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Nitrogen balance calculated daily for MK-677 and placebo treatments is shown in Fig. 1. During the first week of caloric restriction (i.e. diet alone), daily nitrogen losses were similar for both treatment groups (mean ± SE values were −2.67 ± 0.40 g/day and −2.83 ± 0.26 g/day for the MK-677 and placebo groups, respectively). During the second week (diet and study drug), MK-677 improved average daily nitrogen balance to 0.31 ± 0.21 g/day compared with −1.48± 0.21 g/day in the placebo group. Nitrogen losses clearly reversed after the first dose in the MK-677 treatment group (day 8). In the MK-677 treatment group, daily nitrogen balance increased to approximately +1 and approximately +0.3 g/day after 2 and 7 days treatment, respectively [vs. ∼ −2 and ∼ −1 g/day on the same days for placebo (Fig. 1)]. MK-677 improved overall nitrogen balance integrated over the subsequent 7 days of treatment; AUCdays 8–14 nitrogen balance was +2.69 ± 5 (SE) vs. −8.97 ± 5.26 g/day for MK-677 and placebo treatments, respectively (P = 0.001). Further, when the mean AUCdays 8–14 was compared with 0, the 25-mg MK-677 treatment was associated with a nearly significant increase (P = 0.09), whereas placebo treatment was associated with a significant decrease (P = 0.001). Analysis of AUCdays 8–14 based on nitrogen balance corrected for creatinine excretion yielded similar results. Changes in serum urea nitrogen were consistent with the nitrogen balance results. Serum urea nitrogen decreased from a mean of 14.6 ± 2.4 to 12.9 ± 2.1 mg/dL over the last 4 days of each interval of placebo treatment. In contrast, the subjects remaining on MK-677 had a mean serum urea nitrogen that decreased from 13.8 ± 2.3 to 9.55± 1.9 mg/dL. This change was significantly greater than the change that occurred with placebo P < 0.01.
Dietary restriction during the first week (days 1–7) caused all subjects to lose an average approximately 2.5 kg. During the study treatment week (days 8–14), there was less weight loss in the MK-677 treatment group compared with the placebo group (day 14/day 8 mean weight ratio = 0.99 for MK-677 compared with 0.98 for placebo; P < 0.05).
The peak and integrated (AUC0–8 h) GH response for days 8 and 14 are shown in Table 1. MK-677 produced a peak GH response of 55.9 ± 31.7 μg/L after the first dose (day 8) and 22.6 ± 9.3 μg/L after a week of dosing (day 14) compared with peak GH responses of approximately 9μ g/L (day 8) and approximately 7 μg/L (day 14) with placebo (P < 0.05 for both comparisons).
|Treatment||n||Day 8a||n||Day 14a|
|Peak GH (ng/mL)||GH AUC0-8 h (ng · h/mL)||Peak GH (ng/mL)||GH AUC0-8 h (ng · h/mL)|
|MK-677 (25 mg)||8||55.9 ± 9.7b||207 ± 33.7b||8||22.6 ± 3.0c||58.2 ± 4.4c|
|Placebo||8||9.0 ± 0.6||29.4 ± 3.3||8||7.4 ± 2.5||27.3 ± 8.0|
Geometric mean ± SE.
P < 0.001 vs. placebo.
P < 0.05 vs. placebo.
The changes in nitrogen balance were accompanied by changes in IGF-I levels (Fig. 2). Following the initial 7 days of caloric restriction, IGF-I declined for each group from a mean of 236 ± 56 ng/mL to 174 ± 64 ng/mL in the placebo group and from 232 ± 69 ng/mL to 185 ± 53 ng/ml in the group that subsequently received MK-677 [P = not significant (NS)]. IGF-I increased progressively to 256 ± 84 ng/mL by day 3 of MK-677 treatment, then remained elevated through the last treatment day. The placebo group showed no change. When the mean value for the last 5 days of MK-677 treatment (264 ± 31 ng/mL) was compared with the mean value for placebo subjects (188 ± 19 ng/mL), the difference was significant (P < 0.01). When the individual daily values from days 10–14 were compared, the individual values for days 10–14 on MK-677 treatment were significantly greater than the placebo treatment values (P < 0.05). No significant difference in IGFBP-2 was found between the MK-677 and placebo treatments (data not shown). IGFBP-3 also increased significantly during treatment (Fig. 3). Dietary restriction resulted in a decline from 2974 ± 578 ng/mL to 2752 ± 514 ng/mL in the placebo group after 7 days of restriction. The decrease in the MK-677 group was similar from 2871 ± 659 ng/mL to 2747 ± 623 ng/mL (P = NS). Following MK-677, IGFBP-3 increased progressively to a mean day-12 (fifth treatment day) value of 3374± 917 ng/mL (P < 0.05 compared with day 8). In contrast, the placebo group showed no change (day-12 value = 2673 ± 636 ng/mL; P = NS compared with day 8). When the average IGFBP-3 value for the last 5 treatment days on MK-677 (3273 ± 330 ng/mL) was compared with placebo (2604 ± 253 ng/mL), the difference was significant (P < 0.01).
