Attorney Docket No. 1248,090WO Filed Via EFS on 10/24/07

METHODS TO PREVENT VERTICAL TRANSMISSION OF INFECTIOUS DISEASES

CLAIM OF BENEFIT OF FILING DATE

[0001] This application ciaims the benefit of U.S. Provisiona! Application Seria! No. 60/914,638 filed April 27,2007 and U.S. Serial No 11/877,212, aii of which are incorporated herein by reference for a!! purposes,

FIELD OF INVENTION

[0002] The present invention relates to methods of preventing mother to child transmission of infectious diseases during the intrapartum period, especially infectious diseases caused by human immunodeficiency virus type 1 , hepatitis viruses, Group B Streptococcus, cytomegalovirus, Listeria monocytogenes, Chlamydia trachomatis, Escherichia coli, herpes simplex virus, Epstein-Ban" virus, Toxoplasma gondii, and Candida.

BACKGROUND OF THE INVENTION

[0003] Tens of millions of individuals have been infected with human immunodeficiency virus type 1 ("HIV-1") worldwide and millions of new cases are identified every year. About 95% of HIV-1 infections are found in developing countries such as sub-Saharan Africa and Southeast Asia. It has been estimated that 570,000 children became infected with HIV-1 during 1999 and 90% of these infections were acquired in utero, during delivery, or through breast-feeding from their HIV-infected mothers. See Michele L. Dreyfuss and Wafaie W. Fawzi, Micronutrients and Vertical Transmission of HIV-1, Am J Clin Nutr 2002: 75:959- 70.

[0004] Mother to child transmission of infectious diseases, also known vertical transmission, is well established. There is a high risk of vertical transmission of infectious diseases during the intrapartum period due to the presence of the virus in blood and mucus in the birth canal.

Attorney Docket No. 1248.090WO Filed Via EFS on 10/24/07

[0005] For example, a study has shown that a substantial proportion of vertical transmission of HIV-1 occur during the intrapartum period. "Possible mechanisms include transfusion of the mother's blood to the fetus during labor contractions, infection after rupture of membranes, and direct contact of the fetus with infected secretions or blood from the maternal genital tract." See The Mode of Delivery and The Risk of Vertical Transmission of Human Immunodeficiency Virus Type 1, The New England Journal of Medicine, Vol. 340, No. 13, 977-987, 977 (1999).

[0006] Vertical transmission of hepatitis such as hepatitis B virus ("HBV") and hepatitis C virus ("HCV") during the intrapartum period is also known and supported by studies. See Caudai, C, Battiata, M., Riccardi, M. P., Toti, M., Bonazza, P., Padula, M. G., Pianese, M., Valensin, P. E. (2003). Vertical Transmission of the Hepatitis C Virus to Infants of Anti-Human Immunodeficiency Virus-Negative Mothers: Molecular Evolution of Hypervariable Region 1 in Prenatal and Perinatal or Postnatal Infections. J. Clin. Microbiol. 41 : 3955-3959; WaINs ₁ D. E, Boxall, E. H (1999). Immunisation of infants at risk of perinatal transmission of hepatitis B: retrospective audit of vaccine uptake. BMJ 318: 1112-1113. In addition to HIV-1 , HBV and HCV, vertical transmission of other infectious diseases caused by Group B Streptococcus ("GBS"), cytomegalovirus ("CMV"), Listeria monocytogenes, Chlamydia trachomatis, Escherichia coli ("E. coli"), herpes simplex virus ("HSV"), Epstein-Barr virus ("EBV"), Toxoplasma gondii, human papilloma virus (HPV), and Candida has also been documented. See Laszlό Marόdi, Neonatal Innate Immunity to Infectious Agents, Infect Immun. 2006 April; 74(4): 1999-2006; INTRAUTERINE AND PERINATAL INFECTION, www.nuigaiway.ie/bac/student info/I ntrauterine Perinatal lnfection.html; MC Meyohas, V Marechal, N Desire, J Bouillie, J Frottier and JC Nicolas, Study of mother-to-child Epstein-Barr virus transmission by means of nested PCRs, J. Virol., 10 1996, 6816-6819, VoI 70, No. 10.

