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United States Patent 19 11 Patent Number: 5,668,134 Klimstra Et Al

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United States Patent 19 11 Patent Number: 5,668,134 Klimstra Et Al US.005668134A United States Patent 19 11 Patent Number: 5,668,134 Klimstra et al. (45) Date of Patent: Sep. 16, 1997 54 METHOD FOR PREVENTING OR Keiichi Tozawa, et al. "AClinical Study of Lomefloxacin on REDUCNG PHOTOSENSTIWTY AND/OR Patients with Urinary Tract Infections. Focused on Lom PHOTOTOXCTY REACTIONS TO efloxacin-induced photosensitivity reaction”. Acta Urol. MEDCATIONS Jpn., vol.39, pp. 801-805. (1993) *(English translation of Japanese article is attached). 75 Inventors: Paul Dale Klimstra, Northbrook; Pierre Treffel, et al. "Chronopharmacokinetics of 5-Meth Barbara Roniker, Chicago; Edward oxypsoralen'", Acta Derm. Venerol, vol. 70, No. 6, pp. Allen Swabb, Kenilworth, all of Ill. 515-517, (1990). (73) Assignee: G. D. Searle & Co., Chicago, Ill. Primary Examiner-James H. Reamer Attorney, Agent, or Firm-Roberta L. Hastreiter; Roger A. 21) Appl. No.: 188,296 Williams 22 Filed: Jan. 28, 1994 57 ABSTRACT (51 Int. Cl. ... A61K 31/395 The present invention provides a method for preventing or 52 U.S. Cl. .............................................................. 514/254 reducing a photosensitivity and/or phototoxicity reaction which may be caused by a once-per-day dose of a medica 581 Field of Search ........................................ 514/254 tion which causes a photosensitivity and/or phototoxicity 56) References Cited reaction in a patient comprising administering the prescribed or suggested dose of the medication to the patient during the U.S. PATENT DOCUMENTS evening or early morning hours. 4,528,287 7/1985 Itoh et al. ............................... 514/254 The present invention also provides an article of manufac OTHER PUBLICATIONS ture comprising: (1) a packaging material, and (2) a once a-day dose medication which causes a photosensitivity and/ Bowee et al, Abstract of J.A. A.C., vol. 33(10) pp. or a phototoxicity reaction in a patient contained within said 1778-1782 (1989). packaging material, wherein such a reaction is prevented or Stucket al. Abstract of J. Clin. Pharm, vol. 22, pp. 116-131 reduced by administering the medication to the patient (1992). during the evening or early morning hours, and wherein said Searle, Abstract of. J. Antimicrol Agents, vol. 2, pp. 67-78 packaging material comprises a label which indicates that (1992). Kiyoshi Marutani, et al. "Reduced Phototoxicity of a Fluo such a reaction is prevented or reduced by administering the roquinolone Antibacterial Agent with a Methoxy Group at medication to the patient during the evening or early morn the 8 Position in Mice Irradiated with Long-Wavelength UV ing hours, and/or that such medication is to be administered Light', Antimicrobial Agents and Chemotherapy, vol. 37, during the evening or early morning hours, and/or wherein No. 10, pp. 2217-2223, (1993). the packaging material is arranged in a manner which R. Neringer "Lomefloxacin versus Norfloxacin in the Treat releases the medication to the patient during the evening or ment of Uncomplicated Urinary Tract Infections: early morning hours. Three-Day versus Seven-Day-Treatment", Scand. J. Infect, vol. 24, No. 6, pp. 773–780, (1992). 13 Claims, 12 Drawing Sheets U.S. Patent Sep. 16, 1997 Sheet 1 of 12 5,668,134 ||| | (suq)04Dm|DAJ ?SOM | U.S. Patent Sep. 16, 1997 Sheet 2 of 12 5,668,134 C1EW94D|peuluu|OEW9u??9SDE fiu?SOOÕu?ueAE 2(9|-! O O O N CN CN C CN C uuO/ D O Minimum Erythema Dose (MED) U.S. Patent Sep. 16, 1997 Sheet 3 of 12 5,668,134 ; Mean Change from Baseline U.S. Patent Sep. 16, 1997 Sheet 4 of 12 5,668,134 Þu?soqfuqueAÐ fiu?soqôu?uloW O D . O ro 3 g to o CN s Oro Minimum Erythema Dose (MED) U.S. Patent Sep. 16, 1997 Sheet 5 of 12 5,668,134 O an O ?h On S O) Do o g CO n up 5 C S o gh s s Medn Change from Baseline U.S. Patent Sep. 16, 1997 Sheet 6 of 12 5,668,134 (N= 3) Percent of subjects with edemd or blisters U.S. Patent Sep. 16, 1997 Sheet 7 of 12 5,668,134 zuuo/p QEW52 \//\[n 62 ALZ 22 |2 6| O99289ZO 9sop9A??OD?SD||1944DSunoH 9^2 G"| Plasma lomefloxacin concentration (mcg/m) U.S. Patent Sep. 16, 1997 Sheet 8 of 12 5,668,134 62 /...? |2 88 to ro to c\) to - to o Ny CN O Plasma onefloxacin concentration (mcg/ml) U.S. Patent Sep. 16, 1997 Sheet 9 of 12 5,668,134 CJEW94D]pºuluu] fiu?SOQfiu?uuoW O 90°Oz ÞO’O ZO”O on C d do Minimum Erythema Dose (MED) U.S. Patent Sep. 16, 1997 Sheet 10 of 12 5,668,134 P O w CN d O d O P O SassO O - Mean Change from Baseline U.S. Patent Sep. 16, 1997 Sheet 11 of 12 5,668,134 Minimum Erythema Dose (MED) U.S. Patent Sep. 16, 1997 Sheet 12 of 12 5,668,134 | w O - CN d O d O GP P Sidis C.SS O D - Mean Change from Baseline 5,668,134 1. 