners are a novel class of drugs that can inhibit some excessive hormonal states. In this report, the authors summarize an observation made using lanreotide, an investigational somatostatin congener, in treating a patient with a neuroendocrine neoplasm. Lanreotide administration resulted in normalizing the serum calcium levels while decreasing plasma PTHrP concentrations. The chronic administration of lanreotide produced a stable radiographic response and controlled the HCM without adverse side effects. The somatostatin congeners potentially offer another therapeutic modality in managing HCM.

Case report: diabetic ketoacidosis in a patient with glucagonoma.

The development of diabetic ketoacidosis is an unusual complication of a glucagon-secreting pancreatic islet cell neoplasm, with only four reported cases in the literature. In this article, the authors report on a 46-year-old woman with a glucagonoma cosecreting pancreatic polypeptide, somatostatin, and serotonin diagnosed 8 months before the onset of diabetic ketoacidosis. She was treated with hydration, insulin, and octreotide, with improvement in her clinical course and a decrease in the glucagon, pancreatic polypeptide, and chromogranin A plasma levels. With the addition of weekly 5-FU, she has maintained a partial radiographic response and has had no further episodes of diabetic ketoacidosis for a 4.5-year period. Diabetic ketoacidosis can develop in the presence of a glucagonoma, and the pathophysiology remains unknown.

Cytochrome P-450IID6 phenotyping in cancer patients: debrisoquin and dextromethorphan as probes.

The usefulness of substituting dextromethorphan for debrisoquin as a probe for cytochrome P-450IID6 deficiency was investigated in 20 male cancer patients. Each patient was studied on two occasions. An oral dose of dextromethorphan (60 mg) was administered to 13 patients and are week later an oral dose of debrisoquin (10 mg) was administered to each patient. The order was reversed for the other 7 patients. An 8-h urine sample was collected after administration of each test drug and assayed for parent drug and metabolites. Five poor metabolizers (PMs) and 15 extensive metabolizers (EMs) of debrisoquin were tested. The debrisoquin metabolic ratio (DMR), calculated as [parent drug]/[metabolite], correlated with the metabolic ratio of dextromethorphan (R2 = 0.58, P = 0.0001). All PMs of debrisoquin (metabolic ratio > 12.0) were easily identified as being PMs of dextromethorphan (metabolic ratio > 0.30). Within the EM group, there was a significant correlation between the metabolic ratios of debrisoquin and dextromethorphan (R2 = 0.82, P < 0.0001). There was not as clear a correlation in the PM group (R2 = 0.32, P = 0.32). These findings suggest that dextromethorphan can be substituted for debrisoquin in establishing the debrisoquin phenotype in a patient population with metastatic cancer.

The effect of cimetidine on cyclophosphamide metabolism in rabbits.

Six female rabbits were given 20 mg/kg cyclophosphamide (containing 100 microCi [3H-chloroethyl]-cyclophosphamide) alone or 1 h following 100 mg/kg cimetidine. Serial plasma and urine specimens were collected and levels of cyclophosphamide and its metabolites (4-hydroxycyclophosphamide, 4-ketocyclophosphamide, phosphoramide mustard, and carboxyphosphamide) were measured. 4-Ketocyclophosphamide was the major metabolite present in rabbit plasma and urine, with lesser amounts of 4-hydroxycyclophosphamide, carboxyphosphamide, and phosphoramide mustard also being identified. Cimetidine pretreatment resulted in prolongation of cyclophosphamide's half-life from 24.3 +/- 7.3 to 33.5 +/- 9.5 min (mean +/- SD; P = 0.036) but did not significantly alter the AUC0-8 h for the latter drug. Cimetidine pretreatment resulted in a significantly greater AUC0-8 h for 4-hydroxycyclophosphamide (189.4 +/- 77 vs 364.6 +/- 126.7 mumol min/l-1; P = 0.016) as compared with control values. A higher AUC0-8 h value for phosphoramide mustard (53.7 +/- 69.2 vs 95.7 +/- 34.7 mumol min/l-1) was also observed after cimetidine dosing but the difference was not significant (P = 0.21). Kinetics of 4-ketocyclophosphamide and carboxyphosphamide were not significantly affected by cimetidine treatment. Cimetidine was added to hepatic microsomes isolated from phenobarbital-treated rabbits; it did not inhibit cyclophosphamide's metabolism in vitro, suggesting that its in vivo effect may be mediated through mechanisms other than cytochrome P-450 inhibition. Cimetidine pretreatment increases exposure to cyclophosphamide and its major activated metabolite, 4-hydroxycyclophosphamide. Potentiation rather than inhibition of cyclophosphamide's pharmacodynamic effect is to be predicted when cimetidine is given concomitantly with the former. Alterations in hepatic blood flow or mechanisms other than microsomal inhibition by cimetidine may explain this potentiation.

