Rapidly progressing high o,p'DDD doses shorten the time required to reach the therapeutic threshold with an acceptable tolerance: preliminary results.

INTRODUCTION: It has been reported that the therapeutic threshold of mitotane, plasma level above 14 microg/ml, is achieved within 3-5 months after o,p'DDD treatment initiation in patients with adrenocortical carcinoma (ACC). OBJECTIVE AND DESIGN: We evaluated pharmacokinetic and tolerance of a high-dose schedule of pure o,p'DDD treatment given in 500-mg tablets of mitotane (Lysodren, Bristol-Myers Squibb, HRA Pharma, Paris, France) in four patients with ACC and two patients with Cushing's syndrome-related endocrine tumours. It was administered at a starting dosage of 3 g/day, which was rapidly increased to 6-9 g/day within 2 weeks according to digestive tolerance and then adjusted according to tolerance and plasma o,p'DDD monitoring. Patients were followed up until they reached the therapeutic threshold of mitotane, and toxicity was recorded. A relationship between o,p'DDD dose and plasma level was sought. RESULTS: The highest starting dosage given ranged between 6 and 9 g a day, during the first two weeks. The daily maintenance dose ranged 4.5-9 g during the next 2 weeks and 3-9 g by the second month of treatment. The therapeutic threshold was reached in all four patients who received o,p'DDD treatment for at least 1 month. Among these four patients, the toxic threshold (plasma mitotane level > 20 microg/ml) was even reached at 6 weeks of therapy in three patients. Grade 1, 2 or 3 toxicity was observed in 3, 2 and 1 patients, respectively. Toxicity resolved after reduction or discontinuation of o,p'DDD therapy. A significant linear correlation was found between plasma mitotane dose and plasma level. CONCLUSIONS: These results suggest that a high-dose o,p'DDD therapeutic schedule is feasible with an acceptable toxicity and may shorten the time required to reach the therapeutic schedule from 3-5 months to 4 weeks. These patients require a close follow-up, combining clinical and plasma o,p'DDD level monitoring every second week. A confirmatory study is ongoing.

DDT induces DNA damage in blood cells. Studies in vitro and in women chronically exposed to this insecticide.

In this study, DDT-induced DNA damage on blood cells was analyzed both in vitro and in vivo. Peripheral blood mononuclear cells (PBMC) were isolated from healthy donors and incubated in the presence of three different concentrations (40, 80, and 100 microg/mL) of p,p'-DDT, p,p'-DDE, and p,p'-DDD at three different treatment times (24, 48, and 72 h). Then, DNA damage was assessed by the single-cell electrophoresis assay (comet assay) as well as by flow cytometry detection of hypodiploid cells (DNA content assay). All compounds induced significant DNA damage as shown by the comet assay. Accordingly, cells exposed to DDT, DDE, and DDD showed a significant increase in the percentage of hypodiploid cells compared with untreated PBMC. In agreement with the in vitro data, a significant correlation between blood levels of DDT, DDD, and DDE and DNA damage (comet assay) was found in women with different amounts of environmental exposure. This association remained significant after controlling for nutritional status, smoking habits, alcohol ingestion, and reported exposure to other pesticides. Although the precise biological importance remains to be explained, our results strongly suggest that DDT and its metabolites are able to induce DNA damage in PBMC both in vitro and in vivo.

DDT induces apoptosis in human mononuclear cells in vitro and is associated with increased apoptosis in exposed children.

