Clinical PbarmacokineliC!l and Disease Processes
(1,n . Ph~rmaro~'~1. 18 ( 2~ 118·1 30. 1990 OJI 2-S%1{90tOOm.{)IIS!S06.SO/O C ADIS Prns l,m'tw
All
n&ht~
rno:n.W
~~~
Pathophysiology and Pharmacokinetics Following Burn Injury Peter L. Bonate Dtpanmenl of Pharmaeology(Toxieology. College of Pharmacy. WashinglOn State UnU'ersily. Pullman. Washington. USA
Contents
Summary ................... ................... .. 118 I. Ep,dc-m.oIOlY ... ............... ... .............. .. 119 2. 8urn Manageme-nt ... . ............... ................. .. .. 120 J. PaJhoph yslolOCY ........................... .. 120 3.1 Card.o,·ascular ResponSe' .......................... .. ................... 120 3.2 R enal RC'Sponse: .. ............................................... .. 121 J.3 MNabohe Response: ......................................... .. ...... 121 3,4 GastrOIntestinal Response ................... .. ............... 122 3,5 He-paIlI' ResponSe' ............................. .122 3.6 Epidermal Response ............................................ .. ................................................ 124 3.7 ImmunolOSlcal ResponSe' ..... ...... ........ .. ...... 125 4. Thcrapeutlc Drug Monitoring In Ihe- Burn Pallenl . ............. ........ .. 126 5. uJX"nmental Ikslgn Conslderallons USlnS Animal and Human Modcls ....... 127 6. Future Research .............................. 127 7. Conclusion . .................................. .. 128
Therapy for inpatient burn victims IS a clear challcnge for the dlnlClan. sInce directly following m;ury the pharmacokinelic parameters of many dfllp will change drastically. Blood now to the tissues is decreased: the rale of dlstrlbU lion and elimination or intra· venous drugs administered dunng this time is reduced. and absorption of oral drugs ma y be slowed. ApprOXimately 48 hours after inJUry. the blood now inCn'ases. as docs internal core temperat urI': the rates may Increase as a result. Immediatel y after inJUry. plasma albumin level rapIdly decreases and fCmalnS sIgnificantly depressed evcn at 60 da)s post-burn. Thus. the proteon bmdong of aCidic and neutral drugs Will decrease and higher amounts of free fraction will be available al the biophase. On the other hand. nl-acid glycoprotein increases in concentration and remains elevated at least 20 days post-burn. Basic drugs exhiba increased protein binding and will most probably nero an increased dosage to achieve the appropria te pharmacological effect. HepatiC metabolism is also affected: the rate of phase I metabohsm will decrease. whole phaS(' 11 melabolism .s unimpaired and may possibly mcrease. Other liver funclions. such as protdn synthesis. arc also impaired. The effect on phase I dfllg melabolism is be1i(,ved to be due to oXY8en-derived free radica ls released during the courS(' ofin;ury. In those pal1ents wi th full-thickness bums. the epidermal layer IS destroyed. Topical drugs have less of a barner to cross and. consequently. less drug is needed to achie"e effectiveness. In addition. the stomach has been found to secrete excess protons which Will eventually lead to ulcers on the majori ty of patienlS. l'IYp('rchlorhydroa may affecl the dissolution and d,sontegrat,on of orally admlnist('red dfllgs in tablet form . as well as the panitionong of the neutral un·.onised speci('s be tween the stomach and bloodstream. In th(' small InteSllne decreased nutrient absorption and DNA synthesis occurs. butth(, efTectthls rna) have on drug absorption IS questionable.
Pathophysiology and Klnt'lics -\ft extent of burn > age > female sex. e\erylhmg else being equal. II was also found Ihat pallen ts "1\h failure of2 or more organ subsystems had a 98% mortality rate I'S single subs)stem failure (Marshall & Dimick 1983). Funhermore. infection has been named as a major cause in 75% of deaths from burns (Polk 1979). While considerable progress has been achieved III deneaslllg the Incidence of burns. carelessness and human error still take their toll. To date. no world-"Ide epidemiological stud~
elm. Pharnraroklnef. 18 (1) IIJ9Q
120
.-
T,bIe I. Burn
""'"
o.S~bOn'
(Irom Wachtel 1989, with pemllS-
Rrst degree on < 50% TBSA Seoond degree 01'1 < 15% TBSA « TI'Iir 75% T8SA plus systemic symplorns Seoond degree on > 25% T8SA (> 20% In children) Third degree on > 10% TBSA
Borns to ctrtlCal .re., Burns complicated by inhalation injury EleCtrlcll or chemic,l burns Borns complicated by other Ifluma
has been conducted. All the studies presented In this review are from data collected in the Uni ted Siaies. However. it would be reasonable to assume that the conclusions drawn herein can be e:ltlrape lated to other developed countries as well.
