Phase I and clinical pharmacology studies of intravenous and oral administration of 4-demethoxydaunorubicin in patients with advanced cancer.

4-Demethoxydaunorubicin (4-DMDR), an anthracycline analogue available in i.v. and p.o. form, has shown significant antitumor activity in murine tumor models while producing less cardiac toxicity than doxorubicin at equimyelotoxic doses. Phase I and clinical pharmacology studies of the i.v. and p.o. preparation were performed. With i.v. 4-DMDR, consistent myelosuppression was observed at a dose of 15 mg/sq m at a median Day 15; mild nausea and vomiting were observed in 9% of all treatment courses. In patients given p.o. 4-DMDR, myelosuppression occurred at median Day 14 in 10 of 12 patients given 50 mg/sq m. Nausea and vomiting occurred in 25% of all treatment courses, and dividing the dose over 3 days did not decrease the incidence. Alopecia occurred in 13% of evaluable patients treated with the i.v. preparation and 30% of evaluable patients treated p.o. No stomatitis was observed with either preparation, and no patient developed clinical signs of congestive heart failure. Pharmacokinetic studies were performed with both preparations and revealed prolonged plasma levels of the 13-hydroxy metabolite 4-DMDR-ol. The suggested starting dose for Phase II studies is 12.5 mg/sq m given every 21 days for i.v. 4-DMDR with dose escalation by 2.5 mg/sq m in the absence of myelotoxicity. For p.o. 4-DMDR, the suggested starting dose is 40 mg/sq m given every 21 days with escalation by 10 mg/sq m if no myelotoxicity is observed.

Phase I and II clinical and pharmacological study of 4-demethoxydaunorubicin (idarubicin) in adult patients with acute leukemia.

Fifty-two adults treated previously with either acute leukemia (43 patients) or blastic-phase chronic myelogenous leukemia (nine patients) received 4-demethoxydaunorubicin (20 to 45 mg/sq m) i.v. over 2 to 3 days. Three of the ten patients with acute lymphocytic leukemia achieved a complete remission (CR) lasting 5 to 7 weeks. Five of the 28 patients with acute nonlymphocytic leukemia achieved a CR lasting 5 to 80 weeks. All remissions were induced with one course of treatment with a median time to CR of 28 days (range, 22 to 40 days). None of the patients with blastic chronic myelogenous leukemia or secondary leukemia achieved a CR. The drug was well tolerated; mucositis (36%), nausea and vomiting (35%), and hepatic dysfunction (26%) were the most common side effects. Pharmacokinetic observations on five patients demonstrated multiphasic clearance of 4-demethoxydaunorubicin and extensive formation and prolonged retention of 4-demethoxy-13-hydroxydaunorubicin; that metabolite accumulated in plasma on repeated daily dosing. 4-Demethoxydaunorubicin has sufficient antileukemic activity in both acute lymphocytic leukemia and acute nonlymphocytic leukemia to warrant a prospective comparison, in combination regimens, against the conventional anthracyclines, daunorubicin and/or doxorubicin.

Phase I and clinical pharmacological evaluation of 4'-deoxydoxorubicin in patients with advanced cancer.

We have conducted a Phase I and initial clinical pharmacological evaluation of 4'-deoxydoxorubicin (4'-DXDX), administering the drug i.v. on an every 21-day schedule to 60 patients with advanced cancer. Patients were treated at six dosage levels ranging from 10 to 35 mg/sq m. Leukopenia was the dose-limiting toxic effect, and no cardiac, renal, or hepatic toxicity was observed; stomatitis was not seen; and there were no drug-related deaths. Significant alopecia was rare at doses less than 35 mg/sq m, mild nausea and vomiting occurred in one-third of patients at myelosuppressive doses; 12 patients had a transient local urticarial reaction. In the 30 patients with measurable disease, two partial remissions were seen, lasting 5 months in a patient with a nasopharyngeal adenocarcinoma, and 7 months in a patient with endometrial adenocarcinoma. The recommended dose of 4'-DXDX for Phase II studies is 30 mg/sq m in good-risk patients and 25 mg/sq m in moderate-risk or heavily pretreated patients. Pharmacokinetic studies were carried out in ten patients, four of whom received 4'-DXDX at a dose of 10 mg/sq m and six at 30 mg/sq m. Disappearance of 4'-DXDX from plasma was triphasic with a rapid initial phase clearance showing a t1/2 alpha of 1 to 2 min and a prolonged terminal phase with a median t1/2 gamma in excess of 90 h in patients receiving 30 mg/sq m.

