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WO1990009792A1 - Application locale d'amiloride ou de ses analogues dans le traitement d'inflammations - Google Patents

Application locale d'amiloride ou de ses analogues dans le traitement d'inflammations Download PDF

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Publication number
WO1990009792A1
WO1990009792A1 PCT/US1990/001224 US9001224W WO9009792A1 WO 1990009792 A1 WO1990009792 A1 WO 1990009792A1 US 9001224 W US9001224 W US 9001224W WO 9009792 A1 WO9009792 A1 WO 9009792A1
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WO
WIPO (PCT)
Prior art keywords
amiloride
inflammation
arises
compound
mammal
Prior art date
Application number
PCT/US1990/001224
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English (en)
Inventor
Richard D. Granstein
Richard L. Gallo
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The General Hospital Corporation
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by The General Hospital Corporation filed Critical The General Hospital Corporation
Publication of WO1990009792A1 publication Critical patent/WO1990009792A1/fr

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Classifications

    • 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

Definitions

  • This invention relates to the topical therapy of inflammatory skin and eye disorders.
  • Known treatments of disorders of dermal inflammation and cellular proliferation in the skin include systemic treatment with glucocorticoids, antimetabolites, retinoids, cyclosporine, and phototherapy, including the use of psoralens combined with ultraviolet A radiation.
  • treatment typically involves the application of glucocorticosteroids.
  • the mechanism(s) of action of these agents are not fully understood.
  • Corticosteroid therapy has been associated with several adverse side effects, including hypothalmic- pituitary adrenal axis suppression, Cushings Syndrome, growth retardation, epidermal and dermal atrophy, hypopigmentation, and exacerbation of underlying diseases.
  • glucocorticoids When applied to the eye topically, glucocorticoids can produce a number of adverse side- effects including ocular hypertension, posterior subcapsular cataract, thinning of the cornea, defects in visual acuity and field of vision, penetration of the globe, or secondary infection pathogens including Herpes simplex.
  • In vitro biological activities of amiloride include inhibition of lectin-induced human T cell proliferation, phorbol ester induced murine thymocyte proliferation, immunoglobulin production by human peripheral mononuclear cells, differentiation of human leukemic cells, arachidonic acid release by human platelets and inhibition of stimulus provoked fibroblast DNA synthesis.
  • amiloride may also include its ability to inhibit protein synthesis, intercalate within DNA, and inhibit DNA topoisomerase II.
  • Yu et al. in U.S. 4,067,975 discloses some pyrazinamides which can be used topically to treat psoriasis, a disorder characterized chiefly by hyperproliferation of the epidermis.
  • a method for treating inflammation in a mammal comprising topically applying to the mammal an inflammation reducing amount of a compound having the formula:
  • ⁇ is carboxyl, -(NH 2 ) 2 CNNHNH 2 ,
  • R 4 , R 5 , R 6 , R 7 independently is H, a lower alkyl, phenyl, phenyl lower alkyl, or lower alkyl being substituted with phenyl, halogen substituted phenyl, naphthyl or hydroxy;
  • R 2 is
  • R 8 is H, lower akyl, lower alkoxy or lower alkyl substituted with phenyl or furan, R 3 is H or:
  • a lower alkyl, alkoxy and the like, as defined herein are those having 1-6 carbon atoms, inclusive.
  • the compound is amiloride.
  • the compound has the structure where
  • R ⁇ is C-N - C
  • R is -NHt
  • x is Cl
  • Ri is ft.
  • each R n , R 12 is selected from the group consisting of lower alkyls or lower alkenyls.
  • the compound has
  • the compound has the structure:
  • the compound has the
  • the compound has the structure:
  • the compound has the
  • a compound of the invention is applied to the stratum corneum for treatment of inflammation arising from allergic contact dermatitis, irritant dermatitis (non allergic contact dermatitis) , acne vulgaris, acne rosacea, seborrheic dermatitis, atopic dermatitis, cutaneous lupus erythematosus, lichen planus, or exposure to ultraviolet radiation.
