CA2179282A1 - Pharmaceuticals - Google Patents
PharmaceuticalsInfo
- Publication number
- CA2179282A1 CA2179282A1 CA002179282A CA2179282A CA2179282A1 CA 2179282 A1 CA2179282 A1 CA 2179282A1 CA 002179282 A CA002179282 A CA 002179282A CA 2179282 A CA2179282 A CA 2179282A CA 2179282 A1 CA2179282 A1 CA 2179282A1
- Authority
- CA
- Canada
- Prior art keywords
- treatment
- composition according
- compound
- formula
- zap
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
- A61K31/52—Purines, e.g. adenine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/20—Antivirals for DNA viruses
- A61P31/22—Antivirals for DNA viruses for herpes viruses
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Virology (AREA)
- Pharmacology & Pharmacy (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Engineering & Computer Science (AREA)
- Biotechnology (AREA)
- Molecular Biology (AREA)
- Epidemiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Physical Education & Sports Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
A method for the treatment (including prophylaxis) of ZAP in mammals, including humans, which method comprises administering to the mammal in need of such treatment, an effective amount of a compound of formula (A) or a bioprecursor, or a pharmaceutically acceptable salt, phosphate ester and/or acyl derivative of either of the foregoing and the use of a compound of formula (A): or a bioprecursor, or a pharmaceutically acceptable salt, phosphate ester and/or acyl derivative of either of the foregoing in the manufacture of a medicament for use in the treatment (including prophylaxis) of ZAP.
Description
2 1 792~2 ~ c~163 PHARMACEUTICALS
This mvention relates to treatment of ~oster associated pain, and to the use of C~ ,J~ m the ~I~,U~ Liul. of a .,...l;. ,....l for use in the treatment of this condition.
When used herein, 'treatment' includes IJlU!JII.yld~i:> as ~u~ul ' EP-A-141927 (Beecham Group p.l.c.) discloses ~ ,;clvvil, the compound of forrnula (A):
N3~ N`'`lNH
~LH2)2 HO~H2l H~H2~H
(A) and salts, phosphate esters and acyl derivatives thereof, as antiviral agents. The sodium salt hydrate of p~,l~i~luvil is disclosed in EP-A-216459 (Beecham Group p.l.c.). r~,....;clvvil and its antiviral activity is also disclosed in Abstract P.V11-5 p.l93 of 'Abstracts of 14th Int.
Congress of Mh,lub;vlo~,y ', ~ ' ' , England 7-13 September 1986 (Boyd et. al.).
Orally active ~ of the compound of formula (A) are of formula (B)-X
N3~N 1NH2 l H2)2 HO CH2-CH~H2~H
(B) wo951~7190 ` r~ c~163 and salts and derivatives thereof as defined under formula (A); wherein X is C1 6 alkoxy.
NH2 or hydrogen. The ~_u~ )ulld~ of formula (B) wherein X is Cl 6 alkoxy or NH2 are disclosed in EP-A-141927 and the ~ mrolmriC of formula (B) wherein X is hydrogen, disclosed in EP-A-182024 (Beecham Group p.l.c.) are preferred prodrugs. A particularly preferred example of a compound of formula (B) is that wherein X is hydrogen and wherein the two OH groups are in the form of the acetyl derivative, described in Example 2 of EP-A-182024, hereinafter referred to as rcuu,,i~l.,vil.
The ~ of formulae (A) and (B) and salts and derivatives thereof have been described as useful in the treatinent of infections caused by ll~ V;IU~IC~, such as herpes simplex type I, herpes simplex type 2, varicella-zoster and Epstein-Barr viruses.
Zoster associated parn (ZAP) is considered to consist of the pain associated with zoster infection and includes the acute phase pain and post-herpetic neuralgia (PHN), which is by far the most common c~ of herpes zoster infection and one of the most intractable pain disorders (Strommen es a~, r~ y. 1988;8:52-68). Patients who develop PHN
suffer from a ~irl. ~ and often rntractable pain which can persist for months or even years. Although rare in patients under 50 years of age, the frequency of PHN rises steeply with increasing age.
