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The efficacy and safety of Famciclovir for the treatment of herpes zoster in immunocompromised patients
s212
ESDR I JSID I SID Abstracts
1270
1267 THE EFFICACY
AND SAFETY OF FAMClCLOVIR FOR THE TREATMENT OF HERPES ZOSTER IN IMMUNOCOMPROMISBD PATIENTS. w Tvrine. on behalf of the Famciclovir bnmunowmpronused Study Group. University of Texas Medical Branch, Galveston, TX, USA: Hospital MaissoneuvPRosemount, Montreal, Canada; JohannesburgHospital, Johannesburg, South Africa; SmithKline Beecham, UK and USA. The purpose of the study was to compare the efficacy and safety of famciclovir (PCV) for the treabnent of herpes mster (HZ) in immunocomprotied (IC) patients. The double-blind, acyclovir (ACV)-controlled, multicenter study included 148 patients with localized HZ infection. The patients were IC due to bone marrow tmnsplantation (68%), solid organ transplant (Z%), or cancer (30%). 58% of patients were male, with a mean age of 43 years 10 days of treatment was given with either FCV 500 tn8 tid or ACV 800 mg 5x/&y. All patients enrolled within 72 hours of rash onset with 58% reporting severe rash (> 50 lesions) at enrolbnent. The key efficacy parameters were the proportion of patients with new lesion formation, time to heal& and time to loss of acute phase pain. The proportion of patients who developed new lesions on study medication was 75 I, with equivalence being demonstrated bet&n FCV and ACV. Me&n times to healing of 20 davs (FCVl vs. 21 days (ACVI and median times to loss of acute !&se orin of 11 davs (F&j vs.i7 days (A&) indicated that the FCV and ACV trea&nm w&e cotnparable. Few patients were withdrawn due to dissemination of zoster: l(2.896) FCV patients, compared with 6 (7.8%) ACV patients (ns). FCV was well tolerated, with an adverse event profile comparable to ACV. Thii study has clearly demonstrated that FCV three ties daily IS a safe and effective treatment for treatment of HZ in IC patients.
on the pharmacokihics in healthy subjects.
of prwhdsolone
ISE-INDUCED CELLS. By, Dermatology,
HISTAMINE
DIFFERENTIALLY MODULATE ANTIRELEASE FROM HUMAN SKIN MAST Department of
Medical University of LObeck,Lubeck, Germany. Free radical scavenging compounds, such as the mucolytic agents ambroxol and Nacetylcysteine or the antioxidant vitamin E, are known also to display antiinflammatoty properties on a wide variety of leukocytes. Here, we repoti that these agents differentiallv modulate IaE-deoendent activation of human skin mast cells
&amine release &an isolated-hut& skin mast cells stimulated with anti-IgE for 30 min in the absence of the drugs was 17 6 * 4.4 % (corrected for the spontaneous release of 8 6 + 1.7 %). In the presence of ambroxol (I-100 @I, ISmin preincubation), a dosedependent inhibition of histamine release from the cells was observed (IGoz 50 m, n=S). At maximum concentrations (100 pM), ambroxol completely blocked the release ofthe amine. Additionally, vitamin E produced a moderate inhibition (36.0 + 10.7 %, n=5) ofhistamine release at 100 PM, In contrast to these observations, N-acetylcysteine had no effect on the anti-IgE induced mast cell activation at neutral pH These results indicate that immunological activation of human skin ma?.t cells may involve intracellular oxidative processes since only
lipophylic antioxidants such as ambroxol and vitamin E produced effective inhibitory actions, unlike the hvdroohilic went N-acetvlcvsteine Reduction of immunoloeicallv_, I induced histamine r&ask from skin mast cells due to the actions of ambroxol and vitamin E suggests that these free radical scavenging compounds may have clinical applications in the treatment of allergic skin diseases
1271 THEPLATELET-ACTIVATING
1268 Effect OK itraconazole methylprednisohw
FREE RADICAL SCAVENGERS
and
B Lcbnm-Vignesl, 0 Cbosidowl,B Diquetl. JC Levmn*, S HUSOOI.V CorbrionArcherI. Al PuechI. D WamtI. Groupe Hospital& pitic-~alp8tri&rel. Paris. Labaatoire Janssen*. Val de ReuiI. France L&zkwoundzCmticosterokis are IikeIv metabolizd bv CYF3A4 isocnwme. Itrwnwole is a p&t inhibitor of tbis iscenzy& and is often t&d in combiaation~tith gIucwxticoii. Because relevant interacticms exist between ibaconazole and same subswts of cyp3A4. it is immntant to assess ti wtential intaaction with glucocaticoids. A
and metbylprednisolmte (48 mg) were studied in fanteen healthy ti, subjects in a twoperiod cross-aver design. SimuItan~y, plasma cottisoI ~88 dctemuned as a $mrmaccdynamic in&x of gl-rticoid &iv@. Kesultx Itmcotwole increased tile area ttrtdu the tnethyl~lMle CQncenuatiotl-time curve more than two and a half fold (701ti1405 “J 2772f1050 ng.h@ p
GEL INHIBITS W-INDUCED Bal&. L. Kern&w’. A Dobo&.