  • the compound of the invention may be mixed in a stratum corneum transport facilitating vehicle prior to applying.
  • the compound of the invention is applied to the eye for the treatment of allergic conjunctivitis, irritant conjunctivitis, viral conjunctivitis, acne rosacea, keratitis, uveitis, scleritis, or episcleritis.
  • the compound is prepared in a suitable vehicle for application to the eye.
  • Another aspect of the invention provides a method for inhibiting cutaneous cellular ion transport processes by topically applying a therepeutically effective amount of an amiloride or an amiloride analogue capable of inhibiting cellular ion transport.
  • Another aspect provides a method of treating inflammation in a mammal comprising topically applying to the mammal an inflammation reducing amount of amiloride or an amiloride analogue capable of inhibiting cellular ion transport.
  • Yet another aspect of the invention provides a method for inhibiting cellular proliferation by inhibition of cytokine release by topically applying a therapeutically effective amount of amilorides or an amiloride analogue capable of inhibiting cytokine release.
  • Another aspect provides a method for treating inflammation in a mammal comprising topically applying to the mammal an inflammation reducing amount of amiloride or an amiloride analogue capable of inhibiting cytokine release.
  • the invention provides a new topical treatment for a variety of cellular proliferative, and inflammatory diseases of the skin and eye while avoiding side effects associated with prior methods such as corticosteroid application.
  • Fig. 1 is a graph showing the effect of topical application of amiloride hydrochloride on the murine ear swelling response to trinitrochlorobenzene (TNCB) in mice.
  • Fig. 2 is a light micrograph of the ear of a mouse 48 hours after trinitrochlorobenzene application and treated with base cream absent amiloride.
  • Fig. 2a is a light micrograph showing an ear as in Figure 2 but treated with 1% amiloride hydrochloride.
  • Fig. 3 is a graph showing dose response relationship of the trinitrochlorobenzene induced mouse ear swelling response to topical amiloride hydrochloride.
  • Fig. 4 is a graph showing dose response relationship of the dinitrofluorobenzene induced murine ear swelling response to topical amiloride hydrochloride.
  • Fig. 5 is a graph showing time course of ear swelling after ultraviolet exposure and application of amiloride at various time points. Structure
  • Amiloride consists of a substituted pyrazine ring having an acetylguanidine group at ring position 2, amino groups at ring positions 3 and 5 and a chloride is attached at ring position 6.
  • Amiloride analogues include a number of compounds with a variety of modifications at ring positions 2, 3, 5 and 6.
  • amilorides (an amiloride) refers to amiloride and its analogues.
  • amiloride analogues which can be useful for treatment of inflammation are those capable of inhibiting sodium transport across cell membranes.
  • Tables 1-4, taken from Vigne, supra. illustrate amiloride analogues having inhibiting effects on the Na + transport system.
  • 6-halo group is not important for the Na + inhibition activity of amiloride. Only when fluoro was substituted for chloro does the compound lose some activity.
  • the potency of amiloride derivatives for Na + inhibition can be increased by substitution of the 5- amino group.
  • Monosubstituted derivatives generally had about the same activity as amiloride irrespective of the size of the substituent.
  • disubstitited derivatives for example, those including substitution with lower alkyIs, that is, having from 1-6 carbon atoms, exhibited as much as 140 times the potency of amiloride.
  • amiloride analogues which inhibit Na + transport are disclosed, for example, by Benos et al. in "Effects of Amiloride and Some of Its Analogues on Cation Transport in Isolated Frogskin and Thin Lipid Membranes.” J. of General Physiology ⁇ 68, 1976, 43, and Cuthbert et al. in "Effects of Some Pyrazine Carbotyamides on Sodium Transport in Frogskin" J. Pharmacol, 3, 1978, 139, which are hereby incorporated by reference. Use
