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Effects of vitamin D on the lung
158 24,25-DIHYDROXYVI+AMIN D, (24,25-) APPEARS To FAVOUR CORTICAL BONE MASS IN RENAL BONE DISEASE. D . H.Birkenhluer-Frenkel. H A.P.Pols*. A.L.Niaq, JZ.Clermonts. J.C.Birkenh&er*. Depts. of Pathology and Medicine III*, Erasmus University, Rotterdam, The Netherlands. 22 Patrents with pre-dialysis chronic renal insufficiency (27-63 yrs, 10 women, creat.cl. a38 ml/min) were treated Orally with la-hydroxyvitamin D, (la-, av. dose 0.55 us/d1 ._~ . for 9 months (md. ) ; After paired matching Zcr sex, age and creat.cl, 1 patient of each pair was randomly assigned to additional oral ireatment with 24,25- (50 pg twice weekly) for the last 6 mo. Iliac crest bone biopsies were taken at 0, 3 and 9 mo. The histomorphometric effects in cancellous bone of 3 mo treatment of these patients with la- were reported.
157 mEHMMEDIA~M~~~C~OFSALMONCALClMNlNE(SO WlTtt OR WlTliOUT CALCIUM M HEALTltY VOLUNTEERS Bcpc LPLMedic@ UnlwHRy tlaqR4 clt-1011 Lsusanl& Switwriaad. We nported that SC1 doea not maintain full meteboik rctivity in 2
nornul vobmtwm whan given daily. Wo now eramine whether SC1 is tqualiy mtfectlva when givwt ovuy 2nd dry, with or without Calcium (Ca), 01 when @ven In thr evening. 3 group@of 3 herithy male volunteer% aged 2&20 yrs, wem studied durbq 5 day8 on a 8tandardked diet with 1 g 01 Ce and 1.5 I wrtw. Aftw 1 dry ot qulliiwatlon, groupA received 22 U SC1 S.C. &t 2AM on day 2 and 4, group B mwived the ume regimen of SC1 8nd Q5 # Ce glu~onolttrtr with the IIt&8 at 5Akt and 5i’ht tron day 2 ~~~o~&mup C recaiwd 60 U ot SCT S.C. at 5PM on day 2 and 4. corm&d for ribumlnr, and PM were meerured rt 2Aht, 10AM, 12 AH. 6PM, 8PM e8ch day, fractionated urine campier (&12AM, 12AW6PM, elOPR& WM-BAM) were rnaiyzed for Ce, creetinine, CH-
pmilnr.
Piaetn2 Ca deuaaud after uch SClrdminlatmtion.
When oral Ca was
In
added (group B), pLC4 ~28 conetsntly hiQher In the svemga by 0.032 mmol/l, 2nd when SCT m$ given It 0PM (group C), tl increased in the 1veron@ by 0.005 mmol/i (mun IMI under the curve (AUC) over 24 hou$ eokcted for InFUiipbc1). PI’M lnurrud rftef the timt SCT rdminirtmtion by 70-100 %, bul ion dtu the wmnd iniocUon.Themwar no rbnitiunt differencr between
group A end 8. Etiin thr rvefege PTH wrr-&tl p#/mi lower in group B, and A4 w/ml -. lowu in aroup C (mean AUC over 24 hour& coneckd for
lniti2iPTH). . SCT hrd s oaklurio elflcl: in gmup A, t&ok 4wCrOtiOn over 4 h alof SCT inloction WI@increated by t22 mg, in group B by t 18 mg, in group C by t30 mg. In group A, 24 h urine k excretkn wee increesed during ~mrrtlby~lJmg(ts~t~rdfarue~1),in~1oupBbyt114m2 O%), in group C by rbl mg (*41%).
24 h OH-prolino ucretkn (Pmoi/mmoi oreat.) InCreaSedin group A, by 10% uch dry (i.e. by 40%dtw 4 dry@, in the average by t2496, wherear R mup B in the rveraae by tl5% mndin group C by t5M whan lnlected every 2nd dey, SC7 remelna active, in docmaaing pi.Ce end lncreatiq PTH, but tt Increases OH-proiinr oxeretion. A deemae of OH-proiine ucretion with lore PTH atlmubtion b obtained when SCT k given in the evening, or when Calcium ir given Jmultaneouety. 159 EFFECTS OF VITAMIN
the
patients
continuing
on
la-
only,
a
further fall of osteoblast perimeter (Ob.Pm) was seen, while in the (la- + 24,25-) group Ob.Pm was maintained. Mineralizing surfaces fell in the lo- and rGse in the (lu- + 24,25-) group. Bone area did not chanse in either crcun. In contrast, true cortical-area (minus kav&aien Ar) (T.C!t.Ar)appeared to rise significantly in both groups, while cortical width (Ct.Wi) rose and cortical porosity (Ct.Po) fell in the 24,25treated group only: P ct.wi la1824 2279 n.s. la- + 24,25- 1848 2768 (rm) e.01 ct.pc 40.5 34.1 n.s. ::I t 24,25- 41.9 33.8 (8) =.02 T.Ct.Ar la6.12 8.27 a.01 10.23 c.01 (nun'), la- t 24,25- 5.93 Ccncluslop: In the presence of adequate levels of 1,2%dihydroxyvitamin D, levels pharmacological amounts of 24,25- appear to have an anabclic effect on cortical bone.