Attorney Docket No 1248 090WO Filed Via EFS on 10/24/07

[0007] It is an object of the present invention to prevent vertical transmission of infectious diseases using photodisinfection and/or sonophotodisinfection during the intrapartum period. Photodisinfection and sonophotodisinfection can prevent vertical transmission of these diseases by inhibiting and/or eliminating infectious disease causing microorganisms that come into contact with host tissues of the birth canal such as HIV-1 , HBV, HCV, GBS, CMV, Listeria monocytogenes, Chlamydia trachomatis, E. coli, HSV, EBV, Toxoplasma gondii, HPV, Candida, etc.

[0008] Photodisinfection is the use of a photosensitizing composition activated by light to inhibit or eliminate infectious disease causing microorganisms in the desired treatment area. When the photosensitizing composition is activated by light, it is believed to release free radicals causing killing of microorganisms. [0009] Sonophotodisinfection is photodisinfection plus the use of sonic energy to inhibit or eliminate infectious disease causing microorganisms in the desired treatment area. It is believed that the application of sonic energy in a fluid (e.g., photosensitizing composition, blood and mucus in the birth canal, etc.) can create acoustic cavitation. Acoustic cavitation involves the nucleation, growth and collapse of gas/vapor filled bubbles in a fluid. Cavitation is believed to effectively kill microorganisms by physical disruption. For example, the mechanical energy in acoustic cavitation can disrupt the microorganisms surrounding it by the violent shear forces produced around the bubbles. Free radicals in a fluid have also been detected as a direct result of acoustic cavitation. These free radicals are believed to kill microorganisms via eel! wall disruption and/or lipid peroxidation, it is also believed that the collapse of the bubbles during acoustic cavitation can be accompanied by a simultaneous emission of light ("sonoluminescence"). The light emitted by sonoluminescence is very broadband and may contain ultraviolet light, which can also be directly detrimental to microorganisms. It is also believed that light emitted via sonoluminescence, when applied to a photosensitizing composition in the birth canal, can release more free radicals, causing further killing of microorganisms.

Attorney Docket No. !248.090WQ Filed Via EFS on 10/24/07

transmission of an infectious disease comprising: (a) applying a photosensitizing composition to host tissues of birth canal of a mother during the intrapartum period; and (b) applying light to the host tissues after the step (a) at a wavelength absorbed by the photosensitizing composition so as to inhibit or eliminate infectious disease microorganisms that come into contact with the host tissues, preferably without causing physiological damage to the host tissues. The present invention optionally includes applying sonic energy to the host tissues after step (b). It is preferred that the applying the steps (a), (b) and optionally (c) are repeated multiple times during the intrapartum period. [0011] The present invention also provides a method of preventing vertical transmission of human immunodeficiency virus type 1 comprising: (a) applying a photosensitizing composition comprising of methylene blue to host tissues of a birth canai of a mother during intrapartum period; (b) applying light to the host tissues after the step (a) at a wavelength from about 650 nm to about 685 nm that is absorbed by the photosensitizing composition so as to inhibit or eiiminate human immunodeficiency virus type 1 that comes into contact with the host tissues; and repeating the steps (a) and (b) at least every two hour during the intrapartum period.

[0012] The present invention further provides a method of preventing vertical transmission of hepatitis comprising: (a) applying a photosensitizing composition comprising of methylene blue to host tissues of a birth canal of a mother during intrapartum period; (b) applying light to the host tissues after the step (a) at a wavelength from about 660 nm to about 680 nm that is absorbed by the photosensitizing composition so as to inhibit or eliminate at least one type of hepatitis viruses that comes into contact with the host tissues; and repeating the steps (a) and (b) at least every two hour during the intrapartum period. [0013] The present invention provides a vaginal probe comprising: a member having a base portion, an insert portion adapted for insertion into a vagina of a mother and for providing desired illumination pattern for photodisinfection of host tissues of birth canal of the mother, and a pocket adapted for communication with

A.t-oi iεy Docket Nu 124b 090 V\ O Piled V a EFS OP 1 Q'24/O7 a waveguide wherein the pocket includes a light dispersing section that is adapted for light communication with distal end of the waveguide which is connected to a light source for delivering light to the insert portion, and the member further includes an electronic assembly adapted for providing sonic energy for sonophotodisinfection of host tissues of birth canal of the mother.