  • Topical application of the amilorides can be used for treatment of inflammatory skin disorders involving a cutaneous inflammatory response such as those in the dermis, the lower layer of the skin.
  • Afflictions include allergic contact dermatitis, irritant dermatitis, acne vulgaris, acne rosacea, seborrheic dermatitis, atopic dermatitis, cutaneous lupus erythematosus, lichen planus, mycosis fungoides, as well as other cutaneous infiltrations of benign and malignant inflammatory cells.
  • the application of amiloride or its analogues may also favorably modify the inflammation associated with sunburn by application to sun exposed sites after exposure.
  • Topical application of amiloride can also be used for treatment of eye disorders.
  • Therapy for occular inflammation does not require transport through stratum corneum, the main barrier to penetration in the skin, since the conjunctiva and cornea are not cornified.
  • Disorders which may be treated include allergic, irritant, or viral conjuntivitus, acne rosacea, keratitis, uveitis, scleritis, episcleritis, and other inflammatory conditions.
  • Inflammatory cutaneous lesions can be treated topically with amiloride or its analogues at a range of concentrations sufficiently high to produce an antinflammatory effect but not so high as to raise systemic amounts to toxic levels.
  • amilorides may be applied at concentrations between 0.5 and 2.0% w/w in an appropriate vehicle (such as hydrated petrolatum) .
  • the vehicle facilitates penetration of amiloride by increasing the permeability the stratum corneum.
  • these include, for example, dimethylsulfoxide, decylmethyl sulfide, propylene glycol- isopropyl alcohol, laurocaram, Vehicle N (Neutragena Corp. Los Angeles, CA) , hydrated petrolatum, and ethanol.
  • Application can be performed four times per day, with or without occlusion, until a satisfactory clinical response has occurred.
  • the therapeutic efficacy of amiloride as a topical anti-inflammatory agent was examined in the murine ear swelling response as a model of cutaneous inflammation.
  • the tests included treatment of induced allergic contact dermatitis (ACD) and uv radiation (UVR) exposure inflammation.
  • ACD induced allergic contact dermatitis
  • UVR uv radiation
  • mice 8 to 12 weeks of age, of the BALB/c, A/J, or C57BL/6 strain were purchased (Jackson Laboratories, Bar Harbor, Me) and used in all experiments.
  • the degree of reaction was guantitated by measurements of ear swelling with a micrometer (Fowler, Biggsfield, England) . Measurements were taken immediately before and 24 and 48 hours after application of the sensitizing agent. All measurement were made by an investigator in a coded fashion.
  • mice For sensitization and elicitation of the ACD reaction, the abdomens of BALB/c or A/J mice were shaved with electric clippers, and the mice were sensitized by epicutaneous application of 20 ⁇ L of 2% wt/vol 2,4,6- trinitrochlorobenzene (TNCB) at that site in a 4:1 mixture of acetone and corn oil, or 20 ⁇ L of 0.5% vol/vol l-fluoro-2,4-dinitrobenzene (DNFB) in acetone. Sensitization was performed 5 to 7 days before elicitation of the ACD reaction. An ACD reaction was elicited by application of 5 ⁇ L of 1% TNCB or 0.2% DNFB to dorsal and ventral surfaces of ears of mice.
  • TNCB 2% wt/vol 2,4,6- trinitrochlorobenzene
  • DNFB 0.5% vol/vol l-fluoro-2,4-dinitrobenzene
  • Amiloride hydrochloride (sigma Chemical Co., St. Louis, Mo) was dissolved in a small volume of distilled water before thorough mixing with an appropriate weight of hydrated petrolatum (Denison Laboratories, Pawtucket, RI) . At various times after elicitation with sensitizing agents or UVR treatment, the minimal volume of amiloride preparation necessary to cover the treated surface completely with a thin film was applied to both surfaces of the ear. A similar application of hydrated petrolatum alone was made to matched groups of mice to serve as a control. The effect of topical application of 1% wt/wt amiloride on TCNB induced murine ear swelling in sensitized mice is shown in Fig. 1.
  • TNCB The sensitization dose of TNCB was not applied to the negative control group. Positive controls received base cream alone. Amiloride pretreated and amiloride groups received 1% topical amiloride 4 hours before and 1 hour after elicitation, respectively. Data are mean + standard deviation (SD) of five A/J mice per group, representative of three experiments.