2. Burn Management Five factors determine the seriousness of a bum: depth, size, arca(s) of involvement, age and general health of the bum victim (Wachtel 1989). Bums are classified as panial-thickness (first or second degree) or fu ll-thickness (third or fourth degree). and the exten t of a bum wound is calculated as a percentage of the total body surface area (table I). Panial-thickness burns are characterised by superticial injury to varying ponions of the epidermis. such as may be produced by sunburn or scalds. Full-thickness burns involve injury to the entire dermis, including appendages (sweat glands, hair follicles, etc.) and may extend into the fat and musele. These bums are produced by flame, chemical contact or electrical curren t. In itial treatmen t of the bum patient is aimed at
relief of respiratory distress. initiation of fluid resuscitation, and prevention of bum shock (Punch et al. 1989); drug therapy which begins after the patient has been stabilised includes pain control and prevention of infection. After initial treatment. the patient is admitted for funher non-operative treatment including resuscitation, nutrition, infection control, ventilation and other bum wound management techniques.
), Pathophysiology 3.1 Cardiovascular Response The cardiovascular response to thermal injury has 2 distinct phases. The first is the acute or resuscitative phase, which immediately follows the insult, is charactcrised by decreased blood flow to tissues and organs (Martyn 1986) and is believed to be caused primarily by hypovolacmia following injury. In theory, intravenous drugs administered during this period will have a lsower rate of distribu tion and elimination; consequcntly, the onset of action will be delayed with the effect possibly prolonged following administration. Oral absorption of a drug is primarily influenced by passive diffusion along a concentration gradient (Notari 1980). When blood flow across the gastrointestinal tract decreases, so too does the concentration gradient, and therefore the oral absorption of a drug may be decreased, assuming all other factors remain equal. Howcver, th is assumption is not tcnable. As is discussed below, following thermal injury the pH of the stomach becomes morc acidic. which will affect the dissol ution of tablets as well as the partitioning of the neutral species of a drug between the gastrointestinal tract and bloodstream. Very little research has been done during the acute phase of the cardiovascular response, poSSIbly owing to the variabili ty in its length. The acu te p hase generally lasts 48 hours and is followed by the hypermetabolic phase, which is characterised by increased blood flow to the tissues and organs and increased internal core temperature. Aikawa et al. (1918) elegantly demonstrated in 39 patients with an average total body bum size of61% that card iac index (:: cardiac output(TBSA;
III
Palhoph}slologyand KmeliC'S After Burn Injury
normal = 3 L/min . m1) ranged from I to 3 L/ min . m1 at 12 hours post-burn and from 3.5 to 10 L/mln . m2 at 60 hours posl-burn. Wolfe et a1. ( 1987) demonstrated that In 18 patients whose mean burn size .... as 74% internal core temperature rose to 101.8 :t 0.3-F (38.8 :t 0.2·C). Wolfe et al. also report a doubling of the normal metabolic ralc which the} attributed to increased substrate cycling involVing adenOSIne tnphosphate (ATP) thus llberatmg heat (Dcmhng 1985: Wolfe et al. [987). Dunng the h) permetabollc phase rapid oedema formatIOn occurs which rna) require treatment. This has been attributed to h)DOProtemaemia. which has been found to produce oedema via 2 mechamsms: first. a shift in equilibrium of the Starhng forces .... hich regulate water filtration through the eapillanes - hypoprotemaemia favours the outward movement of .... ater from the capillal) to the interstitium: secondl~. an increase in water permeabllit} of the Interstllial space (Dcmhng 198 7). Drugs administered Intravenousl} dUring Ihe h}permetabolic phase "Ill have a quicker onset of action dUl' 10 [III Incrc Journal of Trauma I 'i' ~~~. lIoJ ~
