Ethical issues regarding fee-for-service-funded research within a complementary medicine context.

Ethical issues are presented concerning the appropriate use of a fee-for-service strategy to fund clinical research assessing preventive complementary medicine approaches, particularly the effectiveness of dietary supplements for disease prevention. Reasons for the need for such an alternative funding approach are identified and historical precedents are noted. Presuming a priori key desiderata of doing no harm, not taking advantage of the ill, and pursuing recognized useful purposes, six key ethical questions from the relevant literature are identified and discussed. Arguments are advanced that there is a sound rational, ethical basis (1) to ask patients to pay for clinical experimentation in the focused area of supplement-directed disease prevention; (2) to accept the reality that those who cannot pay may not participate; (3) to permit moderate profit from the ongoing research; (4) to allow researchers to receive fees for their support of such clinical research; (5) to pursue this alternative funding strategy in addition to conventional sources; and (6) to expect that patients can give informed consent in such settings. It is demonstrated that patient-funded research has been an integral component of clinical research for decades and that there is no inherent reason why explicit patient payment of fees need be less ethical than any other commonly accepted funding models. Accordingly, an ethical case is made for the appropriateness and value of significantly expanded fee-for-service-funded research within a complementary medicine context, particularly the assessment of dietary supplements for disease prevention.

Fecapentaene excretion: aspects of excretion in newborn infants, children, and adult normal subjects and in adults maintained on total parenteral nutrition.

People in developed nations such as the United States and Canada have an increased risk of colon cancer. Fecal mutagens have been detected in the feces of individuals at high risk for colon cancer. We describe a rapid, sensitive, reliable, reproducible high-pressure liquid chromatography (HPLC) method for detecting fecapentaenes, the most active and chief mutagen found in human stool. We found fecapentaene in all the stool samples of adults on typical high-fat, low-fiber Western diets. These fecapentaene concentrations remained largely constant when subjects consumed constant diets. Fecapentaene concentrations were reduced for total-parenteral-nutrition (TPN) patients with severe intestinal malabsorption. This finding with TPN patients may reflect changes in important variables of gut microflora in fecapentaene production. Studies with newborns and children showed that fecapentaenes appeared very early in life but are not present in stool at birth.

Hydrazine sulfate influence on nutritional status and survival in non-small-cell lung cancer.

This randomized, prospective, placebo-controlled clinical trial compares the influence on nutritional status and survival of hydrazine sulfate with placebo addition to cisplatin-containing combination chemotherapy in patients with unresectable non-small-cell lung cancer (NSCLC). The trial consisted of 65 patients with advanced, unresectable NSCLC who had had no prior chemotherapy, were at least partially ambulatory (Eastern Cooperative Oncology Group [ECOG] performance status [PS] level 0-2), and who had adequate hematologic, renal, and hepatic function. All patients received the same defined combination chemotherapy (cisplatin, vinblastine, and bleomycin) and the same defined dietary counseling with the addition of either three times daily oral hydrazine sulfate (60 mg) or placebo capsules. Hydrazine sulfate compared with placebo addition to chemotherapy resulted in significantly greater caloric intake and albumin maintenance (P less than .05). Considering all patients, survival was greater for the hydrazine sulfate compared with placebo group (median survival, 292 v 187 days), but the difference did not achieve statistical significance. In favorable PS patients (PS 0-1), survival was significantly prolonged (median survival, 328 days v 209 days; P less than .05) for hydrazine sulfate compared with placebo addition. In a multifactor analysis, PS, weight loss, and liver involvement were the final variables. Objective response frequency and toxicity were comparable on both arms. Hydrazine sulfate may favorably influence nutritional status and clinical outcome of patients with NSCLC. Further definitive studies of hydrazine sulfate addition to therapeutic regimens in NSCLC are warranted.

Antimutagenic effects of taurine in a bacterial assay system.

