CA2095786A1 - Method of stimulating appetite - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE

The present invention relates to a method for treating appetite disorders in a patient and in particular a method for the stimulation of appetite in a patient requiring appetite stimulation. The patient is peripherally administered an effective amount of a growth hormone-releasing factor or a pharmaceutically acceptable derivative, analog, salt or complex thereof. The invention also relates to a pharmaceutical formulation adapted for peripheral administration in a patient having an appetite disorder and to the use of growth hormone-releasing factor or a pharmaceutically acceptable derivative, analog, salt or complex thereof adapted for peripheral administration to treat patients with eating disorders and in particular to stimulate appetite in a patient requiring appetite stimulation.

Description

B&P File No. 3266-052/LI~K
209~P18~

~itle: ~ethod of S$imulatlncl Appetite l?IELD l:?F 1~ I~VENTION
The invention relates to methods and formulations for affecting appetite.
BACRGROVND OF l'HE INV~NTION
Anorexia nervosa (AN) is a serious psychiatric disorder with a high morbidity and moxtality rate. Psychological symptoms associated with AN usually precede extreme dieting, weight loss and amenorrhea. Normal eating patterns are lost as the body's usual response to hunger is overruled. Sexiously underweight individuals require several months of intPnsive medical treatment to promote weight gain and normal eating. To date, the numerous attempts at using various drug therapies to stimulate appetite in AN patients have not demonstrated significant benefits (Kennedy SH et al, in The Biology of Feast and Famine (1992) Chapter 20: New Drugs, New Directions, pp 341-56).

Neuropeptides which have been reported to stimulate eating following central injection include somatostatin, opioid peptides, and the pancreatic peptides neuropeptide Y and neuropeptide YY (Feifel D and Vaccarino FJ (1990) Brain Research 5350189-94; Levine AS and Morley JE (1982) Pharmacology, Biochemistry and Behaviour 160897-902;
Lotter EC et al (1981) J. Compar. and Physiolog. Psychol.
95:278-87; Baile CA et al (1986) Physiological Reviews 66(1):172-234; Morley JE et al (1987) Am. J. Physiol.
252:R599-609).

None of the abovementioned neuropeptides stimulates eating following peripheral injection and in fact, there is a tendency towards decreased eating following peripheral injection. The ineffectiveness of peripherally-' ' ' ,. ' ~
, .

s&P Fil~ No. 3266-052/LMK
~9~786 a~ministered peptides in producing b~!havioral effect~ i~
usually attributed to their difficulty in crossing from peripheral circulation to brain tissuet through the blood brain barrier.

Growth-hormone releasing factor (GRF) is a peptide which has potent endocrine action and stimulates growth hormone (GH, somatotropin) release from the anterior pituitary gland through ~he hypophysial- portal blood system.

Cacabelos et al (Cacabelos R et al (1988) Acta Endocrinol.
117:295-301) reported that intravenous administration of 100 ~g GRF(1-44)NH2 in patients with early onset senile dementia of the Alzheimer type elicited a marked plasma GH
response. Mental performance and behaviour were also evaluated using a number of tests for mental assessment.

The results of recent studies in animals have suggested that in addition to its endocrine effects, GRF has motivationally relevant behavioral effects. Vaccarino et al were the first to demonstrate a behavioral role for centrally (intracerebroventricularly, or i.c.v.) injected GRF (Vaccarino FJ et al ((1985) Nature 314:167-8). They demonstrated that GRF, in picomole doses, stimulated food intake in ood-deprived male Wistar rats. Other studies demons~rated the same effect in free-feeding rats, and further showed that high (nanomole) doses of the peptide do not stimulate food intake and may even cause a depression of feeding behaviour (Vaccarino FJ et al (1988) Peptides NY 9: Suppl 1~ 35-38; Imaki T et al (1985) Brain Res. 340~186-88).

Tanaka et al studied the effects of centrally administered GRF in food-deprived female Sprague-Dawley rats. They found that GRF, in doses of 50 or 100 picomol significantly stimulated food intake as compared wi~h con~rols, whil~ doses of 0.5 and 1.0 nanomol significantly f .
:` :
,', . '.

B&P File No. 3266-052/LMK

2~ 9~ l 8~

decreased food intake (~anaka Y e~ al(l991) Brain Res.
558:273-9). Synthetic human GRF (1~44) has also been reported to stimulate feed:ing in non-lactating ewes (Riviere P. & Bueno L. ((1987), Physiol. Behav. 39:347-50).