Albert Szent-GyGrgyt Medical Ingelheim,
FACTOR ANTAGONIST WEB 2086 DERMATITIS ON HUMAN SKIN E. V Trach’, ‘Department of Dermatology, University, Szeged, Hungary, *Boehringer
Germany
Platelet-actwtmg pathomechanism
factor
(PAF)
has
been
suggested
to
play
a role
m the
of different inflammatory diseases. We have shown earlier in an experimental animal model, that PAF antagonist WEB 2086 gel inhibited the UV light induced mouse ear oedema The goal of our present investigatton was to determtne whether WEB 2086 stm~ress . , the W lieht induced dernwttis on human skm. We Induced dermatitis on healthy volunteers, by irradiating their skm with different doses of UVB (SUP-lamp, Saalmann). The madated area was treated wth WEB 2086 gel (3%) or with the placebo. The erythema was measured wtth spectrofotometer after 24 and 48 hours. The P.&F antagonist WEB 2086 signdicantly inhibited UVB light induced erythema after 24 and 48 hours m comparison wtth the placebo. In OUTexperrnent the PAF antagomst gel proved to be effechve agamts UVB induced dermatitis. Our result may help in the understanding of the relative importance of medlators in UVB induced dermatttls
statistical diEemce oh cortisol areaLtnder cltnes bctwem predaisone and metbylpreanisolonebefm. and following ihaconazolc. Conclusions: The phatmacokinetic intaacticm found bctwetn methylpreanisolone and itraccmazolemay be related to the inhibition of the hepatic CYP3A4 enzyme by itraconazoIe and may explain suppression of catisol concen~~&cmsat 24 h compared to methylprednisolone.
and mtght perhaps pave the way to better therapeutic modalities in this condition.
1269
1272
BALANCE OF OXYGEN SUPPLY OF THF =YM FROM TBE ATMOSPHERE AND CuTANEous BLOODPLOW M. Stilcker, L. Schulz, M. Herde, K. Hoffinann, P. Altmeyer, D.W. Lllbbers*. Depatment of Dermatology, Rti-University Bochum.*Max-Planck-Institute for Molecular Physiology Dartmund, Germany With a new t&sensor, the OI-flux-opt~&, local oxygen uptake ofthe skin was measured. This 01-sensor is luminescence-based, permeable for the anal@ 02, does not consume the analyte t& and monitors the p0rgmdient between the environment (air) and
8.METHOXYPSORALEN PLASMA LEVELS M PATIENTS TREATED WITH PHOTOCHEMOTHERAPY. P.Donath’. ‘Departmentsof Dermatology,ThomasJeffersonUniversity, Phialdelphia PA and ‘University of Vienna, Vienna Austria
skin surface The obtained pOl-gradient (ApO$ across the test layer marks the tmnscutaneous 02-flux tcJ(&) into the tissue when material properties (C)are constant. On lower leg of 10 healthy volunteers we examined simultaneously the influence of a suprasystolic occlusion over 5 minutes on oxygen uptake on tcJ(O& tcpO2 and laser Doppler flow. In a second gmup of 10 healthy volunteers we examined the same parameters before and after an intmcutaneous injection of histamin. During
supmsystolic
5,5%ti,6%).