Cortisol and PRL concentrations are known to be increased by single doses of GHRP-6 and its nonpeptide mimetics (13, 14). The changes in these hormones during MK-677 treatment are shown in Table 2. Although there was an effect of MK-677 on serum cortisol AUC0–8 h on day 8 (120.3 ± 28.0μ g·h/dL vs. 54.8 ± 15.1 μg·h/dL for placebo, P = 0.001), the comparison of the mean cortisol response on day 14 showed no difference between treatment groups (cortisol AUC0–8 h: MK-677 71.2 ± 18.4 μg·h/dL vs. placebo 60.2 ± 14.1 μg·h/dL, P> 0.2). MK-677 also increased urinary cortisol on day 8 (first dose) but not on day 14 (seventh dose) as shown in Table 2.
|Treatment||Study day||n||Peak cortisol (μg/dL)||Cortisol AUC0-8 h (μg·h/dL)||Urinary cortisol (μg/g creatinine)||Peak PRL (μg/dL)||PRL AUC (μg·h/dL)|
|MK-677||8||8||19.3 ± 5.4||120.3 ± 28.0a||18.3 ± 7.4||26.6 ± 12.8a||159.0 ± 58.7a|
|Placebo||8||8||16.8 ± 2.0||54.8 ± 15.0||13.4 ± 4.0||17.4 ± 6.3||101.1 ± 38.0|
|MK-677||14||8||15.9 ± 3.0||71.2 ± 18.4||11.4 ± 3.1||18.4 ± 8.1||110.5 ± 38.2|
|Placebo||14||8||17.0 ± 3.4||60.2 ± 14.1||13.6 ± 3.1||15.2 ± 11.9||87.2 ± 65.9|
Mean ± SD.
P < 0.001 vs. placebo.
There was also a small effect of MK-677 on serum PRL concentrations on day 8 (first dose) that was substantially attenuated by day 14 (seventh dose) (peak PRL = 26.6 ± 12.8 μg/L vs. 17.4 ± 6.3 μg/L for MK-677 and placebo on day 8, respectively, compared with peak PRL = 18.4 ± 8.1 μg/L and 15.2 ± 11.9 μg/L for MK-677 and placebo, respectively, on day 14).
Four of the eight subjects experienced clinical adverse experiences, all of which were rated as mild and rapidly resolved without sequela. Adverse experiences included short-lived complaints of stomach ache and dizziness (n = 1, MK-677), diarrhea (n = 1, placebo), and headache (n = 2, both placebo). Two subjects discontinued participation in the study during the initial week of dietary restriction because they did not wish to comply with caloric restrictions. There were no changes in the serum chemistries or hematological tests that were considered of clinical significance, although an elevated fasting blood glucose concentration (142 mg/dL) was noted on day 14 in one subject on MK-677.
Our results show that 25 mg MK-677 given orally for 7 days in healthy male volunteers improved nitrogen balance during dietary caloric restriction, a model for the treatment of a catabolic state. The effect of MK-677 occurred promptly and persisted for the 7 days of treatment. Nitrogen balance was positive after 2 and 7 days of treatment. The magnitude of this increase relative to response after placebo treatment was clinically meaningful, because the subjects averaged a 1.8 g/day improvement in nitrogen balance. It is not known whether these short-term effects will be maintained beyond 7 days (a slight waning of effect can not be excluded (Fig. 1)). Whether the effect on nitrogen balance would persist beyond 7 days was not evaluated in this study because there was limited clinical experience with longer periods of administration. However, if this response were sustained for several weeks, it would likely diminish the loss of skeletal muscle and visceral protein seen during catabolic states. GH has previously been shown to nearly reverse nitrogen wasting to a mean of −0.2 ± 0.5 g/day after 5 days (29). Using this model and a similar degree of caloric restriction, the magnitude of change in nitrogen balance after MK-677 is similar to that seen after GH treatment. We conclude that MK-677 increases endogenous GH secretion sufficient to reverse this degree of nitrogen loss in normal volunteers who are made catabolic by caloric restriction and is therefore anabolic.
The oral dose of 25 mg MK-677 was chosen for this study because it produced a substantial GH response (peak GH >10 μg/L; mean peak 22.1 μg/L) when administered after an overnight fast to a group of healthy young nonobese males (M. G. Murphy, Merck). The peak GH response to MK-677 was similar in the present study. GH increases were sustained after the last dose of MK-677, documenting persistent secretagogue activity for the duration of the study. This suggests that the catabolic response induced by caloric restriction does not prevent the GH response of the pituitary to this compound.
MK-677-treated subjects had a 36% increase in serum IGF-I levels compared with the placebo-treated subjects, and this was associated with positive changes in nitrogen balance. Because we did not evaluate 24-h GH secretion, it is difficult to determine how this degree of increase in IGF-I would compare with the increase that occurs in response to an equivalent amount of exogenously administered GH. Caloric deprivation can reduce IGF-I response to GH (21) and may have played a role in limiting the IGF-I response to 36%. It is unlikely that a 36% increase in IGF-I at day 14 attenuated the GH response to MK-677, because this is substantially below the serum levels of IGF-I that are required to suppress spontaneous GH release in normal volunteers (30).