Vaccarino et al have shown that central a~ministration of a physiologically inactive pe]ptide analog of GRF produced no effect on feeding. Vaccarino et al have also demonstrated that i.c.v. GRF administration in doses lower than those required to stimulate G~l release stimulated food intake without causing general behavioral arousal (Vaccarino FJ et al (1985) Nature 314:167-8; Vaccarino FJ
et al (1988) Peptides [Suppl 1] 9: 35-38; Feifel D and Vaccarino FJ (1989) Behav. Neurosci. 103: 824-30). Thay also demonstrated tha~ peripheral injections of GRF, in doses effective centrally, had no effect on food intake (Vaccarin~ F.J. et al (1985) Nature 314: 167-8). Rats administered i.c.v. GRF have also been found to have increased motivation to work for food (Feifel D and Vaccarino FJ (1990) Prog. Neuro-Psychopharmacol. & Biol.
Psychiat.14:813-20). Centrally administered anti-GRF
antibodies have been found to attenuate food intake wi hout affecting other behaviours (Vaccarino FJ et al (1990) Ann NY Acad. Sci. 579:227-32).

~apping studies have indicated that the suprachiasmatic nucleus/medial preoptic area (SCN/MPOA) of the hypothalamus, which receives GRF-containing terminals, is a critical site for GRF-induced feeding (Vaccarino FJ and Hayward M (1988) Regul. Pept. 21:21-8; Dickson and Vaccarino (1990) Am. J. Physiol. 259:R651-7).

The role of GRF in the reyulation of eating in humans is not known. Abnormalities in the responsiveness of GH to GRF have been associated with eating disorders (Kennedy SH
et al (1992) in The Biology of Feast and Famine, chapter `
, . .

B&P ~ile No. 3266-052/LMK
2~57~6 D, 20 - New Drugs, New Directions, pp341-356). While obese individuals show a diminished GH response to GH-releasing challenges (including GRF), AN individuals show an exaggerated GH response (Williams T et al (1984) NEJM
311:1403-7; Bramhilla F et al (1987) Psychiatry Res.
20:19-31; (1989) Biol. Psychiatry 25:256-64; Rolla M et al (1990) Biol. Psychiatry 27: 215-222; Tamai H et al (1990) J. Clin. Endocrinol. Netabol. 70: 738-41). ~owever, others have failed to replicate these findings in AN
(Casanueva FF et al (1987) Clin. Endocrinol. 27: 517-23, and Merriam GR et al (1985~ Neuroendocrinol. Lett. 7:
102).

It has been reported that the response of GH to GH-releasing stimuli including GRF in individuals wikh AN
does not correlate with either the duration of the illness nor the degree of weight loss (Brambilla F et al (1989) Biol. Psychiatry 25s 256-64). However, the response can be normalised with increased caloric intake (Rolla M et al (1990) Biol. Psychiatry 27: 215-2~2).

SUMNARY OF Th~ INVENTION
The present inventors have found that growth hormone~
releasing factor affects appetite when admini~tered to a patient. In particular, the present inventors have found that peripherally-administered GRF ~1 ~g per kg body weight) stimulates appetite in anorexia nervosa patients and decreases appetite in con~rol sub~ec~s. Anorexia patients reported increased hunger and ate more following administration of GRF while control subjects had a decreased food in~ake following GRF administration.
Peripherally administered GRF was also found to reduce binging in Bulimia patients.

Broadly stated the invention relates to a method for treating elating disorders comprising administerinq an effective amount of a growth hormone-releasing factor or B&P File No. 3266-052/L~C
2 ~

a pharmaceutically acceptable derivative, analog, salt or complex thereof. The invention also contemplates a pharmaceutical formulation adapted for peripheral administration in a patient ]having an appetite disorder comprising an effective amount of a growth hormone-releasing factor or a pharmaceutically acceptable derivative, analog, salt or complex thereof, and a pharmaceutically acceptable carrier therefor.

An embodiment of the present invention relates to a method for the stimulation of appe-tite in a patient re~uiring appetite stimulation comprising peripherally administering to a patient an effective appetite-stimulating amoun~ of a growth hormone-rel~asing factor or a pharmaceutically acceptable derivative, analog, salt or complex thereof.

The invention also relates to a pharmaceutical formulation adapted for peripheral administration in a patient requiring appetite stimulation comprising an effective appetite-stimulating amount of a growth hormone-releasing factor or a pharmaceutically acceptable derivative, analog, salt or complex thereof, and a pharmaceutically acceptable carrier therefor.

