The growth hormone-releasing activity of a synthetic hexapeptide in normal men and short statured children after oral administration.

It has been shown that iv GH-releasing peptide (GHRP; His-DTrp-Ala-Trp-DPhe-Lys-NH2) specifically releases GH in man. Because of the clinical value of having an orally active peptide to release GH, five normal men were given GHRP orally at dosages of 100 and 300 micrograms/kg. At the 300 micrograms/kg dosage, the GH rise was detectable at 30 min, peaked between 60-75 min, and gradually declined to the baseline level between 150-180 min. Peak GH levels rose 63- and 202-fold above the baseline after administration of 100 and 300 micrograms/kg GHRP, respectively. Nine short stature children with varying degrees of GH deficiency were also included in this study. All children had short stature, slow growth, and delayed bone age and were being treated with biosynthetic human GH. The studies were performed after stopping GH treatment for 2-3 weeks. The oral GHRP dose administered to all of the children was 300 micrograms/kg, because this dosage was found to consistently increase GH levels in adults. The magnitude and pattern of the GH response to oral GHRP in four of the nine children were essentially the same as those in the five normal men. In the other five children, the GH responses were low but still measurable in three and undetectable in two of the children. Serum immunoreactive GHRP (irGHRP) levels were measured before and at 15- to 30-min intervals 3-5 h after oral as well as iv bolus GHRP administration. For comparison of serum irGHRP and GH levels, results were included after iv bolus administration of 0.1, 0.3, and 1.0 micrograms/kg GHRP to normal men. Since 300 micrograms/kg oral GHRP released about the same amount of GH as 1 microgram/kg, iv, in normal men, it was calculated that oral GHRP has about 0.3% the activity of iv GHRP. After iv GHRP, the peak serum irGHRP levels were immediate and proportional to the dosage, and the disappearance rate decreased exponentially. Between 100-240 min, the mean serum irGHRP level was essentially the same and remained slightly elevated. After administration of 300 micrograms/kg GHRP orally to normal men, serum irGHRP was measurable within 15 min, the peak serum irGHRP level coincided with the GH rise at 60 min, and serum irGHRP levels fell more slowly than serum GH levels. The serum half-life was 20 min, and the distribution volume was 2.5 L after both oral and iv administration.(ABSTRACT TRUNCATED AT 400 WORDS)

The growth hormone (GH) response to GH-releasing peptide (His-DTrp-Ala-Trp-DPhe-Lys-NH2), GH-releasing hormone, and thyrotropin-releasing hormone in acromegaly.

In patients with acromegaly, GH-producing pituitary tumors release GH in response to specific stimuli such as GH-releasing hormone (GHRH) and are also responsive to a variety of nonspecific stimuli, such as TRH or GnRH, and may exhibit paradoxical responses to glucose and dopamine. In healthy humans, the synthetic peptide GH-releasing peptide (GHRP) (His-D-Trp-Ala-Trp-D-Phe-Lys-NH2) releases GH by a putative mechanism of action that is independent of GHRH. How these tumors respond to GHRP is not well characterized. We studied the GH responses to GHRH, GHRP, and TRH stimulation in 11 patients with active acromegaly. The peak GH responses to GHRP and GHRH were not correlated (r = 0.57; P = 0.066). In contrast, the peak GH responses to GHRP and TRH were highly correlated (r = 0.95; P < 0.001). In conclusion, in patients with acromegaly, the GH response to GHRP is qualitatively normal and does not appear to depend on GHRH.

A new and potent 2-5A analogue which does not require a 5'-polyphosphate to activate mouse L-cell RNase L.

In order to explore the possibility of supplanting the requirement of a 5'-triphosphate moiety for the activation of the 2-5A-dependent endonuclease (RNase L) of mouse L-cells, two new tetrameric analogues of 2-5A were synthesized. The first tetramer, obtained by both a modified prebiotic synthetic approach as well as a phosphite triester solid phase oligonucleotide synthesis method, was p5'A2'p5'A2'p5'(br8A)2'p5'(br8A). The second oligonucleotide was derived from the former by a sequence involving periodate oxidation, reaction with n-hexylamine, and cyanoborohydride reduction, resulting in conversion of the 2'-terminal adenosine residue to 9-(3'-aza-4'-hexyl-1',2',3',4'-tetradeoxyhexopyranos-1(1)-yl)-8-++ +bromoadenine. Both of these oligomers, bearing only 5'-monophosphate groups, were found to be as potent as 2-5A itself as activators of the RNase L of mouse L-cells.

Incidental detection of hyperthyroidism during a perfusion lung scan for suspected pulmonary emboli.

Striking thyroidal uptake of Tc-99m pertechnetate was observed during the course of a perfusion lung scan performed with Tc-99m MAA to rule out pulmonary embolism in a 49-year-old man. There was no evidence of gastric pertechnetate activity. Radiochemical purity analysis of the Tc-MAA by chromatography in normal saline revealed 98.8% tagging, with 1.2% free pertechnetate. We estimate that a maximum of 60 microCi (2.2 MBq) of pertechnetate was available for thyroid trapping. This amount, given to a euthyroid volunteer studied with conventional gamma camera lung perfusion settings, failed to visualize the thyroid. A follow-up radioiodine thyroid uptake of the patient was markedly elevated, as was his thyroid function tests (T3,T7,T7). When diffuse intense thyroid gland radioactivity is seen during scintigraphy with a technetium radiopharmaceutical (e.g., bone and lung scans), consideration should be given to the possibility of hyperthyroidism. If gastric activity is not concomitantly seen, hyperthyroidism secondary to diffuse hyperplasia of the gland is probably present.

Synthesis and biological activity of uronic acid analogues of 2-5A[5'-O-triphosphoryladenylyl(2----5')adenylyl-(2'----5')adenosine].

The oligonucleotide ppp5'A2'p5'A2'p5'A, known as 2-5A, is a potent translational inhibitor involved in some aspects of interferon action. To explore the specific function of the charged 5'-triphosphate moiety, we prepared a series of congeners in which the 5' region was hypermodified. Thus, uronic acid derivatives were substituted for the 5' terminal adenosine residue of 2-5A. Compounds 9, 10, 11 and 12 carried adenosine 5'-uronic acid, ethyl adenosine 5'-uronate, adenosine 5'-uronamide, and adenosine 5'-(N-ethyl)uronamide, respectively, in place of the 5' terminal adenosine triphosphate moiety of 2-5A. While all the analogues showed some weak interaction with the 2-5A-dependent endonuclease (RNase L), compound 9 showed the strongest binding ability, and while unable to activate the mouse RNase L, could activate human RNase at a concentration 100-fold greater than that required for the parent 2-5A. This result suggests that the function of the 5'(poly)phosphate moiety of 2-5A may be fulfilled by some other anionic moiety.