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Biomedical subjects

S Wallach

Publications and source records attributed to S Wallach.

At least 37 records · Page 2Linked to original sources
PubMed1989

Etoposide admixed with cisplatin. Phase I clinical investigation of 72-hour infusion.

The compatibility of etoposide (VP-16-213) and cisplatin (CDDP) in an admixture solution was established by High Pressure Liquid Chromatography (HPLC) studies in vitro at room temperature. A Phase I dual-dose escalation study of the admixture was subsequently carried out utilizing a 24-hour continuous infusion schedule administered for 3 consecutive days and repeated at 3 to 4 week intervals. Twenty-seven patients received a total of 42 treatment courses. The daily dose rates for VP-16-213 were 50, 75, and 100 mg/m2/day. Cisplatin was delivered at 20, 30, and 40 mg/m2/day for each dose level of VP-16-213. Dose-rate limiting toxicity was observed first at the VP-16 dose of 50 mg/m2/day and CDDP at 30 mg/m2/day. At 100 mg/m2/day for VP-16-213, six of 17 courses were associated with life-threatening leukopenia and four of six patients died with sepsis. All but one of the patients developing severe or life-threatening leukopenia had associated acute renal failure with serum creatinine levels greater than 2 mg/dl. The optimal dose rate of delivery for VP-16 and CDDP administered as a 72-hour infusion admixture is 75 mg/m2/day and 30 mg/m2/day, respectively.

Adult↗
PubMed1989

Cyclophosphamide, methotrexate, and 5-fluorouracil in a three-drug admixture. Phase I trial of 14-day continuous ambulatory infusion.

The compatibility and stability at room temperature for up to 7 days of a three-drug admixture of cyclophosphamide, methotrexate, and 5-fluorouracil (5-FU) (CMF) was established permitting the practical delivery of the combination as an infusion in an ambulatory setting. Fourteen patients received 20 courses of CMF administered on a continuous infusion schedule for 14 days of a 28-day cycle. The dose rates were fixed for 5-FU (300 mg/M2/day) and methotrexate (0.75 mg/M2/day). The cyclophosphamide dose was escalated from 25 to 50, 75, and 100 mg/M2/d. Leukopenia and thrombocytopenia were observed in two of five patients receiving the maximal dose of cyclophosphamide. No other toxicities were observed including alopecia, stomatitis or liver function abnormalities. This Phase I trial suggests that the cumulative doses of cyclophosphamide, methotrexate, and 5-FU are comparable to the maximum doses delivered as single agent infusions. Furthermore, when the infusion CMF is compared to the "standard" bolus schedule for CMF, the infusion schedule delivers 116%, 8%, and 350% of the respective three component drugs (cyclophosphamide, methotrexate, and 5-FU).

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1989

Combined 5-fluorouracil and floxuridine administered as a 14-day infusion. A phase I study.

5-Fluorouracil (5-FU) and floxuridine (FUdR) were admixed in a single solution and administered via a central venous catheter on a continuous infusion schedule for 14 days. The Phase I trial design developed for admixture combinations was employed with starting doses for 5-FU at 250 mg/m2/day and for FUdR at 0.075 mg/kg/day. Twenty patients and 28 courses were studied. Dose rate limiting toxicity was pseudoregional enteritis with or without stomatitis experienced by five of ten of the courses administered at the highest dose rates of the admixture components. The simultaneous delivery of the two agents results in a modest compromise of the cumulative dose delivered for FUdR. Previous Phase I studies of single agent 5-FU and FUdR had demonstrated that the optimal dose rates for the individual agents in a 14-day continuous 24-hour infusion schedule is 350 mg/m2/d and 0.125 mg/Kg/day, respectively. The maximum dose rate of 5-FU at 350 mg/m2/day for 14 days is not restricted even with the addition of FUdR at up to 0.1 mg/kg/day. The optimal dose rates for Phase II trails should be as follows: 5-FU, 350 mg/m2/day; and FUdR, 0.1 mg/kg/day.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1989

A phase I clinical trial of combined fluoropyrimidines with leucovorin in a 14-day infusion. Demonstration of biochemical modulation.