Huff et al, Journal of Medical Virology, .SllMlPmr nf 1:93-96 (1993) and Crooks et al, Scand J Infect - Suppl. 78:000-000, 1991 describe the effects of acyclovir in ZAP.
It has now been discovered that the above compounds are ~ Li~.ulculy effective in reducing the duration of ZAP when given to the patient during the acute infection.
Accordingly, the present invention provides a method of treatment of ZAP in humans, which method comprises the ~ . to the hur~ian in need of such treatment, an effective amount of a compound of formula (A):
o </~D~NH
~cH2)2 HO CH2l~H
(A) or a IJ;U~JICCUI:~/I, or a l.l.~ ly acceptable salt, phosphate ester and/or acyl derivative of either of the foregoing.
WO95117190 r~ .'o1l63 The term 'acyl derivative' is used herein to include any derivative of the CUII~JUUlld~
of formula (A) in which one or more acyl groups are presenl. Such derivatives are included as L~;u~lccul~ul~ of the CUIIIIJUUIId~ of formula (A) in addition to those derivatives which are per se biologically active.
The compound of formula (A) may be in one of the forms disclosed in EP-A-216459 (Beecham Group p.l.c.).
Examples Of L; ~ y acceptable salts and derivatives are as described in the ilrul .. '; . ;i European Patent references, the subject matter of which are ill~Ul,UI ' ' herein by reference.
A particular compoumd of formula (B) of interest is 9-(4-acetoxy-3-a.-,.u~.ylll.,~lyli,u~-l-yl)-2 1 . known as r~u~ luvil (FCV), the well-absorbed oral form of ~ icluvil (PCV).
The compound of formula (A), ~ salts and derivatives may be prepared as described in the drul~ ' European Patent references.
The compound, in particular, r~ull.,i,_luviu, may be ~ ' cd by the oral route tohumans and may be ~ . " ,.I..,., ".1~ A in the form of syrup, tablets or capsule. When in the form of a tablet, any l~ ;, l carrier suitable for r~ "~ ; ,, such solid ~ may be used, for example ,, stearate, starch, lactose, glucose, rice, flour and chalk. The compound may also be in the form of an ingestible capsule, for example of gelatm, to contain the c-lmrol~n~i, or in the form of a syrup, a solution or a Cl.cr~ncil,n Suitable liquid ,.1 carriers include ethyl alcohol, glycerine, saline and water to which flavouring or colouring agents may be added to form syrups. Sustained release r.- " 1- ;..- ~ for example tablets containing an enteric coating, are also envisaged.
For parenteral _ fluid unit dose forms are prepared containing the compound and a sterile vehicle. The compound depending on the vehicle and the ~.",. . .,1.,.1;-." can be either suspended or dissolved. Parenteral soludons are normally prepared by dissolving the compound in a vehicle and filter sterilising before filling into a suitable vial or ampoule and sealing. A.lv ,, '~1, adjuvants such as a local - ,~Ul~.DCIVd~ and buffering agents are also dissolved in the vehicle. To enh~mce the stability, the ~ . can be frozen after filling mto the vial and the water removed under vacuum.
Parenteral -r are prepared in ' - 'Iy the same manner except that the compound is suspended in the vehicle instead of being dissolved and sterilised by exposure to ethylene oxide before suspending in the sterile vehicle. Adv_ ~ " a surfact~mt or wetting agent is mcluded in the cu l~l - to facilitate uniform ~' ' of the compound of the invention.
Preferred parenteral r~ I include aqueous r~ ~ using sterile water or ~. 2 ~ 792~2 wo9s/l71so ~ 0~163 normal saline, at a pH of around 7.4 or greater, m particular, containing ~ UVil sodium salt hydrate.
As is common practice, the ~ ",I~n~;li.,.. ~ will usually be ~ I by written o}printed directions for use in the medical treatment concerned.
A suitable dosage unit might contain from SOmg to lg of active ingredient, for example 100 to 500mg. Such doses may be adll.i.~.cd 1 to 4 times a day or more usually 2 or 3 times a day. The effective dose of compound will, in general, be in the range of from 0.2 to 40mg per kilogram of body weight per day or, more usually, 10 to 20 mglkg per day. in the case of rh~ ,luVil, the dosage unit would be 250 mg, 500 mg or 750 mg, preferably 250 mg or 500 mg.