160
D ON THE
LUNC. N. Balmain, M. J.W. Pike. A. Mnscofian, I? Hauchecorne, I? Motrtm, l Cuisiniar-Cl&es and H. Mathieu. INSERM U.120, Hop. R. B&r&, 4H Bd Stirurier, 75935 Paris Ctdex 19. FRANCE ; ‘Baylor College nf Medicine, Houston, TX, USA.
Tl0m~HKuD-~m~I
W. R, Koren,A. Ravid, Iu9) lQ 1,25-DR.Segal,L. Maroc,R. Arie,B. Shohat,M. David,M. Sandbank, IGRiIS
U.A. Libsrnran. Beilinson Medical center, P-&ah Tiqva, Israel. Psoriasis is associated with partial refractoriness of cells to the action of agents that increase intracellular CAMP (CAMP promoters).Inthis study we examined the association between the therapeutic efficaey of 1 a (OH) vitamin 03 (aD) in psoriatic patients and the sensitivity of lymphocytes from these patients to CAMP praroters and 1,25_dihydroxyvitamin D3 (1,250) before and on oral aD therapy. 27 Psoriatic patientsparticipatedin this study.18 were treated for 14 weeks with a D (lugday),9 were treated with placebe.Patients were divided according to clinical improvement resulting from aD therapy to “responders” (n=6)and “non responders” t n.10). Peripheral bload mononuclear cells (PBMC) were obtained from the patients before and at the end of treatment. PBMC were activated with PRAand cultured with 1,250 (lo-9M) or the CAMPpranoters: PGE2 (lOOng/ml1 and iso~tylmethylxanthine (IBMX, Suq/ml). The biological effect of these agents was assessed by the ability to inhibit lymphocyte mitoqenesis. We observed that befare txeatment P&K! fran “responders” had a reduced response to all three agents tested as compared to “non responders”. The responsiveness to 1,25D was 53% (p=O.O15), to PGE2 36% (p--0.01) and to IBEX16% (p=O.O002) in the “responders” as compared to the “non responder” group. After aD therapy an increase in the biological activity of these agents was observed in the “responders” group only, resulting in the disappearance of the difference between the two patient qrouos. We conclude that: 1. 1~ responsivenese4 of‘PI?K! to-c&? promoters and 1,25D can serve to identify psoriatic Futients likely to benefit fran treatm3nt with active vitamin D analogs: 2. in vivo treatment withaD can modulate the in-vitro responsiveness of PBNCto 1,25D and CAMPpromoters.
kchidc (-II) rats, l’romviruminD-dcprivcd molhcra raised in n UV ii$blicc room ;md red un udc WC. hut vibmin D&x dicl. wcrc u&d in uil qcrimums. NormaY (+D) wcrc ruiscd under Ihc same condilions hut pivun virsmin 0. Rickets was vcrilicd hy thu qpcor;mcc ol’ Lo upiphyscal curdlap and txlnc und vitnmin D mcvdxdi~b% in the strum. Lung lissuc WIIS cstimincd hy !ight and electron micrchscopy and hisltrhcmisq for claslin. Cryuscclions wcrc immunosMncd lilr l.?S(OH)ZD3 rccc ~ors (VDR) using a momrton;li anlihody (,3 A7 )and calhindin- F>Yk ubmg ,’ poiysionui anlibndics (ii eili l’n~mM. Thonrilszcl U. I20 INSEHM). The cniix~s OCl.3(0~+~2b.3 NO~C~~~ww.d 24 hr ;Ilicr giving rachilicrms ;I single
injcwu’nn ol’horronc.
