Esters and lactones of phenolic amino carboxylic acids: prodrugs for iron chelation.

The new iron chelator N,N'-bis(2-hydroxyphenyl)ethylenediamine-N,N'-diacetic acid (1), its dilactone 2, N,N'-bis(2-hydroxybenzyl)-2-hydroxypropylene-1,3-diamine-N,N'- diacetic acid (3), and its methyl ester lactone 4 and a series of esters of N,N'-bis(2-hydroxybenzyl)ethylenediamine-N,N'-diacetic acid (5) were prepared and their iron chelating efficacy and toxicity determined by using the hypertransfused mouse model of iron overload. The biological activities were compared with results obtained with use of the hypertransfused rat. Esterification enhanced the oral iron chelating activity but also increased toxicity. The diisopropyl ester of 5 exhibited the highest therapeutic index. In vitro measurements showed that the rate of ester hydrolysis at pH 7.5 increased by a factor of 10(4) in the presence of 5 X 10(-4) M ferric ion, which may account for the utility of esters and lactones as prodrugs. Seventeen other chelating agents were screened but showed no intraperitoneal or oral activity.

Physiologic and morphologic changes and incidence of neoplasms in mice and rats fed naltrexone HCl for 24 months.

Short-term (acute oral LD50 and 90-day oral subchronic) studies in mice and long-term (24 months) carcinogenesis bioassays were performed in B6C3F1 mice and Fischer 344 rats given naltrexone. The oral LD50 was approximately 1500 mg/kg; convulsions, hypopnea, and cardiac failure were dose-related. Naltrexone mixed with feed over 90 days did not evoke definitive signs of gross toxicity, and histopathology was unrelated to drug treatment. Similar drug/feed admixtures given for 24 months to mice or rats did not disturb behavior. In mice, naltrexone reduced growth rates 5-10% and food intake 9-19%, but survival rates were 70-82% for treated mice and controls. The frequency and location of predominant tumors were similar in treated and untreated mice. In the rat, the same dosages had little effect on growth or food intake. The majority of all sacrificed rats had neoplasms. Neither neoplasms nor nonneoplastic lesions in mice or rats were associated with drug treatment. It is concluded that naltrexone is not a carcinogen.

Effects of delta-9-tetrahydrocannabinol administered subcutaneously to rabbits for 28 days.

Subcutaneous (s.c.) administration of delta-9-tetrahydrocannabinol (delta-9-THC) to rabbits produced dose-related cumulative toxicity. Five groups of three New Zealand albino rabbits each received 28 daily treatments with isotonic saline, sesame oil of 15.9, 45.0 or 153.4 mg/kg/day of delta-9-THC dissolved in sesame oil. Dose-related dermal responses included erythema, edema, ulceration and nodule formation. Some of the granulomatous nodules contained an oily substance and exhibited liquefactive necrosis. The severities of erythema and ulceration were generally maximal during the first week of treatment, but edema and nodule formation were most severe after days 12 and 14, respectively. All rabbits survived treatment, but body weights, liver weights and liver glycogen levels were decreased in a dose-related manner. Maximal body weight effects occurred after day 19. Hemochemical changes occurred only in rabbits treated with 153.4 mg/kg/day and included decreased blood sugar and alkaline phosphatase, and increased serum potassium. Hematology parameters were normal throughout the treatment period. No drug-related pathological lesions occurred in internal organs. The cumulative body weight changes, significantly decreased hepatic glycogen levels and reduced blood sugar and alkaline phosphatase values may have indicated drug-induced metabolic changes.

Comparative usefulness of cytology and peroxidase activity in conjunction with carcinoembryonic antigen levels for the diagnosis of mammary cancer.

