Growth patterns of infants exposed to cocaine and other drugs in utero.

OBJECTIVE: Exposure to cocaine in utero is known to cause intrauterine growth retardation. This study describes the postnatal growth patterns of infants exposed to cocaine and other drugs in utero. DESIGN: A convenience sample of 31 Northern California infants was monitored for 1 year. Infants in foster care were selected to eliminate the environmental effects of a parent's drug-seeking lifestyle. Entrance criteria consisted of age less than 6 months old, in utero drug exposure, and foster-care placement shortly after birth. The infants were predominantly black. ANALYSIS: The infants' growth indexes were compared with the expected growth of infants in three reference populations: the National Center for Health Statistics (NCHS) reference population, all infants in the 1991 Pediatric Nutrition Surveillance System (PNSS-all), and black infants in the 1991 PNSS (PNSS-black) using the one-sample exact binomial test. Infants took in more energy and protein per kilogram than 100% of the Recommended Dietary Allowances at every age interval. RESULTS: At birth, mean weight of the study infants was significantly lower than that of NCHS, PNSS-all, and PNSS-black infants (P < .01); mean length was significantly lower than that of NCHS and PNSS-all infants (P < .01), but not significantly different from PNSS-black infants. By 6 months, there were no significant differences in weight compared with any group. At all age intervals after birth, mean length for the study infants was significantly less than that of NCHS and PNSS-all infants (P < .01), and significantly less than that of PNSS-black infants (P < .05). Our findings indicate that despite adequate nourishment, stunting in length continued through the first year, resulting in infants who were overweight for length.

Intrapleural therapy for malignant pleural effusions. A randomized comparison of bleomycin and tetracycline.

Between December 1985 and August 1988, there were 115 patients at 13 centers who were entered on a randomized comparison of tetracycline and bleomycin for treatment of malignant pleural effusions. Fifteen patients were not treated, primarily due to rapid progression of systemic cancer. Fifteen patients entered on a high-dose regimen of bleomycin (120 units) were excluded from this analysis (following early closure of that arm), leaving 85 patients randomized to low-dose bleomycin (60 units; 44 patients) or tetracycline (1 g; 41 patients). Patients were required to have a cytologically positive pleural effusion, good performance status (0, 1, or 2), lung reexpansion following tube thoracostomy with drainage rates of 100 ml/24 or less, no prior intrapleural therapy, no prior systemic bleomycin therapy, no chest irradiation, and no recent (four weeks) change in systemic therapy. A total of 11 patients (five with bleomycin and six with tetracycline) were not evaluable due to technical problems with tube drainage (one), loss to follow-up (two), sudden death due to pulmonary embolus (one), and rapid progression of systemic disease (seven). There were no clinically significant differences in demographic factors, primary site, performance status, or presence of metastases other than pleural effusion. Overall survival did not differ between the two groups. Median time to recurrence or progression of the effusion was 32 days for tetracycline-treated patients and at least 46 days for bleomycin-treated patients (p = 0.037). The recurrence rate within 30 days of instillation was 36 percent (10/28) with bleomycin and 67 percent (18/27) with tetracycline (p = 0.023) (not all patients were restudied in the first 30 days). By 90 days the corresponding recurrence rates were 30 percent (11/37) for bleomycin and 53 percent (19/36) for tetracycline (p = 0.047). Toxicity was similar between groups.

Etoposide and mitomycin in the treatment of non-small-cell lung cancer. A phase I-II evaluation.

Sixty-five patients (20 patients who had had prior radiotherapy and 45 patients who had not had prior radiotherapy) were entered into a study evaluating escalating doses of etoposide and mitomycin in the treatment of non-small-cell lung cancer (NSCLC). Twenty-two percent of patients who had not received prior radiotherapy responded to the chemotherapy, compared with 5% of patients who had received prior radiotherapy. The best response rate and median survival time was 30% and 31.9 weeks, respectively, seen in three of 10 patients receiving mitomycin 10 mg/M2 i.v. day 1 and etoposide 100 mg/M2 i.v. days 1-3. The major toxicity was hematologic--mainly leukopenia, in 59% of patients who had had no prior radiation therapy and were receiving mitomycin 10 mg/M2 i.v. day 1 and etoposide 150 mg/M2 i.v. days 1-3 (grade 3 and 4 hematologic toxicity). The mitomycin-etoposide drug combination has some activity in patients with NSCLC who have not received prior radiotherapy. The recommended starting dose is mitomycin 10 mg/M2 i.v. day 1 and etoposide 100 mg/M2 i.v. days 1-3, administered every 4 weeks.