After
occlusion the tcJ(02) increased (mean 5%13,1% and the
end
of
occlusion
tcJ(O$
decreased
(2,2%ti%
and
Injection ofhistamin leads to the wellknown hyperemia, demonstrated in risine tcuol (361.5%) and laser Daooler flow (368.9%). At the same time we could see a decrease of Orflux (116%) according to the theory of the balance of Orsupply of the skin from outside and inside. Measurement of oxygen uptake of the skin is a new noninvasive m&ode monitoring cutaneous microcirculation. First experiences show, that it is possible to get two dimensional images of Orflux. Supported by Deutsche Forschungsgemeinschaft DFG, AL 38914-Z. 2,1%fi,4%).
..
lymphoma. While the initial dose of UVA is deteermined biskin type and subsequent doses are carsfullv monitored. the other comrmnent ofthe theram. the n-MOP level in the tar@ tissue cannot be controlled. Over the pas; decade we have p&formed 5214 assays of 8.methoxymoralen (S-MOP) plasma levels in 1040 different patients. We evaluated the dependence of ;he bioa&bili& bf a-MOP on drug type(crystal& methoxsalen vs. oxsomlen ultra@). Average levels at different times atier ingestion were determined for a ranp of ingested doses of both drug types. a-MOP was isolated by solid phase extraction and quantified by HPLC. Cluster analysis was used to sot? the corresponding averages and standard deviations into related groups based on parameters including the average blood level, standard deviation, maximum level and the number of times the blood level was less than 50 ng/mL. The chronological pattern of psoralen levels in 68 patients was determined as was the absorption kinetic in five other patients.A correlationbetweenaverageg-MOP level and ingested dose was observed for doses uo to 60 me. Oxsoralen ultra showed hi&r levels than clystalline methoxsalen. Oxsoralen blood levels were higher at I bra&r it&ion while meihoxsslen levels reached their highest values 2 hrs after ingestion. Patients tested at least IO times could be segregated into three groups corresponding to high, average and low blood levels. Among these patients there was an inverse correlation between the S-MOP level and the ingested dose. In all three groups there were significant variations in S-MOP levels. It may be beneficial for the outcome of photochemotherapy to monitor psoralen levels in order to use this history in the evaluation of patient responses and future therapy regimens.
.~
.
-
ESDR I JSID I SID Abstracts
1270
1267 THE EFFICACY
AND SAFETY OF FAMClCLOVIR FOR THE TREATMENT OF HERPES ZOSTER IN IMMUNOCOMPROMISBD PATIENTS. w Tvrine. on behalf of the Famciclovir bnmunowmpronused Study Group. University of Texas Medical Branch, Galveston, TX, USA: Hospital MaissoneuvPRosemount, Montreal, Canada; JohannesburgHospital, Johannesburg, South Africa; SmithKline Beecham, UK and USA. The purpose of the study was to compare the efficacy and safety of famciclovir (PCV) for the treabnent of herpes mster (HZ) in immunocomprotied (IC) patients. The double-blind, acyclovir (ACV)-controlled, multicenter study included 148 patients with localized HZ infection. The patients were IC due to bone marrow tmnsplantation (68%), solid organ transplant (Z%), or cancer (30%). 58% of patients were male, with a mean age of 43 years 10 days of treatment was given with either FCV 500 tn8 tid or ACV 800 mg 5x/&y. All patients enrolled within 72 hours of rash onset with 58% reporting severe rash (> 50 lesions) at enrolbnent. The key efficacy parameters were the proportion of patients with new lesion formation, time to heal& and time to loss of acute phase pain. The proportion of patients who developed new lesions on study medication was 75 I, with equivalence being demonstrated bet&n FCV and ACV. Me&n times to healing of 20 davs (FCVl vs. 21 days (ACVI and median times to loss of acute !&se orin of 11 davs (F&j vs.i7 days (A&) indicated that the FCV and ACV trea&nm w&e cotnparable. Few patients were withdrawn due to dissemination of zoster: l(2.896) FCV patients, compared with 6 (7.8%) ACV patients (ns). FCV was well tolerated, with an adverse event profile comparable to ACV. Thii study has clearly demonstrated that FCV three ties daily IS a safe and effective treatment for treatment of HZ in IC patients.
on the pharmacokihics in healthy subjects.