The treatment is preferably carried out as soon as possible after symptoms appear usually within 72 hours, preferably within 48 hours of rash onset.
The treatmeM period is usually 7 days.
The treatment is l,.l. Li.,ul~ effective in the case of patients of greater than 50 years of age, and efficacy would be expected to be ,' ' further in patients greater than 60 years of age, especially patients of greater than 70 years of age.
The present invention also provides the use of a compound of formula (A) or a IJ;U,UICCUI:~UI~ or a I ' lly acceptable salt, phosphate ester and/or acyl derivative of either of the foregoing, in the Illr~u A~ of a ' for use in the treatment of ZAP.
Such treatment may be carried out in the manner as I ", ,1 " r~ 1~ c described.
The present invention further provides a I ' ' ... ., - - :' ;. ,.. for use in the treatment of ZAP, which comprises am effective amount of a compound of formula (A) or a b;V~)IC~.UI:.UI, or a 1~ acceptable salt, phosphate ester andlor acyl derivative of either of the foregoing, and a I ' "~, acceptable carrier. Such ~ may be prepared in the manner as hereinafter described.
The compound of formula (A) and its prodrugs show a synergistic antiviral effect m . I .~ j. . ~ .~ l i. .,~ with r UIL~ and treatment using c" ' ~ products comprising these two C~ for sequential or ~i l "; " 1;-~ ~, by the same or different routes, are therefore within the ambit of the present invention. Such products are described in EP-A-271270 (Beecham Group p.l.c.).
The following clinical data illustrate the invention.
Clinical Data Study 1 is described in Degreef et al, ~T ' ' 1 Journal of Microbial Agents, Volume 4, No. 4 (1994), pp 241-246 ~ ' 21 7~282 WO95/17190 P~~ , ..'01163 A l~lU*)--IiVC",.".1.,..,;,. ~1, double-blind study (study 2) was conducted to compare FCV dosed at 500 mg and 750 mg tid for 7 days with placebo in the treatment of ....... ,~.1;. ,.~ .I herpes zoster. 419 ;~ C~ patients, aged > 18 yea}s whose zoster rash had been present for < 72 hours were enrolled. Patients were assessed for lesion condition and pain pre-therapy. daily during week 1, daily until full crusting during week 2 amd then weekly until all crust had been lost. Both FCV doses were equally effective and ~;61 r~ ulLly reduced the duration of VZV recovery from zoster lesions and the time to healing of zoster lesions compared with the placebo-treated group. In addition, a statistically significant decrease m the duration of acute phase pain was detected for r~ .;l,luvil-treated patients presentmg with severe rash when compared with placebo. The effect of ri~ll.;.luvi on PHN (defined as pain at or after healing) was evaluated by assessing pain at 5 monthly visits after healing. The duration of PHN for all age groups was ~i~llirl~ ly reduced from 128 days to 62 and 55 days followmg treatment with FCV 500 mg and 750 mg, IC~ Iy.
There were no significant differences in the safety profiles between r~ luvil and placebo.
"The mediam time to loss of pain from enrolment (i.e. time to loss of ZAP) was 21 days and 27 days for r~ .luvil doses of 500 mg and 750 mg l-~iY.,ly cûmpared with 30 days for placebo. In ~ ' this study c~~~~ that r ~ ~ IVil dûsed tid is an effective and well tolerated treatment for patients with acute herpes zoster infection, ~i3 ~ decreasing the time to cutaneous lesion resolution and the duration of pain measured both as PHN and as ZAP.
The table below the results in ZAP from clinical studies with r~ luYil.
