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Biomedical subjects

R F Walker

Publications and source records attributed to R F Walker.

At least 19 recordsLinked to original sources
PubMed1992

Role of selected endogenous peptides in growth hormone-releasing hexapeptide activity: analysis of growth hormone-releasing hormone, thyroid hormone-releasing hormone, and gonadotropin-releasing hormone.

The purpose of this study was to evaluate the contribution of endogenous GH-releasing hormone (GHRH) to exogenous GH-releasing hexapeptide (GHRP-6) activity, and to determine whether TRH or GnRH are endogenous analogs of GHRP-6. The activity of GHRP-6, a synthetic GH secretagogue, was significantly attenuated in rats administered GHRH antiserum or alpha-methyl-rho-tyrosine to reduce endogenous GHRH concentrations, and also in rats administered 5-50 micrograms/kg of [N-Ac-Tyr1,D-Arg2]-GRF 1-29 amide to block pituitary GHRH receptors. However, GHRP-6 activity was potentiated in rats administered 150 micrograms/kg [N-Ac-Tyr1,D-Arg2]-GRF 1-29 amide, presumably due to partial agonist activity of the GHRH receptor antagonist at the higher dose. These data show that endogenous GHRH contributes to full expression of exogenous GHRP-6 activity in vivo. Like TRH, a subthreshold dose of GHRP-6 was significantly more effective in hypothyroid rats than in euthyroid rats. However, suprathreshold doses of GHRP-6 were less effective in hypothyroid rats. Unlike TRH, GHRP-6 had no effect on GH and prolactin release from GH3 cells, and TRH and GnRH were poor competitors for 3H-GHRP-6 binding sites on pituitary membranes. A GnRH receptor antagonist did not block GHRP-6 activity in vivo, and GnRH administered alone or in combination with GHRP-6, did not stimulate GH release. The results of this study suggest that synergy between GHRH and GHRP-6 seen in pharmacological studies is physiologically relevant, and that TRH and GnRH are not endogenous analogs of GHRP-6.

Animals↗
PubMed1992

Effects of coadministered growth hormone (GH)-releasing hormone and GH-releasing hexapeptide on maladaptive aspects of obesity in Zucker rats.

The purpose of this study was to determine the effect of chronic pharmacological stimulation of the pituitary gland on GH hyposecretion and other maladaptive aspects of obesity. Obese Zucker rats were coadministered GH-releasing hormone (GHRH; 3 micrograms/kg) and GH-releasing hexapeptide (GHRP-6; 300 micrograms/kg), a potent combination of synergistic GH secretagogues, once daily for 60 consecutive days. Although pituitary weights and GH concentrations were higher in obese rats administered the peptides than in obese rats administered saline, stimulated GH secretion was lower in obese rats than in lean rats. However, compared to those in lean rats, plasma insulin-like growth factor-I and insulin concentrations were higher in the obese rats regardless of treatment. The GH secretagogues did not alter food intake or body weight gain in sexually mature obese rats, whereas body weight gain was significantly increased when they were administered to prepubertal obese rats. Although glucose tolerance was impaired in both groups of obese rats, it improved in obese rats administered GHRH and GHRP-6 compared to that in obese rats administered saline. On the other hand, plasma cholesterol concentrations were elevated in obese rats administered the GH secretagogues but not saline. In conclusion, the results of this study suggest that hyposensitivity to GHRH and GHRP-6 in obese Zucker rats results from high concentrations of plasma insulin-like growth factor-I that negatively feedback on stimulated GH secretion. Nonetheless, daily episodes of endogenous GH secretion resulting from chronic coadministration of GH secretagogues significantly influenced the pituitary gland as well as lipid and carbohydrate metabolism.

Animals↗
PubMed1992

Oral testosterone undecanoate in the management of delayed puberty in boys: pharmacokinetics and effects on sexual maturation and growth.