The invention also relates to the use of growth hormone-releasing factor or a pharmaceutically accep~able derivative, analog, salt or complex thereof adapted for peripheral administration to treat an appetite disorder in a patient and in particular, to stimulate appetite in a patient requiring appetite stimulation.

BRIE:F DESCRIPTION OF 1~ DRAW12~GS
Further details of the invention are described below with the help of the examples illustrated in the accompanying drawings in which Figure 1 is a bar graph showing food intake in controls . , - , t ~ :
~: :
.

B~P File ~o. 3266-052/LMK
2~731) who have been administered GRF and a placebo;

Figure 2 is a bar graph showing macronutrient intake in controls who have been administered GRF and a placebo;

Figure 3 is a graph showing macronutrien~ intake in a patient who was administered GRF and a placebo;

Figure 4 is a graph showing macronutrient intake in a patient wAo was administered GRF and a placebo;

Figure 5 is a graph showing % change for protein, fat, and carbohydrate intake during placebo and GRF treatment in anorexia patients, anorexia and bulimia patients, and normals; and Figure 6 is a graph showing ~ change for total caloric intake during placebo and GRF treatment in anorexia patients, anorexia and bulimia patients and normals.

DETAI~D DESCRIPTION OF TH~ INVE~TIO~
As discussed above, the present invention relates to method~ and formulations for treating appetitP disorder~
using GRF or a pharmaceutically acceptable derivative, analog, salt or complex thereof. In one embodiment of the inven~ion a method for the stimulation of appetite in a patient requiring appetite-stimulation is provided I comprising peripherally administering to a patient an effective appetite-stimulatin~ amount of GRF or a pharmaceutically acceptable derivative, analog, salt or complex thereof; to pharmaceutical formulations which are adapted for peripheral administration containing GRF or a pharmaceutically acceptable derivative, analog, salt or complex thereof; and, to the use of G~F or a pharmaceutically acceptable derivative, analog, salt or complex thereof to treat appetite disorders, in particular to stimulate appetite in a patient requiring appetite :

B~P File No. 3266-05Z/LMK
7 8 ~

stimulation.

The term "appetite" used herein means an appetitive efec~
during eating and/or expression of an appetitive effect, including increased food intake.

GRF that may be used in ~he method, composition and use of ~he invention includes the fully bioactive, 44 amino acid peptide from human pancreatic tumor (hpGRF) isolated and characterized by Guillemin R. et al ((1982) Science 218:585); native human hypothalamic GRF (hGRF) (Bohlen et al., (1983~ Biochem. Biophys. Res. Comm. 114:930-36; Ling N. ~t al (1984) Proc. Natl. Acad. Sci. V.S.A. 81:4302), GRF (1-40) and GRF (1-4~) (Rivier J. et al Nature (1982) 300:27 and Guillemin R. et al (1982) Science ~18:585); GRF
(1-29)-NH2 (Rivier J. et al Nature (1982) 300:27);
recombinant GRF; synthetic peptides thereof, pharmaceutically acceptable derivatives, analogs, salts or complexes thereof; and biologically active fragments of GRF displaying growth hormone releasing activity.
Preferably ~Nle27]GRF (1-29)NH2, most preferably Somatrel~
available from Ferring Inc., Willowdale, Canada is used in the present invention. Analogs o GRF such as the analogs dPscribed by Lance et al.in Biochem, Biophys. Res. Comm.
119, 265-272 (1984), Rivier et al. in U.S. Patent No.
4,518,586, in U.S. Patent NO. 4,428,190 and Felix et al.
in Canadian Patent No. 1,270,598 may be used in the present invention. Porcine, bovine, ovine, or caprine GRF
may be used in the present invention.

The method and composition of the invention may be used to treat humans which require stimulation of appetite. In particular, the method and composition may be used to stimulate appetite in humans suffering from anorexia, most particularly anorexia nervosa, loss of appetite due to aging, gene!ral fever or underlying diseases such as cancer, and illness d-~e to damage or lesion of the region ~ , ' j " ~

B&P File No. 3266-052/LMR
2~95~

of the brain controlling appetite. The method and composition may also be used to stimulate appetite in children with appetite dysfunctions, in particular appetite dysfunctions in con~unction with conditions such as dwarfism or short stature. The method and composition of the invention may also be used to normaliæe appetite in patients with conditions such as bulimia.