Taurine (2-aminoethanesulfonic acid) was evaluated as an antimutagen in the Ames Salmonella tester strain assay. Taurine inhibited mutagenesis by doxorubicin (-74%), bleomycin (-55%), mitomycin C (-56%), and 2-aminofluorene (-52%), but not danthrone or benzo(a)pyrene, in strain TA102. In strain TA98, doxorubicin mutagenicity, but not that of 2-aminofluorene or benzo(a)pyrene, was inhibited by taurine. N-Methyl-N'-nitro-N-nitrosoguanidine (-73%), but not dexon, mutagenicity was inhibited by taurine in strain TA100. Taurine inhibited those mutagens against which it was effective in a dose-related fashion. Taurine was more effective in inhibiting doxorubicin mutagenicity in strain TA102 than its analogues hypotaurine, beta-alanine, and guanidinoethanesulfonic acid or alanine or glycine. The observed inhibition may indicate a role for taurine in modulating the activity of oxidant species.

Exercise-induced muscle uptake of technetium-99m MDP.

Intense muscle localization of Tc-99m MDP to upper extremity musculature was noted three days following weight lifting exercises. This phenomenon is due to an unknown mechanism although several causative factors have been suggested.

Hydrazine sulfate in cancer patients with weight loss. A placebo-controlled clinical experience.

Hydrazine sulfate was evaluated using 24-hour dietary recalls and body weight determinations before and after 30 days of either placebo or hydrazine (60 mg, 3 times/d) oral administration in 101 heavily pretreated cancer patients with weight loss. After 1 month, 83% of hydrazine and only 53% of placebo patients completing repeat evaluation maintained or increased their weight (P less than 0.05). In addition, appetite improvement was more frequent in the hydrazine group (63% versus 25%, P less than 0.05). Although caloric intake was only slightly greater in hydrazine-treated patients, an increased caloric intake was more commonly associated with weight gain in patients receiving hydrazine compared with those receiving placebo (81% versus 53%, respectively). Hydrazine toxicity was mild, with 71% of patients reporting no toxic effects. Hydrazine sulfate circulatory levels were obtained from a subset of 14 patients who completed 30 days of treatment, with a single sample obtained in the morning at least 9 hours after the last dose. Mean maintenance hydrazine sulfate levels, determined using a spectrofluorometric assay, ranged from 0 to 89 ng/ml (mean 45 +/- 16 ng/ml). These data, which demonstrate an association between 1 month of hydrazine sulfate administration and body weight maintenance in patients with cancer, suggest future clinical trials of hydrazine sulfate are indicated to definitively assess its long-term impact on important clinical outcome parameters in defined cancer populations.

Influence of nandrolone decanoate on weight loss in advanced non-small cell lung cancer.

The short term addition of nandrolone decanoate to combination chemotherapy given to patients with unresectable non-small cell lung cancer was evaluated in a randomized, prospective trial. Patients were treated with doxorubicin 50 mg/M2 intravenously, cyclophosphamide 300 mg/M2 intravenously, CCNU 50 mg/M2 orally, vincristine 1.4 mg/M2 intravenously, with and without cisplatin 50 mg/M2 intravenously, all given every 28 days. In addition, patients were randomized to receive either nandrolone decanoate 200 mg intramuscularly weekly for 4 weeks or no additional therapy. Patient age, disease extent, performance score, and pretreatment weight loss were similar in the two treatment arms. Objective antitumor response frequency was comparable on both treatment arms with median survival somewhat longer for patients receiving the androgen (median survival 5.5 months without and 8.2 months with nandrolone decanoate). There was a trend for less severe weight loss on the nandrolone decanoate arm (average weight loss 0.8 +/- 0.15 kg versus 0.21 +/- 0.18 kg, respectively), with half as many patients experiencing weight loss on nandrolone decanoate (25% versus 12%). A separate concurrent study has demonstrated decreased free testosterone levels in 66% of patients with advanced cancer studied prior to chemotherapy treatment, therefore, further prospective studies in which pretreatment testosterone levels are used to guide androgen administration are needed to define more precisely a role for androgen replacement therapy in non-small cell lung cancer.

