CON4EI: Short Time Exposure (STE) test method for hazard identification and labelling of eye irritating chemicals.

Assessment of ocular irritancy is an international regulatory requirement in the safety evaluation of industrial and consumer products. Although many in vitro ocular irritation assays exist, alone they are incapable of fully categorizing chemicals. Therefore, the CEFIC-LRI-AIMT6-VITO CON4EI consortium was developed to assess the reliability of eight in vitro test methods and establish an optimal tiered-testing strategy. One assay selected was the Short Time Exposure (STE) assay. This assay measures the viability of SIRC rabbit corneal cells after 5min exposure to 5% and 0.05% solutions of test material, and is capable of categorizing of Category 1 and No Category chemicals. The accuracy of the STE test method to identify Cat 1 chemicals was 61.3% with 23.7% sensitivity and 95.2% specificity. If non-soluble chemicals and unqualified results were excluded, the performance to identify Cat 1 chemicals remained similar (accuracy 62.2% with 22.7% sensitivity and 100% specificity). The accuracy of the STE test method to identify No Cat chemicals was 72.5% with 66.2% sensitivity and 100% specificity. Excluding highly volatile chemicals, non-surfactant solids and non-qualified results resulted in an important improvement of the performance of the STE test method (accuracy 96.2% with 81.8% sensitivity and 100% specificity). Furthermore, it seems that solids are more difficult to test in the STE, 71.4% of the solids resulted in unqualified results (solubility issues and/or high variation between independent runs) whereas for liquids 13.2% of the results were not qualified, supporting the restriction of the test method regarding the testing of solids.

Transdermal versus subcutaneous leuprolide: a comparison of acute pharmacodynamic effect.

Transdermal administration of peptides has been limited by the barrier properties of the skin. We compared the acute luteinizing hormone (LH) response to subcutaneous and transdermal administration of an LH-releasing hormone agonist (leuprolide). Eighteen volunteers received 5 mg leuprolide added to electrically powered patches delivering a current of 0.22 microA (transdermally). One week later, they received a 5 mg subcutaneous dose. LH response was measured. The area under the curve for LH response, maximum LH response, and time to maximum LH response were similar. Time to first response was shorter (147 +/- 108 minutes [transdermally] and 73 +/- 74 minutes [subcutaneously]; p less than 0.05), and the area under the curve for the first 150 minutes was greater (3655 +/- 2246 mIU.min/ml [transdermally] and 8666 +/- 4067 mIU.min/ml [subcutaneously]; p less than 0.05) for subcutaneous delivery. No major adverse effects were seen. This electrically powered transdermal technique merits further study.

Production of 52Fe via proton-induced reactions on manganese and nickel.

Excitation functions for the production of 52Fe in the bombardment of Mn and Ni with protons were measured from threshold up to 200 MeV. Production rates of 52Fe as well as of its 55Fe and 59Fe impurities were also measured in specific energy windows ranging up to 100 MeV. The agreement with previous measurements, where available, is reasonably good, except that considerably higher 55Fe contamination levels than those recently reported below 70 MeV were obtained in the case of Ni. The experimental results were compared with theoretical calculations by means of the computer code ALICE/85/300. Overall agreement to within a factor of two was obtained, and the usefulness of the code in planning a radioisotope production process was demonstrated. Finally, practical production rates and impurity levels, obtained with a 66 MeV proton beam at high intensities (approximately 50 microA), are reported.

Renal function in aging.

