Gilbert H. Mayor

The nephrotoxicity of cisplatin

Cisplatin is a cancer chemotherapeutic agent whose clinical use is complicated by its dose related kidney toxicity. Since the histopathological profile of cisplatin nephrotoxicity appears similar to that of other heavy metals, it has been commonly presumed that cisplatin nephrotoxicity is related to the platinum moiety. However, the delayed time course and development of cisplatin nephrotoxicity is not characteristic of heavy metal nephropathy. Furthermore, cisplatin nephrotoxicity is stereospecific to the cis and not the trans isomer, indicating that the platinum atom is not the proximate nephrotoxicant. It is likely that a metabolite of cisplatin, possibly an aquated and/or hydroxylated complex, mediates the nephrotoxicity of cisplatin.

cis-Dichlorodiammineplatinum nephrotoxicity: Time course and dose response of renal functional impairment☆

Abstract Although administration of cis -dichlorodiammineplatinum (CDDP) is known to induce acute proximal tubular necrosis, more subtle functional damage of the kidney could occur. This study was initiated to examine the renal functional correlates of CDDP nephrotoxicity in male F-344 rats receiving a single iv dose of 0, 1.25, 2.5, 5, 10, or 15 mg/kg CDDP. When compared to pair-fed controls, the following effects were observed 2 days following CDDP treatment: (a) increased 24-hr uv (5, 10, and 15 mg/kg), (b) reduced U osm (2.5 and 5 mg/kg), (c) increased 24-hr urinary K + excretion (10 and 15 mg/kg), (d) glucosuria, accompanied by hyperglycemia (10 and 15 mg/kg), and (e) elevated BUN (15 mg/kg). On Day 4, increased 24-hr uv and reduced U osm persisted in surviving drug treated animals (2.5 or 5 mg/kg). In addition, glucosuria, unaccompanied by hyperglycemia, was observed in the 2.5 and 5 mg/kg group and an elevated BUN was apparent only in the latter treatment group. C inulin (GFR) and C PAH (ERPF) were significantly compromised in drug-treated animals (5 mg/kg) on Day 4, findings consistent with the increased BUN. CDDP administration did not impair the ability of renal cortical slices to accumulate a prototype organic anion ( p -aminohippurate) or cation (tetraethylammonium) in vitro on Day 4. However, accumulation of these organic ions was significantly depressed in kidney slices obtained from untreated animals when 500 or 600 μg/ml CDDP was added to incubation medium. Inasmuch as alterations in urinary excretory function, but not BUN, were apparent in the lower dosage groups on Day 2, these results suggest that urine analyses may provide a more sensitive test for the early detection of CDDP nephrotoxicity than the commonly used measurement of BUN.

Bone mineral analysis of the rat femur by direct photon absorptiometry

SummaryThis report describes a method using direct photon absorptiometry (DPA) for determination in vivo of the bone mineral content to bone width ratio (BMC/W) in the rat femur. A significant correlation was noted between measurements by DPA and whole femur dry weight and ash weight. Measurements were reproducible within repeated determinations of both the same and successive days. Soft tissue, rotation of the femur, or slight differences in the longitudinal positioning of the femur did not significantly affect usefulness of the measurements. A significant positive correlation was seen between body weight and the femur BMC/W, indicating that the method accurately reflected expected physiological changes in bone mineral. The method is suitable for the rapid, simple, accurate, and reproducible measurement of bone mineral in the anesthetized rat and is applicable to serial measurements.

The effects of aluminum on microtubular integrity using in vitro and in vivo models

Since neuronal lesions produced by aluminum (Al) are morphologically similar to lesions produced by microtubule inhibitors, the effect of aluminum on microtubule integrity was investigated. Aluminum inhibited microtubule formation at concentrations as low as 0.1 mM. This approaches the aluminum concentrations found in brains of patients with several disorders which result in progressive dementia.