The GRF in appropriate pharmaceutical formulation may be administered orally, topically, rectally, parenterally, locally or as an inhalant. The pharmaceutical formulations are therefore in solid or semisolid form, for example pills, tablets, creams, ~elatin capsules, capsules, suppositories, soft gelatin capsules, gels, membranes, tubelets. For parenteral use/ those forms for intramuscular, subcutaneous or intraperitoneal administration can be used, or forms for infusion or intravenous injection can be used, and can therefore be prepared as solutions of the active compound or as powders of the active compound to be mixed with one or more pharmaceutically acceptable excipients or diluents, suitable for the aforesaid uses and with an osmolarity which is compatible with the physiological fluids. For local use, thos~ preparations in the form of creams or ointments for topical use or in the form of sprays should be considered; for inhalant uses, preparations in the form of sprays, for example nose sprays, should be considered.
I

The pharmaceutical formulations can be prepared by per se known methods for the preparation of pharmaceutically acceptable formulations which can be administered to patients, and such that an effective amount of the active substance, praferably an appetite stimulating quantity of the active substance, is combined in a mixture with a pharmaceutica:Lly acceptable vehicle. Suitable vehicles are described, for example, in Reming-ton's Pharmaceutical Sciences (Remington's Pharmaceutical Sciences, Nack ' : ~

s&P File No. 3~66-052/LMK
20~786 g Publishing Company, Easton, Pa., USA 1985).

On this basis, the pharmaceutical compositions include, albeit not exclusively, solutions of a growth hormone-releasing factor or derivatives, or analogs, salts or complexes thereof in association with one or more pharmaceutically acceptable vehicles or diluents, and contained in buffered solutions with a suitable pH and iso-osmotic with the physiological fluids.

An effective amount of GRF or a pharmaceutically acceptable derivative, analog, salt or complex thereof is the minimum dose of GRF ad~quate to produce the desired appetite effec~. An effective appetite-stimulating amount of a GRF or a pharmaceutically acceptable derivative, analog, salt or complex thereof is the minimum do~e of GRF
adequate for appetite stimulation. The dose of GRF or a pharmaceutically acceptable derivative, analog, salt or complex thereof will depend on such parameters as the desired effect, the chosen route of administration, and on the body weight and constitution of the patient. For the method according to the invention in humans, for example, the doses of GRF or a pharmaceutically acceptable derivative, analog, salt or complex thereof range from 0.01 to 10.0 ~g per kilogram body weight, preferably 0.1 to 1.0 ~g per kilogram body weight.

I The following non-limiting example is illustrative of the present invention:

E~AMPLE
The effect of intravenous GRF on food intake, macronutrient selection, and perceptions of food preference in anorexia nervosa and control patients under double blind placebo controlled conditions was studied.
The Structural Clinical Interview for DSN III(R) ~Spitzer et al 1988) was administered for patient (SCID-P) and for ., . :
-. ~ , . , :P File No. 3266-05~/LMK
2 ~ 6 control assessment (SCID-NP) by a trained research assistant, who also administered the Hamilton Rating Scale for Depression (Hamilton 1960 J. Neural Neurosurg Psychistry 23: 56-62) to both groups. The self report Eating Disorder Inventory (Garner et al 1983 Eat Dis 2.15-34) and Eating Attitudes Test (G,~rner et al 1982 Psycho Med 12:871-878~ was also given to all subjects, as was the MEQ to obtain patient and control profiles.

Female patients, a~nitted to the Inpatient Eating Disorder Unit at the Toronto General Hospital who met DMS III(R~
criteria for anorexia nervosa and who were free of psychotropic medication for at least 2 weeks were selected as eligible anorexia nervosa patients. The presence or absence of major depression and concurrent bulimia nervosa were noted for statistical evaluation but were not exclusion criteria. Female control subjects were required to be free from major psychiatric disorders, according to the SCID-NP and to be drug free for at least the previous 2 weeks.

A standard lunch which offered food choices from predominantly prote.in, carbohydrate and fat sources was provided and supervised by a physician. Table 1 is list of the foods provided. Both total caloric intake and macronutrient selection were calculated following meal completion. Perceptions of food pref~rence were assessed during and after the study using a Motivation to Eat Questionnaire (NEQ), a series of visual analog scales on which the sub~ect rates subjective feelings of hunger and satiety.
;

The meal was presented twice in a two week period and was preceded by insertion of an i.v. catheter with a two-way lock into the subject's arm of choice. Into this was injected either 1 ml/100 kg body weight of saline or [Nle27]GRF(1-29)~H2 (1 ~g per kg body weight (100 ~g/ml) :

B&P File No. 3266-052/LMlC
2 ~ 8 16 Somatrel~ from Ferring Inc., Nillowdale, Ontario) in saline allocated in random order.

