Two Cases of Malignancy-Associated Hypercalcemia Treated with Mithramycin

The hypocalcemic effect of mithramycin, an antitumor antibiotic,was studied in two consecutive hypercalcemic patients with malignancy.Case 1 was a 60-year-old woman with advanced breast cancer.Severe, generalized bone metastasis seemed to be the cause ofthe hypercalcemia. Serum calcium levels reached 14.6mg/dl (ionizedcalcium 3.84 mEq/I) despite continued therapy with saline (5liters/day) with frosemide (60mg/day, intravenously), high dosesof elcatonin (up to 440 MRC units/day) and prednisolone (30mg/day). Case 2 was a 49-year-old woman with recurrence of ovariancancer. Bone metastasis was not found on X-ray films. Hypercalcemiawas progressive in spite of extensive treatments with saline(2 liters/day) with frosemide (40 mg/day), indomethacin (150mg/day), elcatonin (160 MRC units/day) and prednisolone (30mg/day). Meantime, serum calcium rose to 14.6mg/dl (ionizedcalcium 3.57 mEq/I). In both cases, mithramycin (1.25 mg) wasthen administered intravenously. Serum calcium levels droppedto 9.6 and 9.4 mg/dl two days after the administration of mithramycinin case 1 and case 2, respectively. These observations indicate that mithramycin is more effectivethan any other drug tested for the treatment of hypercalcemiacaused by malignancy irrespective of the presence or absenceof bone metastasis. Therefore, it should be widely used forhypercalcemic emergency.     

Plasmoptysis and Gelation of Erythrocytes in Coagulation of Blood of Freshwater Bony Fishes

1. A clot-like material which results from very rapid plasmoptysis andhydrophyllic swelling of karyoplasm of erythrocytes from freshwater fishwas reported. This attribute was found to a lesser degree in erythrocytes froman amphibian, but it was almost lacking in those of an aquatic reptile.

2. Rapid clotting of fish blood with the usual clinical methods was confirmed in this work. Fish blood clotted more quickly with the slide test thanwith the capillary tube test. In the presence of water, complete coagulationof fish blood occurred in only 65 per cent of the time required for clottingto be completed in air. This speed is attributed to the water-erythrocyte reaction, and not to a quality of the plasma.

3. An attempt was made to correlate the findings with the need forhemostasis and blood coagulation that is peculiar to aquatic vertebrates.

Submitted on September 17, 1958 Accepted on June 28, 1959     

Definitive Diagnosis of Pancreatic Carcinoma with Percutaneons Fine Needle Aspiration Biopsy Under Ultrasonic Guidance

Definitive diagnosis of pancreatic cancer presents difficulties in that positive identification is often possible only by intraoperative biopsy. Recently, ultrasonic visualization of the pancreas has made preoperative diagnosis possible by furnishing a guide to percutaneous biopsy via a flexible 23-gauge, 0.6 mm. needle.     

A Case of Small Cell Carcinoma of the Lung Producing ADH, ACTH, MSH and Calcitonin: Successful Treatment of Severe Hyponatremia with Furosemide and Hypertonic Saline

A 48-year-old man with a small cell carcinoma of the lung presentedhyponatremia and was diagnosed as having the syndrome of inappropriateADH secretion. A plasma ADH bioassay confirmed this syndrome.During the clinical course, the patient developed a hyponatremiccrisis with a serum sodium of 108mEq/l. His hyponatremia wasrapidly corrected by infusing furosemide in conjunction withhypertonic saline. The postmortem studies demonstrated ADH bioactivityin the tumor tissues, as well as immunoreactive ACTH, ß-MSHand calcitonin. Tumor hypersecretion of ACTH appeared to bethe cause of the patient's hyperresponsiveness to exogenousACTH and of the bilateral adrenocortical hyperplasia observedat the time of autopsy. Therefore, this was a case of a multiple hormone-producing smallcell carcinoma of the lung, in which the severe clinical manifestationsof SIADH were successfully treated with furosemide and hypertonicsaline.     

Tamoxifen in Advanced Breast Cancer; Response Rate, Effect on Pituitary Hormone Reserve and Binding Affinity to Estrogen Receptor

Patients with advanced breast cancer were treated with antiestrogen,tamoxifen, 20 mg orally, twice a day. Of the evaluable 23 patients,one achieved complete response with a duration of 16 months,and five achieved partial response lasting from two to eightmonths, indicating that the response rate was 26%. In the fiveperi-and postmenopausal patients, basal and LH-RH stimulatedplasma LH levels decreased but stayed within the postmenopausalrange in three patients during the tamoxifen therapy. Basaland LH-RH stimulated FSH levels decreased also but stayed withinthe postmenopausal range in all five patients. In a premenopausalpatient, basal and stimulated plasma LH and FSH levels did notchange significantly during the tamoxifen therapy. The plasmaTSH responses did not change significantly. In three of thesix patients, basal and TRH-stimulated prolactin levels decreasedslightly during the tamoxifen therapy. These relatively inconsistentand small changes in the pituitary hormone secretion observedduring the tamoxifen therapy suggest that the anti-tumor effectof tamoxifen was not due to alteration of the pituitary hormonesecretion. The binding of tamoxifen for the estrogen receptorwas examined in the estrogen receptor assay system. The doseresponse curve for tamoxifen was parallel to that for estradiol,indicating that tamoxifen competes with estradiol for the estrogenreceptor. The affinity constants of tamoxifen for the estrogenreceptor in eight cytosols of human breast cancer tissues were(139 ±79) X 10^–10M (mean±SD), indicatingthat the binding affinity of tamoxifen was about 0.7% that ofestradiol. The affinity constants for nuclear receptors weresimilar to those for cytosol receptors. These data suggest thattamoxifen is a useful drug for treatment of advanced breastcancer, and that the anti-tumor effect could be related to itsbinding to estrogen receptors in tumor tissues, and not causedby altering the secretion of pituitary hormones.     