19~5
Danld\ J( I ar'un 1>1 \h\1Ck rcl3\anl~ In pal,enl~ "llh burn InJu~ Jour· nal of(lInl1'31 J'harmac IS ~ 6~3·1>!1. 1987 'l oran t... . 'I un~Il'r -\'1 -\lterallons of Ih~ hO\1 dden~ m' (II p-~6. I'I~' 'I un",'r -\\1 lmmunolog, .. alterauon~ follo" 108 InJul) Ad· 'ance~ 10 OrlhoparolC SurgCI) 3!8 1~85 ' 01afl RE 8 10pharmaceulln and clinICal pharmacol lneuo. 3rd ed. pp 119·1 49, \ larcdl lx H er Ine, Y or~ , 1980 0· ' .... 11 J-\ Ptu>u B ... M oncn~f J-\ S(udocs of ~nal funchOn dUrln& earl) po~lburn po:rlod Prcsenled at Ihf Th lfd Inler· nahonal {'ongrc:-ss on R ~'\oCarc h , Burns. Pra8ue. Scplembrr 1015. 1970 O'erman J ... ('a rrllh~" J -\ Quanmau,c ahrrallon~ .n I)mphoC} IC ~ubpopulal,ons In burn pal,enIS, Ch",,,land Labor:llOI) Sc:,cn('(' 2. S!·55. 198;,,,
36~·39J R3'~n P res~. ~ e" ' or ~
198~
C/'" PhurmacfH.lfli'1 18 (}) 1990
IJO
H (' ConKnMHo !.IImlNl!) on Inf«100n. JOIIrMJ or TraumI 19 19-&. 1979 Pond SM 1'tIa~,nnl(' d",- InlC'f¥\l()N.. In Bene!. d aI. tEch) PNrmaroluMIK' N!III rOf dl'Vl U"lmtn!. ptI. 19).2lO. b,'tn Ptns.. Nt'W Yori.. 1984 Pnun BA. Auld and d«IroI)'It ~I ,n lilt burned "Unit Sul'&K1l1 CI,n", of Nonh ,,~ 12: I19L·llll. 1978
PoI~
Punch JO. Smull OJ, Robloon MC HOS!)II.II (';1111' or maJOr burns. POl\&f'adu.alt McOK'lM'~ 20).21$. 1989
RowJflOl AM . l.«~t JA. 8o)k' C'M . Burke JF Epockm,oIoJyof work·l'l'lalC'd bum '"JurlC1 ,n MauachuKIIi ~llIrlnl hOlP" ..lIzallon. JOI.I ..... I of Trauma 26: 1()97·1101. 1916
Roumln I. ('lInl(1ll p:1lII10C'I, 2nd to .. P9. 23-H. 132-117. 224.
and \ , _ ('OIIttTIlnltlonl of('fflILJdllflo:.n bum ..lItnll.. Ellropnn JOIIfNl orO,nlCa1 Pl\armarokJ&) }S S.o-5-I9, 1988 Wnman K. Rtbo:lIo T . p,ndrnl" L. O'Nnl K. Kl\Jn N. C1 II. Pmif'"ioM ~ bum wourMk. JOlimal ofT~IIm.a 21: 1)6rtOC$
1~. 1917
Wolff RIt . Hft'ftdon ON. Jlt.oor F. M,yoWi, H. WoIl(- M EIf«t oflf'n'f bum ,nJury on WMI~te C)'("hnl by &lUf'OK Ind &11) KIds. N"" [ .... 1Id Jou ....1 of Medonflf 31 7: 4Ol-4OI. 1987 zw,f DE. Sawchuk RJ. Gmi'1II ON . Slrlte RG. IncTfl~ dol• ~IIJl'ffllflltl of 1I'"lIm),(,n '" bum ~htllts. JOlimal or TrlUm.a 16 IH-121. 1976 Zu~c DE. SaWfhu ~ RJ. StTite RG. The n«t'Ully of IncTfa~ dosn or ImlkK,n III bum !Mhtnl!. Surwrry S4 60}.6()8. 1978
219. J8 L,pp.nron. Ml,laddphl" 1979
SIIwchuk RJ . Rt("IQr TS. Drul
~III("IK'S
I'tIarmaroluM"\K'S S S48-S56. 1980
In burn 1*\1('",1. ClIn,cal
W.cI,ltl TL Mljor burnl, PoslvadUllt Medl('l~ U : 17'. 196. ]989 W.lIlld RA , A.n.(!truO L ThIHmlnn·N,dloOn E. PhJrmM'(lk,n-
Aulhor's Iddrns.: Dr Pt'lrr L H(JII(Jlr. Wash'lIIlon Slale UIII>crS.ly. C'olklc of f'h.rmJ() . [)eplnmCnl or l'harmlroIOlr/TOli' rolotY. I'ullmln. WA 99164-6~IO. US"'"
(1,n . Ph~rmaro~'~1. 18 ( 2~ 118·1 30. 1990 OJI 2-S%1{90tOOm.{)IIS!S06.SO/O C ADIS Prns l,m'tw
All
n&ht~
rno:n.W
~~~
Pathophysiology and Pharmacokinetics Following Burn Injury Peter L. Bonate Dtpanmenl of Pharmaeology(Toxieology. College of Pharmacy. WashinglOn State UnU'ersily. Pullman. Washington. USA
Contents
