Impact of anticoagulant choice on hospitalized bleeding risk when treating cancer-associated venous thromboembolism.

Essentials Bleeding risk by anticoagulant choice for cancer-associated venous thrombosis (CA-VTE) is unknown. 26 894 people with CA-VTE were followed for bleeding in a claims database in the United States. Hospitalized bleeding risk was similar with direct acting oral anticoagulants vs. warfarin. Relative hospitalized bleeding risk varied by cancer type and anticoagulant choice. SUMMARY: Background Direct acting oral anticoagulants (DOACs) are associated with less bleeding than traditional venous thromboembolism (VTE) treatments in the general population but are little studied in cancer-associated VTE (CA-VTE). Objective To determine whether different anticoagulation strategies for CA-VTE have different hospitalized bleeding rates. Patients/Methods We conducted a retrospective study of patients with CA-VTE, diagnosed between 2011 and 2015, in a large administrative database. Using validated algorithms, we identified 26 894 CA-VTE patients treated with anticoagulants and followed them for hospitalized severe bleeding. Cox models were used to assess bleeding risk, adjusted for age, sex, high dimensional propensity score and frailty. Results Over 27 281 person-years of follow-up (median 0.6 years), 1204 bleeding events occurred, for a bleeding rate of 4.4% per patient-year. Bleeding rates varied by cancer type, with the highest rate for upper gastrointestinal cancers (8.6%) and the lowest for breast cancer (2.9%). In Cox models (hazard ratio [HR]; 95% confidence interval [CI]), compared with warfarin, DOACS and low-molecular-weight heparin (LMWH) had similar hazards of bleeding (HR, 0.88; 95% CI, 0.69-1.11 and 0.98; 0.85-1.13). Compared with LMWH, there was no difference in hazard of bleeding with DOACs (0.86; 0.66-1.12). There was heterogeneity in bleeding risk with DOACs by cancer type, with a higher risk of bleeding in upper gastrointestinal cancers and lower risk of bleeding in prostate cancer and hematologic cancers. Conclusions In this practice-based sample of CA-VTE patients, DOACs were associated with similar bleeding risks to warfarin and LMWH. These findings suggest a complex association of bleeding risk with anticoagulant choice in cancer patients.

On the Cause and Mechanism of Phenoptosis.

Based upon evolvability theory, phenotypes like aging that offer no apparent individual benefit may evolve nonetheless. Pursuant to that concept, the evolution of a hypothetical, genome-based aging program called phenoptosis was proposed. However, while aging may facilitate evolvability, it need not result from a program specifically selected for that purpose. Instead, it is possible that the potential for aging is conserved within the genome as a part of a beneficial program that orchestrates and integrates developmental transformation of the soma from conception to maturation. Because somatic remodeling is inherently unstable, its continued non-programmatic expression beyond young adulthood (developmental inertia) erodes internal order, initiating and exacerbating aging. Thus, aging may result paradoxically from post-maturational expression of the same programmatic function for somatic transformation that previously provided individual benefit. It did so by ensuring acquisition of reproductive competence, post-reproductive development of parents to nurture offspring and thereby, to guarantee species survival. In an attempt to identify genes capable of controlling developmental inertia, we sequenced DNA from a series of subjects displaying extreme neoteny, i.e. retention of youthful characteristics during adulthood. We hoped to identify mutations associated with delayed development and to compare each subject's biological and chronological ages. De novo mutations of coding-genes were found in all the subjects, but they could not be definitively identified as a cause of developmental delay. Nonetheless, genetic and epigenetic studies of neotenic subject's DNA are on-going. We are attempting to determine if phenoptosis specifically evolved to cause aging, or rather if it exists as a cryptic component of the developmental program that expresses its lethal potential serendipitously and only after individual benefit is realized.

Update on the effects of a sierran wildfire on surface runoff water quality.

Wildfire has been shown to increase the short-term (1-3 yr) mobilization of mineral N and P in forest ecosystems of the Sierra Nevada Mountains and Lake Tahoe Basin. The ensuing effects on tributary and lake water quality are uncertain. The purpose of this investigation was to assess the impacts on runoff water quality over an intermediate time frame of 5 yr (2002-2007) after a wildfire event. Our design included fixed plots randomly placed within burned and unburned areas. Because each plot was sampled repeatedly during the study, we treated plots as repeated random effects in the analysis. We used a mixed model approach to analyze nutrient runoff concentrations and load for NH-N, NON and P in phosphate form (designated as ortho P or PO-P) where treatment (unburned vs. burned), time (pre-wildfire, post-wildfire year 1, year 2, etc.), and their interaction were fixed effects. Concentrations and loads of mineral N and P were higher in runoff from the burned areas immediately after wildfire. Because high water years may also contribute to higher runoff nutrient concentrations and loading, a wildfire followed by a high water year within the first season after a wildfire would likely have a much greater impact on runoff (and hence tributary) water quality than a wildfire followed by a low runoff water year.