Therapeutic induction of puberty using oral testosterone (T) undecanoate (TU) 40 mg daily was performed in 4 pubertal boys aged 12.7-17.1 yr with constitutional delayed puberty and/or short stature. Single-dose pharmacokinetics study was performed on matched plasma and saliva samples obtained half-hourly for 10 h after the first dose and then repeated 3 and 6 months later. Treatment was continued for 15-21 months. Peak plasma total T concentration was achieved at 255 +/- 51 (SEM) min after the first 40 mg dose of TU, 300 +/- 76 min at 3 months, and 293 +/- 103 min at 6 months, the levels remaining elevated above baseline for at least 8 h after a single oral dose. Total T levels were initially high (mean 13.0 +/- 2.5; peak 38.7 +/- 4.2 nmol/L) but dropped significantly at 3 months (mean 8.3 +/- 1.8; peak 23.6 +/- 5.6 nmol/L) and at 6 months (mean 9.2 +/- 1.6; peak 24.8 +/- 3.5 nmol/L) paralleled by a dramatic fall in sex hormone binding globulin (73.9 +/- 18.0 to 35.1 +/- 9.7 at 3 month and 29.2 +/- 6.0 nmol/L at 6 month). Mean concentrations of unbound and free T (non-sex hormone binding globulin-bound T, free T, and salivary T) were below the normal adult range and remained unchanged over the same period. Plasma dihydrotestosterone concentrations were elevated after the first dose (mean 5.4 +/- 1.3; peak 11.0 +/- 2.5 nmol/L), the extent of this rise being less after 6 months (mean 4.1 +/- 0.8; peak 7.1 +/- 1.1 nmol/L) as was the case with mean estradiol (51.5 +/- 8.9 to 38.1 +/- 3.7 pmol/L). Signs of virilization progressed to Tanner stage G3 PH2-3 with testicular volumes increasing to 3-4 mL at 12 months, and G4 PH4-5 with further testicular growth to 6-10 mL at 24 months. Height velocity rose from 3.2 +/- 0.3 cm/yr (pretreatment) to 7.2 +/- 1.0 cm/yr in the first year and was maintained at 7.3 +/- 0.4 cm/yr despite cessation of therapy during the second year. Bone age advanced by 1.1 +/- 0.1 yr at 12 months and a further 0.8 +/- 0.3 yr at 24 months. Predicted adult height remained unchanged. No side effects were observed. Our preliminary data suggest that oral TU is a well accepted, effective, and safe treatment for the initiation of male puberty without disproportionate skeletal maturation. Continued pubertal advance was evident after cessation of treatment in all patients.(ABSTRACT TRUNCATED AT 400 WORDS)

Administration, Oral↗
PubMed1991

Robust growth hormone (GH) secretion in aged female rats co-administered GH-releasing hexapeptide (GHRP-6) and GH-releasing hormone (GHRH).

Aging is associated with a blunted growth hormone (GH) secretory response to GH-releasing hormone (GHRH), in vivo. The objective of the present study was to assess the effects of aging on the GH secretory response to GH-releasing hexapeptide (GHRP-6), a synthetic GH secretagogue. GHRP-6 (30 micrograms/kg) was administered alone or in combination with GHRH (2 micrograms/kg) to anesthetized female Fischer 344 rats, 3 or 19 months of age. The peptides were co-administered to determine the effect of aging upon the potentiating effect of GHRP-6 on GHRH activity. The increase in plasma GH as a function of time following administration of GHRP-6 was lower (p less than 0.001) in old rats than in young rats; whereas the increase in plasma GH secretion as a function of time following co-administration of GHRP-6 and GHRH was higher (p less than 0.001) in old rats than in young rats (mean Cmax = 8539 +/- 790.6 micrograms/l vs. 2970 +/- 866 micrograms/l, respectively; p less than 0.01). Since pituitary GH concentrations in old rats were lower than in young rats (257.0 +/- 59.8 micrograms/mg wet wt. vs. 639.7 +/- 149.2 micrograms/mg wet wt., respectively; p less than 0.03), the results suggested that GH functional reserve in old female rats was not linked to pituitary GH concentration. The differential responses of old rats to individually administered and co-administered GHRP-6 are important because they demonstrate that robust and immediate GH secretion can occur in old rats that are appropriately stimulated. The data further suggest that the cellular processes subserving GH secretion are intact in old rats, and that age-related decrements in GH secretion result from inadequate stimulation, rather than to maladaptive changes in the mechanism of GH release.

Aging↗
PubMed1991

Intranasal activity of the growth hormone releasing peptide His-D-Trp-Ala-Trp-D-Phe-Lys-NH2 in conscious dogs.