Endpoint Sub-group ACV FCV FCV FCV PCB
, ' ) 250 500 750 ~1 7AP (Study IIEE) 2501 60 49 28 29 TIZAP (Study IIEE) <48hrs2 69 12i~ 17~ 28~ ~
TI~AP (Study IIEE) ~4812503 69 28~1 56~2 29 TLZAP (Study 21EE) <48hrs2 - 26~ 28~ 64 TLZAP (Study 21EE) 2501 28~ 57~ 76 ; 2 1 79282 17190 F~~ 0~163 I = Patien~s aged 50 years or more lreated within 72 hours 2 = Patients of all ages treateo within 48 hours of rash onset PSatienitf agedb50wyielars or more who were treated within 48 hours o~ r;tsh onset ~2 = Sigluficant by Log Rank Test ITT = Intention to treat population EE = Efficacy evaluable population ACV = Acyclovir 800mg five times daily for seven days PCB = Placebo ueatment TLZAP = Time to loss of ZAP (time to loss of pain from enrolment)
This mvention relates to treatment of ~oster associated pain, and to the use of C~ ,J~ m the ~I~,U~ Liul. of a .,...l;. ,....l for use in the treatment of this condition.
When used herein, 'treatment' includes IJlU!JII.yld~i:> as ~u~ul ' EP-A-141927 (Beecham Group p.l.c.) discloses ~ ,;clvvil, the compound of forrnula (A):
N3~ N`'`lNH
~LH2)2 HO~H2l H~H2~H
(A) and salts, phosphate esters and acyl derivatives thereof, as antiviral agents. The sodium salt hydrate of p~,l~i~luvil is disclosed in EP-A-216459 (Beecham Group p.l.c.). r~,....;clvvil and its antiviral activity is also disclosed in Abstract P.V11-5 p.l93 of 'Abstracts of 14th Int.
Congress of Mh,lub;vlo~,y ', ~ ' ' , England 7-13 September 1986 (Boyd et. al.).
Orally active ~ of the compound of formula (A) are of formula (B)-X
N3~N 1NH2 l H2)2 HO CH2-CH~H2~H
(B) wo951~7190 ` r~ c~163 and salts and derivatives thereof as defined under formula (A); wherein X is C1 6 alkoxy.
NH2 or hydrogen. The ~_u~ )ulld~ of formula (B) wherein X is Cl 6 alkoxy or NH2 are disclosed in EP-A-141927 and the ~ mrolmriC of formula (B) wherein X is hydrogen, disclosed in EP-A-182024 (Beecham Group p.l.c.) are preferred prodrugs. A particularly preferred example of a compound of formula (B) is that wherein X is hydrogen and wherein the two OH groups are in the form of the acetyl derivative, described in Example 2 of EP-A-182024, hereinafter referred to as rcuu,,i~l.,vil.
The ~ of formulae (A) and (B) and salts and derivatives thereof have been described as useful in the treatinent of infections caused by ll~ V;IU~IC~, such as herpes simplex type I, herpes simplex type 2, varicella-zoster and Epstein-Barr viruses.
Zoster associated parn (ZAP) is considered to consist of the pain associated with zoster infection and includes the acute phase pain and post-herpetic neuralgia (PHN), which is by far the most common c~ of herpes zoster infection and one of the most intractable pain disorders (Strommen es a~, r~ y. 1988;8:52-68). Patients who develop PHN
suffer from a ~irl. ~ and often rntractable pain which can persist for months or even years. Although rare in patients under 50 years of age, the frequency of PHN rises steeply with increasing age.
Huff et al, Journal of Medical Virology, .SllMlPmr nf 1:93-96 (1993) and Crooks et al, Scand J Infect - Suppl. 78:000-000, 1991 describe the effects of acyclovir in ZAP.
It has now been discovered that the above compounds are ~ Li~.ulculy effective in reducing the duration of ZAP when given to the patient during the acute infection.
Accordingly, the present invention provides a method of treatment of ZAP in humans, which method comprises the ~ . to the hur~ian in need of such treatment, an effective amount of a compound of formula (A):
o </~D~NH
~cH2)2 HO CH2l~H
(A) or a IJ;U~JICCUI:~/I, or a l.l.~ ly acceptable salt, phosphate ester and/or acyl derivative of either of the foregoing.
WO95117190 r~ .'o1l63 The term 'acyl derivative' is used herein to include any derivative of the CUII~JUUlld~
of formula (A) in which one or more acyl groups are presenl. Such derivatives are included as L~;u~lccul~ul~ of the CUIIIIJUUIId~ of formula (A) in addition to those derivatives which are per se biologically active.
