Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides
  • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
  • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
  • A61K38/22—Hormones
  • A61K38/2292—Thymosin; Related peptides
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • 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
• • 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
  • A61P31/04—Antibacterial agents
• • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
  • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
  • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
  • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
  • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

• the present invention relates to the field of sepsis including prevention of, reduction in severity, or treatment of sepsis by administering an alpha thymosin peptide regimen.
• Septic shock is a condition in which infection is widely disseminated in many areas of the body, the infection generally being disseminated through the blood from one tissue to another and causing extensive damage.
• Septic shock can occur with numerous medical conditions, including (1 ) peritonitis caused by the spread of infection from the uterus and fallopian tubes; (2) peritonitis resulting from rupture of the gut, sometimes caused by intestinal disease or wounds; (3) generalized infection resulting from spread of a simple infection; (4) generalized gangrenous infection resulting specifically from gas gangrene bacilli; and (5) infection spreading into the blood from the kidney, urinary tract or the abdomen.
• Sepsis frequently occurs as a hospital-acquired infection, contributing to the significant patient mortality and morbidity, and add significantly to the overall cost of healthcare [Michael Klompas, Prevention of ventilator-associated pneumonia, Expert Rev. Anti Infect. Ther. 8(7), 791 -800 (2010); Wheeler DS et al., Novel Pharmacologic Approaches to the Management of Sepsis: Targeting the Host Inflammatory Responses, Recent Pat. Inflamm. Allergy Drug Discov. 3(2):96-1 12 (2009)]. In fact, sepsis was reported as the 10 th leading cause of death in 2004. (See, e.g., Wheeler et al. (2009)).
• a strong and rapid immune response to pathogens is important for preventing, treating and/or reducing the severity of sepsis due to viral, bacterial, and fungal infections.
• a means for reducing the impact of infection and to help to prevent, reduce or treat sepsis is of great need.
• the present invention provides methods for treating sepsis.
• the invention involves the administration of an alpha thymosin peptide regimen wherein the administration provides statistically significant therapeutic effect for the treatment of sepsis.
• the subject is human. In some embodiments, the subject is immune deficient.
• the sepsis is hospital acquired. In some embodiments, the sepsis is due to bacterial, fungal or viral infection.
• the subject shows one or more signs or symptoms of an infection. In some embodiments, the subject shows one or more signs or symptoms of sepsis.
• the alpha thymosin peptide is administered at least about 0.5 mg per day, or at about 0.5 to about 3 mg per day, or at about 1 .6 to about 3.2 mg per day or at least at about 1 .6 mg per day.
• the alpha thymosin peptide is administered intravenously.
• the alpha thymosin peptide is administered by continuous infusion or subcutaneous injection.
• alpha thymosin peptide is administered from about 1 to 4 times daily. In some embodiments, alpha thymosin peptide is administered approximately twice daily. In some embodiments, alpha thymosin peptide is administered approximately once per day. In some embodiments, alpha thymosin peptide is administered about twice per day for at least 5 days (e.g., from 5 to 14 days). In some embodiments, alpha thymosin peptide is administered about twice per day for about 5 to 10 days (or about 5 days) followed by about once per day for at least two days, or about 2 to 7 days, or about 2 days.
• the invention provides a method for treating sepsis by administering an alpha thymosin peptide regimen.
• the patient has been diagnosed as having sepsis.
• the sepsis may be of bacterial, viral, fungal, or mixed or unknown etiology.
• the sepsis is associated with an infectious organism selected from Lysteria monocytogenes, Pseudomonas sp. ⁇ e.g., P. aeruginosa), Serratia marcescens, Clostridium difficile, Staphylococcus aureus, Staphylococcus sp., Acinetobacter spp., Enterococcus sp., Enterobacter sp., E. coli, Klebsiella sp., Streptococcus (e.g., S. pneumoniae), Haemophilus influenzae, and Neisseria meningitidis.
• an infectious organism selected from Lysteria monocytogenes, Pseudomonas sp. ⁇ e.g., P. aeruginosa), Serratia marcescens, Clostridium difficile, Staphylococcus aureus, Staphylococcus sp., Acinetobacter spp.,
• the sepsis is associated with one or more drug resistant microorganisms, such as Staphylococcus aureus, Staphylococcus sp., Enterococcus sp., Pseudomonas sp., Klebsiella sp., E. coli, and/or Clostridium Difficile.
• the sepsis is associated with a methicillin-resistant or vancomycin-resistant Staphylococcus aureus, including intermediate resistant isolates, and/or carbapenum-resistant E. coli, Klebsiella, or Pseudomonas, including intermediate resistant isolates.
• the alpha thymosin peptide regimen may be administered concurrently with the standard of care, such as antibiotic or antiviral therapy.
• the alpha thymosin peptide regimen reduces the duration of the sepsis and/or reduces the duration of required antibacterial, antiviral, or antifungal treatment.
• Figure l provides a diagram of the Study Profile for the study described in Example 1 . ( ⁇ 1 , thymosin alpha 1 )
• Figure 2 describes Kaplan-Meier estimate of the probability of 28-day survival in the presence and absence of thymosin alpha 1 . ( ⁇ 1 , thymosin alpha 1 )
• Figure 3 describes the analysis of the rates and risks of death from any cause within 28 days in prespecified subgroups.
• APACHE Acute Physiology and Chronic Health Evaluation
• CI confidence interval
• HLA-DR human leukocyte antigen-DR
• SOFA Sequential Organ Failure Assessment.
• the present invention is based in part on the discovery that certain regimen of alpha thymosin peptide therapy can be used to treat sepsis, especially certain low dosage administration of alpha thymosin peptide therapy can provide statistically significant therapeutic effect for the treatment of sepsis. Accordingly the present invention provides methods for the treatment of sepsis by administering a regimen of alpha thymosin peptide to a subject and wherein the administration provides statistically significant therapeutic effect for the treatment of sepsis.