The aim of the present work was to investigate whether DDT and its metabolites are able to induce apoptosis of human peripheral blood mononuclear cells (PBMC) both in vitro and in vivo. Cells isolated from healthy individuals were incubated in the presence of increasing concentrations of p'p-DDT, p'p-DDE, or p'p-DDD (0-150 microg/mL) for different intervals. Apoptosis was then determined by flow cytometry (DNA cell content analysis) and fluorescence microscopy (Hoechst staining). A significant level of apoptosis was induced by DDT, DDD, and DDE at 80 microg/mL compared to controls, reaching a maximum effect at 100 microg/mL. We began to detect apoptosis at 12h, with a maximum effect at 24h of incubation. These results were confirmed using the TUNEL assay in cells treated with the three compounds tested as well as with o'p-DDT at 100 microg/mL and 24h of incubation. Our data demonstrate that DDT and its metabolites are able to induce apoptosis of human PBMC in vitro. Therefore, we performed a preliminary study in children exposed to this insecticide. When compared to a control population, the exposed children had higher levels of DDT, DDD, and DDE in blood and also had a higher frequency of apoptosis. In the exposed children, a weak positive association was found between the frequency of apoptosis and the exposure to DDT and DDE. Our results showed that more studies are needed in people exposed to DDT, as apoptosis may cause serious public health effects such as immunosuppression.

A case of adrenocortical carcinoma associated with recurrence after laparoscopic surgery.

Laparoscopic adrenalectomy has become increasingly popular because of its minimally invasive nature, but guidelines for selection of cases suitable for this surgical procedure have not been established. We report a 52-year-old woman with adrenocortical carcinoma, manifesting as Cushing's syndrome, treated with laparoscopic adrenalectomy. The tumour was removed in toto and had been histologically diagnosed as adrenocortical adenoma. However, the patient developed intra-abdominal peritoneal dissemination of carcinoma 15 months after surgery. Review of the histopathological findings of the resected adrenocortical tumour revealed that the neoplasm met five out of nine histological criteria for adrenocortical malignancy, and was diagnosed as adrenocortical carcinoma. Histopathological examination of the tumour was also consistent with adrenocortical carcinoma. The patient responded extremely well to chemotherapy, including carboplatin, etoposide and o,p'-DDD (1,1-dichlorodiphenyldichloroethane), and a subsequent CT (computed tomography) scan 12 months after the start of chemotherapy demonstrated no evidence of disease. However, the patient developed neurological impairment, including dysarthria, as a side-effect of o, p'-DDD. The patient died of aspiration pneumonia due to a decreased pharyngeal reflex. Postmortem examination revealed no foci of residual carcinoma. This case report emphasizes the importance of excluing possible adrenocortical malignancy in patients considered for laparoscopic adrenalectomy, histopathological diagnosis of adrenocortical malignancy and careful monitoring for neurotoxicity during o,p'-DDD treatment.

Adrenocortical carcinoma evolving after diagnosis of preclinical Cushing's syndrome in an adrenal incidentaloma. A case report.

A 43-year-old female patient underwent abdominal ultrasonography and CT scan because of uncharacteristic abdominal pain. A 3-cm homogeneous adrenal tumor was diagnosed. The endocrine tests revealed an adrenal preclinical Cushing's syndrome (PCS). Due to the latent hormone excess we decided to operate on the adrenal tumor. Since the tumor was small, laparoscopic adrenalectomy was performed. Histological evaluation showed an adrenocortical tumor of undetermined nature. Four months later the patient presented with a metastasizing cortisol- and androgen-producing adrenocortical carcinoma (ACC). After pretreatment with ketoconazole to suppress the biosynthesis of adrenal steroids under substitution with hydrocortisone, we reduced the tumor load by surgery. Postoperatively we continued ketoconazole and started o, p'-dichlorodiphenyldichloroethane as well as chemotherapy with doxorubicin and suramin. However, the patient died from ACC 7 months after adrenalectomy. It is known from several reports that PCS may persist clinically silently or may progress to full-blown Cushing's syndrome. This is the first time a malignant course of PCS is described. Independent of the initial therapeutic strategy of PCS, i. e. surgery or regular follow-up visits, we must be aware that also relatively small adrenal tumors can harbor malignancy.

Phenobarbital-type P-450 inducers protect rats against metaldehyde toxicity.

