Acta Clinica Belgica International Journal of Clinical and Laboratory Medicine
ISSN: 1784-3286 (Print) 2295-3337 (Online) Journal homepage: http://www.tandfonline.com/loi/yacb20
Longacting Steroid Preparations A. Vermeulen To cite this article: A. Vermeulen (1975) Longacting Steroid Preparations, Acta Clinica Belgica, 30:1, 48-55, DOI: 10.1080/17843286.1975.11716973 To link to this article: http://dx.doi.org/10.1080/17843286.1975.11716973
Published online: 17 May 2016.
Submit your article to this journal
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Citing articles: 3 View citing articles
Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=yacb20 Download by: [Cornell University Library]
Date: 17 July 2017, At: 09:18
CURRENT THERAPY
LONGACTING ST EROID PREPARATIONS
A. VERMEUL EN '
Whenever long te rm medi ca l trea tment is ma ndatory, sooner or later, ei ther th e pa ti ent or the phys ician will be temp ted to o bviate the burde n of da il y intake or injecti on of the dru g by sw itchin g to one or oth er fo rm of depot preparatio n. This ha moreove r th e adva ntage th at it ove rcomes a n occasio nal obli vion of th e pa tie nt. Howeve r, before usi ng these lo ngactin g preparation , the effecti ve th erapeutic levels achieved and the exact d uration of act ivity of these d rugs should be known, informati on which is rare ly ava ilable. In th e steroid fie ld, longactin g prepara ti ons are availa ble for glucocorti co ids, for mi nera locorti coids, for androgens, for a na bolic steroids, for estrogens and fo r progestogens. Bes ides, longacting im pla ntati on tablets, mainl y of estrogens, a re a lso ava il able. In th e view of their irregul ar absorpt ion and th eir progress ive decrease in effecti vity wi th tim e, we are of the opinio n that their use i now outd ated and that a ltern ative forms of therapy sho uld be preferred. Befo re di cussi ng depo t glucoco rtico id preparati ons, we would li ke to di scus briefl y longterm co rticoid thera py. Wheneve r the latter i considered, one should aim at th e minima l effective dose in ord er minimize sid e effects, which so metime may be more da nge rous to th e patient than th e prima ry di sease for which they are given. There is now good evidence th at side effects wi ll be mi nimized when th e sa me th era-
• Dept. of Endocrinology Medical C li nic, Academic Hospita l, Ghen t, Belgi um.
Acta Clinica Belgica, 30, 1 (1975).
peuti c dose is given in a sin gle dose every oth er day, rather than di vid ed ove r 48 hours. The rati onale for thi s th erapeutic approac h is that the th erapeutic effects of steroids appea r to persist longer th an their meta bolic effects. It is however o ur ex peri ence, th at, alth ough th e alternate day th erape utic scheme may be of va lue in th e trea tm ent of chro nic no n-inflammatory di seases such as lipoid nephros is, idiopa thi c thrombopenic purpura or immunolog ic hemolytic diseases, result s are less sa ti sfactory in infl amm atory co nditi ons, exace rba ti ons occurrin g often the day no steroids a re admini stered. In fact, Harter, Reddy and Th orn , in th e ori gina l publicati on ( 1963) in whi ch they advocated for th e first time th e alterna te day trea tm ent, admitted th at in pati ents needin g hi gh doses of co rti coids, the patients tend ed to noti ce flu ctuati ons in th eir sy mpt oms, not feelin g as well durin g the peri od precedin g th e nex t dose. Longactin g steroids are in fact o ppos ite to the a lternate day trea tm ent in that there occurs a co ntinu ous release of free steroids from th e depot preparation and , if altern ate day thera py produ ces les side effects th an the co nve nti onal therapy scheme, it ca n logica lly be ex pected th at at equi va lent doses side effects shoul d be more important with longacting co rti coids. This wo uld however be neutrali zed if, as has bee n cla imed, longacting teroids wo ul d permit to red uce th e dai ly required dose. Longacting glucocorticoid preparations for ge neral (a opposite to local use) are obtain ed by esterifi cati on of the side chain alco hol, or by mak in g an acetonide of th e side chain, or by
LONGACT!NG STEROID
49
modification of the physical state of the product (suspension of microcrystals). This a llows a slow hydrolysis and/or absorption from the site of injections. The actual duration of action is however difficult to evaluate objectively. Indeed , plasma levels of the synthetic steroid have generally not been determined, whereas the suppression of endogenous cortisol levels which can be used as a parameter of biological activity of the steroid is in fact an unwanted side effect, which the manufacturers claim to be of shorter duration than the therapeutic effects. Suppression of clinical signs of disease activity on the other hand, may be difficult to evaluate objectively, taking into account the well known unpredictability of for example dyspnoeic epidoses in an asthmat ic patient, whereas the evaluation of pain in rheumatic diseases is of course highly subjective.