A variety of age-related anatomic and functional alterations in the kidney have been described. Anatomic abnormalities in the aging kidney include a decrease in kidney size, increased glomerular sclerosis, altered tubular structure, and an altered pattern of vascular flow. These anatomic abnormalities are associated with renal functional abnormalities, including decreased renal blood flow, and glomerular filtration rate. Altered renal tubular function, including impaired handling of water, sodium, acid, and glucose, may also be present. Impaired "endocrinologic" functioning manifested by changes in the renin-angiotensin system, vitamin D metabolism, and antidiuretic hormone responsiveness have been reported. The kidney is constantly exposed to the effects of a variety of potentially toxic processes. These range from environmental toxins and drugs, to a variety of chronic medical illnesses including hypertension, diabetes, and atherosclerotic disease. In this context, differentiation of "aging" effects from nephrotoxic effects resulting from these other processes is difficult. It has been argued that hypertension is an important factor in the development and progression of renal insufficiency in the elderly. The relationship between hypertension, glomerular hyperfiltration, atherosclerosis, and progressive renal dysfunction needs further study. Further research may allow the rational recommendation of interventions designed to control age-associated changes in renal function.

The nonutility of chest roentgenographic examination in asymptomatic patients with positive tuberculin test results.

To determine the value of chest roentgenograms in the management of asymptomatic persons with positive tuberculin skin test results, we undertook a retrospective review of all tests administered by our Employee Health Service, North Shore University Hospital, Manhasset, NY, between July 1, 1983 and November 1, 1987. Of 5200 tests, 247 results were positive. Two hundred twenty-one of these charts were reviewed for roentgenographic results and the presence of symptoms. All persons were asymptomatic. Chest roentgenograms revealed the following: normal, 188; unrelated abnormalities, 24; apical pleural thickening, 5; granulomas, 2; calcified hilar node, 1; and calcified node plus granuloma, 1. We noted no active tuberculosis, nor did the chest roentgenographic results influence recommendations for isoniazid prophylaxis. We conclude that chest roentgenograms are of value in 0% to 1.3% of asymptomatic people with positive tuberculin test results. A larger study should be undertaken to further define the usefulness of chest roentgenograms in this population.

Transdermal delivery of human insulin to albino rabbits using electrical current.

The transdermal route of administration for medication has many potential advantages over other routes of administration. However, the stratum corneum is an effective barrier to the absorption of most chemicals from the external environment into the body. To evaluate techniques for alteration of transdermal permeability, the authors studied the effect of low levels of electrical current on transport of a protein across the stratum corneum. Transcutaneous insulin absorption was used as an indicator of altered permeability. Twenty-six albino rabbits had acute diabetes mellitus induced by the intravenous administration of 125 mg/kg of alloxan. The animals then received either cutaneous patches containing insulin and an electrical current of 0.4 mA (active) or patches containing an equal amount of insulin but without electrical current (passive). At 10 and 12 hours after the placement of the patches, animals with active patches had significant elevations in serum insulin levels (p less than .05) and reduction in blood glucose levels (p less than .01). No changes were seen in controls. Animals with active patches also had significant differences from control animals in mean insulin response and peak insulin response (p less than .05). No cutaneous toxicity was observed in any of the animals. The authors conclude that low levels of electrical current can induce changes in stratum corneum permeability that are sufficient to produce the transdermal absorption of physiologic doses of a protein such as human insulin.

Successful transdermal administration of therapeutic doses of a polypeptide to normal human volunteers.

The human stratum corneum constitutes a relatively impermeable barrier to the transdermal absorption of most substances, including polypeptides and proteins. This double-blind, randomized, crossover study in 13 normal men evaluated whether a low level of electrical current could induce changes in cutaneous permeability sufficient to produce absorption of a polypeptide. We compared cutaneous absorption of 5 mg of leuprolide (a 9 amino acid luteinizing hormone releasing hormone analogue) in transdermal patches containing 0.2 mA electrical current (active) and in patches containing no electrical current (passive). Serum luteinizing hormone (LH) concentration was measured 12 times during an 8-hour period as a measure of drug effect. Similar baseline LH levels were seen in each group: active = 11.3 +/- 3.1 mIU/ml and passive = 13.7 +/- 4.7 mIU/ml (p not significant). Significant elevations of LH were seen in active compared with passive patches (p = 0.0084). As predicted, passive patches produced no elevation of LH concentration (LH = 11.8 +/- 7.1 mIU/ml at 4 hours). However, active patches produced elevations comparable to those achieved with subcutaneous administration of the drug (LH = 56.4 +/- 49.6 mIU/ml at 4 hours and p = 0.003 compared with passive). The patches were well tolerated without significant cutaneous toxicity. It is concluded that the use of low levels of electrical current can induce changes in the permeability of the stratum corneum. These changes are sufficient to promote the transdermal absorption of therapeutically relevant amounts of a polypeptide. This has major importance for our understanding of skin permeability and for the development of new techniques for drug administration.