Although a 36% increase in IGF-I is substantially below that noted previously in subjects who were undergoing a similar degree of caloric restriction and received exogenous GH (21, 31), it was nonetheless associated with a positive effect on nitrogen balance. Whether an even greater effect on IGF-I and nitrogen balance would be achieved by increasing the dose of MK-677 was not evaluated in the current protocol because there was limited clinical experience with higher doses. However, the GH response in healthy males does not plateau until 100 mg MK-677 is given (mean peak = 71.2 μg/L) (M. G. Murphy, Merck). This suggests that use of a higher dose of MK-677 in this study might have resulted in a greater increase in GH and possibly a greater change in nitrogen balance.
There was a modest increase in cortisol and PRL after the first dose of MK-677, as previously has been shown for this drug and GHRP-6 (13, 14). These increases in cortisol and PRL were within the normal range, transient, and of a magnitude comparable with normal physiological conditions, such as sleep, exercise, or mental stress (32–34). However, even this small effect was substantially attenuated by the seventh dose of MK-677, such that no significant difference between treatments was evident by day 14. This has been previously reported (35).
Injection of recombinant GH improves nitrogen balance in patients undergoing surgery (7), in patients with chronic obstructive pulmonary disease (36), and in normal subjects receiving glucocorticosteroids (8). Use of GH in these types of catabolic patients may be limited, however, if toxicity to GH such as carbohydrate intolerance (37) or fluid retention (4) occurs. In such situations, MK-677 might prove advantageous because it results in a more physiological pattern of GH release, which might be associated with smaller effects on blood glucose and fluid retention. Whether MK-677 will prove less toxic in catabolic patients who may be predisposed to develop hyperglycemia during illness, or who have underlying glucose intolerance, will need to be carefully assessed in future studies.
In summary, we observed in this short-term study that oral administration of MK-677 reverses the protein catabolism caused by dietary caloric restriction. These data suggest that MK-677 may be useful as adjunctive therapy in certain catabolic states. The degree of GH stimulation observed appears to be sufficient to improve nitrogen balance under the stress of caloric restriction. Whether the short-term anabolic effects observed in our volunteers apply also to patients who are catabolic because of certain acute or chronic disease states remains to be established. Future studies should attempt to determine whether the anabolic effects of MK-677 will persist with prolonged treatment, and whether they will be associated with clinical benefits, such as shorter hospital stay and accelerated convalesence.
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The reversal of diet-induced negative nitrogen balance by GH suggests a possible therapeutic role for GH treatment in catabolic patients. A double-blind, randomized, placebo-controlled, two-period, cross-over study was designed to investigate whether MK-677, an orally active nonpeptide mimic of GH-releasing peptide, can reverse diet-induced protein catabolism. Eight healthy volunteers (ages 24–39 yr) were calorically restricted (18 kcal/kg·day) for two 14-day periods. During the last 7 days of each diet period, subjects received either oral MK-677 25 mg or placebo once daily. There was a 14- to 21-day washout interval between periods. During the first week of caloric restriction (i.e. diet alone), daily nitrogen losses were similar for both treatment groups (mean ± SE; MK-677 group −2.67 ± 0.40 g/day vs. placebo group− 2.83 ± 0.26 g/day). During the second week (diet and study drug), mean daily nitrogen balance was 0.31 ± 0.21 g/day in the MK-677 treatment group compared with −1.48 ± 0.21 g/day in the placebo group (P < 0.01). MK-677 improved nitrogen balance integrated over the 7 days of treatment; area under the curve day 8–14 nitrogen balance response was +2.69 ± 5.0 (SE) for MK-677 and −8.97 ± 5.26 g·day for placebo (P < 0.001). MK-677 produced a peak GH response of 55.9 ± 31.7 μg/L after single dose (day 1 of treatment) and 22.6 ± 9.3 μg/L after a week of dosing compared with placebo treatment peak GH values of approximately 9 (treatment day 1) and approximately 7 μg/L (treatment day 7). Following the initial 7-day caloric restriction, insulin-like growth factor-I (IGF-I) declined from 232 ± 25 to 186 ± 19 ng/mL in the MK-677 group and from 236 ± 19 to 174 ± 23 ng/mL in the placebo group. Mean IGF-I concentration increased significantly during MK-677 to 264 ± 31 ng/mL (mean for the last 5 days of treatment) compared with 188 ± 19 ng/mL with placebo (P < 0.01). No significant difference in IGF binding protein-2 was found between the MK-677 and placebo treatments. However, the mean in IGF binding protein-3 for the last 5 days of MK-677 treatment was also significantly increased to 3273 ± 330 ng/mL (mean ± SE) compared with placebo 2604 ± 253 ng/mL (P < 0.01). Neither the serum cortisol nor the PRL response was significantly greater after 7 days of MK-677 dosing compared with 7 days of placebo. MK-677 (25 mg) was generally well tolerated and without clinically significant adverse experiences. In conclusion, MK-677 reverses diet-induced nitrogen wasting, suggesting that if these short-term anabolic effects are maintained in patients who are catabolic because of certain acute or chronic disease states, it may be useful in treating catabolic conditions.