• sepsis includes any recognized form of sepsis, e.g., hospital-acquired sepsis, medical procedure related sepsis, medical device related sepsis, severe sepsis, or septic shock. Sepsis also includes any recognized condition or symptom associated with sepsis. In general, symptoms of sepsis include but are not limited to fever above 10 ⁇ .3 ⁇ (38.5°C) or below 95°F (35°C), heart rate higher than 90 beats per minute, respiratory rate higher than 20 breaths a minute, and probable or confirmed infection (i.e., presence of one or more infectious agents such as bacteria, fungi or viruses).
• a clinical diagnosis of sepsis includes the presence of a least two symptoms selected from the sepsis symptoms. Symptoms of severe sepsis include but are not limited to significantly decreased urine output, abrupt change in mental status, decrease in platelet count, difficulty breathing, abnormal heart pumping function and abdominal pain. Typically, a clinical diagnosis of severe sepsis includes the presence of a least one additional symptom selected from the severe sepsis symptoms, the presence of which is indicative of organ failure. Symptoms of septic shock can include but are not limited to extremely low blood pressure that does not respond to simple fluid replacement. Typically, a clinical diagnosis of septic shock includes the presence of at least one additional symptom selected from the septic shock symptoms.
• sepsis can be caused due to a variety of infectious agents, including bacteria, fungi, viruses and parasites, and can proceed from merely infection to multiple organ dysfunction syndrome (MODS) and eventual death if untreated.
• MODS organ dysfunction syndrome
• sepsis may involve, for example, bacteremia or fungal infection, such as candidemia or aspergillis infection.
• sepsis may result from severe injury, severe wound, or burn, and may be a postsurgical infection
• treatment of sepsis includes any form of treating or preventing sepsis, e.g., reducing any symptom of sepsis, reducing the severity of any symptom of sepsis, delaying the onset of sepsis, shortening the duration of one or more symptoms of sepsis, reducing the opportunity or occurrence of sepsis, treating or inhibiting any cause or condition associated with sepsis, reducing any clinical criteria or measurement of the degree or condition of sepsis, e.g., ICU frequency, ICU stay, ICU free days, duration of ventilation, ventilation free days, mortality, e.g., 28 day mortality, in-ICU mortality, in-hospital mortality, etc., dynamic change of SOFA, HLA-DR expression, etc.
• the invention involves administering a regimen of alpha thymosin peptide to enhance immune responses to pathogen exposure, or potential pathogen exposure in order to treat sepsis.
• Thymosin alpha was originally isolated from bovine thymus, where it was shown to reconstitute "immune function" in thymectomized animal models. Thymosin is thought to play a role in inflammatory and innate immune responses, and to facilitate discrimination of self from non-self in mammals. Activation of certain Tolllike receptors (TLR; also known as PAMP or pathogen-associated molecular patterns) by thymosin leads to stimulation of intracellular signal transduction pathways resulting in expression of co-stimulatory molecules, pro-inflammatory cytokines, nitric oxide, and eicosanoids. Thymosin may affect, for example, precursor cells, dendritic cells, T cells, B cells, and NK cells.
• TLR Tolllike receptors
• alpha thymosin peptides activate Toll-like Receptor 9 (TLR), resulting in increases in Th1 cells, B cells, and NK cells, thereby priming the immune system for an enhanced immune response.
• TLR Toll-like Receptor 9
• TA1 may increase or enhance lymphocytic infiltration, secretion of chemotactic cytokines, maturation and differentiation of dendritic cells, secretion of thymopoeitic cytokines including IFN-a, IL-7, and IL-15, and B cell production of antibodies.
• alpha thymosin peptides to be used in methods of the present invention include thymosin alpha 1 ("TA1 "; "Ta1 "), and peptides having structural homology to TA1 .
• TA1 is a peptide having the amino acid sequence (N-acetyl)-Ser-Asp-Ala-Ala-Val-Asp-Thr-Ser-Ser-Glu-lle-Thr-Thr-Lys-Asp- Leu-Lys-Glu-Lys-Lys-Glu-Val-Val-Glu-Glu-Ala-Glu-Asn-OH (SEQ ID NO: 1 ).
• TA1 The amino acid sequence of TA1 is disclosed in U.S. Patent 4,079,127, the disclosure of which is hereby incorporated by reference.
• TA1 is a non-glycosylated 28-amino acid peptide having an acetylated N-terminus, and a molecular weight of about 3108.
• a synthetic version of TA1 is commercially available in certain countries under the trade name ZADAXIN.
• alpha thymosin peptides suitable for methods of the present invention include naturally occurring TA1 (e.g., TA1 purified or isolated from tissues), synthetic TA1 , recombinant TA1 as well as any suitable TA1 analogs with substantially the same or better function of TA1 .
• the thymosin peptide comprises the amino acid sequence of SEQ ID NO:1 (where an acylated, e.g., acetylated, N-terminus is optional).
• the thymosin peptide comprises an amino acid sequence that is substantially similar to TA1 , and maintains the immunomodulatory activity of TA1 .
• the substantially similar sequence may have, for example, from about 1 to about 10 amino acid deletions, insertions, and/or substitutions (collectively) with respect to TA1 .
• the thymosin peptide may have from about 1 to about 5 (e.g., 1 , 2, or 3) amino acid insertions, deletions, and/or substitutions (collectively) with respect to TA1 .
• the alpha thymosin peptide may comprise an abbreviated TA1 sequence, for example, having deletions of from 1 to about 10 amino acids, or from about 1 to 5 amino acids, or 1 , 2 or 3 amino acids with respect to TA1 . Such deletions may be at the N- or C-terminus, and/or internal, so long as the immunomodulatory activity of the peptide is substantially maintained.
• the substantially similar sequence may have from about 1 to about 5 amino acid insertions (e.g., 1 , 2, or 3 amino acid insertions) with respect to TA1 , where the immunomodulatory activity of TA1 is substantially maintained.
• the substantially similar sequence may have from 1 to about 10 amino acid substitutions, where the immunomodulatory activity is substantially maintained.
• the substantially similar sequence may have from 1 to about 5, or 1 , 2, or 3 amino acid substitutions, which may include conservative and non-conservative substitutions.
• the substitutions are conservative.
