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From the Clinical Research Centers |
Division of Endocrinology and Metabolism, Department of Medicine, University of Virginia, Charlottesville, Virginia 22908 (I.M.C., E.H.S., S.S.P., M.O.T.); Indiana University, Indianapolis, Indiana 46202 (O.H.P., T.T.); and Merck Research Laboratories, Rahway, New Jersey 07065 (G.M., K.A.C., D.K., B.G., W.J.P.)
Address all correspondence and requests for reprints to: Michael O. Thorner, Department of Medicine, Box 466, University of Virginia Health Sciences Center, Charlottesville, Virginia 22908. E-mail: MOT{at}virginia.edu
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Abstract |
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 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
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0.05 vs.
baseline), and 24 h mean GH concentrations increased 79 ±
19% (0.14 ± 0.01 to 0.26 ± 0.02 µg/L,
P 0.05 vs. baseline). Following
treatment with 50 mg MK-677, IGF-I concentrations increased 79 ±
9% (84 ± 3 to 150 ± 6 µg/L, P
0.05 vs. baseline) and 24-h mean GH concentrations
increased 82 ± 29% (0.21 ± 0.02 to 0.39 ± 0.04
µg/L, P 0.05 vs. baseline),
respectively. Serum IGF binding protein-3 concentrations increased with
both 10 mg (1.2 ± 0.1 to 1.7 ± 0.1 µg/L,
P 0.05) and 50 mg MK-677 (1.7 ± 0.1 to
2.2 ± 0.2 µg/L, P 0.05). The GH response
to MK-677 was greater in subjects who were the least GH/IGF-I deficient
at baseline; by linear regression analysis the increase in 24-h mean GH
concentration was positively related to both baseline 24-h mean GH
concentration (r = 0.81, P = 0.009) and
baseline IGF-I (r = 0.79, P = 0.01) for 10 mg
MK-677. IGF-I responses were not significantly related to any baseline
measurement. Fasting and postprandial insulin and postprandial glucose
increased significantly after MK-677 treatment, and the clinical
significance of these changes will need to be assessed in longer term
studies. Oral administration of such GHRP-mimetic compounds may have a
role in the treatment of GH deficiency of childhood onset. |
Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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There is a general consensus that children with short stature and GH deficiency should be treated to maximize their growth potential. Increasingly, adult GH deficiency is also being treated. Until now, the treatment for GH deficiency has consisted of GH injections, usually administered daily. Although effective, GH treatment has a number of drawbacks, including the need for parenteral administration and high cost. These have provided an incentive to develop GH secretagogues that are effective when taken orally.
GH releasing peptide (GHRP-6) is a synthetic hexapeptide that stimulates GH secretion (7, 8). It appears to act directly on the pituitary (9, 10, 11) and also on the hypothalamus (12, 13). Oral administration of GHRP-6 is able to stimulate GH secretion, but its bioavailability is much greater after parenteral administration (14). Recently, a number of other compounds have been developed that mimic the GH stimulatory actions of GHRP and have greater oral bioavailability and duration of action. Intravenous administration of one of these compounds, the nonpeptide L-692,429, has been shown to stimulate GH secretion when given acutely to healthy young and older adults (15, 16) and as 12- and 24-h continuous infusions to older adults (17).