DESCRIPTION OF THE PREFERRED ESVSBODiM I. Definitions

[0014] The following terms are intended to have the following general meanings as they are used herein:

1. Birth Canal the path through which a fetus travels in order to be born formed by the cervix, vagina, and vulva of a mother. The host tissues of the birth canal include at least some of the tissues of the cervix, vagina, and vulva that may come into contact with the fetus during the intrapartum period

2. Intrapartum period, the time period beginning from the onset of labor to the completion of delivery (including cutting of the umbilical cord) of a fetus from the mother's birth canal.

3. Light: light at any wavelengths that can be absorbed by a photosensitizing composition. Such wavelengths include wavelengths selected from the continuous electromagnetic spectrum such as ultraviolet ("UV"), visible, the infrared (near, mid and far), etc. The wavelengths are generally between about 100 nm to 10,000 nm, with exemplary ranges between about 160 nm to 1600 nm, between about 400 nm to about 900 nm, and between about 500 nm to about 850 nm, although the wavelengths may vary depending upon the particular photosensitizing composition used and the light intensity. Depending on the application, the light produced may be a single wavelength or multiple wavelengths The light may be produced by any suitable art-disclosed light source(s).

4. Light Source' a light emitting device such as laser, light emitting diode ("LEDs"), incandescent source, fluorescent source, or a combination thereof. The output of the light source is preferably adjustable so that the

Attorney Docket No. 1248.090 WO Filed Via EFS on 10/24/07 operator can modify the wavelength, the power output, the size of illumination, or combinations thereof whϋe carrying out the present method. For example, the wavelength of a laser may be adjusted to activate different photosensitizers in the photosensitizing composition. Alternately, the power of the Sight source may be increased or decreased after an application of Sight energy to the treatment area. In addition, the Sight source may comprise a temperature monitoring device so that over heating of the host tissues in and around the treatment area may be avoided. Suitable temperature monitoring devices may comprise an IR device, a fiber optic device, a thermocouple, or a combination thereof.

5. Microorganisms: any and al! disease-related microorganism and/or microorganisms such as virus, fungus, and bacteria. Some examples of microorganisms include but are not limited to, HIV-1 , HBV, HCV, GBS, CMV, Listeria monocytogenes, Chlamydia trachomatis, E. coli, HSV, EBV, Toxoplasma gondii, HPV, and Candida.

6. Photosensitizing composition: a composition comprising at least one suitable art-disclosed photosensitizer that has at least an antimicrobiai action upon application of electromagnetic energy of certain wavelength(s). Suitable photosensitizers inciude both Type I and Type Il photosensitizers, where Type ! photosensitizers produce a free radical upon the application of Sight and Type SI photosensitizers produce singlet oxygen upon the application of Sight. While photosensitizers that have other modes of operation (e.g. generation of heat) are contemplated, those types discussed above are preferred. Suitable classes of compounds that may be used as antimicrobial photosensitizers include tetrapyrroSes or derivatives thereof such as porphyrins, chlorins, bacteriochiorins, phthaiocyanines, naphthalocyanines, texaphyrins, verdins, purpurins or pheophorbides, phenothiazines, etc., such as those described in U.S. Patent Nos. 6,211 ,335; 6,583,117; and 6,607,522 and U.S. Patent Publication No. 2003- 0180224. Preferred phenothiazines inciude methylene blue (MB), toluidine bSue (TBO), and those discussed in U.S. Patent Publication No. 2004-0147508. Other preferred antimicrobial photosensitizers include indocyanine green (ICG). Combinations of two or more photosensitizers, such as MB and TBO or the like,