• conservative substitutions include substitutions of a chemically similar amino acid (e.g., polar, non-polar, or charged).
• Substituted amino acids may be selected from the standard 20 amino acids or may be a non-standard amino acid ⁇ e.g., a conserved non-standard amino acid).
• the alpha thymosin peptide includes a TA1 sequence substituted with one or more non-natural or modified amino acids. In some other embodiments, the alpha thymosin peptide includes a TA1 sequence conjugated to one or more entities. In some embodiments, the alpha thymosin peptide is pegylated to increase its half-life in circulation. Such strategies for increasing the half-life of therapeutic proteins are well known.
• the thymosin peptide comprises an amino acid sequence having at least 70% sequence identity to SEQ ID NO:1 , while maintaining the immunomodulatory activity of TA1 .
• the thymosin peptide may comprise an amino acid sequence having at least 80%, 85%, 90%, 91 %, 92%, 93%, 94%, 95%, 96% or 97% sequence identity to SEQ ID NO:1 .
• the thymosin peptide may comprise an amino acid sequence having 100% sequence identity to SEQ ID NO:1 .
• the N-terminus may be optionally acylated (e.g., acetylated) or alkylated, for example, with a C1 -C10 or C1 -C7 acyl or alkyl group.
• acylated e.g., acetylated
• alkylated for example, with a C1 -C10 or C1 -C7 acyl or alkyl group.
• the substantially similar and homologous peptides described above may function at a level of at least about 50%, 60%, 70%, 75%, 80%, 85%, 90%, 91 %, 92%, 93%, 94%, 95%, 96% or 97% relative to TA1 (SEQ ID NO:1 ).
• the alpha thymosin peptide may be prepared synthetically, for example, by solid phase synthesis, or may be made recombinantly and purified by known techniques.
• the alpha thymosin peptide may be provided in lyophilized form, and reconstituted with sterile (e.g., aqueous) diluent prior to administration.
• sterile e.g., aqueous
• the alpha thymosin peptide of the present invention is administered in a regimen for the treatment of sepsis.
• Such regimen includes dosage per administration, per day, as well as number of days per treatment cycle, or combinations thereof.
• the alpha thymosin can be administered at a dosage of from about 0.2 mg to 20 mg, 0.2 mg to 15 mg, 0.4 to 10 mg, 0.5 mg to 8 mg. 0.5 mg to 6 mg, 0.5 mg to 3 mg. In some embodiments, the alpha thymosin is administered at 0.2 mg, 0.5mg, 0.4 mg, 0.8 mg, 1 mg, 1 .6 mg, 3 mg, 3.2 mg, 6.4 mg or about 8 mg.
• the alpha thymosin peptide is administered to a human patient at a dose corresponding to at least about 0.5 mg (e.g., at least about 0.8 mg, or at least about 1 .6 mg), at least about 3 mg (e.g., at least about 3.2 mg), or at least about 5 mg (e.g., at least about 6.4 mg) of TA1 .
• the thymosin peptide is administered within the range corresponding to about 0.1 to 20 mg of TA1 , or about 1 to 10 mg of TA1 , or about 2 to 10 mg of TA1 , or about 2 to 8 mg of TA1 , or about 2 to 7 mg of TA1 .
• the dosage unit is within a range of about 3 to 6.5 mg, such as about 3.2 or 6.4 mg of TA1 .
• the TA1 dose is adjusted to the size of the patient, and may be provided at from 10 to 100 ig I kg (e.g., about 20, 40, 60, or 80 g / kg). Dosages may also be adjusted for the condition of each patient as well as other drugs taken by the patient. In addition, dosages may be adjusted according to the species of the subject, but in each case, approximately correspond to the human equivalent of TA1 (mg/kg).
• such dosage is administered hourly, daily, weekly or monthly.
• alpha thymosin peptide is administered hourly, about every 1 to 24 hours, 1 to 20 hours, 1 to 16 hours, 1 to 12 hours, 1 to 8 hours, 1 to 6 hours, 1 to 4 hours, 1 to 2 hours or every hour. In some embodiments, the alpha thymosin peptide is administered about every 2, 3, 5, 5, or 6 hours, or is administered about every 10 minutes, 15 minutes, 30 minutes, 45 minutes or 60 minutes.
• the thymosin peptide can be administered by a plurality of injections (sub-doses of thymosin peptide) on a treatment day, so as to substantially continuously maintain an immune stimulating-effective amount of the thymosin peptide in the patient's circulatory system for a longer period of time.
• Suitable injection regimens may include an injection every 2, 3, 4, 6, etc. hours on the day of administration ⁇ e.g., from 2 to 5 injections), so as to substantially continuously maintain the immune stimulating-effective amount of the thymosin peptide in the patient's circulatory system on the day of thymosin treatment.
• the TA1 may be administered by continuous infusion.
• Continuous infusion of TA1 is described in detail in US 2005/0049191 , the entire disclosure of which is hereby incorporated by reference. Briefly, continuous infusion of thymosin peptide maintains an immune stimulating-effective amount of a thymosin peptide in a patient's circulatory system for a longer period.
• the thymosin peptide may be administered to the patient for treatment periods of at least about 2, 4, 6, 10, 12 hours, or longer, which may improve effectiveness in some embodiments.
• the infusion may be carried out by any suitable means, such as by minipump.
• the alpha thymosin is administered by continuous infusion for about 1 to 168 hours, 1 to 144 hours, 1 to 120 hours, 1 to 96 hours, 1 to 72 hours, 1 to 48 hours, 1 to 24 hours, 1 to 20 hours, 1 to 16 hours, 1 to 12 hours 1 to 10 hours, 1 to 8 hours, 1 to 6 hours, 1 to 4 hours to 1 to 2 hours.
• the alpha thymosin peptide is administered by continues infusions for about 10 minutes, 15 minutes, 30 minutes, 45 minutes or 60 minutes.
• the alpha thymosin is administered by continuous infusion for about 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 10 hours, 12 hours, 24 hours or more.
• the continuous infusion periods are separated by periods of non-infusion (i.e., periods where no alpha thymosin is administered).