This series of experiments was conducted to evaluate the growth hormone (GH) releasing activity of intranasally administered His-D-Trp-Ala-Trp-D-Phe-Lys-NH2 (GHRP-6, SK&F 110679) in conscious dogs. Intranasal administration of GHRP-6 increased plasma growth hormone levels in the conscious dog in a dose-related manner. Doses of 0.25 and 0.5 mg/kg produced GH levels of 11.3 +/- 4.8 ng/ml and 28.6 +/- 8.0 ng/ml, respectively. Peak levels were observed 15 minutes after dosing and GH levels were elevated for up to 105 minutes after intranasal dosing. Intranasal administration of isotonic saline did not produce any change in basal (negligable) GH levels. When GHRP-6 was given by the intravenous route, a maximal dose of 0.5 mg/kg, produced a peak plasma GH concentration of 60.8 +/- 10.5 ng/ml. Saline had no effect on GH levels when given intravenously. Using the intravenous and intranasal GH response data (i.e., area under the time-response curves), the intranasal bioavailability of GHRP-6 was estimated to be 34.4 to 44.9%. The results of these studies suggest that significant activity and excellent bioavailability can be achieved when GHRP-6 is administered by the intranasal route to conscious dogs. Based on these results, the intranasal activity of GHRP-6 should be evaluated in man. The successful intranasal administration of this peptide in man should provide GH therapy with reduced patient discomfort and better patient compliance when compared to presently available parenterally administered remedies.

Administration, Intranasal↗
PubMed1991

Sex differences in growth hormone (GH) secretion by rats administered GH-releasing hexapeptide.

The purpose of this study was to compare GH secretion after the administration of GH-releasing hexapeptide (GHRP-6) in conscious male and female rats. Plasma GH was significantly elevated in female rats (six of six) compared to male rats (three of six) 15 min after administration of a single sc injection of GHRP-6 (0.5 mg/kg). In male rats, GHRP-6 administration was associated with suppression of episodic GH secretion and desensitization to a second injection administered 6 h later, whereas in female rats, GH secretion occurred after both GHRP-6 injections. After 14 consecutive days of administering GHRP-6 twice per day, mean plasma GH concentrations in males decreased from 110 +/- 91 to 2.8 +/- 0.6 ng/ml (P less than 0.05) and in females increased from 170 +/- 53 ng/ml to 361 +/- 81 ng/ml (P less than 0.05). Desensitization to GHRP-6 in conscious male rats was not observed in pentobarbital-anesthetized male rats, suggesting that GHRP-6 administration enhanced somatostatin release in the conscious state. After 14 consecutive days of GHRP-6 administration, the mean pituitary GH concentration in female rats was significantly lower than that in male rats (5.1 +/- 0.2 vs. 12.9 +/- 1.2 micrograms/mg, respectively). Lower pituitary GH concentrations in females correlated with higher GH secretion after GHRP-6 administration. Desensitization to GHRP-6 in male rats is attributed to neurohumoral factors producing their unusual pattern of episodic GH secretion, and the response is probably not typical of other species.

Animals↗
PubMed1990

Comparisons of plasma and salivary cortisol determinations for the diagnostic efficacy of the dexamethasone suppression test.

The current status of the saliva dexamethasone suppression test (DST) is discussed and results from the literature reviewed. Evidence is presented that demonstrates that the efficacy of the salivary-based test is equal to that of the plasma DST provided that specifically developed radioimmunoassays are used for determination of salivary cortisol. Such evidence relied on measurement of cortisol in 300 matched samples of plasma and saliva provided by patients admitted to a routine psychiatric ward over a 2-year period. The results according to diagnosis (DSM-III categories) were in line with those generally reported. The influence of anticholinergic medication was examined: this had no significant effects on the performance of the plasma or salivary-based DST.

Depressive Disorder↗
PubMed1990

Oral activity of the growth hormone releasing peptide His-D-Trp-Ala-Trp-D-Phe-Lys-NH2 in rats, dogs and monkeys.