Hydromorphone levels and pain control in patients with severe chronic pain.

To better understand the use of narcotic analgesics, the hydromorphone concentration was measured in serum samples from 43 patients with chronic severe pain who were receiving this drug. At the time of blood sampling, pain intensity, mood, and cognitive performance were assessed. There was large individual variation in the dose-drug level relationship. Seven patients with bone or soft tissue pain and drug levels of greater than or equal to 4 ng/ml had good pain control, whereas 10 did not. None of 15 patients with levels less than 4 ng/ml had pain control, despite drug doses similar to those given patients with higher levels. Thus 60% of the patients without control of their pain had hydromorphone levels below the lowest level that produced pain control. No patient with pain from nerve infiltration or compression had good pain control, irrespective of the drug level or dose. Poor mood correlated with high pain intensity and low drug level. Impaired cognitive performance was not related to drug level. Knowing that there is a low concentration of narcotic in the blood of a patient with chronic severe pain who is receiving high drug doses and who shows lack of both efficacy and side effects may reassure health care professionals that further narcotic dosage escalation is appropriate.

A controlled clinical trial of the addition of transdermal scopolamine to a standard metoclopramide and dexamethasone antiemetic regimen.

A randomized prospective clinical trial was conducted to evaluate the potential utility of adding transdermal scopolamine to a standard regimen of metoclopramide and dexamethasone for the prevention of cisplatin-induced emesis. Thirty-one patients who were about to receive their first cycle of chemotherapy, using a combination regimen including cisplatin at a dose greater than or equal to 60 mg/m2 were randomized to receive an antiemetic regimen of either metoclopramide and dexamethasone alone, or these two drugs plus transdermal scopolamine patches. The mean number of episodes of emesis was .63 +/- 1.31 in the 16 scopolamine-treated patients, and 2.27 +/- 2.66 in the 15 patients who did not receive scopolamine (P less than .01). The scopolamine appeared to inhibit extrapyramidal reactions to the metoclopramide, but the number of cases was too small for statistical significance. We conclude that the addition of transdermal scopolamine to a standard metoclopramide and dexamethasone antiemetic regimen provides additive benefit in the control of cisplatin-induced emesis.

Renal function in the elderly.

A variety of anatomic abnormalities in the aging kidney have been identified, including decreased kidney size, increased glomerular sclerosis, and arteriolar vascular changes. Physiologic changes, including decreased renal blood flow, decreased glomerular filtration rate, altered renal tubular function, and altered renal endocrinologic function, have also been described. The clinical consequence of these changes is an altered ability of the aged kidney to respond to stress, either due to illness or due to therapeutic interventions by physicians. Extra caution and vigilance is therefore needed when caring for the elderly.

New-onset atrial fibrillation: is there need for emergent hospitalization?

Patients with new-onset atrial fibrillation are often hospitalized emergently. To determine whether this is necessary, the authors retrospectively reviewed the care of 97 consecutive patients with this illness. No reason for the atrial fibrillation in 43 patients could be identified. Hypertension, coronary artery disease, and valvular heart disease were the most commonly associated conditions; myocardial infarction occurred in one patient. In 82% of patients, atrial fibrillation reverted to normal sinus rhythm during hospitalization. Three patients needed emergent hospitalization irrespective of the presence of atrial fibrillation. In the remainder, admission was based solely on the diagnosis of new-onset atrial fibrillation. Ninety-eight per cent had an uncomplicated hospital course. It is concluded that hospitalization is not necessary for all patients with new-onset atrial fibrillation. Those in whom reversion to normal sinus rhythm occurs rapidly during digoxin therapy can be discharged. Where no major medical illness is evident patients can be admitted to a bed outside the intensive care unit until reversion to normal sinus rhythm or rate control is achieved.