Developmental changes in the protein profile of cornifying lingual epithelium.

Epithelia from the tongue dorsum of 14- to 21-day embryos, 21-day embryos, 3-week-old, and adult rats were separated from their connective tissues by incubation in balanced salt solution containing EDTA. Aliquots from total extracts of these tissues were electrophoresed on sodium dodecyl sulfate-polyacrylamide gels. Scans of gels stained with fast green (FG) revealed more than 20 peaks. Ten major peaks ranging from apparent molecular weights (MW) of 120,000 to 14,000 daltons comprised about 70% of the total protein on each gel. This report focuses primarily on two pairs of peaks, arbitrarily numbered 2 and 3 (MWs 71,000 and 69,000) and 9 and 10 (MWs 17,500 and 14,000). Peaks 9 and 10 predominated in the 15-day embryos where they comprised about 30% of the total protein. As development proceeded, there was a gradual shift in the protein profile in favor of peaks 2 and 3 until on the 20th day the relative amounts of these peaks reached a maximum and peaks 9 and 10 decreased in relative amounts. The protein profile on the 20th fetal day resembled that of the 3-week-old rats and the adults. The rise in the relative amounts of peaks 2 and 3 coincided with the morphologic appearance of large numbers of tonofilaments and the onset of cornification. When the gel was stained by a procedure specific for sulfhydryl groups, peaks 9 and 10 were especially reactive after the 18th day; plainmetric analysis revealed that these had twice the relative affinity for this stain than for FG whereas other peaks had equal or less affinity. The incorporation of [3H]cystine into peaks 9 and 10 was relatively greater than into the other proteins.

Adult-onset stuttering treated with anticonvulsants.

Stuttering and aphasia emerged as salient clinical features in an adult with multifocal brain damage and paroxysmal EEG activity. Anticonvulsant treatment was associated with reversal of the stuttering and with marked improvement in language abilities.

Coalescence of endothelial cells in the traumatized cornea. III. Correlation between specular and scanning electron microscopy.

Sequential specular microscopy has shown that coalescence of endothelial cells occurs after thawing in cryopreserved rabbit corneas. Scanning electron microscopy of corneas studied in vitro by specular microscopy showed the same large, fused endothelial cells. As observed in the electron micrographs, these cells showed no evidence of the cell borders that had disappeared during the specular microscopic examination. These data support the reliability of our specular microscopic observations and provide additional evidence for the occurrence of fusion or coalescence of corneal endothelial cells.

Prevention of air leaks after pulmonary wedge resection.

Prolonged air leak after a lung volume reduction operation for pulmonary emphysema is a major cause of morbidity and prolonged hospital stay. Staple line reinforcement is recognized as an effective adjunctive technique for decreasing the occurrence of air leaks after pulmonary wedge resection. Numerous materials have been used for staple-line reinforcement. We use expanded polytetrafluoroethylene sleeves that fit over the arms of surgical staplers to facilitate staple-line reinforcement in both thoracoscopic and open lung volume reduction procedures. The expanded polytetrafluoroethylene sleeves do not require rinsing or special handling; they are easy to use and effective in preventing air leaks. We had no prolonged air leaks or infections in any of the cases in which we used the sleeves.

Immunochemical identification and determination of proline-rich proteins in salivary secretions, enamel pellicle, and glandular tissue specimens.

Acidic proline-rich proteins were localized histologically by means of the indirect immunoperoxidase technique in the acinar cells of parotid and submandibular gland sections of both man and Macaca fascicularis. These proteins were also identified as constituents of the long term in vivo-formed acquired pellicle on human tooth surfaces employing the same immunoperoxidase technique. Immunological quantitation of proline-rich proteins in whole and parotid saliva of 42 subjects indicates the presence of high concentrations in parotid secretions varying between 19-80 mg%, while their levels in whole saliva are significantly lower, ranging between 0-18 mg%. The concentrations of these proteins in whole saliva exhibited a negative correlation with plaque accumulation (r = -0.464) and gingival index scores (r = -0.576).

Grid staining--a useful device.

A simple and disposable holder for electron microscope grids can be constructed from discs of silicon rubber. The discs (10 mm thick X 25 mm diameter) are scored 0.4 mm deep with a razor. Flexing the discs opens the scores for insertion of grids. Staining wells can be made from polyethylene snap-in vial tops by cutting away the nipple-like portion. After impaling the holders on the tips of a pair of forceps the grids can be washed by immersion. This holder is rigid, inert and inexpensive. It is of particular advantage for handling single-slotted grids.

Morphogenesis of rat lingual filiform papillae.