The compound of formula (A) may be in one of the forms disclosed in EP-A-216459 (Beecham Group p.l.c.).
Examples Of L; ~ y acceptable salts and derivatives are as described in the ilrul .. '; . ;i European Patent references, the subject matter of which are ill~Ul,UI ' ' herein by reference.
A particular compoumd of formula (B) of interest is 9-(4-acetoxy-3-a.-,.u~.ylll.,~lyli,u~-l-yl)-2 1 . known as r~u~ luvil (FCV), the well-absorbed oral form of ~ icluvil (PCV).
The compound of formula (A), ~ salts and derivatives may be prepared as described in the drul~ ' European Patent references.
The compound, in particular, r~ull.,i,_luviu, may be ~ ' cd by the oral route tohumans and may be ~ . " ,.I..,., ".1~ A in the form of syrup, tablets or capsule. When in the form of a tablet, any l~ ;, l carrier suitable for r~ "~ ; ,, such solid ~ may be used, for example ,, stearate, starch, lactose, glucose, rice, flour and chalk. The compound may also be in the form of an ingestible capsule, for example of gelatm, to contain the c-lmrol~n~i, or in the form of a syrup, a solution or a Cl.cr~ncil,n Suitable liquid ,.1 carriers include ethyl alcohol, glycerine, saline and water to which flavouring or colouring agents may be added to form syrups. Sustained release r.- " 1- ;..- ~ for example tablets containing an enteric coating, are also envisaged.
For parenteral _ fluid unit dose forms are prepared containing the compound and a sterile vehicle. The compound depending on the vehicle and the ~.",. . .,1.,.1;-." can be either suspended or dissolved. Parenteral soludons are normally prepared by dissolving the compound in a vehicle and filter sterilising before filling into a suitable vial or ampoule and sealing. A.lv ,, '~1, adjuvants such as a local - ,~Ul~.DCIVd~ and buffering agents are also dissolved in the vehicle. To enh~mce the stability, the ~ . can be frozen after filling mto the vial and the water removed under vacuum.
Parenteral -r are prepared in ' - 'Iy the same manner except that the compound is suspended in the vehicle instead of being dissolved and sterilised by exposure to ethylene oxide before suspending in the sterile vehicle. Adv_ ~ " a surfact~mt or wetting agent is mcluded in the cu l~l - to facilitate uniform ~' ' of the compound of the invention.
Preferred parenteral r~ I include aqueous r~ ~ using sterile water or ~. 2 ~ 792~2 wo9s/l71so ~ 0~163 normal saline, at a pH of around 7.4 or greater, m particular, containing ~ UVil sodium salt hydrate.
As is common practice, the ~ ",I~n~;li.,.. ~ will usually be ~ I by written o}printed directions for use in the medical treatment concerned.
A suitable dosage unit might contain from SOmg to lg of active ingredient, for example 100 to 500mg. Such doses may be adll.i.~.cd 1 to 4 times a day or more usually 2 or 3 times a day. The effective dose of compound will, in general, be in the range of from 0.2 to 40mg per kilogram of body weight per day or, more usually, 10 to 20 mglkg per day. in the case of rh~ ,luVil, the dosage unit would be 250 mg, 500 mg or 750 mg, preferably 250 mg or 500 mg.
The treatment is preferably carried out as soon as possible after symptoms appear usually within 72 hours, preferably within 48 hours of rash onset.
The treatmeM period is usually 7 days.
The treatment is l,.l. Li.,ul~ effective in the case of patients of greater than 50 years of age, and efficacy would be expected to be ,' ' further in patients greater than 60 years of age, especially patients of greater than 70 years of age.
The present invention also provides the use of a compound of formula (A) or a IJ;U,UICCUI:~UI~ or a I ' lly acceptable salt, phosphate ester and/or acyl derivative of either of the foregoing, in the Illr~u A~ of a ' for use in the treatment of ZAP.
Such treatment may be carried out in the manner as I ", ,1 " r~ 1~ c described.