Effects of mechanical harvest plus chipping and prescribed fire on Sierran runoff water quality.

Fire suppression in Sierran ecosystems creates a substantial wildfire hazard and may exacerbate nutrient inputs into Lake Tahoe by allowing the buildup of O horizon material, which serves as a source for high N and P concentrations in runoff water. The purpose of this study was to evaluate the effects of biomass reduction using cut-to-length mechanical harvest followed by chipping and controlled burning on surface runoff volume and water quality. Based on previous findings regarding N and P leaching flux and soil solution concentrations, we hypothesized that controlled burning and/or mechanical harvest with residue chipping does not increase inorganic N, P, and S concentrations in overland flow. Runoff, snowmelt, and rainfall were collected, volume measurements were taken, and samples were analyzed for NO(3)-N, NH(4)-N, PO(4)-P, and SO(4). Runoff volume, season, and year were identified as important parameters influencing overland flow nutrient concentrations and loads. Higher nutrient concentrations were commonly associated with summer rather than winter runoff, but the opposite was true for nutrient loads due to the higher runoff volumes. Treatment (unharvested, harvested, unburned, burned) effect was a strong predictor for discharge loads of NO(3)-N and SO(4) but was a weak predictor for PO(4)-P. Discharge loads of NO(3)-N and SO(4) were greater for the unburned harvested and the burned unharvested treatments than for the unburned, unharvested control sites or the burned and harvested combined treatment. Although mechanical harvest and/or controlled burning had a small initial impact on increased nutrient loading, the effects were minimal compared with background levels. Hence, these management practices may have the potential to improve forest health without the danger of large-magnitude nutrient mobilization and degradation of runoff water quality found with wildfire.

Inorganic nitrogen and phosphorus in Sierran forest O horizon leachate.

High in situ concentrations of inorganic N and P have been reported in overland/litter interflow from Sierran forests, indicating that these nutrients are derived from the forest floor O horizons. To test this hypothesis, forest floor monoliths consisting of the combined O(e) and O(i) horizons were collected near the South Shore of Lake Tahoe, Nevada, for leaching experiments. Three monoliths were left intact, and three were hand-separated according to horizon for a total of three treatments (combined O(e)+O(i), O(e) only, and O(i) only) by three replications. Samples were randomized and placed into lined leaching bins. Initial leaching consisted of misting to simulate typical early fall precipitation. This was followed by daily snow applications and a final misting to simulate spring precipitation. Leachate was collected, analyzed for NH(4)(+)-N, NO(3)(-)-N, and PO(4)(3-)-P, and a nutrient balance was computed. There was a net retention of NH(4)(+)-N, but a net release of both NO(3)(-)-N and PO(4)(3-)-P, and a net release of inorganic N and P overall. Total contributions (mg) of N and P were highest from the O(e) and O(e)+O(i) combined treatments, but when expressed as per unit mass, significantly (p < 0.05) higher amounts of NO(3)(-)-N and PO(4)(3-)-P were derived from the O(i) materials. The nutrients in forest floor leachate are a potential source of biologically available N and P to adjacent surface waters. Transport of these nutrients from the terrestrial to the aquatic system in the Lake Tahoe basin may therefore play a part in the already deteriorating clarity of the lake.

Wildfire effects on soil nutrients and leaching in a tahoe basin watershed.