2 METHOD FOR PREVENTING OR interaction leads to erythema, fever and, at times, blisters REDUCING PHOTOSENSITIVITY AND/OR similar to those produced by moderate to severe sunburn. PHOTOTOXCITY REACTIONS TO Photoreactions may occur through light clothing, such as MEDICATIONS T-shirts or blouses. The solar spectra that commonly affect human skin are BACKGROUND OF THE INVENTION UVB (ultraviolet B, 290 to 320 nm) and UVA (ultraviolet A, (1) Field of the Invention 320 to 400 nm). UVB is known as the "sunburn spectrum." The present invention generally relates to a method for which can cause burning, tanning, aging and carcinogenic preventing or reducing a photosensitivity and/or phototox changes in the skin. UVA is erythrogenic, but the amount of icity reaction which may be caused by a once-per-day dose 10 energy required to induce an erythemic effect is 1000 times of an over-the-counter or prescription medication which greater than for UVB. It has been shown for most drugs causes a photosensitivity and/or phototoxicity reaction in a associated with photosensitivity reactions that wavelengths human or animal patient comprising administering the pre from approximately 320 nm to approximately 400 nm. scribed or suggested dose of the medication to the patient (UVA) are most important for photoreactions. These reac during the evening or early morning hours, between the 15 tions are evoked when UVA light energy is absorbed by an hours of about 4:00 p.m. and about 4:00 a.m. appropriate concentration of drug in the skin. The resulting The present invention also generally relates to a method photochemical reactions can damage cell membranes and for administering a once-per-day dose of an over-the lysosomes, and induce an exaggerated sunburn with intense counter or prescription medication which causes a photo redness, edema and occasionally blisters. sensitivity and/or phototoxicity reaction to a human or 20 Sunburn is the result of the penetration of the skin by animal patient in a manner which prevents or reduces such ultraviolet (UV) light, primarily the UVB light. An esti a reaction comprising administering the prescribed or sug mated 95% of UVB radiation reaching skin is absorbed. gested dose of the medication to the patient during the The prolonged exposure to UVA light can produce mild evening or early morning hours, between the hours of about burn and hyperpigmentation. UVA radiation penetrates well 4:00 p.m. and about 4:00 a.m. 25 through the epidermis, but tends to tan more than burn the The present invention also generally relates to, in a skin. However, UVA radiation which, while usually burning method for administering atherapeutically effective amount less, will provide a severe burn when an exposed individual of a once-a-day medication which medication in such a has taken a sensitizing agent, such as a medication which once-a-day therapeutic amount achieves a concentration in causes a photosensitivity and/or phototoxicity reaction. UVA the blood which causes a photosensitivity and/or phototox radiation is not limited to direct sun exposure. Cloud cover, icity reaction in the patient to whom the medication is shady areas, light through glass windows and/or car win administered, an improvement in the method comprising dows may still cause a photosensitivity reaction. administering the medication to the patient at a time suffi UVA radiation, which is commonly associated with drug cient for the blood level of such medication to be at a 35 induced phototoxic or photoallergic reactions, has a rela concentration which is less than a concentration which tively constant level during daylight hours. UVB radiation, produces a photosensitivity and/or phototoxicity reaction on the other hand, which causes common Sunburn, and is a during the daylight hours. dose-related risk for melanoma, has its strongest effect The present invention also generally relates to a method between 10:00 a.m. and 2:00 p.m. Thus, avoiding the sun for treating an infection in a patient in a manner which 40 between these hours may help to minimize ordinary prevents or reduces a photosensitivity and/or phototoxicity sunburn, but may not have the same effect on drug-induced reaction which method comprises orally administering to the photoreactions. patient a once-a-day dose of about 25 mg to about 700 mg Sunburn is a complex inflammatory process causing dys of lomefloxacin hydrochloride between the hours of about keratotic cells, spongiosis, vacuolation of keratinocytes and 4:00 p.m. and about 4:00 a.m. 45 edema from capillary leakage 12 to 24 hours after exposure The present invention also generally relates to an article to light (from the sun, or from artificial sources).
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