Modulation of cytotoxicity of menadione sodium bisulfite versus leukemia L1210 by the acid-soluble thiol pool.

We investigated the mechanism of antitumor activity of the water-soluble derivative of menadione, menadione sodium bisulfite (vitamin K3), versus murine leukemia L1210. Vitamin K3, in concentrations greater than 27 microM, caused time- and concentration-dependent depletion of the acid-soluble thiol (GSH) pool. Maximal GSH depletion to 15% of control occurred at 45 microM vitamin K3. Vitamin K3-mediated GSH depletion and vitamin K3-mediated growth inhibition were abrogated by coincubation with 1 mM cysteine or 1 mM reduced glutathione but not by 1 mM ascorbic acid or 180 microM alpha-tocopherol. Low concentrations of vitamin K3 (9-27 microM) elevated both the GSH pool and the total glutathione pool, the latter to a greater degree. Vitamin K3 also caused an increased rate of superoxide anion generation by L1210, maximal at 45 microM vitamin K3 (300% of control), and a concentration-dependent depletion of the reduced nicotinamide adenine dinucleotide phosphate (NADPH) and total nicotinamide adenine dinucleotide phosphate (NADP) pools. Forty-fifty % depletion of the NADPH pool occurred after exposure to 27 microM vitamin K3 and 100% occurred at 36 microM vitamin K3; 27 microM vitamin K3 is a nontoxic concentration of vitamin K3. Loss of NADPH and total NADP was prevented by coincubation with 1 mM cysteine but not by coincubation with ascorbic acid or alpha-tocopherol. We conclude that tumor cell growth inhibition by vitamin K3 is modulated by acid-soluble thiols and may be caused by GSH pool and/or NADPH depletion. Toleration of partial NADPH depletion by L1210 cells may indicate that a threshold level of NADPH loss of greater than 50% is necessary for toxicity. NADPH depletion may be a toxic effect common to quinone drugs. Equitoxic concentrations of vitamin K3, phylloquinone, lapachol, dichlorolapachol, and doxorubicin caused L1210 NADPH pools to deplete to 30 +/- 10 (SD), 60 +/- 10, 60 +/- 11, and 80 +/- 12% of control, respectively. In contrast, GSH depletion may not be a common mechanism of toxicity. Of these quinones, only vitamin K3 caused significant GSH depletion when studied in equitoxic concentrations.

Vitamin K3 inhibition of malignant murine cell growth and human tumor colony formation.

To assess the antineoplastic potential of vitamin K compounds, the effects of vitamin K3 (menadione), vitamin K1 (phylloquinone), and warfarin on L1210 murine leukemia cell growth were studied in a flask culture system. When the cytotoxic potential of vitamin K3 was recognized, the effects of vitamin K3 on human tumor colony formation were studied in 34 tumor explants using a soft agar (clonogenic) assay system. Complete inhibition of L1210 growth in flask culture was achieved at concentrations of 200 micrograms/ml of warfarin, 75 micrograms/ml of vitamin K1, and 4 micrograms/ml of vitamin K3. Combined use of vitamin K and warfarin enhanced cytotoxicity because a concentration of 1 micrograms/ml of vitamin K3 together with 70 micrograms/ml of warfarin resulted in nearly complete inhibition of L1210 growth. Comparable inhibition of growth was seen against malignant murine cell lines in the soft agar assay system, where greater than 70% decrease in colony formation was seen with vitamin K3 at concentrations of 6.4 micrograms/ml for L1210 leukemia and 1 microgram/ml for HII4E hepatoma lines. Vitamin K3 was also cytotoxic in the same dosage range when tested in vitro against the 34 human tumor explants in the soft agar assay system. Tumor types evaluated included adenocarcinoma of the breast (16 patients), ovary (five), colon (two), stomach (two), kidney (two), and unknown primary (two); squamous cell carcinoma of the lung (two); melanoma (one), transitional cell carcinoma of the bladder (one); and hepatocellular carcinoma (one).(ABSTRACT TRUNCATED AT 250 WORDS)

Doxorubicin, cyclophosphamide, CCNU, and vincristine with or without cisplatinum in non-small cell lung cancer.

