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Biomedical subjects

R D Olson

Publications and source records attributed to R D Olson.

At least 19 recordsLinked to original sources
PubMed1992

Effect of a low-protein diet on doxorubicin pharmacokinetics in the rabbit.

Malnutrition involving protein deficiency, which commonly occurs in cancer patients receiving anthracycline treatment, is considered to be a risk factor for the development of cardiotoxicity. Protein deficiency has been shown to impair the metabolism of drugs such as theophylline and acetaminophen. If protein deficiency also impairs anthracycline metabolism, it could explain at least in part the enhanced anthracycline toxicity associated with malnutrition. We tested this idea by determining the effect of a low-protein, isocaloric diet on doxorubicin pharmacokinetics in rabbits. The animals were randomized into two groups for 8-12 weeks. Rabbits in group 1 received a low-protein (5%), isocaloric diet, whereas those in group 2 received a normal-protein (15%) diet. Both groups (group 1, n = 15; group 2, n = 14) were given 5 mg/kg doxorubicin by i.v. bolus. After doxorubicin injection, blood samples were obtained over the next 52 h for the measurement of doxorubicin and doxorubicinol plasma concentrations by high-performance liquid chromatography (HPLC) with fluorometric detection. The low-protein diet significantly decreased doxorubicin clearance (48 +/- 3 vs 59 +/- 4 ml min-1 kg-1; P less than 0.05), prolonged the terminal elimination half-life (28 +/- 2 vs 22 +/- 2 h; P less than 0.05), and increased the area under the plasma concentration/time curve extrapolated to infinity (1722 +/- 122 vs 1405 +/- 71 ng h ml-1; P less than 0.05) as compared with the values determined for rabbits fed the standard rabbit chow (15% protein). The volume of distribution for doxorubicin was not altered by the low-protein diet. In addition, in rabbits fed the the low-protein diet, the terminal elimination half-life of the alcohol metabolite, doxorubicinol was prolonged (52 +/- 5 vs 40 +/- 2 h; P less than 0.05). Thus, a low-protein diet causes a reduction in the ability of rabbits to eliminate doxorubicin and possibly its alcohol metabolite doxorubicinol. If a similar alteration in anthracycline pharmacokinetics occurs in malnourished cancer patients, this phenomenon may contribute to their increased risk of developing cardiotoxicity associated with anthracycline therapy.

Animals↗
PubMed1992

Age- and sex-related changes in Tyr-MIF-1-like immunoreactivity in rat plasma.

The concentrations in plasma of the biologically active endogenous peptide Tyr-MIF-1 (Tyr-Pro-Leu-Gly-NH2) have not been measured during development or in female rats. By radioimmunoassay, we found that Tyr-MIF-1-like immunoreactivity (Tyr-MIF-1-LI) was first consistently detectable in plasma when the rat was 5 days old, and then gradually increased to adult concentrations by day 15. In male rats, the levels remained relatively constant for the next 21 months. In female rats, plasma concentrations of Tyr-MIF-1-LI at day 15 were about the same as in male rats. At 6 months of age, however, the concentrations in females decreased by half and by 21 months of life were only about a third of the concentrations found at day 15 or in age-matched males. The differences with age were not due to the length of time of storage of the samples, because another group of rats 1 month old was killed on the same day as 5-day-old rats and still showed several times more Tyr-MIF-1-LI in the plasma; again, no differences were found between male and female rats at either 5 days or 1 month. A single injection of estradiol followed by progesterone lowered the concentrations in 1-month-old male rats. In female rats that were either ovariectomized or sham-ovariectomized, the expected similarity in their plasma concentrations of Tyr-MIF-1-LI was found at 1 month of age.(ABSTRACT TRUNCATED AT 250 WORDS)

Age Distribution↗
PubMed1991

Aging alters the force-frequency relationship and toxicity of oxidative stress in rabbit heart.