Metoclopramide decreases renal plasma flow.

Intravenous dopamine has been shown to increase renal plasma flow in man. The role of endogenous dopamine in the maintenance of renal plasma flow has not been described. We speculated that if endogenous dopamine activity is important in the maintenance of renal plasma flow, then high doses of a potent dopamine blocking drug such as metoclopramide would decrease renal flow. To test this hypothesis, we measured renal plasma flow using a single-injection technique with 131I-labeled orthoiodohippurate. Measurements were made before and after the administration of high doses of metoclopramide (1 to 2.5 mg/kg) to 20 patients receiving metoclopramide as an antiemetic before chemotherapy. Seven control subjects underwent sequential measurements of renal plasma flow without intervening metoclopramide dosing. Mean (+/- SD) renal plasma flow did not change in the control population (from 441 +/- 198 to 437 +/- 117 ml/min), but declined significantly in the patients who received metoclopramide (443 +/- 115 ml/min before metoclopramide and 387 +/- 137 ml/min after metoclopramide; P less than 0.001). In 25% of our study population the decline in renal plasma flow was greater than 20% below baseline levels. The magnitude of the effect did not appear to correlate with the pretreatment creatinine clearance, age, or sex of the patients. We conclude that high doses of metoclopramide decrease renal plasma flow in man. These data suggest a role for dopamine in the maintenance of renal plasma flow in patients receiving intravenous hydration. Changes of the magnitude we observed may well be of clinical importance. These findings therefore also suggest the possibility of metoclopramide potentiation of cisplatin nephrotoxicity.

Increased urinary enzyme excretion in workers exposed to nephrotoxic chemicals.

Nephrotoxic chemicals are commonly present in the environment, particularly in the workplace. The level of occupational exposure to these chemicals has been so reduced that exposure to these agents now rarely causes clinically evident acute renal disease. A sensitive indicator of renal injury, urinary excretion of N-acetyl-beta-glucosaminidase, was utilized to evaluate persons exposed in the workplace to lead, mercury, or organic solvents, for evidence of renal effects from this exposure. None of the persons had clinically evident renal disease by history, none had hypertension, and all had normal findings on urinalysis. When compared with appropriate control populations, workers exposed to lead, workers exposed to mercury, and two of three groups of workers exposed to organic solvents had significant increases in urinary acetyl glucosaminidase activity. The third group of laboratory workers with low exposure to organic solvents had no increase in urinary acetyl glucosaminidase activity. It is concluded that exposure to environmental nephrotoxins at levels currently considered safe can produce renal effects as manifested by elevations of urinary acetyl glucosaminidase excretion. It is speculated that these renal effects are not always innocuous.

Optimizing metoclopramide control of cisplatin-induced emesis.

Using an original high-pressure liquid chromatographic assay, we measured serum levels of metoclopramide and defined a concentration-response relationship for metoclopramide control of cisplatin-induced emesis. Using a metoclopramide regimen of 2 mg/kg body weight intravenously every 2 hours for four doses, we found that serum levels greater than 850 ng/mL immediately before the third dose were associated with complete control of emesis (less than three episodes) in 78% of patients and partial control (three to five episodes) in 18%. No patient with levels less than 850 ng/mL had complete control of emesis; only 42% had partial control (p less than 0.001). Increases in dosage for patients with low levels and poor responses improved control in four of five patients. Elderly patients had drug levels similar to those of young patients but had fewer episodes of emesis (p = 0.044), suggesting that elderly patients have increased sensitivity to this drug. The metoclopramide dose can be raised up to 2.75 mg/kg with an improvement in emetic control in patients who have an inadequate response to doses of 2 mg/kg and no toxicity.