Diagnosis of cancer via measurement of carcinoembryonic antigen (CEA) levels has been unreliable in early neoplastic stages. In order to improve diagnostic reliability, other cytological parameters were examined with CEA. Fifty specimens of effusion fluid were obtained from 40 hospitalized patients and the levels of CEA determined by radioimmunoassay in conjunction with application of an immunoperoxidase procedure. Simultaneous morphologic assessment was performed without knowledge of the immunoassay findings. In 8 documented cases of mammary cancer, all effusion fluid specimens had CEA levels of 16-1074 ng/ml, 7 cases had morphologically positive cells, but only 3 had a peroxidase positive reaction. Except for one case of ovarian papillary adenocarcinoma, the remaining patients were cancer free, had CEA levels of less than 15 ng/ml and only 2 cases (including the ovarian tumor patient) gave positive peroxidase responses. The presence of mammary metastatic duct carcinoma correlated 88% with CEA measurements but peroxidase response was not diagnostically helpful.

Computed tomography in congenital hip dislocation. The role of acetabular anteversion.

Computed tomography usually can provide accurate documentation of the adequacy of a reduction in congenital dislocation of the hip. It should supplement other radiographic examinations when the status of a reduction is in question because the patient is wearing a plaster cast. The computed tomography scan provides a clear image of the reduction in the transverse plane, so that anterior or posterior subluxation of the femoral head can be easily detected. In addition it allows direct measurement of acetabular anteversion which previously had not been possible with non-invasive studies in the living patient. Radiation exposure is less than that for conventional tomography. We used computed tomography in five patients with congenital dislocation of the hip and our study provided new evidence concerning the role of acetabular anteversion in this condition. Acetabular anteversion was increased on the dislocated side in each patient, and returned to normal as treatment progressed.

Immune response of hospital workers to hepatitis B vaccine.

Hepatitis B vaccine (Heptavax-B vaccine, Merck Sharp and Dohme) was given by injection into the buttock of 109 healthy workers in a community hospital according to the schedule of the U.S.A. Centers for Disease Control. In only 26% of those between 41 and 65 years of age was antibody to hepatitis B surface antigen found after the full course of vaccination whereas 74% of those aged 18-40 years had detectable antibody. We did not find any significant difference between the responses of males and females in either age group. The unusually poor response may be related to injections being given into the buttock rather than the deltoid region of the arm. We, therefore, recommend that injections of hepatitis B vaccine should be given into the deltoid muscle and that vaccinees should be tested after vaccination for evidence of immunity.

Long-term controlled delivery of levonorgestrel in rats by means of small biodegradable cylinders.

Hormone release rates from biodegradable cylindrical implants consisting of a physical matrix of [14C]levonorgestrel and copolymers of [3H]lactic and glycolic acids have been monitored in rats. Two copolymers were evaluated: one consisted of 90 parts L-lactide/10 parts glycolide (90L/10G) containing 33 or 50% hormone by weight, and the other of 50 parts DL-lactide/50 parts L-lactide (50DL/50L) containing 50% hormone. For each system, 4-6 rods (0.8 x 16 mm) providing 19 mg of steroid per rat were subcutaneously implanted into the scapular regions of 5 rats, and 14C and 3H in faeces and urine were determined weekly for 90-724 days. An initial burst of hormone release, peaking at approximately 90 microgram day-1, occurred in the first two weeks. This was followed by an approximately 10-30 microgram day-1 for the 90L/10G system containing 33% hormone, a more uniform rate of approximately 25 microgram day-1 for the 50DL/50L system and the highest rate of approximately 40 microgram day-1 for the 90L/10G system containing 50% hormone. 3H and 14C in residual implants of 90L/10G with 33% hormone removed from animals dying of natural causes during the test were assayed. For this system 3H activity decreased by over 50% within 250 days, compared with < 25% loss in 14C activity. The amounts of 3H and 14C released were similar over much of the subsequent test period. At the end of the test both polymer and drug were essentially depleted. All animals with the 50DL/50L system died late in the test period. Between days 609 and 724 from 13.7-27.2% initial 14C and from 10.0-22.1% initial 3H was measured in recovered rods. Microscopic inspection of recovered rods showed a loss of core material and tissue encapsulation. There were no signs of local tissue irritation or systemic toxicity.

Intraventricular metastases demonstrated by cranial computed tomography.

Intraventricular metastases from extracranial tumors are uncommon. Cranial computed tomography provides a uniquely noninvasive method to diagnose such metastases. However, enhanced intraventricular metastases may mimic normal enhancement of the choroid plexus.