The purpose of this study was to evaluate the growth hormone (GH) releasing activity of orally administered His-D-Trp-Ala-Trp-D-Phe-Lys-NH2 (GHRP-6, SK&F 110679) in rats, dogs and monkeys. Rats were administered GHRP-6 orally by gavage or parenterally through femoral artery catheters. Blood was collected before and after GHRP-6 administration for estimation of plasma GH and comparison of GH changes resulting from enteral and parenteral administration of the peptide. GHRP-6 was administered to dogs intravenously (i.v.) through cephalic vein catheters, intragastrically (i.g.) through esophagostomy tubes or intraduodenally (i.d.) through vascular access ports, and blood was collected before and after peptide administration for estimation of plasma GH. Cynomolgus monkeys were administered GHRP-6 i.g., and blood was collected from abdominal aorta for estimation of changes in plasma GH. Enteral activity of GHRP-6 was observed in all 3 species tested. In rats, ED50's for enteral and parenteral administration of GHRP-6 were 4 mg/kg and 28 micrograms/kg, respectively. Thus in rats, enterally administered GHRP-6 was 0.7% as bioactive as the parenterally administered peptide. In dogs GHRP-6 was slightly less potent than in rats, with ED50's for i.g. and i.v. administration approximately 15 mg/kg and 125 micrograms/kg, respectively. However, enteral potency of GHRP-6 in dogs was 0.8% of parenteral potency, and thus, comparable to that in rats. Additionally, comparison of plasma GH levels following i.g. vs i.d. administration in dogs suggested greater activity by the i.d. route. Monkeys were the species most sensitive to enterally administered GHRP-6, with plasma GH increased in those receiving i.g. doses as low as 0.3 mg/kg and an ED50 of 0.75 mg/kg compared to 4 and 15 mg/kg in rats and dogs, respectively. The results of this study demonstrate that GHRP-6 releases GH when administered directly into the gastrointestinal tract. Although enteral activity is approximately 1% of parenteral activity, GHRP-6 is potent, especially in primates which require relatively low doses to provoke GH release. These data suggest that orally active GHRP-6 may provide a practical therapeutic alternative to parenterally administered peptides such as GHRH, especially if enteral activity is enhanced with appropriate formulation.

Administration, Oral↗
PubMed1990

A non-opioid pattern characterizes inhibition of growth hormone releasing peptide binding by dynorphin-related peptides.

GHRP-6 (His-D-Trp-Ala-Trp-D-Phe-LysNH2; SK&F 110679) is a hexapeptide that specifically releases growth hormone. Although derived from methionine enkephalin, 3H-SK&F 110679 binding profiles suggest that it retains little mu or delta opioid activity. In the present study, dynorphin A was a potent inhibitor of SK&F 110679 binding. However, detailed structure-activity studies using dynorphin-related compounds suggest that the interaction between SK&F 110679 and dynorphin was non-opioid in nature. The non-opioid peptide des-Tyr-dynorphin was virtually as potent an inhibitor of 3H-SK&F 110679 binding as the intact dynorphin peptide. Additionally, the non-peptide, kappa selective ligand U-50,488 was a very weak inhibitor of 3H-SK&F 110679 binding. Since dynorphin but not U-50,488 has been reported to release growth hormone, the present results suggest that a non-opioid dynorphin site participates in SK&F 110679's growth hormone releasing action.

Animals↗
PubMed1990

Dopamine in the cerebrospinal fluid of prepubertal and adult horses.

Catecholamine concentrations (pg/ml) in the cerebrospinal fluid (CSF) of prepubertal (n = 9) and adult (n = 18) horses were determined by radioenzymatic assay. Norepinephrine was low or non detectable in all CSF samples. In contrast, measurable CSF dopamine concentrations were effected by age, reproductive status and exogenous steroid treatments. The concentration of dopamine in the CSF of prepubertal females (733 +/- 92) was greater (p less than 0.05) than the concentration in the CSF of prepubertal males (117 +/- 67). Prepubertal male horses which were treated with testosterone for 5 days (50 mg/day) had elevated (p less than 0.05) dopamine concentrations (2,533 +/- 1,160) in the CSF compared to control males. In adult mares, dopamine was lower (p less than 0.05) in the ovulatory season (25 +/- 10) than during the anovulatory season (200 +/- 101). Daily intramuscular estradiol-17 beta (5 mg/day) injections had no effect (p less than 0.05) on dopamine concentrations in the CSF of seasonally anovulatory mares (250 +/- 35). Further, concentrations of dopamine in the CSF of long-term ovariectomized mares (80 +/- 21) were not influenced (p less than .05) by season. These results suggest that age, sex and gonadal steroids may effect dopamine, but not norepinephrine, concentrations in the brain ventricular system of the equine species. Further, seasonal effects on CSF dopamine concentrations are dependent upon the presence of the ovaries.

Animals↗
PubMed1990

Chronobiology in laboratory medicine: principles and clinical applications illustrated from measurements of neutral steroids in saliva.

A number of chronobiological principles, as they pertain to the practice of laboratory medicine, have been discussed. Without doubt, salivary steroid assays are valuable tools for use in clinical studies, not necessarily as a single time-qualified sample but more often as a series of samples that will describe the underlying endocrinological time-structure. It is also important to appreciate that melatonin, certain drugs, and many dietary constituents such as phyto-oestrogens, are among the myriad of substances that can be monitored, and so hold great promise for the chronobiologist interested in the use of saliva as a sampling medium, both in the present and in the future.