• the non-infusion period ranges from 1 to 168 hours, 1 to 144 hours, 1 to 120 hours, 1 to 96 hours, 1 to 72 hours, 1 to 48 hours, 1 to 24 hours, 1 to 20 hours, 1 to 16 hours, 1 to 12 hours 1 to 10 hours, 1 to 8 hours, 1 to 6 hours, 1 to 5 hours, 1 to 4 hours, 1 to 3 hours, 1 to 2 hours. In some embodiments, the non-infusion period is about 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 10 hours, 12 hours, 24 hours or more.
• a predetermined amount of alpha thymosin peptides may be substantially continuously maintained in a patient's circulatory system by administering the TA1 peptide to the patient at a rate within a range of about 0.0001 - 0.1 mg/hr/Kg patient body weight.
• exemplary administration rates are within a range of about 0.0003-0.03 mg/hr/Kg patient body weight.
• the TAI peptide is present in a pharmaceutically acceptable liquid carrier, such as water for injection, or saline in physiological concentrations.
• the thymosin is administered about every 1 to 20 days, every 1 to 15 days, every 1 to 10 days, every 1 to 7 days, every 1 to 5 days, every 1 to 3 days or daily.
• the alpha thymosin is administered for about 1 to 100 days, 1 to 90 days, 1 to 80 days, 1 to 70 days, 1 to 50 days, 1 to 40 days, 1 to 30 days, 1 to 20 days, 1 to 15 days, 1 to 10 days, 1 to 7 days, 1 to 5 days, 1 to 3 days, 1 to 14 days, 5 to 14 days or 1 to 2 days.
• the alpha thymosin is administered for about 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18 ,19 , 20, 25, 30 or more days.
• alpha thymosin peptide is administered about twice per day for at least 5 days(e.g., from 5 to 14 days).
• alpha thymosin peptide is administered about twice per day for about 5 to 10 days (or about 5 days) followed by about once per day for at least two days, or about 2 to 7 days, or about 2 days.
• the alpha thymosin is administered for about 1 to 8 weeks, about 1 to 6 weeks, about 1 to 5 weeks, about 1 to 4 weeks, about 2 to 4 weeks, or about 1 -2 weeks. In some embodiments, the thymosin is administered for 1 week, 2 weeks, 3 weeks, 4 weeks, 5, weeks, 6 weeks, 7 week, 8 weeks or more. In some embodiments, the thymosin is administered for about 1 month, 2 months, 3 months or 4 months or more. In some embodiments, the alpha thymosin peptide is administered for about 1 to 4 months, 1 to 3 months, 1 to 2 months, or about one month.
• the alpha thymosin peptide is administered about 1 to 8 times per day for about 1 to 8 weeks. In some embodiments, the alpha thymosin peptide is administered about 1 to 7 times per day, 1 to 6 times per day, 1 to 5 times per day, 1 to 4 times per day, 1 to 3 times per day, 1 to 2 times per day, or about 1 times per day for about 1 to 7 weeks, 1 to 6 weeks, 1 to 5 weeks, 1 to 4 weeks, 1 to 3 weeks, 1 to 2 weeks, or about 1 weeks.
• the alpha thymosin peptide is administered about 1 to 8 times per day, 1 to 7 times per day, 1 to 6 times per day, 1 to 5 times per day, 1 to 4 times per day, 1 to 3 times per day, 1 to 2 times per day, or about 1 times per day for about 1 to 30 days, 1 to 25 days, 1 to 20 days, 1 to 15 days, 1 to 7 days or 1 to 5 days. In some embodiments, the alpha thymosin peptide is administered for 1 to 4 times per day for 1 to 30 days. In some embodiments, the alpha thymosin peptide is administered for about 1 -2 times per day for 1 to 15 days or 1 to 7 days or 1 to 5 days.
• the alpha thymosin peptide is administered about 1 to 2 times per day for 5 days followed by once per day for 2 days. In some embodiments, the alpha thymosin peptide is administered about twice daily for 5 days followed by once per day for 2 days. In some embodiments, the alpha thymosin is administered about four times per day for 5 days or 7 days.
• the regimen employs a dosage of alpha thymosin peptide that is at least 0.2 mg, 0.5 mg, 0.8 mg, 1 .6 mg, 3.2 mg, or 6.4 mg, with 1 , 2, 3, 4, 5, 6, 7 or 8 or more. In some embodiments, 3 doses or less can be administered. In some embodiments more dosages may be administered, such as 5, 6, 7, 8, 9 or 10, 1 1 , 12, 13, 14, 15, 20, 25, 30, 35, 40, 45, 50 or more. In some embodiments, the dose of thymosin is a relatively low dose of at least 0.2 mg, 0.4 mg, 0.5 mg, 0.8 mg, or 1 .6 mg,.
• the alpha thymosin administrations may be spaced apart by about 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 16, 20 or 24 hours or about 1 , 2, 3, 4, 5, 6, 7, 8, 9 or 10 days, and may be given weekly in some embodiments, as is described in greater detail herein.
• the thymosin peptide e.g., TA1
• the thymosin peptide is administered at a dose within the range of about 0.5 mg to 3 mg.
• the thymosin peptide (e.g., TA1 ) is administered at a dose within the range of about 1 mg to 2 mg.
• the thymosin peptide is administered at a dosage of about 0.5 mg, about 0.8 mg, about 1 .6 mg, about 3 mg, about 3.2 mg, about 5 mg, or about 6.4 mg or more of thymosin peptide and optionally in combination with one or more treatment schedules described in this paragraph.
• the alpha thymosin peptide is administered 1 , 2, 3, 4 or more times per day for 1 , 2, 3, 4, 5, 6, 7, 8, 9, or 10, 1 1 , 12, 13, 14, 15, 16, 17, 18 ,19, 20, 25 or 30 days or more.
• the alpha thymosin peptide is administered for 1 , 2, 3, 4, 5, 6, 7 or 8 weeks or more.