  • the degree of ear swelling was dramatically decreased relative to the positive control in mice that were treated with topical amiloride 1 and 12 hours after application of TNCB for elicitation of the ACD reaction, and it did not significantly differ from the ear swelling response of nonsensitized mice (negative control) .
  • the relative effectiveness of the application of amiloride 1 and 12 hours after elicitation was constant for 24 hours and 48 hours after initial treatment. All five mice in this experiment responded to the application of amiloride. Maximal swelling on all cases occurred within 24 to 48 hours after application of the elicitation dose of TNCB.
  • Figs. 2-2a micrographs of ear specimens taken from TNCB treated mice are shown.
  • the ear exhibits a large inflammatory cell infiltrate 48 hours after TNCB application.
  • the topical application dramatically reduced the number of mononuclear and polymorphonuclear lymphocytes seen at 48 hours (Fig. 2a) .
  • This decrease in the number of inflammatory cells corrolate ⁇ with the decrease in ear swelling after amiloride application demonstrated in Fig. 1.
  • Fig. 3 The dose response relationship for the TNCB induced ear swelling response to a single application of amiloride is shown in Fig. 3. Positive controls were exposed to hydrated petrolatum alone; negative control mice were not sensitized before application of the elicitation dose. Amiloride was applied 1 hour after elicitation. Results are 24 and 48 hours after elicitation and represent the mean ⁇ SD of five BALB/c mice per group, representative of three experiments.
  • Figs. 3 and 4 show that less ear swelling was induced by DNFB than TNCB. This lesser degree of swelling occurred with both A/J and BALB/c mice.
  • topical amiloride was successful in inhibiting the murine ACD reaction to DNFB.
  • amiloride was found to inhibit ear swelling by DNFB significantly at lower concentrations than TCNB.
  • fluorescent- tubes FS 40; Westinghouse Inc., Bloomfield, NJ
  • Irradiance and spectral output were measured with a meter and ultraviolet B (280 to 320 nm) detector (IL 1700; International Light Research, Newburyport, Mass) and spectroradiometer (model 742; Optronic Laboratories, Orlando, Fla.), respectively.
  • Spectral output for the UVR source peaked at 312 nm, with 57% of the output in the ultraviolet B range (200 to 320 nm) , 38.6% in the ultraviolet A range (320 to 400 nm) , and 4,4% in the ultraviolet C range (200 to 290 nm) .
  • mice were exposed for 3 hours with intermittent rotation every 30 minutes, 25 cm from the overhead light source, at an average irradiance of 3.0 X 10 "4 /cm2, while held individually in specially constructed divided cages with open caged tops. Swelling was evaluated by measurements of ear thickness immediately before and 24 and 48 hours after irradiation.
  • Ultraviolet radiation will induce a distinct inflammatory response in murine skin, which may be quantified by measurements of ear swelling similar to those described for evaluation of the ACD reaction.
  • the effect of topical amiloride on UVR-induced inflammation was, therefore, evaluated by serial measurements of ear thickness. Amiloride in aqueous solution strongly absorbs light in the ultraviolet region. Therefore, to avoid effects secondary to UVR absorption, amiloride was applied to the site of interest only after irradiation.
  • the relative effect of topical amiloride on UVR- induced ear swelling over time is shown in Fig. 5. In Fig.
  • open squares ⁇ indicate base cream alone applied at 0, 12, and 24 hours; closed squares D, 1% amiloride hydrochloride applied at 0 and 12 hours (P. ⁇ 005) at 24 and 48 hours) ; and closed circles , 1% amiloride applied only at 24 hours (p. ⁇ .05 at 48 hours).
  • Data represent the mean ear swelling of ten C57BL6 mice per group in two separate experiments. Maximal ear swelling was observed 48 hours after UVR exposure to approximately 3000 mJ/cm2 of ultraviolet B (290 to 320 nm) radiation. Amiloride cream, 2%, applied immediately and 12 hours after irradiation significantly (P. ⁇ 005) decreased the total ear swelling response measured at 24 and 48 hours (Fig. 5) .