Summary ................... ................... .. 118 I. Ep,dc-m.oIOlY ... ............... ... .............. .. 119 2. 8urn Manageme-nt ... . ............... ................. .. .. 120 J. PaJhoph yslolOCY ........................... .. 120 3.1 Card.o,·ascular ResponSe' .......................... .. ................... 120 3.2 R enal RC'Sponse: .. ............................................... .. 121 J.3 MNabohe Response: ......................................... .. ...... 121 3,4 GastrOIntestinal Response ................... .. ............... 122 3,5 He-paIlI' ResponSe' ............................. .122 3.6 Epidermal Response ............................................ .. ................................................ 124 3.7 ImmunolOSlcal ResponSe' ..... ...... ........ .. ...... 125 4. Thcrapeutlc Drug Monitoring In Ihe- Burn Pallenl . ............. ........ .. 126 5. uJX"nmental Ikslgn Conslderallons USlnS Animal and Human Modcls ....... 127 6. Future Research .............................. 127 7. Conclusion . .................................. .. 128
Therapy for inpatient burn victims IS a clear challcnge for the dlnlClan. sInce directly following m;ury the pharmacokinelic parameters of many dfllp will change drastically. Blood now to the tissues is decreased: the rale of dlstrlbU lion and elimination or intra· venous drugs administered dunng this time is reduced. and absorption of oral drugs ma y be slowed. ApprOXimately 48 hours after inJUry. the blood now inCn'ases. as docs internal core temperat urI': the rates may Increase as a result. Immediatel y after inJUry. plasma albumin level rapIdly decreases and fCmalnS sIgnificantly depressed evcn at 60 da)s post-burn. Thus. the proteon bmdong of aCidic and neutral drugs Will decrease and higher amounts of free fraction will be available al the biophase. On the other hand. nl-acid glycoprotein increases in concentration and remains elevated at least 20 days post-burn. Basic drugs exhiba increased protein binding and will most probably nero an increased dosage to achieve the appropria te pharmacological effect. HepatiC metabolism is also affected: the rate of phase I metabohsm will decrease. whole phaS(' 11 melabolism .s unimpaired and may possibly mcrease. Other liver funclions. such as protdn synthesis. arc also impaired. The effect on phase I dfllg melabolism is be1i(,ved to be due to oXY8en-derived free radica ls released during the courS(' ofin;ury. In those pal1ents wi th full-thickness bums. the epidermal layer IS destroyed. Topical drugs have less of a barner to cross and. consequently. less drug is needed to achie"e effectiveness. In addition. the stomach has been found to secrete excess protons which Will eventually lead to ulcers on the majori ty of patienlS. l'IYp('rchlorhydroa may affecl the dissolution and d,sontegrat,on of orally admlnist('red dfllgs in tablet form . as well as the panitionong of the neutral un·.onised speci('s be tween the stomach and bloodstream. In th(' small InteSllne decreased nutrient absorption and DNA synthesis occurs. butth(, efTectthls rna) have on drug absorption IS questionable.
Pathophysiology and Klnt'lics -\ft extent of burn > age > female sex. e\erylhmg else being equal. II was also found Ihat pallen ts "1\h failure of2 or more organ subsystems had a 98% mortality rate I'S single subs)stem failure (Marshall & Dimick 1983). Funhermore. infection has been named as a major cause in 75% of deaths from burns (Polk 1979). While considerable progress has been achieved III deneaslllg the Incidence of burns. carelessness and human error still take their toll. To date. no world-"Ide epidemiological stud~
elm. Pharnraroklnef. 18 (1) IIJ9Q
120
.-
T,bIe I. Burn
""'"
o.S~bOn'
(Irom Wachtel 1989, with pemllS-
Rrst degree on < 50% TBSA Seoond degree 01'1 < 15% TBSA « TI'Iir 75% T8SA plus systemic symplorns Seoond degree on > 25% T8SA (> 20% In children) Third degree on > 10% TBSA
Borns to ctrtlCal .re., Burns complicated by inhalation injury EleCtrlcll or chemic,l burns Borns complicated by other Ifluma
has been conducted. All the studies presented In this review are from data collected in the Uni ted Siaies. However. it would be reasonable to assume that the conclusions drawn herein can be e:ltlrape lated to other developed countries as well.