• the thymosin is administered for 1 or 2 months or more. In some embodiments, the thymosin peptide is administered 1 , 2, 3, 4 or more times per day for 2, 3, 4, 5, 6, 7 or 8 days. In some embodiments, the thymosin peptide is administered 1 , 2, 3, 4 or more times per day for 4, 5, 6 or 7 days. In some embodiments, the thymosin peptide is administered 1 , 2, 3, 4 or more times per day for 5, 6, or 7 days.
• the thymosin peptide is administered 1 , 2, 3, 4 or more times per day for 1 , 2, 3, 4, 5, 6, 7, 8, 9, or 10 days or more, followed by 1 , 2, 3, 4 or more times per day for 1 , 2, 3, or 4 days or more. In some embodiments, the thymosin peptide is administered 1 , 2, 3, 4 or more times per day for 2, 3, 4, 5, 6, 7, or 8 days, followed by 1 , 2, 3, 4 or more times per day for 1 , 2, 3, or 4 days. In some embodiments, the thymosin peptide is administered 1 , 2, 3, 4 or more times per day for 4, 5, 6 or 7 days, followed by 1 , 2, 3, 4 or more times per day for 1 , 2, 3, or 4 days.
• the thymosin peptide is administered 1 , 2 or 3 times per day for 4, 5, 6 or 7 days, followed by 1 , 2 or 3 times per day for 1 , 2, 3, or 4 days. In some embodiments, the thymosin peptide is administered 2 times per day for 7 days. In some embodiments, the thymosin peptide is administered 2 times per day for 5 days. In some embodiments, the thymosin peptide is administered 1 time per day for 5 days. In some embodiments, the thymosin peptide is administered 2 times per day for 5 days, followed by once per day for 2 days. In some embodiments, about 1 .6 mg of the thymosin peptide is administered 2 times per day for 5 days, followed by once per day for 2 days.
• the timing of thymosin administration may be selected to enhance the immune response including antibody titers ⁇ e.g., the development or level of antibody titers) to cover a period of increased risk of sepsis.
• the thymosin peptide administrations are given about 5 days to about 9 days apart, and in various embodiments are administered about 1 , 2, 3, 4, 56, 7, or 8 days apart.
• the thymosin administrations may be given about 7 days apart (e.g., approximately weekly administration). In other embodiments, the thymosin peptide administrations are given 1 , 2, 3, or 4 days apart
• the regimen can be initiated at about 1 to 10 days (in some embodiments 5 to 9 days) prior to an event predicted (or with a significant risk) to result in sepsis, in order to provide for treatment/prevention of sepsis. Exemplary events are described herein.
• the efficient regimen involves from about 1 to 5 administrations of alpha thymosin peptide, such as 3 or less. The alpha thymosin peptide administrations may be spaced apart by about 1 , 2, 3, 4, 5, 6, 7, 8, 9 or 10 days, and may be given weekly in some embodiments.
• the alpha thymosin peptide is first administered prior to an event (as described), such as admittance to a healthcare facility, scheduled surgery, or placement of invasive medical device, and again on the day of the event, and optionally after the event.
• an event such as admittance to a healthcare facility, scheduled surgery, or placement of invasive medical device
• thymosin peptide may be administered from 1 to 10 days prior to the event, such as from about 5 to about 9 days prior to the event, and again on the day of the event.
• the thymosin peptide may be administered about 7 days prior to the event, and again on the day of the event, and optionally within 2 to 10 days after the event [e.g., from 4 to 8 days after the event).
• patients receiving two doses of TA1 in accordance with certain embodiments of the invention are likely to achieve a faster and/or larger response to sepsis, and which may be protective for at least 21 days, at least 42 days, or longer.
• the alpha thymosin peptide is administered prior to, along with and/or after an event predicted to result in pathogen exposure or introduction of an opportunistic environment, as described herein.
• the event may be admittance to a hospital or health care facility for a period of time ⁇ e.g., at least 3 days, at least one week, or at least ten days, or at least one month).
• the event is a scheduled surgery or invasive medical procedure, as described.
• the event is the placement of an invasive medical device as described.
• the event is kidney dialysis or initiation of chemotherapy or radiation therapy for cancer treatment (as described).
• the thymosin is administered within the first about 1 hour, 2 hours, 4, hours, 6 hours, 8 hours, 10 hours, 12 hours, 24 hours, 72 hours, 96 hours, 120 hours, 144 hours, or 168 hours, of a determination of sepsis.
• the alpha thymosin peptide is administered within the first about 10 minutes, 15 minutes, 30 minutes, 45 minutes or 60 minutes of a determination of sepsis.
• the regimen involves from 1 to 4 administrations of alpha thymosin peptide, such as 3 or less, and the regimen is timed to begin prior to an event anticipated to lead to sepsis.
• the regimen may be initiated from 2 to 10 days prior to the event, such as from 5 to 10 days prior, and a second dose may be administered on the day of the event.
• the alpha thymosin peptide administrations may be spaced apart by about 1 , 2, 3, 4, 5, 6, 7, 8, 9 or 10 days, and may be given weekly in some embodiments.
• the regimen involves a dose of alpha thymosin peptide, provided approximately weekly ⁇ e.g., every 5 to 9 days), for 2, 3, 4 or more weeks.
• the patient receives 2 doses of an alpha thymosin peptide (such as 2 mg to 8 mg per dose), and such doses are spaced by about 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 16, 20 or 24 hours or about 1 , 2, 3, 4, 5, 6, 7, 8, 9 or 10 days, or approximately weekly.
• This regimen may be repeated approximately monthly, or every other month, and may be particularly beneficial for protecting chronically ill and immunodeficient patients from sepsis.
• the thymosin peptide ⁇ e.g., TA1 is administered at a dose within the range of about 0.5 mg to 3 mg.
• the thymosin peptide ⁇ e.g., TA1 is administered at a dose within the range of about 1 mg to 2mg.
• the alpha thymosin peptide regimen is part of an institutional program to reduce the rate or incidence of sepsis, e.g., hospital-acquired sepsis.
• the regimen of alpha thymosin peptide involves administering the agent to the subject at a dose sufficient to enhance antibody titers, and/or sufficient to speed the development of antibody titers, to pathogen exposure.