Diethyl Phthalate: A Perspective

Diethyl phthalate (DEP) is widely used as a solvent and fixative for cosmetic products and as a plasticizer for cellulose-based packaging materials that have broad applications in the food and pharmaceutical industries. Packaging composed of cellulose acetate plastics may contain up to 20% DEP. Considering the annual production of 26 million pounds of this compound1 and its varied uses, there is the potential for widespread, albeit low level, human exposure to DEP. It is thus important to determine what, if any, adverse health effects in humans might be expected due to these low levels of exposure. Until the 1930s, the main commercial thermoplastic material was celluloid, and the plasticizer of choice was camphor. During this decade, polyvinyl chloride (PVC) plastics became commercially available and di-(2-ethylhexyl) phthalate (DEHP), a PVC plasticizer, was first synthesized. The flexibility of polyvinyl chloride provided a significant advantage over celluloid and contributed to the rapid growth in its use. Although DEP could not be used in PVC fabrication, it also gained wide use as a plasticizer because it had two significant advantages compared with camphor-lower volatility and less odor. DEP and DEHP both belong to the general class of compounds known as phthalic anhydride esters (PAEs). There are approximately 20 different PAEs in current use, mostly as plasticizers, and they can be found in products representing virtually every major product category including construction materials, consumer goods, medical products, and packaging. U.S. production of these PAEs totaled approximately 1.6 billion pounds in 1988.1 DEP and DEHP are sometimes confused because of their similar uses and the single letter difference in the abbreviated forms of their chemical names. However, they have different toxic potencies as will be demonstrated in this article.

Subclinical Hypothyroidism and Euthyroid Sick Syndrome in Patients with Moderate-to-Severe Congestive Heart Failure.

Thyroid function tests were performed on baseline plasma that had been taken from 34 patients with NYHA Class II or Class III congestive heart failure (CHF). All patients were negative for thyroid disease on history and physical examination and none was taking medication known to alter thyroid metabolism. Analysis of thyroid function revealed abnormalities in 16 of 31 patients. These abnormalities fell into two categories: nine patients had elevated baseline thyroid stimulating hormone (TSH) above the normal limit while only one of these nine had subnormal thyroxine (T4) concentrations, suggesting the possibility of subclinical hypothyroidism. Seven patients demonstrated changes consistent with euthyroid sick syndrome (ESS). Weak correlations were observed between age and concentrations of T4 and tri-iodothyronine (T3) and this suggests that changes in thyroid function cannot be explained solely on the basis of age. Although previous studies have demonstrated the presence of ESS in CHF, the present study suggests the possibility of a significant prevalence of subclinical hypothyroidism.

Effect of Prenatal Administration of Aluminum and Parathyroid Hormone on Fetal Development in the Rat

Summary Oral aluminum (Al) exposure is a consequence of the elements presence in food, cosmetics, drinking water and its use in preparations administered therapeutically in large quantities as antacids or phosphate binders. Al is neurotoxic in animals and elevated concentrations of Al have been detected in brains of patients with certain encephalopathies. Protein synthesis, ribosomal RNA content and microtubular polymerization may be altered by Al. Since there are critical periods of protein synthesis and cellular division during embryonic development it was of interest to determine the teratogenic potential of Al. Since parathyroid hormone (PTH) increases tissue Al concentrations the effects of combined treatment of Al and PTH were also evaluated. Rats were maintained on diet supplemented with Al and/or calcium and treated with PTH or vehicle from day 6 of pregnancy through day 19, when fetuses were removed by Caesarean section. Combined or separate treatment with PTH and Al did not alter the number of live fetuses, fetal size, incidence of gross, soft-tissue or skeletal anomalies. Al concentration in whole fetal carcass was not affected. Combined treatment was accompanied by a significant increase in resorption rate. Histopathological alterations were not detected in animals from any treatment group. These results suggest that although combined maternal treatment with PTH and 1000 ppm Al may increase embryolethality, it may not enhance the potential for Al-induced toxic effects in surviving rat fetuses.