A wildfire burned through a previously sampled research site, allowing pre- and post-burn measurements of the forest floor, soils, and soil leaching near Lake Tahoe, Nevada. Fire and post-fire erosion caused large and statistically significant (P < or = 0.05) losses of C, N, P, S, Ca, and Mg from the forest floor. There were no statistically significant effects on mineral soils aside from a decrease in total N in the surface (A11) horizon, an increase in pH in the A11 horizon, and increases in water-extractable SO4(2-) in the A11 and A12 horizons. Burning caused consistent but nonsignificant increases in exchangeable Ca2+ in most horizons, but no consistent or statistically significant effects on exchangeable K+ or Mg2+, or on Bray-, bicarbonate-, or water-extractable P concentrations. Before the burn, there were no significant differences in leaching, but during the first winter after the fire, soil solution concentrations of NH4+, NO3-, ortho-P, and (especially) SO4(2-) were elevated in the burned area, and resin lysimeters showed significant increases in the leaching of NH4+ and mineral N. The leaching losses of mineral N were much smaller than the losses from the forest floor and A11 horizons, however. We conclude that the major short-term effects of wildfire were on leaching whereas the major long-term effect was the loss of N from the forest floor and soil during the fire.

Is aging a disease? A review of the Serono Symposia Workshop held under the auspices of the 3rd World Congress on the Aging Male. February 9, 2002, Berlin, Germany.

On February 9, 2002, Serono Symposia sponsored a workshop at The 3rd World Congress on The Aging Male that was held in Berlin, Germany at the Hotel Inter-Continental. The title of the workshop 'Is aging a disease?', was intended to convey recent interest in the subject of aging as a clinically relevant entity and to discuss causes and approaches to its management. The Workshop was co-chaired by Drs Viktor Büber and Richard F. Walker. Speakers included Drs George R. Merriam, Heinrich M. Schulte, Felice Strollo and Richard F. Walker. Topics were arranged to proceed from a general overview of fundamental aspects of the aging process and their clinical consequences to specific aspects of the diagnosis and treatment of age-related disorders that could be associated with neuroendocrine dysfunction. F. Strollo initiated the series of lectures by reviewing some of the biological theories of aging and suggesting that maladaptive changes within the central nervous and endocrine systems play a major role in contributing to the cascade of events defined as senescence. R. Walker expanded upon this background by differentiating aging and disease. He suggested that while the process of aging is not a disease, it is directly responsible for the development of functional decrements causal of the intrinsic disease, frailty and general morbidity that occur in direct relation to advancing chronological age. From this generalized approach of linking age and disease, G. Merriam discussed a specific example in which age-related decrements in neuroendocrine dysfunction could contribute, at least in part, to senescent changes in body composition and physiological function. Specifically, he provided evidence that the gradual decline in growth hormone (GH) and testosterone secretion during aging is accompanied by anatomical and functional changes resembling pathogenic hormone deficiency. He went on to discuss possible interventions into this process, specifically showing data to support the view that a combination of GH secretagogues and sex hormones may be of value in sustaining health and vitality in the elderly. As an extension of this discussion, H. M. Schulte compared and contrasted age changes in sex hormone secretion between genders, and also stressed that the diagnosis and management of endocrine changes during life has become a serious challenge to those physicians intending to intervene in the aging process. Because the relationship of reduced hormone secretion to disease in the elderly is presently unclear, the Workshop concluded on a note of caution that guidelines for the replacement of endocrine substances as a prophylactic approach to aging have yet to be defined.

Growth hormone secretagogues in children with altered growth.

A diagnostic test was devised to evaluate pituitary growth hormone (GH) secretory potential. GH secretory dynamics were assessed in children with and without GH deficiency. The GH response was measured to GH-releasing hormone (GHRH) and the GH-releasing peptide GHRP-2, administered sequentially. The mean (+/- SEM) peak GH response to GHRP-2 was 20.1 +/- 5.5, 63.6 +/- 24.9 and 42.2 +/- 4.3 micrograms/l for GH-deficient, slowly growing non-GH-deficient and control children, respectively (p < 0.02 and p < 0.05 for GH-deficient vs controls and slowly growing children, respectively). Corresponding values for area under the curve (AUC) were 995 +/- 371. 2460 +/- 953 and 1598 +/- 274 micrograms/l x minute. Peak GH (and AUC) responses to GHRH were 19.6 +/- 5.1 micrograms/l (924 +/- 232 micrograms/l x minute), 31.4 +/- 8.4 micrograms/l (1544 +/- 449 micrograms/l x minute) and 39.8 +/- 7.8 micrograms/l (2201 +/- 437 micrograms/l x minute) for the same three groups, respectively (p < 0.05 for peak GH in GH-deficient patients vs controls, and p < 0.02 and p < 0.01 for AUC in GH-deficient vs slowly growing children and controls, respectively). The ratio of the peak GH response to GHRP-2 and GHRH was similar in all three groups. As these secretagogues stimulate different aspects of hypothalamic function (i.e., they are functional complements), robust GH secretion in response to GHRH or GHRP could suggest adequate endogenous GHRP or GHRH, respectively. A poor response to either GH secretagogue administered individually could represent inadequacy of its endogenous complement. The integrity of functional pituitary elements could be differentiated from inadequate complements by administering both GH secretagogues simultaneously. Application of these principles should allow a better definition of the underlying disorder and provide the basis for therapeutic strategies for those patients with abnormal GH production and/or secretion.