Adrenal Glands↗
PubMed1990

Potential value of salivary steroids in chronoepidemiological and endocrine-related studies.

Experience from Institute studies has clearly demonstrated the advantages of salivary steroids in clinical endocrinological research and their potential value in chronoepidemiological studies of many kinds that may involve hormones. Of course, the examples and suggestions for areas of research involve many more covariates than those mentioned; but sufficient evidence has been presented to indicate the chronobiological potential of salivary steroid assays in studies of mental health, aggression and behaviour, stress, the endocrine changes occurring from birth to old age and those relating to endocrine cancer. The pioneering studies of Halberg et al (1981) and Haus et al. (1987) have demonstrated the feasibility of carrying out international epidemiological studies as they relate to breast cancer risk and studies of the general population. The potential value of salivary steroid assays in clinical, physiological and epidemiological studies is judged to be considerable.

Chronobiology Phenomena↗
PubMed1989

Binding of a growth hormone releasing hexapeptide to specific hypothalamic and pituitary binding sites.

The drug SK&F 110679 (His-D-Trp-Ala-Trp-D-Phe-LysNH2), is an enkephalin-derived hexapeptide, which specifically releases growth hormone in a wide variety of species in vivo and in vitro. Previous binding studies, using ligands which are specific for mu and delta opioid binding sites, demonstrated an inverse relationship between the opioid binding potency and the potency in releasing growth hormone of a series of peptides related to SK&F 110679. In an attempt to understand its mode of action better, a binding assay for the peptide was established using a ligand which had been tritium labelled at the D-Trp2 residue. Membrane fragments from both the hypothalamus and anterior pituitary tissue were found to contain sites to which [3H]SK&F 110679 reversibly and saturably bound. The binding curves for [3H]SK&F 110679 to membrane fragments of both hypothalamus and anterior pituitary were resolved into two binding components with the computer program LIGAND. The Kd's obtained were in the 10(-8) M and 10(-5) M range. The relationship of these binding sites to the growth hormone-releasing activity of the peptide was explored by examining the relationship between the binding and potency in releasing growth hormone of a series of peptides related to SK&F 110679. For sites in both the hypothalamus and pituitary, a significant correlation between binding and the release of growth hormone was obtained. Thus, these binding sites appeared to be involved in the release of growth hormone by SK&F 110679-related peptides.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

Implementation of a primary screen for developmental neurotoxicity.

A battery of tests to evaluate physical growth/development and neurobehavioral function was conducted with 78 litters of control Sprague-Dawley rats given purified water by intubation. The objectives of this study were to optimize test methods and to document the range and variability of the experimental endpoints. Data are presented for maternal evaluations (body weight gain, food consumption), gestation length, litter size, and postnatal survival. Pup body weight was used to assess postnatal somatic growth rate from birth to 85 days of age, while whole and regional brain weight measurements at 7, 28, and 85 days provided a more specific measure of physical growth relevant to a neurobehavioral study. Physical landmarks of development evaluated were pinna unfolding, incisor eruption, and eye opening while reflex landmarks of development evaluated were the negative geotaxis and pupillary reflexes. The mean percentage of litters acquiring a physical trait or reflex increased sigmoidally with age, and the data suggest that the potential to detect developmental delays would be optimal when ca. 90% of control litters reach the test landmark. Functional evaluations were arranged according to four testing subsets so that each litter was evaluated in each test (1 pup/sex/litter), but repeated testing on pups was minimized. Auditory and tactile startle reflexes, as well as prepulse inhibition, were measured at ages 22 days and 60-64 days and found to increase with age. A passive avoidance paradigm (age 40-43 days) was used to assess exploratory behavior (approach) and memory (avoidance). Swimming performance in a water maze was used to evaluate learning. In this test, escape times and error rates improved to their highest level by five or six trials and showed acceptable degrees of variability. Spontaneous motor activity was monitored for 23 hr at age 54-61 days to evaluate exploratory activity, photoperiod entrainment, and catecholamine-induced locomotion (amphetamine challenge). Finally, landmarks of sexual maturation (balanopreputial separation evident at 45 days of age, vaginal perforation evident at 33 days) and estrous cyclicity (4.8 cycles per 21 days) were evaluated as measures of reproductive neuroendocrine function. In sum, the test battery provided an efficient yet comprehensive screen for evaluating effects on physical growth/development and neurobehavioral function which meets practical criteria for preclinical testing of pharmaceutical agents.

Animals↗