of prwhdsolone
ISE-INDUCED CELLS. By, Dermatology,
HISTAMINE
DIFFERENTIALLY MODULATE ANTIRELEASE FROM HUMAN SKIN MAST Department of
Medical University of LObeck,Lubeck, Germany. Free radical scavenging compounds, such as the mucolytic agents ambroxol and Nacetylcysteine or the antioxidant vitamin E, are known also to display antiinflammatoty properties on a wide variety of leukocytes. Here, we repoti that these agents differentiallv modulate IaE-deoendent activation of human skin mast cells
&amine release &an isolated-hut& skin mast cells stimulated with anti-IgE for 30 min in the absence of the drugs was 17 6 * 4.4 % (corrected for the spontaneous release of 8 6 + 1.7 %). In the presence of ambroxol (I-100 @I, ISmin preincubation), a dosedependent inhibition of histamine release from the cells was observed (IGoz 50 m, n=S). At maximum concentrations (100 pM), ambroxol completely blocked the release ofthe amine. Additionally, vitamin E produced a moderate inhibition (36.0 + 10.7 %, n=5) ofhistamine release at 100 PM, In contrast to these observations, N-acetylcysteine had no effect on the anti-IgE induced mast cell activation at neutral pH These results indicate that immunological activation of human skin ma?.t cells may involve intracellular oxidative processes since only
lipophylic antioxidants such as ambroxol and vitamin E produced effective inhibitory actions, unlike the hvdroohilic went N-acetvlcvsteine Reduction of immunoloeicallv_, I induced histamine r&ask from skin mast cells due to the actions of ambroxol and vitamin E suggests that these free radical scavenging compounds may have clinical applications in the treatment of allergic skin diseases
1271 THEPLATELET-ACTIVATING
1268 Effect OK itraconazole methylprednisohw
FREE RADICAL SCAVENGERS
and
B Lcbnm-Vignesl, 0 Cbosidowl,B Diquetl. JC Levmn*, S HUSOOI.V CorbrionArcherI. Al PuechI. D WamtI. Groupe Hospital& pitic-~alp8tri&rel. Paris. Labaatoire Janssen*. Val de ReuiI. France L&zkwoundzCmticosterokis are IikeIv metabolizd bv CYF3A4 isocnwme. Itrwnwole is a p&t inhibitor of tbis iscenzy& and is often t&d in combiaation~tith gIucwxticoii. Because relevant interacticms exist between ibaconazole and same subswts of cyp3A4. it is immntant to assess ti wtential intaaction with glucocaticoids. A
and metbylprednisolmte (48 mg) were studied in fanteen healthy ti, subjects in a twoperiod cross-aver design. SimuItan~y, plasma cottisoI ~88 dctemuned as a $mrmaccdynamic in&x of gl-rticoid &iv@. Kesultx Itmcotwole increased tile area ttrtdu the tnethyl~lMle CQncenuatiotl-time curve more than two and a half fold (701ti1405 “J 2772f1050 ng.h@ p
GEL INHIBITS W-INDUCED Bal&. L. Kern&w’. A Dobo&.
Albert Szent-GyGrgyt Medical Ingelheim,
FACTOR ANTAGONIST WEB 2086 DERMATITIS ON HUMAN SKIN E. V Trach’, ‘Department of Dermatology, University, Szeged, Hungary, *Boehringer
Germany
Platelet-actwtmg pathomechanism
factor
(PAF)
has
been
suggested
to
play
a role
m the
of different inflammatory diseases. We have shown earlier in an experimental animal model, that PAF antagonist WEB 2086 gel inhibited the UV light induced mouse ear oedema The goal of our present investigatton was to determtne whether WEB 2086 stm~ress . , the W lieht induced dernwttis on human skm. We Induced dermatitis on healthy volunteers, by irradiating their skm with different doses of UVB (SUP-lamp, Saalmann). The madated area was treated wth WEB 2086 gel (3%) or with the placebo. The erythema was measured wtth spectrofotometer after 24 and 48 hours. The P.&F antagonist WEB 2086 signdicantly inhibited UVB light induced erythema after 24 and 48 hours m comparison wtth the placebo. In OUTexperrnent the PAF antagomst gel proved to be effechve agamts UVB induced dermatitis. Our result may help in the understanding of the relative importance of medlators in UVB induced dermatttls
statistical diEemce oh cortisol areaLtnder cltnes bctwem predaisone and metbylpreanisolonebefm. and following ihaconazolc. Conclusions: The phatmacokinetic intaacticm found bctwetn methylpreanisolone and itraccmazolemay be related to the inhibition of the hepatic CYP3A4 enzyme by itraconazoIe and may explain suppression of catisol concen~~&cmsat 24 h compared to methylprednisolone.
and mtght perhaps pave the way to better therapeutic modalities in this condition.