The lung prcnc’hynxlUCthe -D rm w;lh ,hncrrmal.wirh Ihickcncd alwriur purcnchymcl imd rcduccdtilvo~li;lrlumen.indicaung inrcntikll lihnrit?, The cunncclivcGssuchld li’w. I‘r;lcmcmcd ;III~ disor??;mi,wd ciestin lihrcb. The rntrht 4king uhnrrrm&ica involved thu ~ypcII pncumrryrcs : Ihcir numhor WPS incrcascd.while Ihc conlcm ol’ iamcllar hodics wits rcduccd. indicating, &normal surl’xtanc symhb%is.The tp! II ucils Al +D rats comemcdnuclc;lr VDR und cyKaplusmic c4hmdin D9k. Typ ii ceils or -D ruts aml;dncd nt, o;dhindin-Wk, hul rhc rolcin nxppwrcd in lhcsc ceils when -I) rBp, f WCn: given 12Z(OH)..D.~. .&Wliilr mticnlphilgcsshowed nuclcilr VDR.W ccmcludcIhitI 1.2S(OH)ZD3 PC& dirccdy on the luuq, prriculariy on IyX ii pnsumocylcs. and csscnli;il f& sur&iml synlhL%ls. lllily
hc
114
157 mEHMMEDIA~M~~~C~OFSALMONCALClMNlNE(SO WlTtt OR WlTliOUT CALCIUM M HEALTltY VOLUNTEERS Bcpc LPLMedic@ UnlwHRy tlaqR4 clt-1011 Lsusanl& Switwriaad. We nported that SC1 doea not maintain full meteboik rctivity in 2
nornul vobmtwm whan given daily. Wo now eramine whether SC1 is tqualiy mtfectlva when givwt ovuy 2nd dry, with or without Calcium (Ca), 01 when @ven In thr evening. 3 group@of 3 herithy male volunteer% aged 2&20 yrs, wem studied durbq 5 day8 on a 8tandardked diet with 1 g 01 Ce and 1.5 I wrtw. Aftw 1 dry ot qulliiwatlon, groupA received 22 U SC1 S.C. &t 2AM on day 2 and 4, group B mwived the ume regimen of SC1 8nd Q5 # Ce glu~onolttrtr with the IIt&8 at 5Akt and 5i’ht tron day 2 ~~~o~&mup C recaiwd 60 U ot SCT S.C. at 5PM on day 2 and 4. corm&d for ribumlnr, and PM were meerured rt 2Aht, 10AM, 12 AH. 6PM, 8PM e8ch day, fractionated urine campier (&12AM, 12AW6PM, elOPR& WM-BAM) were rnaiyzed for Ce, creetinine, CH-
pmilnr.
Piaetn2 Ca deuaaud after uch SClrdminlatmtion.
When oral Ca was
In
added (group B), pLC4 ~28 conetsntly hiQher In the svemga by 0.032 mmol/l, 2nd when SCT m$ given It 0PM (group C), tl increased in the 1veron@ by 0.005 mmol/i (mun IMI under the curve (AUC) over 24 hou$ eokcted for InFUiipbc1). PI’M lnurrud rftef the timt SCT rdminirtmtion by 70-100 %, bul ion dtu the wmnd iniocUon.Themwar no rbnitiunt differencr between
group A end 8. Etiin thr rvefege PTH wrr-&tl p#/mi lower in group B, and A4 w/ml -. lowu in aroup C (mean AUC over 24 hour& coneckd for
lniti2iPTH). . SCT hrd s oaklurio elflcl: in gmup A, t&ok 4wCrOtiOn over 4 h alof SCT inloction WI@increated by t22 mg, in group B by t 18 mg, in group C by t30 mg. In group A, 24 h urine k excretkn wee increesed during ~mrrtlby~lJmg(ts~t~rdfarue~1),in~1oupBbyt114m2 O%), in group C by rbl mg (*41%).
24 h OH-prolino ucretkn (Pmoi/mmoi oreat.) InCreaSedin group A, by 10% uch dry (i.e. by 40%dtw 4 dry@, in the average by t2496, wherear R mup B in the rveraae by tl5% mndin group C by t5M whan lnlected every 2nd dey, SC7 remelna active, in docmaaing pi.Ce end lncreatiq PTH, but tt Increases OH-proiinr oxeretion. A deemae of OH-proiine ucretion with lore PTH atlmubtion b obtained when SCT k given in the evening, or when Calcium ir given Jmultaneouety. 159 EFFECTS OF VITAMIN
the
patients
continuing
on
la-
only,
a
further fall of osteoblast perimeter (Ob.Pm) was seen, while in the (la- + 24,25-) group Ob.Pm was maintained. Mineralizing surfaces fell in the lo- and rGse in the (lu- + 24,25-) group. Bone area did not chanse in either crcun. In contrast, true cortical-area (minus kav&aien Ar) (T.C!t.Ar)appeared to rise significantly in both groups, while cortical width (Ct.Wi) rose and cortical porosity (Ct.Po) fell in the 24,25treated group only: P ct.wi la1824 2279 n.s. la- + 24,25- 1848 2768 (rm) e.01 ct.pc 40.5 34.1 n.s. ::I t 24,25- 41.9 33.8 (8) =.02 T.Ct.Ar la6.12 8.27 a.01 10.23 c.01 (nun'), la- t 24,25- 5.93 Ccncluslop: In the presence of adequate levels of 1,2%dihydroxyvitamin D, levels pharmacological amounts of 24,25- appear to have an anabclic effect on cortical bone.
