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WO2003088997A2 - Reduction des reactions immunitaires indesirables - Google Patents

Reduction des reactions immunitaires indesirables Download PDF

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Publication number
WO2003088997A2
WO2003088997A2 PCT/NL2003/000297 NL0300297W WO03088997A2 WO 2003088997 A2 WO2003088997 A2 WO 2003088997A2 NL 0300297 W NL0300297 W NL 0300297W WO 03088997 A2 WO03088997 A2 WO 03088997A2
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antigen
salbutamol
ova
reaction
adrenergic agonist
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WO2003088997A3 (fr
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Jacoba Johanna Heijnen
Anna Maria Agnes Antonius Kavelaars
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Universiteit Utrecht Holding BV
UMC Utrecht Holding BV
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Universiteit Utrecht Holding BV
UMC Utrecht Holding BV
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/39—Medicinal preparations containing antigens or antibodies characterised by the immunostimulating additives, e.g. chemical adjuvants

Definitions

  • the invention relates to the field of immunology, more in particular to the field of immune therapy, more in particular to the induction of tolerance against a predefined antigen, more specifically to the treatment of autoimmune disease and/or transplant rejection, and/or graft versus host reaction and/or allergic reaction and/or a delayed type hypersensitivity reaction.
  • Antigen-specific oral tolerance induction has been suggested as a novel approach to treat autoimmune diseases, such as rheumatoid arthritis and multiple sclerosis (1).
  • clinical trials using soluble auto-antigens or related antigens have not been very successful so far.
  • EAE experimental autoimmune encephalomyelitis
  • it has been shown to be difficult to achieve tolerance by feeding antigen during the disease process whereas feeding the antigen before disease induction was shown to be successful in decreasing the disease symptoms (2-8).
  • tolerance induction during disease or in previously primed animals despite the fact that this is the relevant clinical set-up to investigate the efficiency of therapeutic strategies for the treatment of inflammatory autoimmune diseases.
  • Animals can be rendered tolerant only when high doses of antigen are administered orally immediately after immunization, before the onset of clinical signs. Similarly, multiple feedings of low doses of antigen during disease result in only a very modest suppression of immune responses or disease activity (9-12). In summary, we can conclude that feeding soluble antigen alone is not sufficient to suppress an ongoing immune response or disease process.
  • Oral feeding of antigen in the context of an activated immune system can only induce immune tolerance when an additional therapeutic strategy is applied to modulate the local cytokine milieu in the gut.
  • the abovementioned unwanted immune reactions trigger the ⁇ 2 -adrenergic receptor (AR).
  • Triggering of the ⁇ 2 -adrenergic receptor (AR) results in accumulation of intracellular cyclic adenosine mono phosphate (camp), which will influence immune functioning (13)(14,15).
  • ⁇ 2 -AR stimulation of monocytes and macrophages leads to a decrease in IL-12 production and an increase in IL-10 production thereby favoring an anti- inflammatory response (16,17)(19-21).
  • ⁇ 2-adrenergic agonists are known to inhibit mitogenic responsiveness of lymphocytes among others by decreasing interleukin (IL)-2 production (14,15)(16-18). In addition they have an important effect on the production of regulatory cytokines.
  • the present invention teaches in one embodiment a method for treating unwanted immune reactions by co-administering a 62 —adrenergic agonist, and a predefined antigen, wherein said antigen is correlated with said unwanted immune reaction.
  • a 62 -adrenergic agonist changes the production of regulatory cytokines thus changing the immune response against said antigen, thereby improving the induction of immunotolerance against said antigen.
  • Said unwanted immune reaction comprises any immune reaction having a (prolonged) deleterious effect on the body, such as for example, an auto-immune disease and/or an allergic disease and/or transplant rejection, and/or graft versus host reaction and/or a delayed type hypersensitivity reaction, for example, but not limited to, Crohn's disease, rheumatoid arthritis, Hashimoto's disease, asthma, allergic skin reaction, hypersensitivity to food allergens like celiac disease, multiple sclerosis, atopic dermatitis and contact dermatitis.
  • Said predefined antigen is related with said unwanted reaction, and/ or belongs to the group of allergens such as food allergens like for example but not limited to, ovalbumin or protein from milk or wheat gluten, and/or inhaled allergen like for example but not limited to pollen, and/or autoimmune antigen like for example but not limited to myelin basic protein or sperm antigens or ocular antigens, and or a tissue antigen like a transplantation antigen, and/or heat shock protein, a functional equivalent of any of these, or a combination of any of these, or a mimotope thereof, mimotope being defined as an epitope having a different sequence but eliciting the same kind of immune response.