A Study in Normal Human Volunteers to Compare the Rate and Extent of Levothyroxine Absorption from Synthroid® and Levoxine®

Numerous branded and generic formulations of levothyroxine (LT4) sodium tablets are currently available. Results from previous studies attempting to examine the comparative bioavailability of these formulations are difficult to interpret because of subject heterogeneity, single time‐point blood sampling, varying degrees of hypothyroidism, and other factors. This study was devised to compare the rate and extent of absorption of LT4 from different LT4 sodium tablet formulations, in a simple model using a single‐dose two‐way single‐blind, randomized cross‐over design in 30 normal, healthy, nonpregnant, female subjects. This design controlled for many factors that limited previous LT4 bioavailability studies. Subjects were given a single 600 fig dose of LT4 as either Synthroid (Boots Pharmaceuticals, Inc., Lincolnshire, IL) tablets (formulation A) or Levoxine tablets (Daniels Pharmaceuticals, St. Petersburg, FL; formulation B). Measurements of baseline‐corrected total T4 serum concentrations determined at multiple time points demonstrated statistically significant differences between the two formulations at the 1.00, 3.00, 5.00, and 18.00 hour sampling times. Statistically significant differences for area under the curve (AUC) (0 to 48 hours) (formulation A, 159.9 ± 9.4 fig‐hour/dL; formulation B, 193.4 ± 10.1 μg‐hour/dL) and maximum peak plasma concentration (Cmax) (formulation A, 5.91 ± .34; formulation B, 7.12 ± .32) also were demonstrated. Furthermore, the ratio of the baseline‐corrected total T4 concentrations (B/A × 100) were 120.9% for AUC and 120.5% for Cmax. These data demonstrate that the administration of Synthroid and Levoxine result in a significantly different rate and extent of absorption of LT4, and therefore these two formulations cannot be considered bioequivalent. Interchange between these products can be expected to produce a different serum T4 concentration.

The effects of aluminum loading on selected tissue calcium and magnesium concentrations in rats.

Considerable evidence implicates elevated brain aluminum (Al) concentration in the pathogenesis of several forms of central nervous system dysfunction seen particularly among dialysis patients. In animals Al intoxication also leads to cerebral dysfunction. Since increased brain calcium (Ca) concentration has been associated with similar disturbances of cerebral function, this study was initiated to examine the effects of increased Al concentration on Ca and magnesium (Mg) concentrations in brain and other selected tissues. Daily intraperitoneal injection of Al (2.7 mg) for 10 d resulted in a significant increase in brain, liver, spleen, bone, and heart Al concentrations when compared to controls receiving saline injection. In brain, liver, and spleen, but not heart, Ca concentration was significantly higher in Al-treated rats than controls. In brain there was a significant correlation between Ca and Al concentration. Total plasma Ca concentration was not significantly different between the groups. Al loading had no significant effect on tissue Mg concentration. These results indicate that Al affects selected tissue Ca concentrations which ultimately may be involved in Al organ toxicity.

The effects of cisplatin and other divalent platinum compounds on glucose metabolism and pancreatic endocrine function

Three divalent platinum compounds, cis-dichlorodiammineplatinum (cis-DDP), trans-dichlorodiammineplatinum (trans-DDP), and ammonium tetrachloroplatinate, were examined for their effects on glucose metabolism in male F-344 rats. Rats were treated with a single iv dose of cis-DDP (0, 2.5, or 5 mg/kg), trans-DDP (0, 5, 7.5, or 15 mg/kg) or tetrachloroplatinate (0, 6, or 18 mg/kg). Glucose tolerance was evaluated 2, 4, 7, and 14 days following platinum treatment by serially measuring plasma glucose before and following an ip glucose load. Administration of 5 mg/kg cis-DDP impaired glucose tolerance on Days 2 and 4, but not on Days 7 and 14. Plasma immunoreactive glucagon (IRG) was elevated at all times following cis-DDP treatment and thus was not correlated with the transient impairment in glucose tolerance. Plasma immunoreactive insulin (IRI) response to a glucose load was deficient relative to the degree of hyperglycemia in cis-DDP-treated (5 mg/kg) animals on Days 2 and 4. However, neither histopathological damage of the pancreas nor pancreatic stores of IRI were affected by cis-DDP treatment. In contrast to cis-DDP, equimolar or greater than equimolar doses of trans-DDP or tetrachloroplatinate did not significantly affect glucose tolerance at any time examined. These results indicate that cis-DDP-mediated glucose intolerance is unique to the geometry of the complex and is related to properties other than the presence of a divalent platinum atom. Furthermore, glucose intolerance following cis-DDP treatment appears to be related to a relative deficiency in insulin secretion.