A randomized trial to compare intravenous and oral etoposide in combination with cisplatin for the treatment of small cell lung cancer.

In a randomized multi-center study, 83 patients with small cell lung cancer were randomly assigned to treatment with cisplatin 100 mg/m2 intravenously (IV) day 1 and etoposide 120 mg/m2 IV days 1, 2, and 3 or cisplatin 100 mg/m2 IV day 1 and etoposide 120 mg/m2 IV day 1 and 240 mg/m2 orally days 2 and 3. Both regimens were repeated every 4 weeks. Prior to randomization, patients were stratified by extent of disease, performance status, and gender. A total of 41 patients were randomly assigned to the parenteral treatment only regimen, and 42 patients received cisplatin and IV/oral etoposide therapy. Both treatment arms were comparable regarding patient characteristics. Limited disease (LD) patients constituted 52% and 49% of the patient population for the oral and IV etoposide regimens, respectively. The overall complete response (CR) and partial response (PR) rate was 50% (95% confidence interval [CI] 35% to 65%) for the oral etoposide regimen and 59% (95% CI 44% to 74%) for the IV etoposide regimen (P = 0.438). For both regimens, 55% of the LD patients achieved either CR or PR. Time to progression and survival were comparable for both treatment arms. Hematologic toxicity was comparable in both treatment arms, with 80% of patients experiencing grade 3 or 4 neutropenia or thrombocytopenia. Moderate to severe anemia and weight loss were more predominant with the IV than with the oral regimen.

Mitomycin C skin toxicity studies in mice: reduced ulceration and altered pharmacokinetics with topical dimethyl sulfoxide.

A series of toxicologic and pharmacokinetic studies were performed in BALB/c mice administered intradermal (ID) mitomycin C (MMC) at doses of .015 to 0.25 mg. Dose-dependent skin ulcers were produced at clinically relevant MMC dose levels of .05 and .075 mg (3.6 to 10.7 mg/m2). These doses produced peak ulcers of 0.15 to 0.22 cm2, respectively, one to five days after injection. The integrated ulcer area X time values (area under the curve [AUC] ulceration) were 0.89 and 3.11 cm2 X d. A large number of local pharmacologic adjuvants were found to be ineffective at reducing MMC ulceration after proximal ID injection. These included diphenhydramine, catalase, heparin, hyaluronidase, hydrocortisone, cysteine, N-acetylcysteine, lidocaine, vitamin E, and superoxide dismutase. Also, neither topical heating nor cooling of skin reduced MMC ulcerations. In contrast, a single topical application of a 100% dimethyl sulfoxide (DMSO) solution completely prevented 0.025 mg MMC-induced skin ulceration and significantly reduced .075 mg MMC ulceration (P less than .05 by multiple range tests). Topical DMSO also altered the disposition of ID MMC in mouse skin but not in plasma. Unexpectedly, the DMSO applications slowed MMC elimination from the skin. DMSO significantly increased the AUC for MMC in skin from 0.89 to 2.25 ng/h/mL of tissue (P less than .05). DMSO did not alter the degree of protein binding in skin tissue nor the in vitro chemical stability of MMC in skin tissue homogenates. These results show that experimental MMC-induced skin ulcers in mice can be ameliorated with an immediate application of topical DMSO. This effect is not due to enhanced systemic drug uptake, but may be due to reduced reactivity of MMC with target cellular nucleophiles.

Oxidation and hydrolysis determination of sulfur amino acids in food and feed ingredients: collaborative study.