1269
1272
BALANCE OF OXYGEN SUPPLY OF THF =YM FROM TBE ATMOSPHERE AND CuTANEous BLOODPLOW M. Stilcker, L. Schulz, M. Herde, K. Hoffinann, P. Altmeyer, D.W. Lllbbers*. Depatment of Dermatology, Rti-University Bochum.*Max-Planck-Institute for Molecular Physiology Dartmund, Germany With a new t&sensor, the OI-flux-opt~&, local oxygen uptake ofthe skin was measured. This 01-sensor is luminescence-based, permeable for the anal@ 02, does not consume the analyte t& and monitors the p0rgmdient between the environment (air) and
8.METHOXYPSORALEN PLASMA LEVELS M PATIENTS TREATED WITH PHOTOCHEMOTHERAPY. P.Donath’. ‘Departmentsof Dermatology,ThomasJeffersonUniversity, Phialdelphia PA and ‘University of Vienna, Vienna Austria
skin surface The obtained pOl-gradient (ApO$ across the test layer marks the tmnscutaneous 02-flux tcJ(&) into the tissue when material properties (C)are constant. On lower leg of 10 healthy volunteers we examined simultaneously the influence of a suprasystolic occlusion over 5 minutes on oxygen uptake on tcJ(O& tcpO2 and laser Doppler flow. In a second gmup of 10 healthy volunteers we examined the same parameters before and after an intmcutaneous injection of histamin. During
supmsystolic
5,5%ti,6%).
After
occlusion the tcJ(02) increased (mean 5%13,1% and the
end
of
occlusion
tcJ(O$
decreased
(2,2%ti%
and
Injection ofhistamin leads to the wellknown hyperemia, demonstrated in risine tcuol (361.5%) and laser Daooler flow (368.9%). At the same time we could see a decrease of Orflux (116%) according to the theory of the balance of Orsupply of the skin from outside and inside. Measurement of oxygen uptake of the skin is a new noninvasive m&ode monitoring cutaneous microcirculation. First experiences show, that it is possible to get two dimensional images of Orflux. Supported by Deutsche Forschungsgemeinschaft DFG, AL 38914-Z. 2,1%fi,4%).
..
lymphoma. While the initial dose of UVA is deteermined biskin type and subsequent doses are carsfullv monitored. the other comrmnent ofthe theram. the n-MOP level in the tar@ tissue cannot be controlled. Over the pas; decade we have p&formed 5214 assays of 8.methoxymoralen (S-MOP) plasma levels in 1040 different patients. We evaluated the dependence of ;he bioa&bili& bf a-MOP on drug type(crystal& methoxsalen vs. oxsomlen ultra@). Average levels at different times atier ingestion were determined for a ranp of ingested doses of both drug types. a-MOP was isolated by solid phase extraction and quantified by HPLC. Cluster analysis was used to sot? the corresponding averages and standard deviations into related groups based on parameters including the average blood level, standard deviation, maximum level and the number of times the blood level was less than 50 ng/mL. The chronological pattern of psoralen levels in 68 patients was determined as was the absorption kinetic in five other patients.A correlationbetweenaverageg-MOP level and ingested dose was observed for doses uo to 60 me. Oxsoralen ultra showed hi&r levels than clystalline methoxsalen. Oxsoralen blood levels were higher at I bra&r it&ion while meihoxsslen levels reached their highest values 2 hrs after ingestion. Patients tested at least IO times could be segregated into three groups corresponding to high, average and low blood levels. Among these patients there was an inverse correlation between the S-MOP level and the ingested dose. In all three groups there were significant variations in S-MOP levels. It may be beneficial for the outcome of photochemotherapy to monitor psoralen levels in order to use this history in the evaluation of patient responses and future therapy regimens.
.~
.
-