To evaluate the role of cisplatinum in the treatment of advanced non-small cell lung cancer, 48 patients received either a doxorubicin (adriamycin) 50 mg/m2 I.V., cyclophosphamide 300 mg/m2 I.V., lomustine (CCNU) 50 mg/m2 p.o., vincristine (oncovin) 1.2 mg/m2 I.V. (ACCO) combination or the same drugs plus cisplatinum 50 mg/m2 I.V. (PACCO) in a prospective sequential trial. No patient had received prior chemotherapy. Patients receiving the two regimens were comparable with regard to median age, performance status, histologic subtype, disease extent, and weight loss. Objective response frequency was only 5% in the initial 20 patients receiving ACCO treatment compared to a response frequency of 28% (7% complete) in the 28 patients receiving cisplatinum in the PACCO treatment arm (p less than 0.06). Patients achieving objective response lived significantly longer than nonresponders (9.1 months vs. 3.8 months, p less than 0.05). Although median survival was similar on the two regimens (6.1 months for ACCO vs. 7.6 months for PACCO), more than four times as many patients were alive after 1 year in the PACCO treatment group (24% vs. 5%). Predominant toxicity consisted of moderately severe nausea and vomiting (63% on PACCO vs. 34% on ACCO, p less than 0.05) and myelosuppression with WBC less than 3,000/mm3 occurring in the majority of patients on both regimens. These results suggest cisplatinum addition to a doxorubicin, cyclophosphamide, lomustine, and vincristine combination may be associated with increased 1-year survival in the non-small cell lung cancer patient population.

Neurologic complications of systemic cancer.

Neurologic complications of systemic cancer may result from metastatic spread of tumor to the central nervous system, from paraneoplastic effects of peripheral tumor, or from side effects of anticancer therapy. This article outlines currently available data on clinical presentations of these complications and diagnostic modalities for their recognition, data which may help the clinician ameliorate the often devastating sequelae of these neurologic complications.

Hepatocellular carcinoma. Diagnostic and prognostic features in North American patients.

Diagnostic and prognostic characteristics of 121 North American patients with hepatocellular carcinoma seen in one metropolitan area over a 6-year period were assessed using multivariate analysis. Presenting symptoms commonly included abdominal pain (53%) or mass (34%), anorexia (31%), and ascites (20%); however, the ability to make an early diagnosis was complicated by a variety of unusual symptoms accounting for 25% of presentations. While cirrhosis (63%) and hepatitis B surface antigen (HBsAg) positivity (52%) were common associated findings, the majority of patients (67%) had no prior diagnosis of liver disease. Despite the vascular nature of these malignancies, percutaneous biopsy procedures performed in 66 patients provided diagnostic material in over 85% of cases with little morbidity. Histologic diagnosis was made by blind percutaneous biopsy (41 done, 83% positive), peritoneoscopy with directed percutaneous biopsy (25 done, 88% positive), laparotomy (42 done, 98% positive), or autopsy (19). Percutaneous hepatic biopsy procedures were associated with no mortality and rare bleeding (three cases). Overall median survival was only 18 weeks; multivariate analysis indicated increased bilirubin or presence of pulmonary metastases adversely influenced outcome. Unexpectedly, patients younger than 45 years of age had a significantly (P less than 0.01) greater survival (median, 40 versus 9 weeks) than did older patients with this disease. We conclude: (1) hepatocellular carcinoma can be rapidly and safely diagnosed using percutaneous biopsy procedures; (2) North American patients with hepatocellular carcinoma younger than 45 years of age have a more favorable prognosis.

Abnormal deoxyuridine suppression as a rapid predictor for antimetabolite chemosensitivity: correlation with in vitro tests of growth inhibition.