Two consecutive Phase I trials of continuous infusion 5-fluorouracil (5-FU) or floxuridine (5-FUdR) admixed with leucovorin (LCV) were performed and involved 19 and 24 patients, respectively. The studies were carried out to identify the optimal dose rate of delivery for the two admixtures (5-FU + LCV and 5-FUdR + LCV) administered for 14 days, and to determine if biochemical modulation could be identified. The optimal dose rates for 5-FU plus LCV were 200 mg/m2/d and 5 mg/m2/d, respectively. The optimal dose rates for 5-FUdR plus LCV were 0.075 mg/kg/d and 5 mg/m2/d, respectively. The dose rate limiting toxicity for 5-FU plus LCV was stomatitis and for 5-FUdR plus LCV it was diarrhea. LCV administered as an admixture with either 5-FU or 5-FUdR on an infusion schedule decreases the optimally tolerated dose rates for these two agents to 83% and 60%, respectively. This is achieved with low-dose LCV infusions.

Adult↗
PubMed1988

Combined floxuridine and cisplatin in a fourteen day infusion. Phase I study.

Twenty patients received 28 courses of 5FUDR (floxuridine) admixed with Cisplatin (CDDP) and administered as a continuous infusion for 24 hours for 14 consecutive days. Pharmaceutical studies of the admixture of 5FU with CDDP and 5FUDR with CDDP demonstrated that only 5FUDR was compatible with CDDP and that the admixture was stable for 7 days. This Phase I study established the optimal dose rate for the individual components of the admixture and demonstrated that CDDP decreases the maximum tolerated dose rate for 5FUDR. The optimal dose rate for 5FUDR is 0.075 mg/Kg/d, and for CDDP the optimal dose rate is 7.5 mg/M2/d. Dose rate limiting toxicity is an enteritis which is radiographically similar to regional enteritis and is related to the 5FUDR. An ancillary finding was a significant decrease in serum magnesium levels in 11 of 13 monitored courses presumably related to the platinum.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1988

Availability of body magnesium during magnesium deficiency.

Extensive experimental and clinical studies in animals and humans during the past 25 years have yielded considerable data regarding the availability of internal magnesium (Mg) stores for the maintenance of extracellular and critical tissue concentrations of Mg during periods of Mg deprivation. The bulk of body Mg is present in bone and skeletal muscle, and it is these two sites that provide essentially all the available Mg. In the rat, approximately 15% of bone Mg (equivalent to 1.5 mmol/kg body weight) can be lost, whereas less than one tenth of that amount is available from skeletal muscle. In the human, up to 35% of bone Mg can be lost, but the mean loss in extant studies is 18% (equivalent to 1.2 mmol/kg body weight). In contrast to the rat, up to 40% of human skeletal-muscle Mg can be lost with an average loss of 15% (equivalent to 0.45 mmol/kg). In the human, the bone and skeletal-muscle Mg pools can provide an average of 1.7 mmol/kg body weight equivalent to 15% of total body Mg. Release of Mg from these stores appears to depend on the presence of hypomagnesemia which may also result in small, significant and potentially adverse Mg losses from certain vital organs such as the heart, kidney and brain. The liver and other organs appear not to lose Mg despite Mg deprivation although intracellular Mg shifts of importance cannot be ruled out. These data indicate that the body reserve to combat Mg depletion is not designed to protect the extracellular Mg pool and certain critical organs from Mg deficiency. A continuous optimal intake of Mg is needed for good nutrition and health.

Animals↗
PubMed1987

Consistent N-myc copy number in simultaneous or consecutive neuroblastoma samples from sixty individual patients.

Amplification of the N-myc oncogene is detected in about 30% of untreated neuroblastomas. Amplification is associated with advanced stages of disease and rapid tumor progression. However, it was not known if the N-myc copy number was homogeneous in tumor tissue of an individual patient, or if it changed with time in vivo. Therefore, we have made 66 observations on multiple simultaneous or consecutive tumor samples from 60 patients with neuroblastoma. (a) Simultaneous samples were obtained from different areas of 31 tumor masses from 30 patients: a similar N-myc copy number (1-2, 3-10, or greater than 10) was found in all samples from each patient. (b) Simultaneous samples were obtained from different anatomical sites in ten patients. No difference in N-myc copy number was seen. (c) Finally, 25 patients had two or more tumor samples obtained over time. Thirteen patients had a single copy of N-myc in all samples, and 12 had consistent levels of amplification in all samples. Two of the latter cases had single copy of N-myc in a second-look surgery sample, but no tumor was evident histologically. This study demonstrates that the N-myc copy number in human neuroblastomas is usually consistent within a tumor, not only at different tumor sites, but also at different times in vivo. Overall, these findings suggest that N-myc amplification is an intrinsic biological property of a subset of neuroblastomas, and if amplification is going to occur, it is generally present at the time of diagnosis.

Child↗
PubMed1987

Tissue magnesium content in diabetic rats.