Samples of 6 food and feed ingredients and a purified protein, beta-lactoglobulin, were analyzed by 7 laboratories to determine the concentrations of cysteine as cysteic acid and methionine as methionine sulfone. Samples were oxidized by reaction with performic acid before hydrolysis with 6N HCl. The free amino acids were then separated and measured by ion-exchange chromatography on dedicated amino acid analyzers. Each laboratory was provided with a detailed method as well as sealed vials containing solutions of standards. For the determination of cysteine as cysteic acid, the coefficients of variation between laboratories for duplicate samples ranged from 7.13 to 10.8% for the 6 ingredients. For the determination of methionine as methionine sulfone, the coefficients of variation between laboratories for duplicate samples ranged from 1.18 to 12.8% for the 6 ingredients. Cysteine and methionine recoveries were determined by analysis of beta-lactoglobulin and were based on expected levels of each amino acid from amino acid sequence data. The mean recovery of cysteine was 95% with a range of 91-101%. The mean recovery of methionine was 101% with a range of 98-106%. This method has been adopted official first action.

Serum sialic acid is a biologic marker for malignant disease.

Serial serum sialic acid (N-acetylneuraminic acid) was measured in 16 patients with advanced cancer of various histologic types. In the 15 evaluable patients serial changes in sialic acid correlated with the clinical course. Isolated sialic acid values were not predictive of clinical response. Serial determination of serum sialic acid appears to be a useful monitor of tumor burden.

Management of breast cancer.

Hormonal therapy, surgical and medical ablation procedures, and the use of palliative cytotoxic and adjuvant chemotherapy in the management of breast cancer are reviewed. Breast cancer staging systems are described that use various clinical and histological criteria in choosing the most appropriate therapy and in predicting therapeutic response. Estrogen and progesterone receptor titers now allow for a more reliable prediction of whether palliative hormonal therapy or cytotoxic drug therapy is preferable. Endocrine methods include surgical ablative procedures, additive hormonal therapy, and antiestrogenic therapy with tamoxifen or aminoglutethimide. Aminoglutethimide appears to be at least as efficacious as surgical adrenalectomy and hypophysectomy in treating hormonally sensitive tumors in women with advanced breast cancer, and it is associated with a lower incidence of complications than surgical ablation procedures. Tamoxifen appears to be at least as effective as other forms of endocrine treatment, and it is now preferred to diethylstilbestrol in the treatment of postmenopausal women. Compared with androgens, progestogens, and glucocorticoids, estrogens have the highest rate of objective response in the treatment of advanced breast cancer; however, the use of estrogens has diminished since tamoxifen is associated with similar efficacy and a lower incidence of side effects. Palliative cytotoxic chemotherapy is used for those women who have low titers of hormone receptors, rapidly progressing disease, widespread disease to visceral organs, or tumors that are refractory to hormonal therapy. Combinations of cytotoxic agents yield response rates and durations of response that are superior to single-agent therapy. Attempts are being made to enhance the "cure" rate, postoperative disease-free intervals, and survival times for women who have undergone surgical resection of the breast tumor. The benefits of adjuvant cytotoxic chemotherapy are particularly evident for pre- and postmenopausal women with three or less involved lymph nodes. The potential merits of adjuvant hormonal therapy and combination therapy with hormones and cytotoxic agents are being studied.

Stability of cancer chemotherapeutic agents in a totally implanted drug delivery system.

The stability and compatibility of serveral chemotherapeutic agents with an implantable infusion device were evaluated. The totally implantable drug delivery system can be placed subcutaneously in an ambulatory patient to permit the regional administration of antineoplastic drugs. The in vitro method of assessing the stability of three chemotherapeutic agents with the pumping device involved placing the pumps, filled with cytarabine, dichloromethotrexate, and vinblastine, in a 37 degree C water bath with mild agitation. Control solutions placed in amber vials were maintained under simulated physiological conditions. Samples (1 ml) were removed periodically, frozen at -20 degrees C and later toward and batch assayed by high pressure liquid chromatography to determine drug concentrations. An in vivo assessment of the stability of floxuridine was also conducted in five patients receiving intra-arterial hepatic infusions by the device. The concentrations placed in the pump were compared with the contractions removed at the time of refill. Cytarabine and dichloromethotrexate showed no appreciable drug decomposition in the control vials or the pump over the 15-day and 28-day study periods, respectively. Vinblastine underwent a 48% and 20% drugs loss in the pump and control, respectively, during a 14-day period. In the vivo assessment of floxuridine, less than 5% drug degradation was found for infusion times ranging from four to 12 days. Cytarabine, dichloromethothrexate, and floxuridine were stable and compatible with the implantable infusion evice, and vinblastine was found to be unstable. The compatibility of all agents with the infusion device should be evaluated before clinical application.