• the regimen of alpha thymosin peptide involves a regimen provides serum level of alpha thymosin at about 0.01 to 10.0 ng/ml, 0.1 to 1 .0 ng/ml, or 0.05 to 5 ng/ml during treatment.
• the peak plasma levels of alpha thymosin peptide is at least about 10ng/ml, 20 ng/ml, 30 ng/ml, 40 ng/ml, 50 ng/ml, 60 ng/ml, 70 ng/ml, 80 ng/ml, 90 ng/ml, or 100 ng/ml.
• the regimen of alpha thymosin peptide involves administering the agent to the subject in a regimen so that the subject's pharmacokinetic (pK) profile is substantially the same, e.g., within at least 60%, 70%, 80%, 90% of the pK profile of a subject treated with 1 .6 mg of alpha thymosin twice a day for 5 days and then once a day for 2 days.
• the pK profile is increased to greater than 100% of the pK profile of a subject treated with 1 .6 mg of alpha thymosin twice a day for 5 days and then once a day for 2 days.
• the thymosin peptide may be provided in lyophilized form, and reconstituted with sterile ⁇ e.g., aqueous) diluent prior to administration.
• the thymosin peptide e.g., TA1
• the thymosin peptide may be administered by any effective route, including by subcutaneous injection, intramuscular injection, intravenous injection or infusion, and orally. In certain embodiments, the thymosin peptide is administered by subcutaneous injection or by intravenous infusion.
• the scheduled dose of thymosin may be administered as a single dose ⁇ e.g., injection), or may be spaced out over the course of 24 hours or less, for example, by continuous infusion or repeated injection of subdose, or the like or as described extensively herein.
• the scheduled dose of thymosin peptide may be administered as a single injection or as multiple injections.
• the alpha thymosin peptide is administered at a dose twice a day for a period of time and then administered at the same dose once a day for a period of time.
• alpha thymosin peptide is administered at about 1 .6 mg twice per day for 5 days and then
• the alpha thymosin peptide is administered at about 1 .6 mg three or four times per day for 5 to 7 days and then once or twice a day for 2 or 4 days.
• the patient receives TA1 at a dose of from 2 to 8 mg ⁇ e.g., at 0.8, 1 .6, 3.2 or 6.4 mg per dose) either once or two times daily, or every other day, for from 3 to 14 days (e.g., 3, 5, 7, 10, or 14 days).
• Such regimen may be timed with respect to an event that places the patient at further risk for exacerbation of the infection or complicating illness, such as those events described herein [e.g., surgery, hemodialysis, initiation of cancer treatment, placement of medical device).
• the event may be scheduled at a time between day 2 and day 10 of the regimen, including day 3, day 5, day 7, or day 10.
• the regimen may be concurrent with antibacterial, antiviral, or antifungal therapy, including with active agents described herein.
• the thymosin is administered within the first 24 hours, 48 hours, 72 hours, 96 hours, 120 hours or 144 hours.
• the patient receives approximately weekly administration of TA1 , at a dose between 0.5 and 8 mg [e.g., about 0.8, 1 .6, 3.2 or 6.4 mg), to protect or reduce the severity of sepsis.
• the regimen may continue in some embodiments for two to four weeks.
• the invention results in a reduced incidence of sepsis, reduced number of days in ICU, and/or reduced antimicrobial therapy.
• the alpha thymosin peptide of the present invention is administered to a subject with a regimen sufficient to treat sepsis.
• the alpha thymosin peptide regimen in some embodiments is an "efficient" regimen. That is, the regimen achieves its goal with relatively few administrations of alpha thymosin peptide and/or by timing the administration of alpha thymosin peptide with events anticipated to result in sepsis.
• the "event” is not a vaccination, but an exposure or increased susceptibility to the potential infectious agent that has the potential to lead or does lead to sepsis, severe sepsis or septic shock.
• the alpha thymosin peptide used in methods of the present invention can be administered either alone or in combination with a standard of care for sepsis, or as part of treatment regimen involving the standard of care for sepsis.
• the standard of care is a protease inhibitor, activated protein C, corticosteroids, intensive insulin therapy synthetic fluid replacement substance (pentastarch), drotrecognin alfa (activated; DrotAA), volume resuscitation, hydrocortisone and fludrocortisone.
• the methods provided by the present invention are applicable to both human and veterinary health.
• the subject is generally a mammal, such as a human, livestock (e.g., cow, horse, pig, sheep, etc.), or domestic mammal (e.g., cat or dog).
• livestock e.g., cow, horse, pig, sheep, etc.
• domestic mammal e.g., cat or dog.
• subject and patient and derivatives thereof can be used interchangeably for the methods of the present invention.
• the subject is immunodeficient.
• An immunodeficient subject e.g. , a human subject
• immunodeficient subjects include an elderly patient, newborn, leukemic or neutropenic patient, a patient on hemodialysis (e.g., for treatment of chronic renal disease), patient receiving immunosuppressant therapy, AIDS patient, diabetic patient, patient receiving chemotherapy or radiation therapy for cancer, immunodeficiency caused by a genetic defect, malnutrition, drug abuse, alcoholism, or other immunocompromising illness or condition.
• the immunocompromised subject is elderly. As humans and animals age, their immune response is reduced, and the robustness of the immune response is diminished due to the prevalence of low affinity antibody response. Accordingly, the subject in these embodiments may be a human patient over the age of 45, or over the age of 50. In some embodiments, the subject is a human patient 60 years of age or older, 65 years of age or older, or 70 years of age or older. [0067] In some embodiments, the subject is at risk of hospital-acquired sepsis, severe sepsis or septic shock.
• the regimen of thymosin peptide is administered to treat/prevent sepsis, in a patient at risk for sepsis.
• the alpha thymosin peptide regimen is used to prime the patient's immune system to provide a more rapid response to a pathogen exposure, which in some embodiments may be anticipated for the patient based upon a scheduled event, and can prevent sepsis.
• the subject may be scheduled for an invasive surgical procedure, and in these embodiments, the alpha thymosin peptide regimen reduces the risk and/or severity of post-surgical sepsis.