The present study was designed to determine the effect of short-term oral administration of another of these compounds, the spiropiperidine MK-677, on the GH/IGF-I axis in selected adults with GH deficiency. Because it acts by increasing somatotrophe secretion of GH, MK-677 would not be expected to increase circulating GH in individuals with absent pituitaries or severely damaged somatotrophes. Therefore, we studied GH- deficient young adults who had been diagnosed with GH deficiency during childhood and who had not had pituitary or hypothalamic tumor, surgery, or radiotherapy. GH deficiency in such subjects is often idiopathic, and in the majority of cases, the deficiency persists into adulthood. The GH deficiency is thought to be caused by a functional deficiency of GH stimulatory signals to the pituitary (18). We hypothesized that MK-677 treatment would be well tolerated and increase circulating GH and IGF-I concentrations in adults with this condition.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Nine men, age 17–34 yr with idiopathic GH deficiency of childhood
onset were studied. All had been treated with GH during childhood, but
had not been treated with GH or any GH secretagogue for at least 6
months before taking part in this study. None had a past history of
pituitary or hypothalamic tumor, surgery, or radiotherapy. Persistent
GH deficiency was confirmed by a reduced GH response to insulin-induced
hypoglycemia; on a prestudy insulin tolerance test all subjects had a
peak serum GH concentration of <5 µg/L with at least one glucose
concentration 45 mg/dL after 0.1–0.15 U/kg iv regular insulin. (The
insulin tolerance test for four of the subjects enrolled was
discontinued after 30 min because of severe hypoglycemic symptoms.) All
subjects were generally in good health on the basis of medical history,
physical examination, and laboratory screening. Subjects had normal
urinalyses, electrocardiograms, and chest x-rays, and normal serum
concentrations of biochemical indices of renal, hepatic, and
hematological function, thyroid function studies, PRL, and
testosterone, except where stated in Table 1
. Subjects were not taking any
medications on a regular basis, apart from replacement doses of thyroid
hormone, glucocorticoids, and testosterone, which were stable for at
least 6 months prestudy, and occasional (documented) acetaminophen or
ibuprofen. One of the subjects was on adequate testosterone replacement
for hypogonadism throughout the study. Based on plasma testosterone
concentrations at the time of screening, six of the nine subjects were
hypogonadal during this study (Table 1). Two of these six subjects were
currently being treated with monthly testosterone injections (treatment
begun at least 4 yr before the study). Their low testosterone levels at
screening may reflect an inadequate replacement regimen and/or
measurement of testosterone just before testosterone injection. One
subject had previously been treated with testosterone during adult
life, but had stopped it at least 3 months before the study. The other
three had not been treated with testosterone as adults. None of the
subjects started testosterone or any other regular medication during
the study. Prestudy subject characteristics are summarized in Table 1.
Four potential subjects who had been treated with GH during childhood
for a presumptive diagnosis of GH deficiency were excluded from the
study because of a peak GH response to hypoglycemia greater than 7
µg/L.
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Subjects were entered into a randomized, double-blind,
placebo-controlled study in which they received the study drug (MK-677
or placebo) orally each day for 4 days during each of two study
periods, separated by a 28- to 150-day washout period (Fig. 1). There were two study groups: group I
(n = 4) received placebo and 10 mg MK-677 in a cross-over fashion
in periods 1 and 2; Group II (n = 5) received 10 mg MK-677 in the
first study period, then 50 mg MK-677 in the second study period.
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Subjects were admitted to the Clinical Research Center in the evening. An intravenous cannula was inserted into an arm vein for subsequent blood sampling, and subjects spent the night in the Research Center to equilibrate to sleep conditions (day -2). At 2240 h the following night subjects received an oral dose of single-blind placebo (day -1). At 2240 h for the next four nights they received an oral dose of double-blind study drug (MK-677 or placebo). Each dose was taken with 150 mL water, and lights were turned off immediately following dosing. Blood samples for GH measurement were collected through the indwelling cannula at 20-min intervals for 24 h after the single-blind placebo dose on the first night (2240 h day -1) and for 8 h after the first administration of study drug at 2240 h (day 1). Samples were again collected for 24 h after the fourth day of study drug administration.
All overnight blood sampling was performed from outside the subject’s room through long tubing to minimize disturbance of the subjects. Additional blood samples were drawn at designated time points for measurement of PRL, cortisol, thyroid hormones, IGF-I, and IGF-I binding protein-3 (IGFBP-3). Two 24-h urine collections were saved for measurement of urinary free cortisol and creatinine starting at the time of single-blind placebo dosing (day -1) and at the start of the fourth dose of study drug administration (day 4). Vital signs (heart rate and blood pressure) were measured and an electrocardiogram was performed 9 h postdose each morning, and a physical examination and routine laboratory tests were performed before discharge after completion of the treatment period. A physical examination, an electrocardiogram, and collection of a fasting blood sample for laboratory testing were performed 5–7 days after completion of each period.
During all admissions, subjects were required to stay awake until just after dosing at 2240 h, at which time lights were turned out. Alcohol consumption was not permitted, and regular research center diets were consumed by all subjects, with the following exceptions: an evening snack was served at approximately 2000 h on sampling days, and subjects then fasted until breakfast the following morning; and to assess peak glucose and insulin concentrations, subjects consumed 8 oz (237 mL) Sustacal Plus (Mead Johnson Nutritionals, Evansville, IN) instead of breakfast on two occasions. This liquid nutrition supplement [containing 360 cal made up of 14 g fat (98 cal), 45 g carbohydrate (180 cal), and 14 g protein (56 cal)] was given the next morning 10 h after the day -1 placebo dose and 10 h after the fourth dose of study drug. On these occasions, blood samples for glucose and insulin measurement were obtained immediately before the Sustacal and 0.5, 1, 2, and 4 h following administration.
Subjects were required to remain in the research unit on sampling days (days -2, -1, 1, and 4). On days 2 and 3 they were permitted to leave the unit as outpatients and self-administer the study drug at home.