Adult (6 months) and senescent (greater than 5 years) rabbit atria were studied under conditions known to increase cytoplasmic calcium (increased frequency of contraction and oxidative stress). At a contraction frequency of 1/sec, cardiac relaxation (90% relaxation time) was similar in senescent and adult atria but at a frequency of 2 or 3/sec, relaxation was significantly slower in senescent preparations (P less than 0.05). Additional experiments indicated that H2O2 (500 microM), a powerful oxidant, increased resting force and decreased developed force (DF) much more rapidly in senescent than adult atria; the maximum decrease in DF, however, was less in senescent preparations (adult = 81 +/- 6% and senescent = 42 +/- 27% of pre-H2O2 values; P less than 0.05). Age-related differences in effects of H2O2 did not result simply from a decreased ability of senescent hearts to detoxify an oxidative stress by the glutathione pathway. Both basal glutathione (GSH) concentrations and the H2O2-mediated decreases in GSH were similar in adult and senescent ventricular preparations, as were activities of glutathione peroxidase and glutathione reductase. These observations suggest that interventions known to increase cytoplasmic calcium can amplify age-related impairments of cardiac relaxation through mechanisms that may be independent of the glutathione pathway.

Aging↗
PubMed1990

Taurine deficiency and doxorubicin: interaction with the cardiac sarcolemmal calcium pump.

An anticancer drug, doxorubicin, and a naturally occurring beta-amino acid, taurine, exert opposing actions on myocardial calcium content and lipid peroxidation. Thus, we tested the hypothesis that the two agents may interact to modify cardiac calcium metabolism and indices of lipid peroxidation. Cardiac taurine levels were reduced by half in rats given tap water containing a beta-amino transport inhibitor, beta-alanine. Taurine deficiency was associated with an increased susceptibility of the heart to doxorubicin-mediated calcium accumulation, a phenomenon commonly associated with doxorubicin cardiotoxicity. Taurine deficiency also predisposed the heart to enhanced formation of malondialdehyde caused by doxorubicin administration. While increases in malondialdehyde levels are often associated with lipid peroxidation, the failure of doxorubicin to cause changes in oxidized glutathione content makes peroxidative mechanisms a less likely explanation for the potentiation of doxorubicin-mediated myocardial calcium accumulation in taurine-deficient rats. A more likely possibility is the interaction between taurine deficiency and doxorubicin to inhibit the sarcolemmal calcium pump. The data also suggest that the interaction between doxorubicin and taurine deficiency does not involve alterations in the pharmacokinetics of doxorubicin or the cardiotoxic metabolite, doxorubicinol. It is concluded that reduction in sarcolemmal calcium pump activity by taurine deficiency may contribute to myocardial calcium accumulation in hearts whose calcium homeostasis has been compromised by doxorubicin.

Animals↗
PubMed1990

Doxorubicin cardiotoxicity: analysis of prevailing hypotheses.

Anthracyclines, such as doxorubicin and daunorubicin, are highly effective anticancer agents that produce a well-described but incompletely understood cardiac toxicity. According to a popular hypothesis, anthracyclines injure the heart by generating oxygen-centered free radicals. This free radical hypothesis, however, appears to be inconsistent with many observations, such as the frequent failure of anthracyclines at cardiotoxic doses to produce evidence of increased free radical generation. Other explanations of cardiotoxicity involve platelet-activating factor, prostaglandins, histamine, calcium, and C-13 hydroxy anthracycline metabolites. These C-13 hydroxy metabolites, on the basis of in vitro data, are considerably more potent than parent compounds as myocardial depressants and as inhibitors of ATPases of sarcoplasmic reticulum, mitochondria, and sarcolemma. Further studies will be required to determine whether metabolites or the other putative injurious agents discussed contribute substantially to the cardiomyopathy of anthracycline therapy. The hypotheses presented in this paper should provide a useful framework for subsequent investigations into the mechanisms of anthracycline cardiotoxicity.

Animals↗
PubMed1989

MIF-1 is active in a chronic stress animal model of depression.

MIF-1 was tested in an animal model of depression that used unpredictable chronic stress. In this paradigm, rats received either no stressors or a daily protocol of a variety of stressors for 20 days, during which time daily, intraperitoneal injections of various compounds were given. The tricyclic antidepressant imipramine (5 mg/kg) and low doses (0.1 and 1.0 mg/kg) of MIF-1 significantly increased activity and decreased defecation in an open field on day 21. No dose of naloxone (0.01-10.0 mg/kg) acted as an antidepressant. A high dose (10.0 mg/kg) of MIF-1 significantly increased the effects of chronic stress and produced hyperalgesia. Chronically-stressed rats were significantly more analgesic than controls. The results indicate that MIF-1 can act as an antidepressant in this model.