The deoxyuridine (dU) suppression test, which estimates the activity of the de novo pathway to DNA synthesis from dU, was evaluated as a predictor of antimetabolite growth inhibition. Observations of growth inhibition were made using flask cell culture and soft agar clonogenic assay and correlated with results of the rapidly performed dU suppression test in human (SK-L7) leukemia cells, in methotrexate-sensitive and -resistant murine (L1210) leukemia cells, and in human tumor explants. The concentration of methotrexate resulting in a positive dU suppression test was closely correlated with the methotrexate concentrations required for growth inhibition in flask and soft agar culture systems. The fact that the dU suppression test can be rapidly interpreted in 4 hours compared to the longer period required for clonogenic assay suggests that further evaluation of this procedure as a rapid predictor for clinical antimetabolite response is warranted.

Doxorubicin (75 mg/m2) for hepatocellular carcinoma: clinical and pharmacokinetic results.

Of 157 consecutive patients who had histologically diagnosed hepatocellular carcinoma, 52 with a good performance score, bilirubin less than 2 mg/dl, and absence of bloody ascites were treated with a 75-mg/m2 dose of doxorubicin (unadjusted for hepatic function) every 3 weeks in a prospective trial. Forty-six patients were treated in West Africa and six in Southern California. No complete responses were seen and only six patients (11%) achieved partial objective responses. Plasma concentrations of doxorubicin and doxorubicinol (adriamycinol) were determined at four selected time points for up to 72 hours, corresponding to the terminal phase of disposition in eight African patients. The African patient results were compared to those seen in North American patients with hepatocellular carcinoma and other malignancies. In African patients with hepatocellular carcinoma, terminal half-life of doxorubicin was prolonged at 39.8 +/- 15.9 hours. The ratios of the corresponding concentration X time values of doxorubicinol to doxorubicin, which reflect the overall metabolite to parent drug ratio, ranged from 0.7 to 4.6, with a mean ratio of 2.03 +/- 1.20 in the African patients with hepatocellular carcinoma compared to a mean ratio of 0.76 +/- 0.31 in North American patients with other malignancies. Pharmacokinetic findings in hepatocellular carcinoma patients in North America and Africa were similar, reflecting elevation and prolongation of doxorubicinol metabolite relative to doxorubicin in the plasma of patients with this disease from both areas. We conclude that: (a) doxorubicinol disposition is altered in African as well as North American patients with hepatocellular carcinoma; and (b) even when given in full dose to patients with favorable prognostic features, iv doxorubicin has only limited activity against hepatocellular carcinoma.

Influence of hydrazine sulfate on abnormal carbohydrate metabolism in cancer patients with weight loss.

Thirty-eight patients with advanced cancer and weight loss were tested in a prospectively randomized, double-blind, placebo-controlled trial to evaluate the influence of hydrazine sulfate on carbohydrate metabolism in cancer cachexia. All patients had an initial 3-day inpatient metabolic evaluation including: standard 5-hr p.o. glucose tolerance test, hormone studies, and total glucose production by infusion of [6-3H]glucose. After 30 days of treatment with capsules containing either placebo or hydrazine sulfate in a 60-mg, 3 times/day dosage, inpatient evaluation was repeated. A total of 62 metabolic inpatient evaluations were performed. The pretreatment characteristics of age, sex, prior therapy experience, nutritional parameters and tumor types were comparable in placebo and hydrazine treatment groups. On initial evaluation, abnormal glucose tolerance and increased glucose production were frequently seen. Serial assessment of glucose tolerance showed no improvement after 30 days of placebo treatment. However, the glucose tolerance was significantly improved in patients receiving 30 days of hydrazine sulfate [2-hr glucose; initial 169 +/- 24 (S.E.) mg/dl versus final 128 +/- 12 mg/dl; p less than 0.05]. In addition, the rate of total glucose production was significantly decreased after 30 days of hydrazine sulfate compared to placebo treatment (2.46 mg/kg/min versus 3.07 mg/kg/min, respectively; p less than 0.05). Toxic effects of hydrazine sulfate were minimal. Our results suggest that hydrazine sulfate can influence the abnormal carbohydrate metabolism associated with weight loss in patients with cancer.