Study period 2
The same procedures as study period 1 were performed, with these
exceptions: the dose of treatment drug was different (see above and
Fig. 1
), and after the equilibration night, the single-blind day -1
placebo administration was omitted.
Analytic methods
Assays. Serum GH concentrations were measured in duplicate by a chemiluminescence assay (Nichols Institute Diagnostics, San Juan Capistrano, CA) modified to enhance sensitivity as previously described (19). All GH assays were performed in the same laboratory, and all samples from a single subject were run in the same assay. The sensitivity of the assay was 0.002 µg/L, and the measured GH concentrations in all samples were above this detection limit. The intraassay coefficients of variation were 10.1% at 0.03 µg/L, 8.1% at 0.3 µg/L, and 15.0% at 6.8 µg/L. Interassay coefficients of variation were 7.4% at 0.03 µg/L, 18.5% at 0.3 µg/L, and 8.8% at 6.8 µg/L. Cortisol, PRL, IGF-I, IGFBP-3, thyroid function, urine free cortisol, glucose, and insulin assays were performed by Endocrine Sciences Laboratories (Calabasas Hills, CA). Routine laboratory analyses were performed at the respective study sites, and testosterone was measured at the University of Virginia Medicine Clinical Laboratory.
Analysis of pulsatile GH release. The GH concentration profiles were analyzed by the cluster peak detection program version 6.0 (20). The threshold parameters used (test peak = 1, test nadir = 1, t statistic = 1) had a sensitivity of 75% for detection of GH concentration pulses and a positive predictive accuracy of 93% determined in a validation study employing computer simulations of 30 24-h GH series at 20-min intervals, in which the exact locations of the secretory episodes and consequent GH concentration peaks were known.
Statistical methods
Data for the 10 mg MK-677 dose in the two study groups were
combined (n = 9). Absolute and percentage changes from baseline
were calculated. Baseline GH values were those at the beginning of
period 1; all other baseline values were those at the beginning of the
treatment period under analysis. t tests were calculated to
compare values after treatment with MK-677 and placebo with baseline
levels. ANOVA was used to obtain a pooled estimate of within-subject
standard deviation so that the t tests comparing levels
following placebo or 10 mg or 50 mg MK-677 with baseline levels could
be calculated with the same estimate of variability. For some
parameters, it was necessary to transform data to the natural log scale
to satisfy basic statistical assumptions, in which case results are
reported as geometric mean ± an appropriately backtransformed
estimate of within-subject SE. Otherwise, results are
reported as mean ± SE. The design of this study,
which was chosen in light of expected difficulties recruiting
GH-deficient adults and safety concerns common to initial studies of a
new drug, prevented a definitive statistical assessment of differences
between treatments. The relationship between measures was determined by
univariate linear regression analysis. A P value of 0.05
was considered statistically significant.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Oral treatment with both 10 mg and 50 mg/day MK-677 was associated
with statistically significant increases in circulating concentrations
of GH, IGF-I, and IGFBP-3, whereas placebo treatment was without a
significant effect on these parameters (Table 2).
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), and there were
similar stimulatory effects by the two doses (Table 2). Representative
individual 24-h GH concentration profiles are shown in Fig. 3, and 24-h mean concentration profiles
are shown in Fig. 4. The 24-h mean GH
concentration (µg/L) rose 79 ± 19% (range 28–219) from
baseline (0.14 ± 0.01 to 0.26 ± 0.02, P
0.05) after four doses of 10 mg MK-677 and increased 82 ± 29%
(3 to 165) from baseline (0.21 ± 0.02 to 0.39 ± 0.04,
P 0.05) after four doses of 50 mg MK-677.
However, 24-h mean GH concentrations remained below the age-adjusted
normal range in all subjects after 4 days treatment. Eight hour mean GH
concentrations (µg/L) were significantly greater after the first than
the fourth dose of both 10 mg (0.56 ± 0.07 vs 0.35 ± 0.04,
P 0.05) and 50 mg MK-677 (0.99 ± 0.16 vs
0.54 ± 0.09, P 0.05), and were
significantly greater than baseline at both times.
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The results of cluster analysis of 24-h GH concentration profiles are
summarized in Table 2. The increase in GH concentrations produced by
MK-677 treatment was because of an increase in GH pulse, amplitude, and
interpeak valley and nadir GH concentrations and not because of
increased pulse frequency.