2. Burn Management Five factors determine the seriousness of a bum: depth, size, arca(s) of involvement, age and general health of the bum victim (Wachtel 1989). Bums are classified as panial-thickness (first or second degree) or fu ll-thickness (third or fourth degree). and the exten t of a bum wound is calculated as a percentage of the total body surface area (table I). Panial-thickness burns are characterised by superticial injury to varying ponions of the epidermis. such as may be produced by sunburn or scalds. Full-thickness burns involve injury to the entire dermis, including appendages (sweat glands, hair follicles, etc.) and may extend into the fat and musele. These bums are produced by flame, chemical contact or electrical curren t. In itial treatmen t of the bum patient is aimed at
relief of respiratory distress. initiation of fluid resuscitation, and prevention of bum shock (Punch et al. 1989); drug therapy which begins after the patient has been stabilised includes pain control and prevention of infection. After initial treatment. the patient is admitted for funher non-operative treatment including resuscitation, nutrition, infection control, ventilation and other bum wound management techniques.
), Pathophysiology 3.1 Cardiovascular Response The cardiovascular response to thermal injury has 2 distinct phases. The first is the acute or resuscitative phase, which immediately follows the insult, is charactcrised by decreased blood flow to tissues and organs (Martyn 1986) and is believed to be caused primarily by hypovolacmia following injury. In theory, intravenous drugs administered during this period will have a lsower rate of distribu tion and elimination; consequcntly, the onset of action will be delayed with the effect possibly prolonged following administration. Oral absorption of a drug is primarily influenced by passive diffusion along a concentration gradient (Notari 1980). When blood flow across the gastrointestinal tract decreases, so too does the concentration gradient, and therefore the oral absorption of a drug may be decreased, assuming all other factors remain equal. Howcver, th is assumption is not tcnable. As is discussed below, following thermal injury the pH of the stomach becomes morc acidic. which will affect the dissol ution of tablets as well as the partitioning of the neutral species of a drug between the gastrointestinal tract and bloodstream. Very little research has been done during the acute phase of the cardiovascular response, poSSIbly owing to the variabili ty in its length. The acu te p hase generally lasts 48 hours and is followed by the hypermetabolic phase, which is characterised by increased blood flow to the tissues and organs and increased internal core temperature. Aikawa et al. (1918) elegantly demonstrated in 39 patients with an average total body bum size of61% that card iac index (:: cardiac output(TBSA;
III
Palhoph}slologyand KmeliC'S After Burn Injury