  • allergens such as food allergens like for example but not limited to, ovalbumin or protein from milk or wheat gluten, and/or inhaled allergen like for example but not limited to pollen, and/or autoimmune antigen like for example but not limited to myelin basic protein or sperm antigens or
  • said method of the invention improves the induction of immune tolerance against said antigen and can also be applied to other parts of the body.
  • This has the advantage of offering different routes of administration like for example dermal or nasal or oral or enteral administration.
  • Dermal administration is useful for antigens that are digested too fast in the digestive tract or have a strong taste or any other adverse characteristic, like for example but not limited to, oral toxicity, that makes them less suitable for oral administration.
  • the antigen and a 62 —adrenergic agonist are suspended in a fluid, or a cream or a fatty substance to facilitate the application.
  • Nasal or oral administration is useful because of its ease of administration.
  • the antigen may be given in capsules or tablets with an enteric coating.
  • the antigen and a 62 -adrenergic agonist can also be administered in a suppository to assure delivery at the intestinal mucosa without digestion in the stomach.
  • the invention in one embodiment discloses a method for improved induction of immune tolerance against said predefined antigen comprising nasal, more preferably dermal, and even more preferably oral or enteral co- administration of a ⁇ 2 -adrenergic receptor and said predefined antigen, said 62 -adrenergic agonist applied in an amount and in a form capable of decreasing the pro-inflammatory cytokine pattern and increasing the anti-inflammatory cytokine pattern (at least) at the site of antigen uptake and/or antigen handling.
  • Many substances have a ⁇ 2 - adrenergic agonist function.
  • ⁇ 2 -adrenergic agonists are for instance SALBUTAMOL, TERBUTALINE, or CLENBUTEROL, or PROCATEROL, or SALMETEROL, or FORMOTEROL, or FENOTEROL, but other substances are a functional derivative or analogue thereof (that at least in kind if not in amount have the same function as for example SALBUTAMOL as disclosed herein).
  • abovementioned methods for treating unwanted immune reactions and improving the induction of immune tolerance by co-administration of a 62 —adrenergic agonist and a predefined antigen comprises as a 62 -adrenergic agonist for example SAMBUTAMOL, TERBUTALINE, or CLENBUTEROL, or PROCATEROL, or SALMETEROL, or FORMOTEROL, or FENOTEROL, or a functional derivative thereof that at least in kind if not in amount, has the same function as SALBUTAMOL or a combination of any of these.
  • ⁇ 2 -adrenergic agonist temporarily modulates the local immune response to an antigen
  • said co- administration comprises applying ⁇ 2 -adrenergic agonist, for example SAMBUTAMOL, and said antigen in the same period of time at the same site of the body, said body comprising a mammal. More preferably, said mammal comprises a human. The same or even a better effect can be achieved by administering ⁇ 2-adrenergic agonist separately from said antigen to the same body. Therefore, co-administration also comprises applying ⁇ 2-adrenergic agonist and a predefined antigen separately but in such a way that both compounds are bio-available in said body at the same time.
  • ⁇ 2 -adrenergic agonist for example SAMBUTAMOL
  • the site of antigen uptake may differ from the site of antigen handling, for instance in lymphoid tissue.
  • the cytokine modulating effect of ⁇ 2 -adrenergic agonist is important for both antigen uptake and/or antigen handling.
  • co-administration also comprises applying ⁇ 2 -adrenergic agonist orally, and/or enterally and/or nasally, and/or dermally, at an amount and in a form sufficient to decrease the pro-inflammatory cytokine pattern and to increase its anti-inflammatory cytokine pattern (at least) at the site of antigen uptake and/or antigen handling.
  • SALBUTAMOL potentiated the efficacy of oral tolerance induction.
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a 62 -adrenergic agonist like for example SALBUTAMOL and a predefined antigen with a suitable diluent or carrier substance.
  • a suitable diluent or carrier substance comprises any liquid, fatty substance or solid substance, suitable for oral, and/or nasal, and/or dermal administration of the pharmaceutical composition.
  • said 62 - adrenergic agonist is administered to a patient 9separately from said antigen.
  • said 62 -adrenergic agonist like for example SALBUTAMOL and said predefined antigen are combined before administration to a patient.
  • said pharmaceuticals are disclosed, the invention also teaches the use of said pharmaceutical compositions for treating patients with unwanted immune reactions.