Blood samples for GH were drawn at the times indicatad in Table 2 during the study. MEQs were also completed as outlined above. On each occasion patients were presented with the same lunch tray in the same dining room for 60 minutes. The following week t:he alternative in~ection was given and the study repeated. Table 2 summarizes the study protocol.

Patients were asked to eat freely under o~servation. Since meal supervision is standard practice for all AN patients from the time of admission, it was unlikely to alter their behaviour. It is also noted that previous eating studies, including those in which bulimic subjects are free to binge eat, have been carried out successfully with an intravenous line in-situ.

Two out of 4 AN patients studied reported increased hunger and ate more following GRF treatment (Figures 3 and 4).
GRF was found to decrease food intaXe in normal subjects (Figures 1 and 2, and Table 3). The stimulatory affect in AN patients is particularly significant in light of the inhibitory effect found in normal subjects. The appetitive effect of GRF in AN patients suggest that they responded to GRF in a low dosP manner, unlike normals, who responded in a high dose manner to the same dose. These results are consistent with a role of GRF in human eating regulation.
Also, they provide evidence that GRF augmentation may be ~herapeutic in AN patients and that AN pa-tients have an underactive GRF-eating system compared to normals.

Additional patients were studied using the above described protocol. In total, four anorexia nervosa patients, 4 mixed anorexia nervosa and bulimia patients~ and 8 normals were studied. The data representing the averages of each ;

. . .
": ........ ~ . .. . ' , .. ..
.- ~

B&P File No. 3266-052/LMK
~9~78~

of these groups is shown in Figures 5 and 6. The present inventors have also obsarved that GRF administration decreased binging in the bulimia patient~. Thus, GRF
appears to be normalizing appetite in the anorexia and bulimia patients.

The present invention has been described in detail and with particular reference ~;o the preferred embodiments;
however, it will be understood by onP having ordinary skill in the art that changes can be made thereto without departing from the spirit and scope thereof.

., '' ~
.~
, , :. , :~:

~* ~ : , .. ~ . .

B&P File No. 3266-052/LlK
%~78t~

Table 1 Contents of Buffet Lunch Schneiders "Life ~tyle" Meats - Turkey (6 slices) - Ham (6 slices) - ~ologna (6 slices) Dempster's Bread - white (6 slices) - whole wheat (6 slices) Cheese (225 g pk~.) ~ayonnaise (2 x 35 g containers) Butter (2 x 35 g containers) Fruit (1 apple + 1 pear) Dessert: 5 oreo/5 oatmeal/5 chocolate chip cookies Beverages: 2% milk (250 ml)/apple ~uice (250 ml)/
orange juice (250 ml) . ' ' ' ''' .. ~ , , : ' , . .' i , ' ! , ~
. , , : ' ':': ' . .' ` '~

B~P File No. 3266-052/LMK
2~578~
i Table 2 Time Item __________ __________________. __________________. _______ 11:29 Motivationto Eat Questionnaire 11: 30 Insertion of Intravenolls Line 12:00 Notivation to Eat Questionnaire 12 :15 ;~1 Baseline 5 ml sample for GH
1~:29 Motivation toEat Questionnaire 12: 30 #2 Baseline 5 ml sample for GH
12: 31 1 ml saline or saline/GRF
into IV
12:44 Buffet stylelunch presented 12:44 Motivation toEat Questionnaire 12: ds5 #35 ml sample for GH
Start to eat aft~r # 3 sample dxawn 1: 00 #4 5 ml sample for GH
1:15 #5 5 ml for GH
1:29 Motivation toEat Questionnaire 1: 30 #6 5 ml sample for GH
1:44 E n d o f M e a l Quest ionnaire* *
1: 45 #7 5 ml sample for GH
1: 45 Food tray is removed 1:45 End of study . : ~ ~,.: ~.: .:

.~ . .
::
. ; .:
:. - . ::
, B~P File No. 3266-052/LMR
~957~6 Table 2 cont'd ** The end of meal questionnaire is also administered when the subject has finished eating in cases where meal termination occurs before 1:45.