The morphogenesis of filiform papillae on rat tongue was investigated with the electron microscope. Tongue rudiments were first seen on the 12th day of gestation. At 15-17 days, dermal papillae had formed and were arranged in hexagonal array on the dorsal lingual surface. Capping each dermal papilla was a two-layered epithelium that protruded slightly above the lingual surface, thus forming the early filiform papilla. In the next stage of development, at 18-19 days of gestation, the epithelium lining the papilla had differentiated into two cell populations, one producing hard keratin, the other producing soft keratin. Some of the keratinized epithelial cells assumed a position at an acute angle to the tongue surface and extended deep into the epithelium. In the next stage, 20-21 days, a cleft appeared within these angularly oriented cells. This resulted in the division of the epithelium into keraatin-lined individual filiform papillae. Finally, the individual papillae increased in size to the adult form.

Blood gas studies during labaroscopy under general anesthesia.

PIP: The effects of the laparoscopy procedure on the arterial blood gases were studied. In particular, the authors were interested in 1) what the effect of carbon dioxide is in the peritoneal cavity on arterial carbon dioxide partial pressure and pH and 2) whether the head down position together with an elevated immobile diaphragm can cause a significant change in arterial oxygen pressure or oxygen saturation. The subjects of the study were 20 patients hospitalized for laparoscopy. The patients were divided into 3 groups: 1) controlled respiration, 1-2% halothane in oxygen, 2) spontaneous respiration, 1-2% halothane in oxygen, and 3) controlled respiration, 1% halothane, 74% nitrous oxide, 25% oxygen. Blood gases were analyzed with the Clark electrode for oxygen tension and with the Severinghaus electrode for carbon dioxide tension at 37 degrees centigrade. Samples were obtained in each group of patients just before laparoscopy, after 15 minutes of carbon dioxide insufflation, and 15 minutes after the carbon dioxide was removed. In group 1, mean arterial carbon dioxide was maintained at about 25 mm mercury before, during, and after carbon dioxide insufflation. The mean arterial oxygen fell during laparoscopy, but the change was not statistically significant. In group 2, mean arterial carbon dioxide rose from 44.4 to 49.2 mm mercury during the procedure (p less than .05) and fell to 45.9 mm mercury after removal of carbon dioxide. Arterial oxygen was consistently lower as compared with those in group 1, but did not change significantly during laparoscopy. In group 3, mean arterial carbon dioxide rose from 30.5 to 37.3 mm mercury after insufflation of carbon dioxide. It fell to 31.8 mm after the procedure. Mean arterial oxygen decreased from 92.2 mm to 81.4 mm mercury during laparoscopy and returned to 87.2 mm mercury afterwards. The data indicated that with adequate controlled respiration the arterial carbon dioxide does not rise significantly in spite of the presence of carbon dioxide in the peritoneal cavity at the pressure of 50 cm water. In the patients breathing spontaneously, the arterial carbon dioxide rose during laparoscopy despite an increased minute volume. This and further interpretation of the data led the authors to recommend that patients undergoing laparoscopy breathe a gas mixture containing at least 50% oxygen, while ventilation is controlled with an endotracheal airway in place.^ieng

Treatment of fracture-dislocation of the hip with complete destruction of the proximal end of femur by total hip arthroplasty.

A case of fracture-dislocation of the hip with loss of bone from the proximal part of the femur due to a war injury is described. It is concluded that a total hip arthroplasty after 3 months is a suitable treatment.

Changes in blood urea nitrogen (BUN) concentration during pregnancy in the rat with or without obstructive uremia.

Bilateral ureteral ligation changes the blood urea nitrogen (BUN) concentration in pregnant and non-pregnant rats. Marked increases of the BUN concentration occurred in both pregnant and non-pregnant specimens after ligation. The BUN concentration in sham-ligated rats did not change from day 16 through 19 of pregnancy, but increased on day 20 of pregnancy and thereafter. There was no significant difference in BUN between ligated pregnant rats on days 16 and 17 of pregnancy and ligated non-pregnant rats. As pregnancy progressed from day 18 onward, the BUN in ligated pregnant rats decreased when compared with that of ligated non-pregnant rats, but did not reach the level in sham-ligated pregnant rats. The BUN of mothers and fetuses both in the ligated and the sham-ligated groups were similar. Amniotic fluid urea nitrogen levels were higher than in blood on late fetal days. In ligated mothers, a significant relationship between maternal BUN and the number of fetuses was noted on day 22 of pregnancy. These results suggest that the fetal kidney becomes functional for excreting urea in late fetal life.