• invasive medical procedures carry a risk of infection
• exemplary procedures include joint replacement, organ or tissue transplantation or graft, introduction of a prosthesis, tissue removal including a tumor or cancerous tissue, tonsillectomy, appendectomy, splenectomy, thymectomy, kidney removal, amputation, removal of bone marrow, or other invasive medical procedure.
• the TA1 regimen may reduce the risk of sepsis.
• the patient may require assistance from an invasive medical device, which causes exposure of the body to microbes, and introduces an opportunistic environment for sepsis to occur.
• an invasive medical device which causes exposure of the body to microbes, and introduces an opportunistic environment for sepsis to occur.
• the device may lead to increased exposure to potential opportunists and pathogens.
• Such devices include without limitation, a ventilator, a urinary catheter, an arterial catheter, a feeding tube, i.v., stent, kidney dialysis, or artificial organ.
• the alpha thymosin peptide regimen helps to prime the patient's immune system to prevent or reduce the severity of any resulting sepsis, severe sepsis or septic shock.
• the patient is in need, or is under assistance of a pulmonary ventilator, and the TA1 regimen helps to prime the patient's immune system, and retain the immune system in a primed state, so as to reduce the risk or severity of ventilator-associated pneumonia.
• Ventilator-associated pneumonia occurs in patients on mechanical ventilation through an endotracheal or tracheostomy tube, and results from infection in the alveoli.
• Pseudomonas aeruginosa is the most common gram-negative bacterium causing VAP, and Pseudomonas has natural resistance to many antibiotics.
• VAP causative species for VAP
• Klebsiella pneumoniae which has natural resistance to some beta- lactam antibiotics such as ampicillin and/or carbapenum, as well as cephalosporins and aztreonam.
• Serratia marcescens, Enterobactersp., and Acinetobactersp. may also be associated with VAP, and can also be resistant to antibiotics.
• Staphylococcus aureus including MRSA
• the patient is on hemodialysis ⁇ e.g., due to chronic renal disease), or is scheduled to undergo hemodialysis. Since hemodialysis requires access to the circulatory system, patients undergoing hemodialysis may expose their circulatory system to microbes, which can lead to sepsis. Thus, in certain embodiments the TA1 regimen as described herein is initiated to prepare a patient for hemodialysis.
• the patient is a cancer patient, and is undergoing or scheduled to initiate chemotherapy and/or radiation therapy, which often negatively affects the patient's immune system.
• the chemotherapy is generally one that has deleterious effects on the immune cells, and may include one or more alkylating agents ⁇ e.g., cisplatin, carboplatin, and ifosfamide), antimetabolite (5-fluorouracil or antifolate), topoisomerase inhibitor ⁇ e.g., camptothecin, etoposide), or taxane ⁇ e.g., paclitaxel), among others.
• alkylating agents e.g., cisplatin, carboplatin, and ifosfamide
• antimetabolite (5-fluorouracil or antifolate
• topoisomerase inhibitor e.g., camptothecin, etoposide
• taxane e.g., paclitaxel
• the alpha thymosin peptide regimen is administered to prime the patient's immune system prior to cancer therapy in order to prevent or reduce sepsis.
• a regimen of alpha thymosin peptide as described herein is provided to leukemic and/or neutropenic patients, thereby preventing or reducing the severity of catheter-related sepsis, severe sepsis or septic shock that can be caused by drug resistant Streptococcus aureus ⁇ e.g., MRSA and VRSA).
• a regimen of alpha thymosin peptide as described herein is provided to bone marrow transplant patients, thereby preventing or reducing the severity of sepsis, such as those commonly caused by aspergillus, Candida, or CMV.
• a regimen of alpha thymosin peptide as described herein is provided to organ ⁇ e.g., kidney) transplant recipients, to thereby prevent organ rejection, which is sometimes a result of CMV based sepsis.
• the symptoms of sepsis are not present or are minor at the time of initiating the TAI regimen, but the presence of the microorganism or illness is determined by culture, ELISA, or other diagnostic test.
• the regimen of alpha thymosin peptide helps to prime the immune system to more rapidly develop an antibody response capable of resolving the infection.
• the alpha thymosin peptide regimen is an efficient regimen that is provided concurrently with the standard antibacterial, antiviral, or antifungal therapy.
• a variety of diagnostic tests for sepsis or its related conditions are known in the art and can be employed with the methods of the present invention as such tests would be well known to those of skill in the art.
• Such tests can include but are not limited to blood tests, other laboratory tests, and imaging scans.
• Blood tests can include but are not limited to tests for evidence of infection (i.e., presence of bacteria, fungi or viruses), clotting problems, abnormal liver or kidney function, impaired oxygen availability, electrolyte imbalances, depressed immune function (such as decreased levels of monocyte HLA-DR), other laboratory tests.
• laboratory tests can include but are not limited to urine tests (e.g., testing urine for infectious agents), wound secretion tests (e.g., testing wound secretions for infectious agents) and respiratory secretion tests (e.g., testing respiratory secretions such as sputum mucus for infectious agents).
• Imaging tests can include but are not limited to X-ray
• CT computerized tomography
• ultrasound e.g., for visualizing infections in the gallbladder or ovaries
• MRI magnetic resonance imaging
• the patient (or a patient sample, susceptible site for sepsis, or immediate surrounding environment) has tested positive for the presence of a gram positive or gram negative bacteria, including one or more infectious organisms, including, but not limited to: Lysteria monocytogenes, Pseudomonas sp. ⁇ e.g., P. aeruginosa), Serratia marcescens, Clostridium difficile, Staphylococcus aureus, Staphylococcus sp., Acinetobacterspp., Enterococcus sp., Enterobacteria sp., E.
• the infection involves, or an isolate is identified, as a drug resistant or multi-drug resistant microorganism, such as Staphylococcus aureus, Enterococcus sp., Pseudomonas sp., Klebsiella sp., E. coli, and/or Clostridium Difficile.
• the infectious agent is a drug-resistant S.