Efficacy and safety of hepatitis B vaccination in haemodialysis patients

Antibody response to vaccination with hepatitis B vaccine was evaluated in 39 haemodialysis patients. Three injections of 20 μg of the vaccine were given at time 0, 1 and 6 months. The seroconversion rate for the antibody to hepatitis B surface antigen (anti-HBs) was 2.6% at 1 month, 15.4% at 2 months, 33.3% at 4 months, 41.0% at 6 months and 59.0% at 7 months (males 53.6%, females 72.7%). Thus, with three injections, the seroconversion rate was significantly smaller and antibody titres were lower compared with 348 healthy control subjects. No correlation was observed between the anti-HBs seroconversion rate and lymphocyte subsets (OKT4/OKT8). When two additional injections were given at 9 and 10 months to 19 haemodialysis patients with an S/N ratio (the ratio of ct/min in the sample to mean ct/min in negative controls) smaller than 10 at 7 months, 16 patients (84.2%) developed anti-HBs and elevated antibody titres. Accordingly, the response rate of all haemodialysis patients 12 months after the first injection was elevated to 92.3% and was as high as that in normal subjects. At 24 months, the response rate had gradually declined to 64.1% accompanied with lowered antibody titres. There were no serious side effects.
From these results, it was concluded that the most effective dose and schedule for optimal hepatitis B immunization and booster injections should be decided in haemodialysis patients with low antibody titres.     

Psychiatric manifestations accompanying interferon therapy for patients with chronic hepatitis C: An overview of cases in Japan

Abstract  Thirty case reports published in Japan that refer to psychiatric symptoms accompanying interferon (IFN) therapy were examined. These papers covered a total of 49 cases. We categorized these 49 cases into 35 cases of mood disorder, 10 of delirium and four of psychotic disorder. The key findings of our study of these cases are as follows: (i) in total, 11 patients had psychiatric past histories: five patients in the mood disorders group were susceptible to the influence of social or psychological factors; (ii) whereas the symptoms of mood disorder or delirium appeared soon after IFN was administered, the symptoms of psychotic disorders appeared later. The patients with delirium displayed many neurological abnormalities, which were reduced by suspending IFN therapy. This suggests the neurological toxicity of IFN; (iii) the outcome of most patients was good; and (iv) we suspect that IFN-induced psychiatric symptoms other than delirium are connected with psychoneuroimmunological functions.     

Assessment of autonomic nervous activity during gastrointestinal endoscopy: Analysis of blood pressure variability by tonometry

We continuously measured blood pressure by tonometry in 30 patients during endoscopy to determine the influence of upper gastrointestinal endoscopy on cardiac events. Patients were divided into two groups: one group treated with scopolamine butylbromide as premedication (SB group) and another group without premedication (C group). Time- and frequency domain analyses of beat-to-beat systolic blood pressure variability were performed for 128 consecutive beats. For time-domain analysis, we calculated the coefficient of variation of systolic blood pressure (CV_BP). For the frequency domain analysis, we determined the low-frequency (LF_BP; 0.04–0.15 Hz) and high-frequency (HF_BP; 0.15–0.40 Hz) powers of the variation in systolic blood pressure and the ratio of LF_BP to HF_BP (LF_BP/HF_BP) during endoscopy. The CV_BP and HF_BP, indicators of parasympathetic tone, increased in the early phase of endoscopy but decreased significantly in the middle and late phases compared with the pre-endoscopy value. The ratio of LF_BP/HF_BP, an indicator of indirect sympathetic tone, increased throughout the endoscopic procedure. Moreover, premedication with scopolamine butylbromide prevents the excessive parasympathetic nervous reflex when an endoscope passes through the upper digestive tract and also brings both decreased parasympathetic tone and increased sympathetic tone at the late phase of endoscopic procedure. Our results indicate that gastrointestinal endoscopy induced an autonomic nervous abnormality, which may contribute to the occurrence of cardiac events during endoscopic procedures.     

Use of Enzymatic Activity for Design of Orally Administered Enteric Dosing Forms

Abstract— Liquid and semi-solid enteric dosage forms were prepared by entrapping drug with an appropriate partition coefficient in a lipid base vehicle which would then be released by the action of intestinal enzymes. Lipid ester derivatives such as glyceryl monocaprylate and polysorbate 80 were used as vehicles. These vehicles readily dissolved the poorly water-soluble compounds used in the study, itazigrel, indomethacin and the dye, sudan II, and were digested by lipase and esterase, releasing the test drugs with time profiles similar to those observed in dissolution studies. The vehicles released little or only a small amount of the drugs into aqueous medium in the absence of an appropriate enzyme. The enzyme-sensitive enteric vehicles when containing sudan II did not release the dye in the stomach of rats after oral administration, but released significant amounts of the dye in the small intestine.