Attorney Docket No 1248 090WO Filed V-a FFS on ' 0/24/07 are also suitable. The photosensitizer may be present in the photosensitizer composition in any suitable amounts. Examples are between about 0.001 percentage of total weight (wt %) and 10 wt %, between about 0.005 wt % and about 1 wt %, between about 0.01 wt % to about 0.5 wt %, and between about 0.02 wt % to about 0.1 wt %. The photosensitizing composition may optionally contain a therapeutic agent, which is any chemical, drug, medication, proteinaceous molecule, nucleic acid, lipid, antibody, antigen, hormone, nutritional supplement, cell or any combination thereof that helps ameliorate a condition. Preferred therapeutic agents include those that promote wound healing, have antimicrobial action, have anti-inflammatory action, and/or provide pain relief. The photosensitizing composition may also optionally contain carriers, diluents, or other solvents for the photosensitizer or other components of the composition and may be used to adjust the concentration of photosensitizer. The photosensitizing composition may be any suitable phase such as a liquid, gel, paste, putty, or solid. Preferably, the compositions has a viscosity low enough to flow into the treatment site while also having a viscosity high enough to maintain the composition within the treatment site. Further compositions that become liquid after application to the treatment site are contemplated such as those that melt or go into solution at the treatment site. Alternately, the composition may gel after application to the treatment site as a liquid; this would permit the composition to cover the treatment site effectively, while also maintaining the composition in the treatment site. The photosensitizers mentioned above are examples and are not intended to limit the scope of the present invention in any way.

7. Sonic energy; ultrasound, sonic waves or energy produced by a sonic or ultrasonic device. The sonic energy (e.g., vibration) is generally between the range of about 1 MHz to about 7MHz, with exemplary ranges between about 2KHz to about 5MHz and between about 2MHz to about 4MHz.

Attorney Docket No 124S 090WO Filed Via EFS on 10/24/07

H. Methods to Prevent Vertical Transmission of infectious Diseases [0015] The present invention provides a method of preventing vertical transmission of an infectious disease comprising applying a photosensitizing composition to host tissues of a birth canal of a mother during the intrapartum period, in one embodiment, the photosensitizing composition includes the photosensitizer methylene blue at exemplary concentration ranges of from about 0.001 wt % and about 10 wt %, from about 0,01 wt % to about 5 wt%, and from about 0.1 wt % to about 1 wt %. This applying step can be accomplished with any art-disciosed applicator. It is preferred that the applicator is sterile. For example, a iarge sterile swab or soft foam-tipped appiicator can be used. [0016] After the photosensitizing composition has been applied to the birth canal, the method further includes applying light to the host tissues of the birth canal at a wavelength absorbed by the photosensitizing composition so as to inhibit or eϋminate disease causing microorganisms that come into contact with tissues of the birth canai. it is preferred that prior to the light application step, the photosensitizing composition is placed into contact with the host tissues of the birth canai for a period of time. Exampiary ranges are for at least about 1 second, at least about 5 seconds, at least about 10 seconds, at ieast about 30 seconds, and at least about 1 minute.

[0017] Depending on the formulation of the photosensitizing composition, the application of light can be at various wavelength(s). For example, for the photosensitizing composition containing methylene biue, the wavelength may range from about 650 nm to 685 nm, from about 660 nm to about 680 nm, and from about 665 nm to about 675 nm.

[0018] Furthermore, the amount of time desired for the light application step is generally depended upon nature of the light source and the formuiation of the photosensitizing composition (e.g., the concentration of the photosensitizer(s) or the like). ExampSary duration of time for the Sight appiication step ranges from about 30 seconds to about 20 minutes, from about 1 minute to about 15 minutes, and from about 3 minutes to about 10 minutes. The light energy provided during each light application step preferably ranges from about 1 J/cm ² to about 25

Attorney Docket No. 1248.000WO Filed Via EFS on 10/24/07

J/cm ² , more preferably at about 5 J/cm ² to about 20 J/cm ² , and most preferably at about 6 J/cm ² to about 12 J/cm ² .

[0019] It is preferred that during the intrapartum period, the method of applying the photosensitizing composition and light to the host tissues of the birth canai is repeated multiple times. For example, this method can be applied from about 30 minutes to every 2 hours (e.g., at least every 30 minutes, every 45 minutes, every hour, every VA hours, every 2 hours, etc.) during the intrapartum period. The method may optionally further include applying the photosensitizing composition and Sight to the host tissues of the birth canal prior to the intrapartum period. For example, a practitioner may appiy the photosensitizing composition and light to the host tissues of the birth cana! from at least about 5 minutes to at least about 1 hour prior to the intrapartum period.