Diabetes mellitus is a known cause of hypomagnesemia but soft tissue magnesium depletion has not as yet been demonstrated clinically or experimentally. Direct measurements of soft tissue Mg and calcium in control, streptozotocin (STZ)-diabetic and STZ-insulin-treated-diabetic rats were made and failed to demonstrate consistent decreases in soft tissue Mg content despite the induction of modest hypomagnesemia. In addition, soft tissue Ca content was variably influenced and showed no interrelation with tissue Mg levels. These data do not support the presence of soft tissue Mg depletion nor excessive intracellular Ca uptake in an experimental diabetic model in which modest hypomagnesemia is induced.

Animals↗
PubMed1986

Abnormal calcium metabolism caused by increased circulating 1,25-dihydroxyvitamin D in a patient with rheumatoid arthritis.

A 35-year-old white male with rheumatoid arthritis who had developed hypercalcemia, hypercalciuria, and nephrolithiasis was found to be abnormally sensitive to vitamin D as a result of lack of regulation of circulating 1,25-dihydroxyvitamin D (1,25-(OH)2D). An increase in daily intake of vitamin D from 10 micrograms (400 units) per day to 50 micrograms (2000 units) per day produced an abnormal elevation in serum 1,25-(OH)2D, hypercalcemia, and hypercalciuria which were corrected by prednisone. Serum 25-hydroxyvitamin D initially was abnormally low, and increased with vitamin D to values which were in the low normal range. There were significant positive correlations between serum 1,25-(OH)2D (p less than .05) and serum calcium and between serum 1,25-(OH)2D and urinary calcium (p less than .05). Serum immunoreactive parathyroid hormone, initially in the lower range of normal, decreased further during hypercalcemia. A radiograph of the chest, gallium scan, and serum angiotensin-converting enzyme activity were normal. No granulomas or evidence of lymphoma were found in biopsies of the liver and of several lymph nodes. It is concluded that the abnormal calcium metabolism in this patient resulted from increased circulating 1,25-(OH)2D and that the defect in vitamin D metabolism was not related to sarcoidosis, other granulomatous disease, Hodgkin's disease, or lymphoma. The relationship, if any, of the abnormal metabolism of vitamin D and calcium to rheumatoid arthritis remains to be established.

Adult↗
PubMed1986

Radiochromium distribution in aged rats.

Fragmentary studies suggest that tissue chromium (Cr) levels decrease with age. Regardless of the mechanism for such a decline, decreased tissue exchange with administered radiochromium (51Cr) should result. Accordingly, body retention, urinary excretion, and serum (plasma) and tissue levels of 51Cr were determined in 2-month-old male control rats and in 9-18-month-old experimental male rats 3 days after the intravenous injection of high specific activity trivalent 51Cr. The older rats retained relatively less 51Cr than the 2-month-old rats in comparison to body weight but had similar urinary excretions of 51Cr. Serum (plasma) 51Cr levels were generally higher and tissue 51Cr levels generally lower in the older rats, with the exception of spleen 51Cr content, which increased. Skeletal 51Cr content was markedly decreased, by 30-85%. These data suggest that aging alters 51Cr distribution by decreasing cellular Cr content and transport. Other mechanisms must be operative in bone since skeletal Cr is primarily extracellular.

Aging↗
PubMed1986

Radiochromium distribution during saline diuresis.

Free water diuresis in vasopressin-deficient Brattleboro rats does not influence body conservation of chromium (Cr+3), suggesting a proximal tubular site for renal Cr reabsorption. Other data suggest that Cr conservation is accomplished primarily by lack of glomerular filtration or by tissue binding to a specific Cr-binding substance. To provide further data, radiochromium (51Cr) retention and tissue distribution were studied in SHR and WKY rats undergoing saline diuresis. Despite high urine flows, body retention and urinary excretion of 51Cr were unchanged. Tissue content of 51Cr was minimally and not consistently influenced by saline diuresis in either rat strain. Compared to WKY rats, the SHR rats had a trend to lower serum and tissue 51Cr content but higher tissue/serum 51Cr ratios. These data fail to incriminate collecting duct reabsorption in Cr conservation but are compatible with proximal Cr reabsorption or either of the two hypotheses mentioned above. The decreased serum 51Cr content of SHR rats may be due to the mechanical effect of increased plasma and extracellular volumes. One possible explanation for the increased tissue/serum 51Cr ratios may be the presence of a factor in SHR rats promoting cellular Cr transport. However, there is no present evidence to suggest that any of the hormones believed capable of increasing Cr transport (insulin, growth hormone, thyroxine, ADH) are increased in the SHR rat.

Animals↗
PubMed1986

Tissue magnesium in spontaneously hypertensive rats.