IGF-I
All subjects had baseline IGF-I concentrations below the age-adjusted
normal range for the assay (202–456 µg/L), further supporting the
diagnosis of GH/IGF-I deficiency. IGF-I concentrations increased in all
subjects after four doses of 10 mg or 50 mg MK-677 (Fig. 5), and the mean increases in IGF-I
concentrations were statistically significant with both doses (Table 2). IGF-I concentrations increased into the age-adjusted normal range
after drug treatment in two subjects treated with 50 mg/day MK-677. The
IGF-I concentration changes after MK-677 treatment were not
significantly related to any baseline measurement (all P
values >0.2).
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, Fig. 6).
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. After 4 days of treatment with 50 mg,
but not 10 mg MK-677, fasting insulin concentrations were significantly
higher than at baseline (19.5 ± 3.2 vs. 8.3 ±
1.4 µU/ml, P 0.05). Fasting serum glucose
concentrations were not significantly affected by either dose of
MK-677. Post-Sustacal glucose and insulin, measured as both the peak
concentration and area under the curve (AUC), were significantly higher
than baseline after four doses of 10 mg MK-677, and there were
nonsignificant increases in both measures of glucose and insulin after
treatment with 50 mg MK-677. Post-Sustacal insulin concentrations were
also significantly different from baseline after placebo treatment.
Neither placebo nor MK-677 treatment resulted in significant changes
from baseline in circulating concentrations of serum T4,
T3, TSH (data not shown), cortisol, PRL, or 24-h urinary
free cortisol levels (Table 3).
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MK-677 treatment was generally well tolerated and no symptoms developed that were definitely attributed to study drug. There were no serious adverse events during this study, and no subjects were discontinued or had treatment interrupted because of an adverse experience.
Five out of nine subjects who were treated with 10 mg MK-677 had clinical adverse experiences that the investigator considered to be possibly drug related. These included one episode each of headache and diarrhea and three occurrences of dry skin. The occurrences of dry skin did not require treatment or medical consult. Except for the diarrhea, which was moderate, these adverse experiences were rated by the investigator as mild.
Two out of five subjects who received 50 mg MK-677 had clinical adverse experiences. One subject had night sweats and another subject had numbness in the ulnar nerve distribution area of the right hand that lasted one day. Both adverse experiences were rated as mild.
One subject treated with 10 mg MK-677 demonstrated an increased serum aspartate amino transferase (98 U/L; normal range 0–50 U/L) at the post period I evaluation. This elevation resolved and was rated as possibly drug related by the investigator.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The increased IGF-I and GH concentrations induced by short-term oral MK-677 treatment most likely resulted from actions on both the pituitary and hypothalamus. MK-677 and GHRP-6, whose GH stimulatory actions it is thought to mimic (24), bind to a recently identified unique G protein-coupled receptor on the pituitary (9, 10, 11, 25, 26) to directly stimulate somatotrophe GH secretion via phospholipase C and calcium-dependent mechanisms (27, 28, 29, 30, 31). In addition, GHRP and its analogs have a synergistic stimulatory effect on GH secretion when coadministered with GHRH (17, 32). They also increase c-fos activity and electrical activity in hypothalamic arcuate nucleus neurons that secrete GHRH (12, 33, 34). Stimulation of GH release by GHRP-6 and GHRP-mimetics such as MK-677 is therefore likely to be dependent, at least in part, on extrapituitary factors, particularly the background GHRH and somatostatin tone. The smaller GH secretory response to MK-677 treatment in subjects with lower baseline GH and IGF-I concentrations in this study might reflect a greater degree of GHRH deficiency in these subjects, and suggests the possibility of combined therapy with MK-677 and GHRH in such subjects.
Inspection of the GH profiles suggested that MK-677 increased serum GH concentrations by enhancing the preexisting pulsatile pattern of GH release. This was supported by the results of cluster analysis, which revealed a significant increase in GH peak height without change in peak number. Interpeak nadir GH concentrations were also significantly increased by MK-677 treatment. We have previously administered a compound related to MK-677 (L-692,429) to healthy older subjects by continuous 12- and 24-h intravenous infusions and assessed pulsatility by deconvolution analysis (17). We have also administered daily oral MK-677 to healthy older subjects for up to 4 weeks and assessed GH pulsatility by the cluster and ultra algorithms and deconvolution (35). There is agreement among all methods and studies that these compounds increase circulating GH concentrations by increasing the size, but not the number, of existing pulses, and that despite an increase in interpulse GH concentrations, GH secretion remains pulsatile. This enhancement of GH pulsatility occurs whether these compounds are administered continuously as intravenous infusions or as daily administrations of the long-acting compound MK-677. This suggests that these compounds amplify the normal signals responsible for episodic GH release. This could occur via relief of an inhibitory effect, such as that of somatostatin, enhancement of a stimulatory effect, such as that of GHRH, or a combination of both.