[0020] As noted above, the practitioner may apply multiple cycles of the light application steps (e.g., about 2 to about 10, about 3 to about 5, etc.) to the host tissues of the birth canal thereby resulting in a total accumulated light energy applied to the host tissues that can be substantially higher than the light energy provided during each light application step. It is preferred that the appiication of light to the host tissues does not cause physiological damage to such host tissues.

[0021J The application of light can be delivered by using any suitable art- disclosed light source. For example, the light source can be the light delivery devices and systems disclosed in commonly owned co-pending U.S. patent application number 11/741 ,584 titled "Photodisinfection Delivery Devices And Methods" filed on April 27, 2007, which is hereby incorporated by reference. [0022] The method of the present invention optionally further includes applying sonic energy to the host tissues of the birth canal during the intrapartum period. The sonic energy application step is achieved by applying an art- disclosed ultrasound gel either to the host tissues of the birth canal and/or the skin in the abdominal area above the birth and then applying sonic energy to the host tissues of the birth canal. The sonic energy can be supplied by any art- disciosed sonic device. For example, the sonic device can be ultrasound

Attorney Docket No 1248.090WO Filed Via EFS on 10/24/07 machines that are currently available in the market for OB/GYN uses such as the Logia models manufactured by Genera! Electric and other models manufactured by Toshiba, Siemens, and Philips. The sonic energy (e.g., vibration) is generally preferred to be between the range of about 1 MHz to about 7MHz, with exemplary ranges between about 2MHz to about 5MHz and between about 3MHz to 4MHz. [0023] In one embodiment of the present invention, the applications of photosensitizing composition, light and sonic energy to the host tissues of the birth canal are repeated multiple times during the intrapartum period. For example, this method can be applied from about 30 minutes to every 2 hours (e.g., at least every 30 minutes, every 45 minutes, every hour, every VA hours, every 2 hours, etc.) during the intrapartum period. The method optionally includes the applications of photosensitizing composition, light and sonic energy to the host tissues of the birth canal from at least about 5 minutes to at !east about 1 hour prior to the intrapartum period.

[0024] The methods described above are to be used to prevent vertical transmission of infectious diseases during the intrapartum period, especially infectious diseases caused by HIV-1 , HBV, HCV, GBS, CMV, Listeria monocytogenes, Chlamydia trachomatis, E. coli, HSV, EBV, Toxoplasma gondii, HPV, and Candida.

[0025] In another embodiment of the present invention, the applications of light and sonic energy are accomplished with a vaginal probe that incorporates a suitable art-disclosed light source into a conventional vaginal ultrasound probe. Another embodiment of the vaginal probe is the light delivery device disclosed in commonly owned co-pending U.S. patent application number 11/741 ,584 comprising: a member having a base portion, an insert portion adapted for insertion into a vagina of a mother and for providing desired illumination pattern for photodisinfection of host tissues of birth canal of the mother, and a pocket adapted for communication with a waveguide wherein the pocket includes a light dispersing section that is adapted for light communication with distal end of the waveguide which is connected to a light source for delivering light to the insert portion. The member further includes an art-disclosed electronic assembly

λttorne> Docket No. 1248.090 WO Filed Via EFS on 10/24/07 adapted for providing sonic energy for sonophotodisinfection of host tissues of birth cana! of the mother.

[0026] The explanations and illustrations presented herein are intended to acquaint others skilled in the art with the invention, its principles, and its practical application. Those skilled in the art may adapt and apply the invention in its numerous forms, as may be best suited to the requirements of a particular use. Accordingiy, the specific embodiments of the present invention as set forth are not intended as being exhaustive or limiting of the invention. The scope of the invention should, therefore, be determined not with reference to the above description, but should instead be determined with reference to the appended claims, along with the full scope of equivalents to which such claims are entitled. The disclosures of all articles and references, including patent applications and publications, are incorporated by reference for all purposes.