  • Said pharmaceutical compositions can be used for reducing unwanted immune reactions, and/or improving induction of immune tolerance, and/or treating an allergic reaction or autoimmune disease, or delayed type hypersensitivity.
  • Said pharmaceutical composition can be given orally or administered by the enteral or intranasal or dermal route for the reasons as described above.
  • the invention also provides the use of said pharmaceutical composition by enteral, and/or intranasal, and/or dermal administration to increase induction of immunotolerance and/or to decrease unwanted immune reactions, said reactions comprising for example an autoimmune disease, and/or an allergic reaction and/or transplant rejection, and/or graft versus host reaction and/or a delayed type hypersensitivity reaction.
  • enterocytes express ⁇ 2-adrenergic receptors (unpublished results, Cobelens et al.).
  • enterocytes or enterocytic cell lines can actively produce a number of cytokines, including TNF- ⁇ , TGF- ⁇ , IL-10, and IL-lRa (20,21)(24-30).
  • Macrophages also express ⁇ 2 -adrenergic receptors and in vitro exposure to a ⁇ 2 -agonist results in decreased TNF- ⁇ production as well as in increases in TGF- ⁇ , IL-lRa and IL-10 presumably via accumulation of intracellular cAMP (19,20,31-34)16,22,23).
  • modulation of cytokine production by oral SALBUTAMOL may be the result of a direct effect of the drug on enterocytes as well as macrophages.
  • Another immediate effect of OVA/SALBUTAMOL administration is an increase in antigen-induced IL-10 production by splenocytes.
  • Sanders et al. have shown that only THI cells express ⁇ 2-adrenergic receptors, whereas mature TH2 cells do not, either at the mRNA or receptor protein level (24).
  • OVA-induced IL-10 increases in cells of mice fed with OVA and SALBUTAMOL probably do not result from a direct effect of SALBUTAMOL on TH2 cells.
  • SALBUTAMOL will act by inhibiting IL-12 production or increasing IL-10 production by macrophages, thereby favouring IL-10 production by antigen- specific cells. It may well be possible that the IL-10 is produced by Trl-cells, which may express ⁇ 2-AR (25,27).
  • the invention also shows here that co- administration of OVA/SALBUTAMOL results in long-lasting tolerance for at least 12 weeks. At this time point, however, cytokine patterns in the intestine are no longer different from PBS-treated animals (data not shown). Moreover, antigen-induced IL-10 production has returned to normal levels.
  • IFN- ⁇ plays an important role in the maintenance of tolerance.
  • tolerance could not be achieved in IFN- ⁇ knockout mice (27).
  • results from studies on animal models of autoimmune diseases suggest that IFN- ⁇ plays a role in down-regulating tissue inflammation (28).
  • This invention discloses that long-lasting tolerance induction is not simply mediated by a decrease in the balance between pro- and anti-inflammatory cytokines, but will involve immediate up regulation of anti-inflammatory cytokines during oral antigen administration as well as long-lasting up regulation of some pro- inflammatory mediators, i.e. IFN- ⁇ , to control the ongoing immune or disease process.
  • the present invention among others discloses that both the cytokine production (intestinal and systemic) and the specific antibody responses are involved in the potentiating effect of ⁇ 2-adrenergic agonist, for example SALBUTAMOL, on tolerance induction, for example in an ovalbumin (OVA) - specific delayed-type hypersensitivity (DTH) model.
  • OVA ovalbumin
  • DTH delayed-type hypersensitivity
  • the invention further discloses the clinical relevance of oral co-administration of ⁇ 2-adrenergic agonist, for example SALBUTAMOL, with a predefined antigen for tolerance induction in a rat model of adjuvant arthritis (AA).
  • this invention discloses a method to induce immune tolerance, it is clear to anyone skilled in the art that also a method is disclosed with which antigens can be selected that cause unwanted immune reactions. This can for example be achieved by administering a number of candidate antigens in combination with a 62 -adrenergic agonist, to groups of experimental animals suffering from an unwanted immune reaction, and recording in which group of animals the unwanted immune reaction is diminished of decreased.
  • SALBUTAMOL or other ⁇ 2 -adrenergic agonists
  • SALBUTAMOL or other ⁇ 2 -adrenergic agonists
  • the use of SALBUTAMOL, or other ⁇ 2 -adrenergic agonists, is also of great value for improving the therapeutic efficacy of oral tolerance induction protocols using allergens for the treatment of allergic disease symptoms in man and mammals.
  • the invention is further explained in the detailed description.