PLASMA CORTISOL LEVELS AFTER METHYLPREDNISOLONACETATE 80mg F
n-4
\lg/IOOml
20
6
4
2 10
12 D .
PLASMACORTISOL LEVELS AFTER Triamcinolonacctonide 80mg
2
6CII.Methylprednisol CPP J20mgiM
ug/JOOml
18
16 14 12 10
'
4
2
0
10D
140
Fig. 1 and 2 - Plasma cortisol levels after I.M . injection of 80 mg 6a. methylpredniso/on-acetate, 120 mg of methylprednisolon cyclopentyl propionate, respectively 80 mg triamcinolonacetonide. Acta Clinica Belgica, 30, I (1975) .
LONGACT!NG S TEROID
50 We have used mainly 3 preparations: methy lprednisolon acetate (40 mgfml), methylpredniso lon cyclopentyl propionate (80 mg/ manole = ± 60 mg methylprednisolon) and finally tria mcinolon-acetonide (40 mgf ml I.M .). These products were administered to patients with rheumatoid arthritis. As far as suppression of endogenous cortiso l levels are concerned, it can be see n (F ig. I and 2) th at: I. After 80 mg of predniso lon acetate, cortisol levels return to their basal leve ls in 4-5 days. 2. After 80 mg of triamcinolon acetonide, pretreatment plasma co rti sol levels are reached within 5-6 days. 3. After 120 mg of methylprednisolon cyclopentylpropionate plas ma cortisol leve ls are nearly norma lized after ± 14 days. As far as the clinical effect is concerned, evaluation of mobility of joints, local inflammatory signs and general we ll being of the patients revealed th at beneficial effects persisted ge nerall y for 3-4 days after methylpredniso lon acetate, about 4-5 days after tria mcinolone aceton ide and about 8- 12 days after methylpredni so lon cyclopentylpropionate.
As an addition al, alth ough im pe rfect parameter of the duration of act ion of th ese steroids, we determined the plasma leve ls of tota l metabolites in plasma, as we ll as the urin ary excretio n of th ese metabolites after I. M. inj ecti on of tritium labe ll ed steroid * in the sa me physical state as the commercial preparation . In the view of th e still largely unknown metabolism of 6-methylpredniso lon, yieldin g hi ghl y polar metabolites, and the small a mount of unchanged steroid in plasma, it was not poss ible to rnesure th e concentrations of biologica ll y active hormone. After methylpredniso lon acetate radioactivity was com pletely excreted within 18 days, whereas after injection of 120 mg of meth ylpred ni so lon cyclope ntyl propionate, 60% of radioactivity was excreted within 20 days, at whi ch time about I% of th e dose was exc reted daily. As far as plasma metabolites are conce rned (fig. 3), the latter disa ppear completely from pl as ma wit hin 20 days after meth ylpredniso lon acetate, whereas 24 days a fter injecti on of • We thank Hoechs t A.G . for the preparation and gift o f these labell ed compound.
PLA SMA LEVELS OF METABOLITES AFTER
6 methylpredni solon CPP 120mg
6 methylpredni so lonacetate 80 mg
D
Fig . 3 - Plasma levels of metabolites after I. M . injection of 120 mg of6 methyl-prednisolon-cyc/openrylpropionate, respectively 80 mg of the acetate. (mean and range). Acta Clinica Belg/ca, 30, I (1975 ).
LO N GA C TI N G S T E ROID
51 INFLUENCE OF TESTOSTERONE -ESTERS ON PLASMA
"911001'1'11
T. LEVELS TPP SOrng
T.a.n.tnti\Mt 100mg I.M. n= 3
2
'
I
B
10
0
2
4
6
8
10
12
li
14
11
20d.tys
T. PROPIONATE SOmg lt-4
n:3
Fig. 4 and 5 -
2
'
6
'
10
12
•
'721n.
Plasma testosterone levels after J.M. injection of different testosterone esters. Acta Clinica B elgico, 30, I (1975 ) .
6
5
~
4
....c:
CIS
c Q)
3
-. !Ill
0
i
6 5 4
Q)
.!l!