  • delayed application of amiloride was effective in delaying the rate of increase in ear thickness induced by UVR and significantly (P. ⁇ 05) descreased the 48 hour ear swelling response.
  • Topical application of amiloride was shown in the experiments above to inhibit the inflammatory response to contact sensitizing agents in sensitized animals, as well as UVR induced tissue swelling. The response to amiloride seen in these experiments was both rapid and persistent.
  • Diffusion of amiloride through normal human epidermis and hairless mouse skin was determined by placing clinically normal human abdominal epidermis obtained at autopsy, or normal hairless mouse dorsal skin with fat removed, in a glass diffusion chamber. A 2mM aqueous solution of amiloride hydrochlorine in normal saline was used as the donor solution. Concentrations of amiloride in the receptor chamber were determined by fluorescence spe ⁇ troscopy. Flux calculations for amiloride through human epidermis showed an average value of 1.083 nm/cm /hr. Similar calculations for mouse skin yielded a value of 11.86 nm/cm /hr. These values represent amiloride flux in a non-optimized vehicle for penetration through the stratum corneum.
  • Inflammatory ocular conditions will be treated by topical application of amiloride and its analogues at concentration ranges sufficient to reduce inflammation but not so high such that systematic levels are toxic.
  • concentration ranges sufficient to reduce inflammation but not so high such that systematic levels are toxic.
  • a 0.5 to 2.0% w/w preparation of amiloride or its analogues in appropriate vehicles can be applied to the conjunctival sac of the inflammed eye four times per day intil a satisfactory clinical response occurs.
  • Appropriate vehicles would be sterile, nonirritating, and preferably include an aqueous component for solubilizing amiloride.
  • opthalmic solutions such as Methopto 1/4% Sterile Opthalmic Solution (Professional Pharmacol Co., Amityville, NY) or Duolube (white petrolatum, liquid petrolatum, available from Moro ⁇ Pharm. , Tewksbury, MA) or Lacri-Lube (white petrolatum, 55% mineral oil, 42.5%, nonionic lanolin, 2%, chlorobutanol, 0.5% and available from Allergan, Irvine, CA) or other sterile opthalmic ointments mixed with an aqueous phase of amiloride solution.
  • Mechanism of Action such as Methopto 1/4% Sterile Opthalmic Solution (Professional Pharmacol Co., Amityville, NY) or Duolube (white petrolatum, liquid petrolatum, available from Moro ⁇ Pharm. , Tewksbury, MA) or Lacri
  • Inflammation is a physiological response which may occur as a result of a variety of events within the skin. Initiation and regulation of this inflammatory response is influenced by a number of cellular processes. These events include direct interactions with the cell membrane and the release of soluble molecules which mediate further inflammatory reactions.
  • amiloride's ability to inhibit i ⁇ n transport is an important step by which cell activation occurs.
  • inhibition of sodium transport, calcium transport, and shifts in cytoplasmic pH are important in its anti-inflammatory activity.
  • These inhibitory actions are also capable of preventing cell proliferation through specific action on these ion transport phenomena.
  • Na + /H + exchange is not obligatory for cell proliferation and the antiproliferative actions of amiloride may be attributed to other events associated with amiloride exposure, for example, its ability to inhibit protein synthesis and intercalate within DNA and inhibit DNA topoisomerase II.
  • amiloride in vitro, inhibits the release of the pluripotent stimulator of cellular proliferation, Interleukin-3.
  • proliferation may be inhibited by interrupting cytokine mediated cellular activation systems initiated by keratinocytes or other cells within the skin.
  • Amiloride when applied topically to the stratum corneum is absorbed through the epidermis to the region of the dermis where it may act directly by any of the above discussed mechanisms. It is also possible that action in the epidermis, for example, inhibition of cytokine release may contribute to its effective treatment of cellular proliferation in the skin.
  • amiloride analogues which inhibit proliferation by mechanisms other than by inhibiting Na + ion transport can be used topically to treat inflammation according to the invention.