1. Non-patient subjects came in for breakfast at ~:00 am.

2. Lunch time food trays stayed throughout the study (even if subject reported finishing meal). When subject felt that she had completed the meal, she filled out end of meal questionnaire.

3. If subject continued to eat after the end of meal questionnaire, she noted the time of this additional eating at the bottom of the end of meal questionnaire.

- ' . . ~
;

~ ~ .
.

: .

.: .-: : . .

B~P File No. 3266-052/LMK
2~9~7~

T~ble 3 GRF ~FFECTS IN NORMAI,S
Vehicle GHRH p~0 . 05 T o t a 1 Calories: 1143 793 *
Protein (g) 46 34 *
F~t (g) 47 34 *
c a r b o -hydrates 141 95 *
(g) T o t a 1 Solids: 891 628 *
P r o t e i n 37 29 (g) ~at (g) 4~ 30 *
C a r b o -hydrates 95 65 *
(g~
Percentage Proteins 16 18 Fat 37 37 C a r b o -hydrates 50 49 : : -.. , : :
j: ; ' ' '~: : .

- .: : : . :.

.
`.: , , , '' ~ ' . '' :"
: . ,

Claims (17)

1. B&P File No. 3266-052/LMK
   
   THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
   PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
   
   l. A method for treating appetite disorders in a patient comprising peripherally administering to a patient an effective amount of a growth hormone-releasing factor or a pharmaceutically acceptable derivative, analog, salt or complex thereof.
2. 2. A method for the stimulation of appetite in a patient requiring appetite stimulation comprising peripherally administering to a patient an effective appetite-stimulating amount of a growth hormone releasing factor or a pharmaceutically acceptable derivative, analog, salt or complex thereof.
3. 3. The method of claim 1 or 2 wherein said growth hormone-releasing factor is growth hormone-releasing factor (1-40), growth hormone-releasing factor (1-44), or growth hormone-releasing factor (1-29)NH2.
4. 4. The method of claim 1 or 2 wherein said growth hormone-releasing factor is administered in a dose of between 0.01-10 µg/Rg body weight.
5. 5. The method of claim 1 or 2 wherein said growth hormone-releasing factor is administered to a patient with anorexia nervosa.
6. 6. The method of claim 1 or 2 wherein said growth hormone-releasing factor is administered parenterally, orally, topically, rectally, locally, or by inhalation.
7. 7. The method of claim l or 2 wherein said growth hormone-releasing factor is intravenously administered.
8. 8. The method of claim 2 wherein the growth B&P File No. 3266-052/LMK
   
   hormone-releasing factor is administered to a patient suffering from loss of appetite due to aging, general fever, or cancer, illness due to damage or lesion of the region of the brain controlling appetite, appetite dysfunctions in conjunction with dwarfism or short stature.
9. 9. The method of claim 1 wherein the patient has bulimia.
10. 10. A pharmaceutical formulation adapted for peripheral administration in a patient having an appetite disorder comprising an effective amount of a growth hormone-releasing factor or a pharmaceutically acceptable derivative, analog, salt or complex thereof, and a pharmaceutically acceptable carrier therefor.
11. 11. A pharmaceutical formulation adapted for peripheral administration in a patient requiring appetite stimulation comprising an effective appetite-stimulating amount of a growth hormone-releasing factor or a pharmaceutically acceptable derivative, analog, salt or complex thereof, and a pharmaceutically acceptable carrier therefor.
12. 12. The pharmaceutical formulation of claim 10 or 11 which is adapted for parenteral, oral, topical, rectal, local or inhalation administration.
13. 13. The pharmaceutical formulation of claim 10 or 11 which is adapted for intravenous administration.
14. 14. The pharmaceutical formulation of claim 10 or 11 wherein the concentration of growth hormone-releasing factor is in the range of 0.01-10.0 µg/Kg body weight.
15. 15. The pharmaceutical formulation of claim 10 or 11 B&P File No. 3266-052/LMK
    
    wherein said growth hormone-releasing factor is growth hormone-releasing factor (1-40), growth hormone-releasing factor (1-44), or growth hormone-releasing factor (1-29)NH2.
16. 16. The pharmaceutical formulation of claim 11 for use in treating a patient who suffers from anorexia, loss of appetite due to aging, general fever, or cancer, illness due to damage or lesion of the region of the brain controlling appetite, appetite dysfunctions in conjunction with dwarfism or short stature.
17. 17. The pharmaceutical formulation of claim 10 for use in treating a patient with bulimia.