Magnesium (Mg) is a vasodilator which may play a role in the regulation of blood pressure. The present study measured tissue Mg and calcium (Ca) levels in a hypertension model, the spontaneously hypertensive (SHR) rat, using the Wistar-Kyoto rat as a control. Mean serum Mg levels were normal in both types of rats. In SHR rats given H2O ad libitum, four of nine tissues (kidney, heart, lung, bone) had significant 6-16% decreases in Mg content (less than 0.025-0.0005). In SHR rats undergoing chronic saline diuresis, seven of nine tissues (liver, kidney, testis, heart, lung, spleen, bone) had significant 7-18% decreases in Mg content. Tissue Ca in these same rats was significantly decreased by 6-39% in four of nine tissues, but was increased in other tissues. These observations indicate that both Mg and Ca depletion can occur in selected tissues in SHR rats and the number of tissues with Mg depletion doubles during chronic saline diuresis. If Mg depletion is also found in the vascular smooth muscle of this hypertension model, it may be a contributory factor in the hypertension.

Animals↗
PubMed1985

Clinical and biochemical aspects of chromium deficiency.

The essentiality of chromium (Cr) in animal and human nutrition is now well accepted. In animals, Cr deficiency can cause a diabetic-like state, impaired growth, elevated blood lipids, increased aortic plaque formation, and decreased fertility and longevity. The ability of Cr to potentiate insulin sensitivity has considerable experimental support. In the human, Cr deficiency has been demonstrated unequivocally in only one clinical situation, patients on total parenteral nutrition without added Cr. In such patients, impaired glucose tolerance, hyperglycemia, relative insulin resistance, peripheral neuropathy, and a metabolic encephalopathy have been noted with reversal of the clinical phenomena by Cr repletion. Many studies have been performed to determine whether Cr deficiency may be important in other clinical conditions, namely, diabetes mellitus, pregnant and parous women, and the aged population. Available data indicate that Cr supplementation can improve glucose metabolism in glucose intolerant individuals and decrease the total/HDL cholesterol ratio regardless of the status of glucose tolerance. However, whether Cr supplementation has long-term health benefits is unknown. Further, despite many tantalizing observations, it is still unclear whether Cr deficiency, latent or overt, is common in any human situation other than generalized malnutrition and total parenteral nutrition without added Cr. Technical uncertainties in the analysis of Cr, Cr contamination of food by the use of stainless steel processing equipment and eating utensils, and the lack of a clinically feasible test for Cr deficiency continue to impede progress in Cr research. Nevertheless, there is considerably more clarity as to plasma and urine Cr levels, food and tissue Cr content, and metabolic pathways of Cr metabolism than existed a decade ago. It is expected that progress will accelerate, since critical questions can now be addressed regarding the role of Cr in human nutrition.

Absorption↗
PubMed1984

Optic neuropathy in Paget's disease.

Of 22 patients (18 men and four women ranging in age from 50 to 89 years) with radiographic and clinical evidence of Paget's disease, nine had visual field defects. All nine had arcuate scotomas and five of the nine had generalized constriction. The visual field changes were asymptomatic in six of nine patients and progressive in two patients. Only two patients had radiographic evidence of optic canal constriction by bony impingement. There was no objective improvement in the optic neuropathy in the three patients treated with synthetic salmon calcitonin. Our data suggested that the optic neuropathy of Paget's disease cannot be explained solely on the basis of bony compression and the cause of optic neuropathy in patients with normal optic canals remains unknown.

Aged↗
PubMed1984

Pancreatic exocrine function and cyclic nucleotides in the diabetic rat.

Streptozotocin-induced diabetes mellitus in the rat results in a 30% decrease in serum amylase and an 80% decrease in pancreatic amylase levels. Pancreatic trypsinogen levels decrease 50% whereas pancreatic lipase levels increase 30%. Plasma cyclic nucleotide levels (cAMP and cGMP) increase 40-100%, urine cyclic nucleotide levels decrease 75-99%, but pancreatic cyclic nucleotide levels are unchanged. Short-term insulin treatment restores pancreatic amylase and trypsinogen levels to normal but has no effect on serum amylase or pancreatic lipase levels. Plasma cAMP levels decrease 20% toward normal during insulin treatment, but no other effects on cyclic nucleotide levels occur. These data confirm the profound but reversible effect of experimental diabetes mellitus on pancreatic secretion of amylase and trypsinogen. The results suggest that cyclic nucleotides do not play a direct role in the generation of pancreatic exocrine deficiency in diabetes mellitus or its reversal by insulin.

Amylases↗