Animals↗
PubMed1989

Differential effects of Tyr-MIF-1 and naloxone in two animal models involving benzodiazepine.

It has been shown previously that the endogenous brain peptide Tyr-MIF-1 (Tyr-Pro-Leu-Gly-NH2) can act as an antiopiate and can also increase binding and function at the GABAA/benzodiazepine receptor complex. We now describe the effects of this tetrapeptide in two models in which the antiopiate naloxone has been reported to decrease the activity of benzodiazepines. Unlike naloxone, Tyr-MIF-1 and MIF-1 neither prevented chlordiazepoxide-induced locomotor hyperactivity in mice on a tilting floor nor suppressed chlordiazepoxide-induced eating in rats. Thus, in these two systems, Try-MIF-1 did not act as an antiopiate or alter the effects of a benzodiazepine, indicating a selectivity in the actions of Tyr-MIF-1.

Animals↗
PubMed1979

Systemic administration of Met-enkephalin, (D-Ala2)-Met-enkephalin, beta-endorphin, and (D-Ala2)-beta-endorphin: effects on eating, drinking and activity measures in rats.

Rats were given four daily, interperitoneal injections (80 micrograms/kg) of Met-enkephalin, (D-Ala2)-Met-enkephalin-NH2, beta-endorphin, (D-Ala2)-beta-endorphin or the diluent (0.9% NaCl acidified to, 0.01 M with acetic acid). Animals were subsequently tested for food and water inake and activity. Met-enkephalin injections did not affect any of the measures but its (D-Ala2) analog reduced food intake and some of the activity measures in a complicated way. beta-Endorphin injections did not affect food or water intake; in familiar situations these animals were less active while novel situations seemed to potentiate activity. The (D-Ala2) analog reduced wheel running over 24 hours.

Animals↗
PubMed1979

Effects of an enkephalin analog on complex learning in the rhesus monkey.

Facilitation of the learning of a discrimination reversal task for a reward of food was found in rhesus monkeys after subcutaneous administration of a potent pentafluorinated enkephalin analog. (D-Ala2)-F5-Phe4-enkephalin-NH2. General activity, short-term memory, startle, and analgesia, however, were not significantly affected. In a within-subject design, each of 6 monkeys (3 males and 3 females) received each of 5 doses of the enkephalin analog (0.1, 1, 10, 100, and 1,000 microgram/kg). One daily injection was made for 7 consecutive days, including pre- and posttests on the first and last days with the diluent control. The enkephalin doses, with the exception of the 0.1 microgram/kg level, produced significantly faster learning than the diluent. Some sex differences were suggested by the data, but these effects are difficult to interpret. The results suggest that relatively small amounts of this analog given systematically can exert a reliable effect on a complex behavior such as reversal learning at doses devoid of opiate effects, due perhaps to enhanced cognitive flexibility rather than improvement in short-term memory or association formation.

Analgesia↗
PubMed1979

Possible non-narcotic component to action of opiate peptides on tonic immobility.

Chickens were tested in a tonic immobility paradigm after a single intraperitoneal injection of either 0.0, 0.1, 1.0, 10.0; 100.0, or 1000.0 microgram/kg of the potent opiate analog, (D-Ala2, F5Phe4)-Met-enkephalin-NH2. An inverted-U relationship was obtained, with 100 microgram/kg being the most effective in prolonging immobility. This dose was used in subsequent studies involving pretreatment with naloxone or diluent followed by treatment with diluent, (D-Ala2, F5Phe4)-Met-enkephalin-NH2 (a strong opiate), or (D-Phe4)-Met-enkephalin (a weak opiate). The results indicated that although naloxone had mixed effects in attenuating the duration of tonic immobility, even the analog with negligible opiate activity reliably potentiated the response. Therefore, a component of the effect of opiate peptides on tonic immobility could be due to a non-narcotic action.