  • SOD superoxide dismutase
  • mice Since AA in rats is a mono-phasic disease, the model cannot be used to determine whether SALBUTAMOL modulates long-term tolerance induction during an ongoing immune process. Therefore we examined the effect of SALBUTAMOL on oral tolerance induction in a murine model of OVA- induced delayed type hypersensitivity (DTH).
  • DTH OVA- induced delayed type hypersensitivity
  • mice that had been treated with one regimen of OVA/SALBUTAMOL from day 5-10 after immunization received a second and a third booster (i.p. injection of OVA in IFA) on day 43 and 68 after immunization.
  • a second and a third booster i.p. injection of OVA in IFA
  • OVA/SALBUTAMOL-treated animals were still tolerant after the second booster and even after a third booster (Fig. 2b).
  • SALBUTAMOL modulates intestinal cytokine production.
  • mice received a single dose of SALBUTAMOL orally. Eight hours later we prepared a homogenate of whole intestinal samples and determined pro and anti-inflammatory cytokine expression on both mRNA and protein level.
  • Oral SALBUTAMOL treatment resulted in down regulation of IFN- ⁇ and up regulation of IL-10 mRNA expression in the small intestine (Fig. 3 ⁇ ). The expression of IL-12 mRNA was below detection limit.
  • SALBUTAMOL did not affect mRNA expression of the pro-inflammatory cytokine IL-l ⁇ . However, mRNA encoding the anti-inflammatory mediator IL-lRa was significantly augmented in mice given oral SALBUTAMOL compared to those given oral PBS (Fig. 3 ⁇ ).
  • SALBUTAMOL modulates cytokine production by peritoneal macrophages.
  • SALBUTAMOL modulates antigen-induced cytokine production by splenocytes.
  • Feeding OVA/SALBUTAMOL results in long-term changes in antigen- induced cytokine production in vitro by splenocytes.
  • mice orally with OVA/SALBUTAMOL from day 5 after immunization with OVA in CFA. Mice received a booster at day 18 after immunization. Two weeks later (day 35) we cultured the splenocytes in vitro in the presence of OVA for 72 hours. At this time point, IFN- ⁇ production was significantly enhanced in OVA SALBUTAMOL-treated animals as compared to PBS-treatment, whereas treatment with OVA or SALBUTAMOL alone did not significantly change IFN- ⁇ production (Fig. 5c).
  • Salbutamol reduces disease severity in human patients suffering from rheumatoid arthritis.
  • rheumatoid arthritis Patients suffering from rheumatoid arthritis are selected from a group of well described patients (UMCU). Inclusion criteria are as follows: established diagnosis of rheumatoid arthritis for more than 2 years with active arthritis. Exclusion criteria are: treatment with more than 10 mg prednisolone per day. The patients are randomly divided in four groups: group 1, 2, 3 and 4.
  • Patients in group 1 are treated by oral administration every other day for a total of 5 doses of Salbutamol (4.2 mg/person and bovine type II collagen (0.5 mg/person).
  • Patients in group 2 are treated in the same way as the patients in group 1, except that they receive ovalbumin as a control antigen.
  • Patients in group 3 are treated in the same way as the patients in group 1, except that Salbutamol is replaced by a harmless placebo substance.
  • Patients in group 4 are treated in the same way as the patients in group 1, except that both Salbutamol and the antigen are replaced by a harmless placebo substance.
  • the observation period is 6 months during which period the patients are examined at regular monthly intervals and a questionnaire is filled out at every examination.
  • Results of group 1 are significantly different from groups 2 to 4, meaning that in the patients in group 1, disease activity scores are significantly reduced.
  • Lewis rats (6-8 weeks) (University of Limburg, Maastricht, The Netherlands) and Balb/c mice (6-8 weeks) (Charles River, Sulzfeld, Germany) were kept at the Utrecht University animal facility, fed a standard diet (Hope Farms, Woerden, The Netherlands) and water ad libitum.
  • AA was induced in male Lewis rats by a single intradermal injection of 100 ⁇ l of Freund's complete adjuvant (5 mg M tuberculosis (strain
  • H37Ra H37Ra/ml incomplete Freund's adjuvant (IFA) (Difco, Detroit, MI) in the base of the tail. Severity of arthritis was assessed daily by standard methods in a blinded protocol (29)(38). A cumulative score was calculated for each individual animal by summation of the individual disease scores from day 11 until day 20.