ISSN: 1784-3286 (Print) 2295-3337 (Online) Journal homepage: http://www.tandfonline.com/loi/yacb20
Longacting Steroid Preparations A. Vermeulen To cite this article: A. Vermeulen (1975) Longacting Steroid Preparations, Acta Clinica Belgica, 30:1, 48-55, DOI: 10.1080/17843286.1975.11716973 To link to this article: http://dx.doi.org/10.1080/17843286.1975.11716973
Published online: 17 May 2016.
Submit your article to this journal
View related articles
Citing articles: 3 View citing articles
Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=yacb20 Download by: [Cornell University Library]
Date: 17 July 2017, At: 09:18
CURRENT THERAPY
LONGACTING ST EROID PREPARATIONS
A. VERMEUL EN '
Whenever long te rm medi ca l trea tment is ma ndatory, sooner or later, ei ther th e pa ti ent or the phys ician will be temp ted to o bviate the burde n of da il y intake or injecti on of the dru g by sw itchin g to one or oth er fo rm of depot preparatio n. This ha moreove r th e adva ntage th at it ove rcomes a n occasio nal obli vion of th e pa tie nt. Howeve r, before usi ng these lo ngactin g preparation , the effecti ve th erapeutic levels achieved and the exact d uration of act ivity of these d rugs should be known, informati on which is rare ly ava ilable. In th e steroid fie ld, longactin g prepara ti ons are availa ble for glucocorti co ids, for mi nera locorti coids, for androgens, for a na bolic steroids, for estrogens and fo r progestogens. Bes ides, longacting im pla ntati on tablets, mainl y of estrogens, a re a lso ava il able. In th e view of their irregul ar absorpt ion and th eir progress ive decrease in effecti vity wi th tim e, we are of the opinio n that their use i now outd ated and that a ltern ative forms of therapy sho uld be preferred. Befo re di cussi ng depo t glucoco rtico id preparati ons, we would li ke to di scus briefl y longterm co rticoid thera py. Wheneve r the latter i considered, one should aim at th e minima l effective dose in ord er minimize sid e effects, which so metime may be more da nge rous to th e patient than th e prima ry di sease for which they are given. There is now good evidence th at side effects wi ll be mi nimized when th e sa me th era-
• Dept. of Endocrinology Medical C li nic, Academic Hospita l, Ghen t, Belgi um.
Acta Clinica Belgica, 30, 1 (1975).
peuti c dose is given in a sin gle dose every oth er day, rather than di vid ed ove r 48 hours. The rati onale for thi s th erapeutic approac h is that the th erapeutic effects of steroids appea r to persist longer th an their meta bolic effects. It is however o ur ex peri ence, th at, alth ough th e alternate day th erape utic scheme may be of va lue in th e trea tm ent of chro nic no n-inflammatory di seases such as lipoid nephros is, idiopa thi c thrombopenic purpura or immunolog ic hemolytic diseases, result s are less sa ti sfactory in infl amm atory co nditi ons, exace rba ti ons occurrin g often the day no steroids a re admini stered. In fact, Harter, Reddy and Th orn , in th e ori gina l publicati on ( 1963) in whi ch they advocated for th e first time th e alterna te day trea tm ent, admitted th at in pati ents needin g hi gh doses of co rti coids, the patients tend ed to noti ce flu ctuati ons in th eir sy mpt oms, not feelin g as well durin g the peri od precedin g th e nex t dose. Longactin g steroids are in fact o ppos ite to the a lternate day trea tm ent in that there occurs a co ntinu ous release of free steroids from th e depot preparation and , if altern ate day thera py produ ces les side effects th an the co nve nti onal therapy scheme, it ca n logica lly be ex pected th at at equi va lent doses side effects shoul d be more important with longacting co rti coids. This wo uld however be neutrali zed if, as has bee n cla imed, longacting teroids wo ul d permit to red uce th e dai ly required dose. Longacting glucocorticoid preparations for ge neral (a opposite to local use) are obtain ed by esterifi cati on of the side chain alco hol, or by mak in g an acetonide of th e side chain, or by
LONGACT!NG STEROID
49
modification of the physical state of the product (suspension of microcrystals). This a llows a slow hydrolysis and/or absorption from the site of injections. The actual duration of action is however difficult to evaluate objectively. Indeed , plasma levels of the synthetic steroid have generally not been determined, whereas the suppression of endogenous cortisol levels which can be used as a parameter of biological activity of the steroid is in fact an unwanted side effect, which the manufacturers claim to be of shorter duration than the therapeutic effects. Suppression of clinical signs of disease activity on the other hand, may be difficult to evaluate objectively, taking into account the well known unpredictability of for example dyspnoeic epidoses in an asthmat ic patient, whereas the evaluation of pain in rheumatic diseases is of course highly subjective.