The influence of ranitidine on the pharmacokinetics and toxicity of doxorubicin in rabbits.

The influence of ranitidine on the pharmacokinetics and toxicity of doxorubicin was studied in six female New Zealand white rabbits. Plasma pharmacokinetic data were first obtained from rabbits given 3 mg/kg doxorubicin. After 1 month, the same rabbits were treated with ranitidine, 2.5 mg/kg or 25 mg/kg, before and during doxorubicin administration. The plasma doxorubicin assays to determine pharmacokinetic parameters were repeated. Drug toxicity was evaluated using complete blood counts, and hepatic function was measured using a 14C-aminopyrine breath test. High-dose ranitidine increased the total exposure to doxorubicin (area under the curve of doxorubicin alone = 1.44 +/- 0.88 microM.h/ml vs 4.49 +/- 2.35 microM.hr/ml for doxorubicin given with high-dose ranitidine; P = 0.06). Low-dose ranitidine did not alter doxorubicin pharmacokinetics. Exposure to doxorubicinol was altered by either high-dose or low-dose ranitidine. 14C-Aminopyrine half-life was altered by a ranitidine dose of 25 mg/kg (aminopyrine half-life after placebo control = 97 +/- 6 min as against aminopyrine half-life after ranitidine = 121 +/- 7 min; mean +/- SEM; P less than 0.02). Low-dose ranitidine did not exacerbate doxorubicin-induced myelosuppression. High-dose ranitidine enhanced doxorubicin-induced erythroid suppression while sparing the myeloid series. At cytochrome P-450-inhibitory doses, ranitidine's effects upon doxorubicin plasma pharmacokinetics are similar to those previously seen with cimetidine. These changes did not appear to alter drug detoxification and are not related to microsomal inhibition of doxorubicin detoxification. Low doses of ranitidine do not alter doxorubicin plasma pharmacokinetics or toxicity in rabbits.

Effect of allyl alcohol-induced sublethal hepatic damage upon doxorubicin metabolism and toxicity in the rabbit.

A model of hepatic dysfunction in vivo has been developed in rabbits to determine the effects of sublethal hepatocellular necrosis upon doxorubicin pharmacology. Eight New Zealand white rabbits were given 3 mg/kg doxorubicin i.v. Plasma doxorubicin and metabolite pharmacokinetics were determined and toxicity assessed by nadir complete blood counts. Hepatic function was assessed by the pulmonary excretion rate of 14CO2 from [14C]aminopyrine. Hepatocellular necrosis was produced by i.v. injection of 1.35 mg/kg of a 2% allyl alcohol solution. Doxorubicin administration and pharmacokinetics were repeated. Doxorubicin enhances the hepatotoxicity of allyl alcohol. Hepatocellular necrosis does not alter the plasma pharmacokinetics of doxorubicin but does increase the plasma exposure of doxorubicinol. Doxorubicin-induced myelosuppression is enhanced by allyl alcohol pretreatment. These data suggest that in circumstances of reduced hepatocellular volume or acute hepatocellular necrosis, a key plasma marker of doxorubicin-induced acute toxicity may be doxorubicinol.

Antiemetic effect of oral versus intravenous metoclopramide in patients receiving cisplatin: a randomized, double-blind trial.

In a study of the antiemetic effectiveness of high-dose oral metoclopramide, 66 previously untreated patients receiving 60 mg/m2 cisplatin were entered into a double-blind randomized trial. Patients were stratified according to age and tumor type, then randomized to receive either oral or intravenous (IV) high-dose metoclopramide. Patients were evaluated for antiemetic protection, toxicity, affect (anxiety, hostility, and depression), and autonomic arousal (pulse rate and blood pressure) at three-hour intervals on the day of their chemotherapy. Metoclopramide serum levels were measured by high-performance liquid chromatography. Results indicated no significant differences between the oral and IV groups on any measurement of antiemetic protection, affect, or autonomic arousal. There were also no significant differences in side effects except for frequency of stools; patients who received oral metoclopramide had significantly more stools than patients who received IV metoclopramide. The mean (+/- SD) serum metoclopramide level at four hours achieved orally was 1,171 +/- 660 ng/mL; the mean (+/- SD) level achieved IV was 1,030 +/- 392 ng/mL (P = .498). We conclude that high-dose oral and IV regimens of metoclopramide as administered in this study have equivalent antiemetic efficacy in previously untreated patients receiving 60 mg/m2 cisplatin.