The stimulatory effect of MK-677 on mean GH concentrations in the 8 h after drug administration declined between the first and fourth day of drug administration, although the fourth day value was still significantly greater than baseline. This decline may indicate desensitization to the GH stimulatory effects of the drug and foreshadow an eventual loss of stimulatory effect. Alternately, and probably more likely, it may result from negative feedback effects of IGF-I on GH secretion. There is evidence that IGF-I acts at pituitary and/or hypothalamic sites to suppress GH secretion (36, 37, 38, 39). The negative feedback effects of IGF-I would be expected to increase as circulating IGF-I concentrations increase in the days to weeks after starting MK-677 treatment. This would eventually result in a new set point at which IGF-I and GH concentrations are higher than at baseline, but GH concentrations are lower than immediately after initiation of treatment. Such changes have been reported in beagle dogs treated with oral MK-677 for 2 weeks (40).
IGF-I and GH concentrations were significantly increased after 2 weeks treatment with oral MK-677 in healthy older subjects (35). Moreover, IGF-I concentrations increased further between 2–4 weeks of treatment, indicating that the full effect of MK-677 on IGF-I concentrations took longer than 2 weeks to develop, and that significant stimulation of the GH/IGF-I axis was sustained for at least a month. In addition, IGF-I concentrations increased slightly more after daily morning than evening administration of MK-677 in that study. The drug was administered at night to subjects in the present study. We do not yet know whether the response to MK-677 is sustained for as long in persons with idiopathic GH deficiency as in healthy older persons. Nevertheless, the response suggests that mean IGF-I concentrations, which increased significantly (but not into the normal range) within 4 days of starting MK-677 treatment in the present study, may have increased even more if the drug had been administered in the morning rather than at night, and if the treatment period had been longer. Gonadal steroids stimulate GH secretion (41). Although there was no association between baseline serum testosterone and 24-h mean serum GH concentration either at baseline or in response to MK-677, a number of subjects were testosterone deficient during this study, and the effect of adequate testosterone replacement on their GH response to MK-677 is not known.
The drug was generally well tolerated with few reported and no significant clinical adverse events. The increase in fasting and postprandial (Sustacal) insulin concentrations, and less marked but still statistically significant increases in postprandial glucose concentrations, are consistent with the known effect of GH to enhance insulin resistance. However, an insulin resistance-enhancing action of MK-677, independent of its effect on GH secretion, cannot be excluded. It is worth noting that fasting insulin concentrations increased significantly during placebo as well as MK-677 treatments. This may reflect alterations to their normal exercise and dietary patterns that the subjects experienced in the Clinical Research Center. Therefore, although the findings suggest that a degree of glucose intolerance and hyperinsulinemia may accompany chronic use of this drug, it remains to be determined whether this is the case, and if so, whether it is of clinical significance. This will need to be carefully evaluated in subsequent studies. Favorable changes in body composition because of MK-677-induced increases in GH secretion could conceivably counteract any unfavorable effects on insulin resistance. GH therapy in GH-deficient subjects has been reported to increase insulin resistance at 6 weeks, but have a diminished effect at 26 weeks when significant decreases of body fat have occurred (42).
In conclusion, daily oral administration of the GH secretagogue MK-677 for 4 days to selected GH-deficient men was generally well tolerated and was associated with significantly increased circulating concentrations of GH, IGF-I, and IGFBP-3. Although responses to the drug were modest (relative to responses seen with exogenous GH), some degree of stimulation of the GH/IGF-I axis was observed in all subjects. These subjects were severely GH deficient as determined by prestudy insulin tolerance test. Therefore, the small statistically significant increases are encouraging. It is likely that these severely deficient adults represent less than 25% of childhood patients currently defined as GH deficient. These preliminary results suggest that oral administration of this compound may have a therapeutic role in the treatment of some patients with GH deficiency. Further studies are needed to determine its effects in other populations, such as women and children with idiopathic GH deficiency, as well as its long-term safety and efficacy.
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Acknowledgments |
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Footnotes |
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2 Supported in part by a C.R.B. Blackburn Overseas Traveling
Fellowship of the Royal Australasian College of Physicians, and a Mark
Jolley Fellowship of the South Australian Postgraduate Medical
Education Association.
Received March 18, 1997.
Revised June 12, 1997.
Accepted June 23, 1997.
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References |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Endocrinology | Endocrine Reviews | J. Clin. End. & Metab. |
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) and
at end of day 4 of 10 mg/day (
) and 50 mg/day (
) oral MK-677.
Twenty four-hour mean GH and IGF-I data are shown for reference, and
patient numbers correspond to those in Table 1