PLASMA CORTISOL LEVELS AFTER METHYLPREDNISOLONACETATE 80mg F
n-4
\lg/IOOml
20
6
4
2 10
12 D .
PLASMACORTISOL LEVELS AFTER Triamcinolonacctonide 80mg
2
6CII.Methylprednisol CPP J20mgiM
ug/JOOml
18
16 14 12 10
'
4
2
0
10D
140
Fig. 1 and 2 - Plasma cortisol levels after I.M . injection of 80 mg 6a. methylpredniso/on-acetate, 120 mg of methylprednisolon cyclopentyl propionate, respectively 80 mg triamcinolonacetonide. Acta Clinica Belgica, 30, I (1975) .
LONGACT!NG S TEROID
50 We have used mainly 3 preparations: methy lprednisolon acetate (40 mgfml), methylpredniso lon cyclopentyl propionate (80 mg/ manole = ± 60 mg methylprednisolon) and finally tria mcinolon-acetonide (40 mgf ml I.M .). These products were administered to patients with rheumatoid arthritis. As far as suppression of endogenous cortiso l levels are concerned, it can be see n (F ig. I and 2) th at: I. After 80 mg of predniso lon acetate, cortisol levels return to their basal leve ls in 4-5 days. 2. After 80 mg of triamcinolon acetonide, pretreatment plasma co rti sol levels are reached within 5-6 days. 3. After 120 mg of methylprednisolon cyclopentylpropionate plas ma cortisol leve ls are nearly norma lized after ± 14 days. As far as the clinical effect is concerned, evaluation of mobility of joints, local inflammatory signs and general we ll being of the patients revealed th at beneficial effects persisted ge nerall y for 3-4 days after methylpredniso lon acetate, about 4-5 days after tria mcinolone aceton ide and about 8- 12 days after methylpredni so lon cyclopentylpropionate.
As an addition al, alth ough im pe rfect parameter of the duration of act ion of th ese steroids, we determined the plasma leve ls of tota l metabolites in plasma, as we ll as the urin ary excretio n of th ese metabolites after I. M. inj ecti on of tritium labe ll ed steroid * in the sa me physical state as the commercial preparation . In the view of th e still largely unknown metabolism of 6-methylpredniso lon, yieldin g hi ghl y polar metabolites, and the small a mount of unchanged steroid in plasma, it was not poss ible to rnesure th e concentrations of biologica ll y active hormone. After methylpredniso lon acetate radioactivity was com pletely excreted within 18 days, whereas after injection of 120 mg of meth ylpred ni so lon cyclope ntyl propionate, 60% of radioactivity was excreted within 20 days, at whi ch time about I% of th e dose was exc reted daily. As far as plasma metabolites are conce rned (fig. 3), the latter disa ppear completely from pl as ma wit hin 20 days after meth ylpredniso lon acetate, whereas 24 days a fter injecti on of • We thank Hoechs t A.G . for the preparation and gift o f these labell ed compound.
PLA SMA LEVELS OF METABOLITES AFTER
6 methylpredni solon CPP 120mg
6 methylpredni so lonacetate 80 mg
D
Fig . 3 - Plasma levels of metabolites after I. M . injection of 120 mg of6 methyl-prednisolon-cyc/openrylpropionate, respectively 80 mg of the acetate. (mean and range). Acta Clinica Belg/ca, 30, I (1975 ).
LO N GA C TI N G S T E ROID
51 INFLUENCE OF TESTOSTERONE -ESTERS ON PLASMA
"911001'1'11
T. LEVELS TPP SOrng
T.a.n.tnti\Mt 100mg I.M. n= 3
2
'
I
B
10
0
2
4
6
8
10
12
li
14
11
20d.tys
T. PROPIONATE SOmg lt-4
n:3
Fig. 4 and 5 -
2
'
6
'
10
12
•
'721n.
Plasma testosterone levels after J.M. injection of different testosterone esters. Acta Clinica B elgico, 30, I (1975 ) .
6
5
~
4
....c:
CIS
c Q)
3
-. !Ill
0
i
6 5 4
Q)
.!l!