Animals↗
PubMed1979

MIF-I's differential actions as an opiate antagonist.

The effects of MIF-I (Pro-Leu-Gly-NH2) were examined in three experimental conditions in which the opiate antagonist naloxone is active. MIF-I was found to block the analgesic effects of enkephalins and also morphine in the tail-flick test but not in the vas deferens assay. Unlike naloxone, MIF-I did not seem to reduce food intake in VMH-lesioned rats. The results suggest the possibility that MIF-I may represent a class of naturally occurring opiate antagonists with varying activities in independent situations.

Analgesics↗
PubMed1979

Naloxone-induced suppression of food intake in normal and hypothalamic obese rats.

Intraperitoneal injections of naloxone hydrochloride (1, 2, 4, and 8 mg/kg) suppressed food intake in both normal and hypothalamic obese rats maintained on a 4-hr per day feeding schedule. The decrease in feeding was more pronounced in the animals with ventromedial hypothalamic lesions. Appetitively motivated feeding, i.e., the consumption of sweetened milk under nondeprived conditions, was also suppressed by naloxone, but there was no reliable difference between groups. It is concluded that opiate receptors located in the ventromedial hypothalamus are not essential for the effects of opiate agonists and antagonists on feeding behavior.

Animals↗
PubMed1979

Endogenous opiates: through 1978.

The discovery of receptors in the brain for opiates and the structure of the endogenous peptides for these receptors has led to an explosion of interest in this field. The present review is the first of an annual series. It summarizes many of the highlights of research with opiate peptides published with a date of 1978 or earlier.

Animals↗
PubMed1979

Computer handling of occupational exposure data.

A system has been developed for the computer handling of industrial hygiene data in the Michigan Division of Dow Chemical U.S.A. With the implementation of this system, future epidemiological studies might be completed in a few weeks as opposed to months when done menually. The system is capable of providing lists, either current or historical, of the chemicals used in a particular building; and all the available exposure data for specific employees can be obtained throughout their entire periods of employment. The system is also capable of summarizing all available exposure information for a given chemical. The heart of the chemical exposure data system lies in the record content. Each record contains: 1. Chemical identification number; 2. Employee number; 3. Job classification number; 4. Department index number; 5. Data type code; 6. Exposure data; 7. Units code; 8. Date; 9. Building number and 10. Reference. A detailed discussion of each of these parameters is contained in the text.

Chemical Industry↗
PubMed1979

An effective hearing conservation program.

In a major chemical producing complex, noise problems of all kinds are encountered. One complex of The Dow Chemical Company, the Michigan Division, has approached this problem by setting up a Hearing Conservation Committee consisting of various disciplines: Safety, Industrial Hygiene, Medical, Engineering, and Production. This committee reviews each plant's Hearing Conservation Program bi-annually until all equivalent exposure ratios are less than one. Audiometric data is entered on a computer for rapid evaluation of periodic audiograms.

Engineering↗
PubMed1978

Neuropeptides and the blood-brain barrier in goldfish.

The general activity level of a goldfish is easily monitored by placing it in water to a depth of 2.5 cm in an aquarium on top of an activity meter. With this system, goldfish were administered a 5 microliter (80 microgram/kg) intracranial (IC) or intraperitoneal (IP) injection of one of 21 compounds and tested for general activity. The results indicated that activity decreased significantly over time and the peptides differentially decreased activity, with the greatest alterations in activity produced by two new enkephalin analogs: D-Ala2, F5Phe4-enkephalin-NH2 and Nalpha Nepsilon-bis-(D-Ala2-enkephalin)-Lys-NH2. Overall, decreased activity began approximately 3 min after an IC injections and 6 min after an IP injection. The longer latency after IP injections may indicate the time required for the substance, either in its original or fragmented form, to reach and cross the blood-brain barrier and makes a primary peripheral effect unlikely. Most of the peptides or possibly their metabolites appeared to enter the brain since no significant difference in activity existed after IC and IP injections, with both producing reliable decreases from the control. In summary, peptides can exert behavioral effects after both IC and IP administration in goldfish.

Animals↗