The present invention further provides a I ' ' ... ., - - :' ;. ,.. for use in the treatment of ZAP, which comprises am effective amount of a compound of formula (A) or a b;V~)IC~.UI:.UI, or a 1~ acceptable salt, phosphate ester andlor acyl derivative of either of the foregoing, and a I ' "~, acceptable carrier. Such ~ may be prepared in the manner as hereinafter described.
The compound of formula (A) and its prodrugs show a synergistic antiviral effect m . I .~ j. . ~ .~ l i. .,~ with r UIL~ and treatment using c" ' ~ products comprising these two C~ for sequential or ~i l "; " 1;-~ ~, by the same or different routes, are therefore within the ambit of the present invention. Such products are described in EP-A-271270 (Beecham Group p.l.c.).
The following clinical data illustrate the invention.
Clinical Data Study 1 is described in Degreef et al, ~T ' ' 1 Journal of Microbial Agents, Volume 4, No. 4 (1994), pp 241-246 ~ ' 21 7~282 WO95/17190 P~~ , ..'01163 A l~lU*)--IiVC",.".1.,..,;,. ~1, double-blind study (study 2) was conducted to compare FCV dosed at 500 mg and 750 mg tid for 7 days with placebo in the treatment of ....... ,~.1;. ,.~ .I herpes zoster. 419 ;~ C~ patients, aged > 18 yea}s whose zoster rash had been present for < 72 hours were enrolled. Patients were assessed for lesion condition and pain pre-therapy. daily during week 1, daily until full crusting during week 2 amd then weekly until all crust had been lost. Both FCV doses were equally effective and ~;61 r~ ulLly reduced the duration of VZV recovery from zoster lesions and the time to healing of zoster lesions compared with the placebo-treated group. In addition, a statistically significant decrease m the duration of acute phase pain was detected for r~ .;l,luvil-treated patients presentmg with severe rash when compared with placebo. The effect of ri~ll.;.luvi on PHN (defined as pain at or after healing) was evaluated by assessing pain at 5 monthly visits after healing. The duration of PHN for all age groups was ~i~llirl~ ly reduced from 128 days to 62 and 55 days followmg treatment with FCV 500 mg and 750 mg, IC~ Iy.
There were no significant differences in the safety profiles between r~ luvil and placebo.
"The mediam time to loss of pain from enrolment (i.e. time to loss of ZAP) was 21 days and 27 days for r~ .luvil doses of 500 mg and 750 mg l-~iY.,ly cûmpared with 30 days for placebo. In ~ ' this study c~~~~ that r ~ ~ IVil dûsed tid is an effective and well tolerated treatment for patients with acute herpes zoster infection, ~i3 ~ decreasing the time to cutaneous lesion resolution and the duration of pain measured both as PHN and as ZAP.
The table below the results in ZAP from clinical studies with r~ luYil.
Endpoint Sub-group ACV FCV FCV FCV PCB
, ' ) 250 500 750 ~1 7AP (Study IIEE) 2501 60 49 28 29 TIZAP (Study IIEE) <48hrs2 69 12i~ 17~ 28~ ~
TI~AP (Study IIEE) ~4812503 69 28~1 56~2 29 TLZAP (Study 21EE) <48hrs2 - 26~ 28~ 64 TLZAP (Study 21EE) 2501 28~ 57~ 76 ; 2 1 79282 17190 F~~ 0~163 I = Patien~s aged 50 years or more lreated within 72 hours 2 = Patients of all ages treateo within 48 hours of rash onset PSatienitf agedb50wyielars or more who were treated within 48 hours o~ r;tsh onset ~2 = Sigluficant by Log Rank Test ITT = Intention to treat population EE = Efficacy evaluable population ACV = Acyclovir 800mg five times daily for seven days PCB = Placebo ueatment TLZAP = Time to loss of ZAP (time to loss of pain from enrolment)
Claims (13)
1. A method for the treatment (including prophylaxis) of ZAP in mammals, including humans, which method comprises administering to the mammal in need of such treatment, an effective amount of a compound of formula (A):
(A) or a bioprecursor, or a pharmaceutically acceptable salt, phosphate ester and/or acyl derivative of either of the foregoing.