The mechanism of metaldehyde toxicity is unclear. It may be due to the compound itself or, at least in part, to acetaldehyde resulting from the hydrolysis of metaldehyde in the stomach. In this study, we orally dosed rats with twice the LD50 of metaldehyde following no pretreatment (control) or pretreatment with 1 of 3 different cytochrome P-450 inducers either phenobarbital or o,p'-DDD (inducers of cytochromes P-450 IIB and IIIA) or 3-methylcholanthrene (an inducer of P-450 IA). Our results show strong protection against metaldehyde poisoning afforded by the phenobarbital-DDD P-450 inducers, but only weak protection with 3-methylcholanthrene pretreatment. Acetaldehyde administered at the same molarity failed to produce the clinical signs of metaldehyde toxicity and no clinical differences were observed between any of the pretreated groups.

Arctic indigenous women consume greater than acceptable levels of organochlorines.

Exposure to polychlorinated biphenyls and organochlorine pesticides through traditional food resources was examined for Arctic Indigenous women living in two cultural and environmental areas of the Canadian Arctic--one community representing Baffin Island Inuit in eastern Arctic and two communities representing Sahtú Dene/Métis in western Arctic. Polychlorinated biphenyls, toxaphene, chlorobenzenes, hexachlorocyclohexanes, dichlorodiphenyltrichloroethane, chlordane-related compounds and dieldrin were determined in local food resources as normally prepared and eaten. Quantified dietary recalls taken seasonally reflected normal consumption patterns of these food resources by women in three age groups: 20-40 y, 41-60 y and > or = 61 y. There was wide variation of intake of all organochlorine contaminants in both areas and among age groups for the Sahtú. Fifty percent of the intake recalls collected from the Baffin Inuit exceeded the acceptable daily intake for chlordane-related compounds and toxaphene, and a substantial percentage of the intake records for dieldrin and polychlorinated biphenyls exceeded the acceptable or tolerable daily intake levels. Primary contributing foods to organochlorine contaminants intake for the Baffin Inuit were meat and blubber of ringed seal, blubber of walrus and mattak and blubber of narwal. Important foods contributing organochlorine contaminant to the Sahtú Dene/Métis were caribou, whitefish, inconnu, trout and duck. The superior nutritional benefits and potential health risks of traditional food items are reviewed, as are implications for monitoring organochlorine contaminant contents of food, clinical symptoms and food use.

[Pharmacokinetics of chlodithane tablets in the treatment of Cushing's syndrome]. / Farmakokinetika khloditana v tabletkakh pri lechenii bol'nykh bolezn'iu Itsenko-Kushinga.

The results of pharmacokinetic studies of chlodithane tablets hydrophilized with aerosil have shown that the maximum blood concentration of the drug is seen 6 hours after its administration. The most intensive chlodithane absorption by the gastrointestinal tract was noted after using single 1- and 2-g doses (94.9 and 90.8%, respectively). The drug excretion with feces with comparatively low when the daily dose of 4 to 8 g (15.9 to 25.9%) was used. The drug excretion rose to about 50% after the inhibitor dose was increased to over 8 g. It was found that 73.59 +/- 1.87% of the drug is absorbed by the gastrointestinal tract. Thus, it is recommended that chlodithane be administered in a dose of 1 to 2 g 30 minutes after meals with 3- to 4-hour intervals, the daily dose not exceeding 8 g. The recommended scheme provides sufficiently high drug absorption by the gastrointestinal tract and the constant inhibitor concentration in the blood.

o,p'DDD therapy in invasive adrenocortical carcinoma.

Invasive adrenocortical carcinoma was diagnosed in two patients, 3 1/2 and 69 years of age, respectively. Therapy with o,p'DDD was begun immediately, and the patients have survived 4 1/12 and 7 9/12 years, respectively. The prolonged survival represents possible "cure" of inoperable disease following early initiation of therapy.