normal = 3 L/min . m1) ranged from I to 3 L/ min . m1 at 12 hours post-burn and from 3.5 to 10 L/mln . m2 at 60 hours posl-burn. Wolfe et a1. ( 1987) demonstrated that In 18 patients whose mean burn size .... as 74% internal core temperature rose to 101.8 :t 0.3-F (38.8 :t 0.2·C). Wolfe et al. also report a doubling of the normal metabolic ralc which the} attributed to increased substrate cycling involVing adenOSIne tnphosphate (ATP) thus llberatmg heat (Dcmhng 1985: Wolfe et al. [987). Dunng the h) permetabollc phase rapid oedema formatIOn occurs which rna) require treatment. This has been attributed to h)DOProtemaemia. which has been found to produce oedema via 2 mechamsms: first. a shift in equilibrium of the Starhng forces .... hich regulate water filtration through the eapillanes - hypoprotemaemia favours the outward movement of .... ater from the capillal) to the interstitium: secondl~. an increase in water permeabllit} of the Interstllial space (Dcmhng 198 7). Drugs administered Intravenousl} dUring Ihe h}permetabolic phase "Ill have a quicker onset of action dUl' 10 [III Incrc Journal of Trauma I 'i' ~~~. lIoJ ~
19~5
Danld\ J( I ar'un 1>1 \h\1Ck rcl3\anl~ In pal,enl~ "llh burn InJu~ Jour· nal of(lInl1'31 J'harmac IS ~ 6~3·1>!1. 1987 'l oran t... . 'I un~Il'r -\'1 -\lterallons of Ih~ hO\1 dden~ m' (II p-~6. I'I~' 'I un",'r -\\1 lmmunolog, .. alterauon~ follo" 108 InJul) Ad· 'ance~ 10 OrlhoparolC SurgCI) 3!8 1~85 ' 01afl RE 8 10pharmaceulln and clinICal pharmacol lneuo. 3rd ed. pp 119·1 49, \ larcdl lx H er Ine, Y or~ , 1980 0· ' .... 11 J-\ Ptu>u B ... M oncn~f J-\ S(udocs of ~nal funchOn dUrln& earl) po~lburn po:rlod Prcsenled at Ihf Th lfd Inler· nahonal {'ongrc:-ss on R ~'\oCarc h , Burns. Pra8ue. Scplembrr 1015. 1970 O'erman J ... ('a rrllh~" J -\ Quanmau,c ahrrallon~ .n I)mphoC} IC ~ubpopulal,ons In burn pal,enIS, Ch",,,land Labor:llOI) Sc:,cn('(' 2. S!·55. 198;,,,
36~·39J R3'~n P res~. ~ e" ' or ~
198~
C/'" PhurmacfH.lfli'1 18 (}) 1990
IJO
H (' ConKnMHo !.IImlNl!) on Inf«100n. JOIIrMJ or TraumI 19 19-&. 1979 Pond SM 1'tIa~,nnl(' d",- InlC'f¥\l()N.. In Bene!. d aI. tEch) PNrmaroluMIK' N!III rOf dl'Vl U"lmtn!. ptI. 19).2lO. b,'tn Ptns.. Nt'W Yori.. 1984 Pnun BA. Auld and d«IroI)'It ~I ,n lilt burned "Unit Sul'&K1l1 CI,n", of Nonh ,,~ 12: I19L·llll. 1978
PoI~
Punch JO. Smull OJ, Robloon MC HOS!)II.II (';1111' or maJOr burns. POl\&f'adu.alt McOK'lM'~ 20).21$. 1989
RowJflOl AM . l.«~t JA. 8o)k' C'M . Burke JF Epockm,oIoJyof work·l'l'lalC'd bum '"JurlC1 ,n MauachuKIIi ~llIrlnl hOlP" ..lIzallon. JOI.I ..... I of Trauma 26: 1()97·1101. 1916
Roumln I. ('lInl(1ll p:1lII10C'I, 2nd to .. P9. 23-H. 132-117. 224.
and \ , _ ('OIIttTIlnltlonl of('fflILJdllflo:.n bum ..lItnll.. Ellropnn JOIIfNl orO,nlCa1 Pl\armarokJ&) }S S.o-5-I9, 1988 Wnman K. Rtbo:lIo T . p,ndrnl" L. O'Nnl K. Kl\Jn N. C1 II. Pmif'"ioM ~ bum wourMk. JOlimal ofT~IIm.a 21: 1)6rtOC$
1~. 1917
Wolff RIt . Hft'ftdon ON. Jlt.oor F. M,yoWi, H. WoIl(- M EIf«t oflf'n'f bum ,nJury on WMI~te C)'("hnl by &lUf'OK Ind &11) KIds. N"" [ .... 1Id Jou ....1 of Medonflf 31 7: 4Ol-4OI. 1987 zw,f DE. Sawchuk RJ. Gmi'1II ON . Slrlte RG. IncTfl~ dol• ~IIJl'ffllflltl of 1I'"lIm),(,n '" bum ~htllts. JOlimal or TrlUm.a 16 IH-121. 1976 Zu~c DE. SaWfhu ~ RJ. StTite RG. The n«t'Ully of IncTfa~ dosn or ImlkK,n III bum !Mhtnl!. Surwrry S4 60}.6()8. 1978
219. J8 L,pp.nron. Ml,laddphl" 1979
SIIwchuk RJ . Rt("IQr TS. Drul
~III("IK'S
I'tIarmaroluM"\K'S S S48-S56. 1980
In burn 1*\1('",1. ClIn,cal
W.cI,ltl TL Mljor burnl, PoslvadUllt Medl('l~ U : 17'. 196. ]989 W.lIlld RA , A.n.(!truO L ThIHmlnn·N,dloOn E. PhJrmM'(lk,n-
Aulhor's Iddrns.: Dr Pt'lrr L H(JII(Jlr. Wash'lIIlon Slale UIII>crS.ly. C'olklc of f'h.rmJ() . [)eplnmCnl or l'harmlroIOlr/TOli' rolotY. I'ullmln. WA 99164-6~IO. US"'"