  • IFA incomplete Freund's adjuvant
  • Mycobacterial HSP65 from Mycobacterium bovis was expressed in Escherichia coli and isolated as described (28). Rats were treated orally with 450 ⁇ g of SALBUTAMOL (Sigma; St. Louis, MO) together with 30 ⁇ g of HSP65 or superoxide dismutase (SOD)(Sigma) in 1 ml of PBS using an 18-gauge animal-feeding needle (Popper & Sons, In., New York, NY). Treatment was started when most of the animals lost weight, that is, at the onset of clinical arthritis. Oral administration of HSP65 or SOD and SALBUTAMOL was repeated every other day for an additional 4 doses.
  • mice Female Balb/c mice were immunized i.p. with 20 ⁇ g of OVA (grade V; Sigma) emulsified in Freund's complete adjuvant (CFA, Difco). Eighteen days after immunization, mice were boosted i.p. with 20 ⁇ g of OVA in IFA (Difco). One week later, mice were challenged by a subcutaneous injection into the footpad with 50 ⁇ l PBS containing 400 ⁇ g/ml OVA and 1 mg/ml AIOH3. After 24 hours we measured thickness of the footpad.
  • OVA grade V
  • CFA Freund's complete adjuvant
  • mice were treated orally with 10 ⁇ g of SALBUTAMOL and 250 ⁇ g of OVA dissolved in 0,5 ml PBS using a 20-gauge stainless steel animal-feeding needle (Popper & Sons, In.). Treatment was started 5 days after the first immunization. Oral administration of the drugs was repeated five times every other day. To analyse long-term effects of the tolerance protocol, mice were boosted again with OVA in IFA on day 43 and day 68 after immunization, followed by a challenge 7 days later. In the pre-treatment protocol, mice were fed six times 10 ⁇ g of
  • OVA-specific antibody production Microtiter plates (Maxisorp F96; Nunc, Roskilde, Denmark) were coated with OVA (5 ⁇ g/ml) in PBS. After washing the plates with PBS/Tween (0.05%), the plates were blocked with 200 ⁇ l/well PBS/1% BSA (Sigma). Diluted serum samples were added to the wells and incubated for 2 hours at room temperature. Biotin-conjugated goat anti-mouse IgG (Zymed; San Francisco, CA) diluted in PBS/1% BSA/0.005% Tween-20 (IgG to tai: 1:10000; IgGi and IgG 2 a: 1:1000) was added and incubated.
  • Splenocytes were cultured serum-free in quadruplicate in 200 ⁇ l at 1.5 x 10 5 cells per well in presence or absence of OVA (125 ⁇ g/ml final concentration).
  • mice Five days after immunization with OVA in CFA, mice were treated orally with 10 ⁇ g SALBUTAMOL. Eight hours later mice were sacrificed and peritoneal lavages were obtained as a source of macrophages. In addition, 2 cm of distal ileum was collected, homogenized in PBS and used for determining cytokine production.
  • IFN- ⁇ and TNF- ⁇ were determined using ELISA kits from U-Cytech (Utrecht, The Netherlands).
  • IL-10 and TGF- ⁇ were determined using OptEIA kits from PharMingen.
  • Each Proventil Repetab extended-release tablet contains a total of 4 mg (2 mg in the coating for immediate release and 2 mg in the core for release after several hours) of salbutamol as 4.8 mg of salbutamol sulphate.
  • the inactive ingredients for salbutamol extended-release tablets include: butylparaben, calcium phosphate, calcium sulphate, lactose, magnesium stearate, oleic acid and titanium dioxide.
  • the slower acting extended release tablets have a duration of action of at least 12 hours after a single dose.
  • Collagen II tablets are prepared by absorption onto a lactose base.
  • Clinical assessments are performed at weeks -1, 0, 1, 4, 8, 12, 16, 20, and 24. Assessments are based on the ACR and European League against Rheumatism core data sets and included duration of early morning stiffness, fatigue score, the number offender and swollen joints (28-joint score), visual analogue scale for pain, patient's and physician's global assessment of disease activity, ESR, and modified Health assessment Questionnaire.
  • Oral OVA/SALBUTAMOL after immunization reduces cellular and humoral immune responses.
  • mice At day 0 we immunized the mice and at day +5 we started treatment every other day with oral administration OVA and sal. We boosted the mice with OVA in IFA at day +18 (a), day +43 (6), and day +68 (b). One week later, we determined the DTH response (a and b). At day +35 (c) and day +82 (d) we analyzed sera for OVA-specific antibody production. All data represent mean ⁇ SEM of 8 individual animals in each group and are representative for two independent experiments.