Evaluation of pituitary function in children using growth hormone secretagogues.

We have devised a diagnostic test to directly evaluate pituitary secretory potential, and also to identify the most appropriate therapy for slow growing children. The test compares responses to GH releasing hormone (GHRH) and GH releasing peptides or their non-peptidyl mimics (GHRP) administered sequentially and in combination. Since they are functional complements, robust GH secretion in response to GHRH or GHRP could be interpreted as representing adequate endogenous GHRP or GHRH, respectively. Alternatively, assuming that all pituitary cellular and molecular elements for GHRH- and GHRP-mediated GH secretion are functional, a poor response to either GH secretagogue administered individually could represent inadequacy of its endogenous complement. The integrity of functional pituitary elements could be differentiated from inadequate endogenous complement by administering both GH secretagogues simultaneously. Based upon this hypothesis, the proposed pituitary function diagnostic scheme could be used to test for endogenous GH secretagogue adequacy, as well as pituitary secretory capacity. The data resulting from application of these principles would allow appropriate selection of therapeutic entities, ranging from GHRH or GHRP administered separately or in combination, or alternatively, recombinant GH for those patients lacking a pituitary mechanism for GH production and/or secretion.

Effects of stimulated growth hormone secretion on age-related changes in plasma cholesterol and hepatic low density lipoprotein messenger RNA concentrations.

Growth hormone (GH) secretion declines during aging. Since GH alters plasma cholesterol (PC) concentrations, it was of interest to determine how GH secretagogues affect age-related hypercholesterolemia. Fischer 344 rats (3 and 14 months old) were co-administered (s.c.) GH releasing hormone (3 micrograms/kg; GHRH) and GH releasing hexapeptide (100 micrograms/kg; GHRP) for 120 consecutive days. Aging was associated with a progressive increase in PC, which was reduced in rats administered GHRH and GHRP compared to those administered vehicle, i.e. changes in PC during the study were 26.5 +/- 1.2 mg/dl vs. 40.1 +/- 0.9 mg/dl (P < 0.05) in the younger rats and 17.6 +/- 2.3 mg/dl vs. 31.6 +/- 5.3 mg/dl (P < 0.05) in the older rats, respectively. The lower concentrations of PC in GH secretagogue-treated older rats were associated with higher mean concentrations of hepatic LDL receptor mRNA (1.27 +/- 0.4 vs. 0.4 +/- 0.1; P < 0.05) but not cholesterol 7-alpha hydroxylase mRNA. Although GH secretagogue treatment was also associated with lower plasma cholesterol in the younger rats, it was not accompanied by quantitative changes in mean group concentrations of hepatic LDL receptor mRNA. Instead, daily administration of GHRH and GHRP in the younger rats correlated with a significant reciprocal relationship (P < 0.05) between PC and hepatic LDL receptor mRNA for individual group members. The results of this study suggest that reduced GH secretion during aging contributes, at least in part, to a progressive increase in plasma cholesterol that can be partially prevented with GH secretagogues. Furthermore, the effects on PC may result from GH-mediated, qualitative and quantitative changes in hepatic LDL receptor mRNA that increase receptor-mediated cholesterol clearance.

Saliva as a medium for chronobiological studies: its particular potential in steroid endocrinology.

This paper indicates the potential of saliva as a medium for chronobiological studies. It has principally focussed on the work of the Tenovus Institute for Cancer Research, at the University of Wales College of Medicine over the past decade or more, particularly for steroid hormones, so as to give an authoritative viewpoint based on practical experience. The article discusses issues ranging from technical to clinical aspects of hormone assay in saliva, showing disadvantages and limitations of use. Increasingly, many other investigators are developing and applying assays for salivary steroids and it is timely that such assays become tools in the hands of the chronobiologist. The clinical-biochemical importance of saliva resides also in the fact that in its context it is possible to assay enzymes, toxic substances and drugs.

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.

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)

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.

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.

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.

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.

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.