(A) or a bioprecursor, or a pharmaceutically acceptable salt, phosphate ester and/or acyl derivative of either of the foregoing.
2. The use of a compound of formula (A):
(A) or a bioprecursor, or a pharmaceutically acceptable salt, phosphate ester and/or acyl derivative of either of the foregoing in the manufacture of a medicament for use in the treatment (including prophylaxis) of ZAP.
(A) or a bioprecursor, or a pharmaceutically acceptable salt, phosphate ester and/or acyl derivative of either of the foregoing in the manufacture of a medicament for use in the treatment (including prophylaxis) of ZAP.
3. A pharmaceutical composition for use in the treatment (including prophylaxis) of ZAP, which comprises a compound of formula (A):
(A) or a bioprecursor, or a pharmaceutically acceptable salt, phosphate ester and/or acyl derivative of either of the foregoing, and a pharmaceutically acceptable carrier.
(A) or a bioprecursor, or a pharmaceutically acceptable salt, phosphate ester and/or acyl derivative of either of the foregoing, and a pharmaceutically acceptable carrier.
4. A method, use or composition according to claim 1, 2 or 3 wherein the treatment is first administered within 72 hours of rash onset.
5. A method, use or composition according to claim 4 wherein the treatment is within 48 hours of rash onset.
6. A method, use or composition according to any one of claims 1 to 5 where thetreatment period is 7 days.
7. A method, use or composition according to any one of claims 1 to 6 wherein the treatment is carried out on patients of greater than 50 years of age.
8. A method, use or composition according to claim 7 wherein the treatment is carried out on patients of greater than 60 years of age.
9. A method, use or composition according to claim 8 wherein the treatment is carried out on patients of greater than 70 years of age.
10. A method, use or composition according to any one of claims 1 to 9 wherein the Compound is famciclovir.
11. A method, use or composition according to claim 10 wherein famciclovir is administered at a dose of 250 mg, 500 mg or 750 mg three times a day.
12. A method, use or composition according to claim 11 wherein famciclovir is administered at a dose of 250 mg three times a day.
13. A method, use or composition according to claim 11 wherein famciclovir is administered at a dose of 500 mg three times a day.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB939326177A GB9326177D0 (en) | 1993-12-22 | 1993-12-22 | Pharmaceuticals |
| GB9326177.4 | 1993-12-22 | ||
| PCT/EP1994/004163 WO1995017190A1 (en) | 1993-12-22 | 1994-12-14 | Pharmaceuticals |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2179282A1 true CA2179282A1 (en) | 1995-06-29 |
Family
ID=10747023
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002179282A Abandoned CA2179282A1 (en) | 1993-12-22 | 1994-12-14 | Pharmaceuticals |
Country Status (8)
| Country | Link |
|---|---|
| EP (1) | EP0735878A1 (en) |
| JP (1) | JPH09506883A (en) |
| CN (1) | CN1084622C (en) |
| AU (1) | AU697290B2 (en) |
| CA (1) | CA2179282A1 (en) |
| GB (1) | GB9326177D0 (en) |
| WO (1) | WO1995017190A1 (en) |
| ZA (1) | ZA9410113B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR19980028023A (en) * | 1996-10-19 | 1998-07-15 | 김준웅 | Ο-acyl-Ο-amino acid 9- (4-hydroxy-3-hydroxymethylbut-1-ylguanine ester derivative |
Family Cites Families (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3485225D1 (en) * | 1983-08-18 | 1991-12-05 | Beecham Group Plc | ANTIVIRAL GUANINE DERIVATIVES. |