160
D ON THE
LUNC. N. Balmain, M. J.W. Pike. A. Mnscofian, I? Hauchecorne, I? Motrtm, l Cuisiniar-Cl&es and H. Mathieu. INSERM U.120, Hop. R. B&r&, 4H Bd Stirurier, 75935 Paris Ctdex 19. FRANCE ; ‘Baylor College nf Medicine, Houston, TX, USA.
Tl0m~HKuD-~m~I
W. R, Koren,A. Ravid, Iu9) lQ 1,25-DR.Segal,L. Maroc,R. Arie,B. Shohat,M. David,M. Sandbank, IGRiIS
U.A. Libsrnran. Beilinson Medical center, P-&ah Tiqva, Israel. Psoriasis is associated with partial refractoriness of cells to the action of agents that increase intracellular CAMP (CAMP promoters).Inthis study we examined the association between the therapeutic efficaey of 1 a (OH) vitamin 03 (aD) in psoriatic patients and the sensitivity of lymphocytes from these patients to CAMP praroters and 1,25_dihydroxyvitamin D3 (1,250) before and on oral aD therapy. 27 Psoriatic patientsparticipatedin this study.18 were treated for 14 weeks with a D (lugday),9 were treated with placebe.Patients were divided according to clinical improvement resulting from aD therapy to “responders” (n=6)and “non responders” t n.10). Peripheral bload mononuclear cells (PBMC) were obtained from the patients before and at the end of treatment. PBMC were activated with PRAand cultured with 1,250 (lo-9M) or the CAMPpranoters: PGE2 (lOOng/ml1 and iso~tylmethylxanthine (IBMX, Suq/ml). The biological effect of these agents was assessed by the ability to inhibit lymphocyte mitoqenesis. We observed that befare txeatment P&K! fran “responders” had a reduced response to all three agents tested as compared to “non responders”. The responsiveness to 1,25D was 53% (p=O.O15), to PGE2 36% (p--0.01) and to IBEX16% (p=O.O002) in the “responders” as compared to the “non responder” group. After aD therapy an increase in the biological activity of these agents was observed in the “responders” group only, resulting in the disappearance of the difference between the two patient qrouos. We conclude that: 1. 1~ responsivenese4 of‘PI?K! to-c&? promoters and 1,25D can serve to identify psoriatic Futients likely to benefit fran treatm3nt with active vitamin D analogs: 2. in vivo treatment withaD can modulate the in-vitro responsiveness of PBNCto 1,25D and CAMPpromoters.
kchidc (-II) rats, l’romviruminD-dcprivcd molhcra raised in n UV ii$blicc room ;md red un udc WC. hut vibmin D&x dicl. wcrc u&d in uil qcrimums. NormaY (+D) wcrc ruiscd under Ihc same condilions hut pivun virsmin 0. Rickets was vcrilicd hy thu qpcor;mcc ol’ Lo upiphyscal curdlap and txlnc und vitnmin D mcvdxdi~b% in the strum. Lung lissuc WIIS cstimincd hy !ight and electron micrchscopy and hisltrhcmisq for claslin. Cryuscclions wcrc immunosMncd lilr l.?S(OH)ZD3 rccc ~ors (VDR) using a momrton;li anlihody (,3 A7 )and calhindin- F>Yk ubmg ,’ poiysionui anlibndics (ii eili l’n~mM. Thonrilszcl U. I20 INSEHM). The cniix~s OCl.3(0~+~2b.3 NO~C~~~ww.d 24 hr ;Ilicr giving rachilicrms ;I single
injcwu’nn ol’horronc.
The lung prcnc’hynxlUCthe -D rm w;lh ,hncrrmal.wirh Ihickcncd alwriur purcnchymcl imd rcduccdtilvo~li;lrlumen.indicaung inrcntikll lihnrit?, The cunncclivcGssuchld li’w. I‘r;lcmcmcd ;III~ disor??;mi,wd ciestin lihrcb. The rntrht 4king uhnrrrm&ica involved thu ~ypcII pncumrryrcs : Ihcir numhor WPS incrcascd.while Ihc conlcm ol’ iamcllar hodics wits rcduccd. indicating, &normal surl’xtanc symhb%is.The tp! II ucils Al +D rats comemcdnuclc;lr VDR und cyKaplusmic c4hmdin D9k. Typ ii ceils or -D ruts aml;dncd nt, o;dhindin-Wk, hul rhc rolcin nxppwrcd in lhcsc ceils when -I) rBp, f WCn: given 12Z(OH)..D.~. .&Wliilr mticnlphilgcsshowed nuclcilr VDR.W ccmcludcIhitI 1.2S(OH)ZD3 PC& dirccdy on the luuq, prriculariy on IyX ii pnsumocylcs. and csscnli;il f& sur&iml synlhL%ls. lllily
hc
114