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Abstract

Traitement de troubles inflammatoires de la peau et des yeux par application locale d'amiloride ou de ses analogues.
PCT/US1990/001224 1989-03-03 1990-03-05 Application locale d'amiloride ou de ses analogues dans le traitement d'inflammations WO1990009792A1 (fr)

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Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0467369A3 (en) * 1990-07-20 1992-03-25 Hoechst Aktiengesellschaft Use of furosemide to treat allergic conjunctivitis
EP0451130A3 (en) * 1990-04-05 1992-08-05 Baltimore Biotech, Inc. Use of amiloride and other pyrazine derivatives for preventing or treating ocular neovascularization
US5618557A (en) * 1994-11-22 1997-04-08 E.R. Squibb & Sons, Inc. Prophylactic treatment of allergic contact dermatitis
US5686100A (en) * 1994-11-22 1997-11-11 E.R. Squibb & Sons, Inc. Prophylactic and therapeutic treatment of skin sensitization and irritation
EP1121128A4 (fr) * 1998-10-12 2004-10-27 Univ Australian Procede de modulation de l'activite fonctionnelle du canal ionique
US6958324B2 (en) 1998-12-02 2005-10-25 Inotek Pharmaceuticals Corporation Inosine compounds and their use for treating or preventing an inflamation or a reperfusion disease
AU2003250495B2 (en) * 2002-09-17 2009-06-04 Jin Jun Zhang A treatment solution and method for preventing posterior capsular opacification by selectively inducing detachment and/or death of lens epithelial cells
US7875270B2 (en) 2002-09-17 2011-01-25 Abbott Medical Optics Inc. Treatment solution and method for preventing posterior capsular opacification by selectively inducing detachment and/or death of lens epithelial cells
WO2022159028A2 (fr) 2021-01-25 2022-07-28 Phamri Norden Ab Méthode de traitement d'une maladie cutanée

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5412389A (en) * 1977-06-29 1979-01-30 Merck & Co Inc Production of amyloid and other novel 66 substituted derivative

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5412389A (en) * 1977-06-29 1979-01-30 Merck & Co Inc Production of amyloid and other novel 66 substituted derivative

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACTS, Volume 90, Number 25, issued 18 June 1979, (Columbus, Ohio, USA); Merde and Company; "Inc. Amiloride and its 6-substituted derivatives"; & JP,A,54 012 389. *

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0451130A3 (en) * 1990-04-05 1992-08-05 Baltimore Biotech, Inc. Use of amiloride and other pyrazine derivatives for preventing or treating ocular neovascularization
EP0467369A3 (en) * 1990-07-20 1992-03-25 Hoechst Aktiengesellschaft Use of furosemide to treat allergic conjunctivitis
US5258374A (en) * 1990-07-20 1993-11-02 Hoechst Aktiengesellschaft Method of treatment of allergic conjuctivitis
US5618557A (en) * 1994-11-22 1997-04-08 E.R. Squibb & Sons, Inc. Prophylactic treatment of allergic contact dermatitis
US5686100A (en) * 1994-11-22 1997-11-11 E.R. Squibb & Sons, Inc. Prophylactic and therapeutic treatment of skin sensitization and irritation
EP0802731A4 (fr) * 1994-11-22 1999-08-04 Bristol Myers Squibb Co Traitement prophylactique de la dermatite de contact allergique
EP1121128A4 (fr) * 1998-10-12 2004-10-27 Univ Australian Procede de modulation de l'activite fonctionnelle du canal ionique
US7179803B1 (en) 1998-10-12 2007-02-20 Australian National University Method of modulating ion channel functional activity
US6958324B2 (en) 1998-12-02 2005-10-25 Inotek Pharmaceuticals Corporation Inosine compounds and their use for treating or preventing an inflamation or a reperfusion disease
AU2003250495B2 (en) * 2002-09-17 2009-06-04 Jin Jun Zhang A treatment solution and method for preventing posterior capsular opacification by selectively inducing detachment and/or death of lens epithelial cells
US7875270B2 (en) 2002-09-17 2011-01-25 Abbott Medical Optics Inc. Treatment solution and method for preventing posterior capsular opacification by selectively inducing detachment and/or death of lens epithelial cells
US8114432B2 (en) 2002-09-17 2012-02-14 Jin Jun Zhang Treatment solution and method for preventing posterior capsular opacification by selectively inducing detachment and/or death of lens epithelial cells
WO2022159028A2 (fr) 2021-01-25 2022-07-28 Phamri Norden Ab Méthode de traitement d'une maladie cutanée

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