| DE3582399D1 (en) * | 1984-09-20 | 1991-05-08 | Beecham Group Plc | PURINE DERIVATIVES AND THEIR PHARMACEUTICAL USE. |
| DE3671227D1 (en) * | 1985-07-27 | 1990-06-21 | Beecham Group Plc | 9-SUBSTITUTED GUANINE MONOHYDRATES. |
| GB8628826D0 (en) * | 1986-12-02 | 1987-01-07 | Beecham Group Plc | Pharmaceutical products |
| GB8904855D0 (en) * | 1989-03-03 | 1989-04-12 | Beecham Group Plc | Pharmaceutical treatment |
| GB8917959D0 (en) * | 1989-08-05 | 1989-09-20 | Beecham Group Plc | Pharmaceutical formulation |
| GB9001886D0 (en) * | 1990-01-26 | 1990-03-28 | Beecham Group Plc | Pharmaceutical formulation |
| GB9015051D0 (en) * | 1990-07-07 | 1990-08-29 | Beecham Group Plc | Pharmaceutical treatment |
| GB9114939D0 (en) * | 1991-07-11 | 1991-08-28 | Smithkline Beecham Plc | Pharmaceutical formulation |
-
1993
- 1993-12-22 GB GB939326177A patent/GB9326177D0/en active Pending
-
1994
- 1994-12-14 CA CA002179282A patent/CA2179282A1/en not_active Abandoned
- 1994-12-14 WO PCT/EP1994/004163 patent/WO1995017190A1/en not_active Application Discontinuation
- 1994-12-14 EP EP95905068A patent/EP0735878A1/en not_active Withdrawn
- 1994-12-14 CN CN94194994A patent/CN1084622C/en not_active Expired - Lifetime
- 1994-12-14 AU AU13834/95A patent/AU697290B2/en not_active Expired
- 1994-12-14 JP JP7517157A patent/JPH09506883A/en active Pending
- 1994-12-20 ZA ZA9410113A patent/ZA9410113B/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| CN1084622C (en) | 2002-05-15 |
| GB9326177D0 (en) | 1994-02-23 |
| ZA9410113B (en) | 1995-08-25 |
| CN1142769A (en) | 1997-02-12 |
| JPH09506883A (en) | 1997-07-08 |
| EP0735878A1 (en) | 1996-10-09 |
| AU1383495A (en) | 1995-07-10 |
| WO1995017190A1 (en) | 1995-06-29 |
| AU697290B2 (en) | 1998-10-01 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| KR101838764B1 (en) | Improved stable aqueous formulation of (e)-4-carboxystyryl-4-chlorobenzyl sulfone | |
| JP2008088189A (en) | Use of aminopurine antiviral agent for treatment and prophylaxis of latent herpesvirus infection | |
| EP0388049B1 (en) | Derivatives of penciclovir for the treatment of hepatitis-B infections | |
| JPH0320222A (en) | Remedy for ischemic disease in brain | |
| CA2179282A1 (en) | Pharmaceuticals | |
| US4892876A (en) | Method for inhibiting HIV and an pharmaceutical composition therefor | |
| CA2173505C (en) | Use of penciclovir for the treatment of post-herpetic neuralgia | |
| AU696833B2 (en) | Use of 2-amino purine derivatives for the treatment and prophylaxis of human herpes virus 7 infection | |
| EP0830862A1 (en) | Anti-hiv drugs | |
| EP0728001B1 (en) | Use of 2-amino purine derivatives for the treatment and prophylaxis of human herpes virus 6 infections | |
| WO1995011027A1 (en) | Use of peniclorin for the treatment of posttherapeutic neuralgia | |
| JPH11130672A (en) | Lipid peroxidation inhibitor | |
| JPH06227982A (en) | Antiviral agent | |
| JPH11501625A (en) | Use of penciclovir for the treatment of human herpesvirus-8 | |
| JPH0395116A (en) | Reverse transcriptase-inhibiting composition | |
| GB2201343A (en) | Lowering blood uric acid levels | |
| JPH04139128A (en) | Antiviral composition | |
| MXPA97004336A (en) | Use of antiviral agents for the treatment and prophylaxis of latent infections of herpesvi | |
| JPS63295579A (en) | Remedy for osteoporosis | |
| JPH04139130A (en) | Antiviral composition | |
| WO1999022730A1 (en) | Use of (+)-6-carboxamido-3-methylamino-1,2,3,4-tetrahydrocarbazole for treating hyperalgesia | |
| JPH01168614A (en) | Antiulcer agent |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request | ||
| FZDE | Dead |