  • Oral SALBUTAMOL changes cytokine production in the small intestine mRNA (a) and protein cytokine expression (b) of homogenates from the small intestine from PBS- ( ⁇ ) and SALBUTAMOL- ( GH ) treated mice.
  • mRNA cytokine expression is expressed as percentage of household gene expression (L32). All data represent mean ⁇ SEM of 8-10 individual animals in each group. *, P ⁇ 0.05, SALBUTAMOL vs PBS **, P ⁇ 0.01 SALBUTAMOL vs PBS
  • Oral SALBUTAMOL changes cytokine production in peritoneal macrophages.
  • mRNA cytokine expression is expressed as percentage of household gene expression (L32). All data represent mean ⁇ SEM of 8-10 individual animals in each group. *, P ⁇ 0.05, SALBUTAMOL vs PBS **, P ⁇ 0.01 SALBUTAMOL vs PBS
  • Oral OVA SALBUTAMOL alters antigen-induced cytokine production by splenocytes.
  • Data represent mean ⁇ SEM of 6 individual animals in each group. *, P ⁇ 0.05, OVA/SALBUTAMOL vs PBS, **, P ⁇ 0.01 OVA/SALBUTAMOL vs PBS Reference List
  • Haque, M. A. et al. Suppression of adjuvant arthritis in rats by induction of oral tolerance to mycobacterial 65-kDa heat shock protein.
  • IFN- ⁇ plays a critical down-regulatory role in the induction and effector phase of myelin oligodendrocyte glycoprotein- induced autoimmune encephalomyelitis. J.Immunol. 157, 3223-3227 (1996).

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Abstract

Cette invention relève du domaine des produits pharmaceutiques et de la thérapie. Cette invention concerne des moyens et des méthodes permettant d'améliorer l'induction de la tolérance pour le traitement de maladies auto-immunes, de réactions d'hypersensibilité retardée et/ou de rejet de greffe et/ou de réactions du greffon contre l'hôte et/ou de réactions allergiques. Selon cette invention, l'administration par voie mucosale ou dermique d'un agoniste β2-adrénergique améliore considérablement l'induction de la tolérance envers l'administration d'antigènes. Cette invention concerne également des compositions pharmaceutiques renfermant un agoniste β2-adrénergique et un antigène, ainsi que l'utilisation de ces compositions.
PCT/NL2003/000297 2002-04-22 2003-04-22 Reduction des reactions immunitaires indesirables Ceased WO2003088997A2 (fr)

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Cited By (5)

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US8753644B2 (en) 2009-02-05 2014-06-17 Circassia Limited Grass peptides for vaccine
US8821887B2 (en) 2008-08-15 2014-09-02 Circassia Limited T-cell antigen peptide from allergen for stimulation of IL-10 production
CN115645374A (zh) * 2022-12-25 2023-01-31 山东理工职业学院 一种硫酸沙丁胺醇片的制备方法

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Title
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Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1719507A1 (fr) 2005-04-13 2006-11-08 Astion Development A/S Des agonistes de bêta-2 adrénocepteur pour le traitement de maladies du tissus conjonctifs
WO2006108424A3 (fr) * 2005-04-13 2006-12-14 Astion Dev As Traitement de maladies du tissu conjonctif cutane
EA016082B1 (ru) * 2005-04-13 2012-02-28 Астион Фарма А/С Применение r-сальбутамола для местного лечения накожных форм красной волчанки
US8426475B2 (en) 2005-04-13 2013-04-23 Astion Development A/S Treatment of connective tissue diseases of the skin
US9907765B2 (en) 2005-04-13 2018-03-06 Cipher Pharmaceuticals Inc. Treatment of connective tissue diseases of the skin
US8491910B2 (en) 2008-08-15 2013-07-23 Circassia Limited Vaccine comprising AMB A 1 peptides for use in the treatment of ragweed allergy
US8821887B2 (en) 2008-08-15 2014-09-02 Circassia Limited T-cell antigen peptide from allergen for stimulation of IL-10 production
US9347937B2 (en) 2008-08-15 2016-05-24 Circassia Limited Vaccine comprising Amb a 1 peptides for use in the treatment of ragweed allergy
US8753644B2 (en) 2009-02-05 2014-06-17 Circassia Limited Grass peptides for vaccine
CN115645374A (zh) * 2022-12-25 2023-01-31 山东理工职业学院 一种硫酸沙丁胺醇片的制备方法
CN115645374B (zh) * 2022-12-25 2024-04-26 山东理工职业学院 一种硫酸沙丁胺醇片的制备方法

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