• the drug-resistant microorganism is methicillin-resistant or vancomycin-resistant Staphylococcus aureus (MRSA or VRSA), including intermediate resistant isolates, or is carbapenum-resistant E. coli, Klebsiella, or Pseudomonas including intermediate resistant isolates.
• MRSA methicillin-resistant or vancomycin-resistant Staphylococcus aureus
• the presence of such organisms may be determined or confirmed using diagnostics tests known in the art, or determined by a spike in the incidence of such infection at the healthcare facility.
• the patient is a neutropenic patient inflicted with a Pseudomonas, Acinetobacter, or E. coli infection, and the resulting sepsis, severe sepsis or septic shock may be due drug resistant microorganisms, or the patient is inflicted with ventilator-associated pneumonia, which may involve infection with Pseudomonas or Serratia, which may also lead to drug resistant sepsis, severe sepsis or septic shock.
• the regimen of alpha thymosin peptide may be administered concurrently with antibiotic therapy, including with beta-lactam antibiotic ⁇ e.g., methicillin, ampicillin, carbapenem, piperacillin); cephalosporin; fluoroquinolone (e.g., ciprofloxacin, levofloxacin, moxifloxacin), and/or macrolide ⁇ e.g., azithromycin, clarithromycin, dirithromycin, and erythromycin).
• the antibiotic therapy may be administered with additional therapeutics, such as a beta-lactamase inhibitor (tazobactam).
• alpha thymosin peptide reduces the duration of sepsis, and reduces the duration of required antibiotic treatment.
• the infection is determined to be resistant to such agent, prior to initiating alpha thymosin peptide treatment.
• the alpha thymosin peptide regimen is initiated, or continued, or repeated, after apparent resolution of sepsis, to help prevent recurrence after antibiotic therapy is complete.
• An efficient regimen of alpha thymosin peptide (e.g., 1 , 2, 3, 4, 5, or 6 doses) may span the full course of antibacterial therapy, and provide a boost in immune response for the entire period.
• the patient has sepsis resulting from a viral infection selected from cytomegalovirus (CMV), RSV, influenza virus, herpes simplex virus type 1 , and parainfluenza virus.
• CMV cytomegalovirus
• RSV cytomegalovirus
• influenza virus influenza virus
• herpes simplex virus type 1 herpes simplex virus type 1
• parainfluenza virus a viral infection selected from cytomegalovirus (CMV), RSV, influenza virus, herpes simplex virus type 1 , and parainfluenza virus.
• the alpha thymosin peptide regimen described herein may reduce the severity and/or duration of the viral based sepsis, severe sepsis or septic shock, and may be provided alongside the appropriate antiviral therapy, which may be a virus-neutralizing antibody or a small molecule inhibitor, such as Tamiflu.
• the alpha thymosin peptide regimen is initiated, or continued, or repeated, after apparent resolution of the viral based sepsis, severe sepsis or septic shock, to help prevent recurrence after other therapy is complete.
• the patient has a sepsis resulting from a fungal infection of Aspergillus (e.g., A. fumigatus) or Candida (e.g., Candida albicans), and these may also show resistance to antibiotic treatments.
• the thymosin peptide regimen is administered with antifungal treatment.
• Antifungal therapies include azole drug such as an imidazole (e.g., ketoconazole) or a triazole (e.g. fluconazole).
• the alpha thymosin peptide regimen is initiated, or continued, or repeated, after apparent resolution of the infection, to help prevent recurrence after antifunga [0082]
• administering of alpha thymosin peptide according to the methods of the present invention provides statistically significant therapeutic effect.
• the statistically significant therapeutic effect is determined based on one or more standards or criteria provided by one or more regulatory agencies in the United States, e.g., FDA or other countries.
• the statistically significant therapeutic effect is determined based on results obtained from regulatory agency approved clinical trial set up and/or procedure.
• the statistically significant therapeutic effect is determined based on a patient population of at least 300, 400, 500, 600, 700, 800, 900, 1000 or 2000. In some embodiments, the statistically significant therapeutic effect is determined based on data obtained from randomized and double blinded clinical trial set up. In some embodiments, the statistically significant therapeutic effect is determined based on data with a p value of less than or equal to about 0.05, 0.04, 0.03, 0.02 or 0.01 . In some embodiments, the statistically significant therapeutic effect is determined based on data with a confidence interval greater than or equal to 95%, 96%, 97%, 98% or 99%. In some embodiments, the statistically significant therapeutic effect is determined on approval of Phase III clinical trial of the methods provided by the present invention, e.g., by FDA in the US.
• the statistically significant therapeutic effect is determined by a randomized double blind clinical trial of a patient population of at least 300 or 350; treated with alpha thymosin peptides in combination with standard care, but not in combination with any protease inhibitor.
• the statistically significant therapeutic effect is determined by a randomized clinical trial of a patient population of at least 300 or 350 and using 28 day mortality rate, in-hospital mortality rate, ICU mortality rate, ICU duration, ICU free days, sequential organ failure assessment score (SOFA), relative risk of death, ICU frequency, duration of ventilation, frequency of ventilation, ventilation free days, HLA-DR expression or any combination thereof or any other commonly accepted criteria for sepsis assessment.
• SOFA sequential organ failure assessment score
• statistical analysis can include any suitable method permitted by a regulatory agency, e.g., FDA in the US or China or any other country.
• statistical analysis includes non-stratified analysis, log-rank analysis, e.g., from Kaplan-Meier, Jacobson-Truax, Gulliken-Lord-Novick, Edwards-Nunnally, Hageman-Arrindel and Hierarchical Linear Modeling (HLM) and Cox regression analysis.
• sepsis, severe sepsis or septic shock biomarkers can be used for predicting treatment response and/or determining treatment efficacy.
• mHLA-DR can be measured and improvement in mHLA-DR levels employed as an indicator of positive treatment response.
• decreased or reduced levels of mHLA-DR biomarker including protein expression levels, mRNA transcript levels, reduced number of mHLA-DR positive monocytes, which later increase upon administration of an alpha thymosin peptide is predictive of treatment response.
• this information can be employed in determining a treatment regimen (as described herein) for the treatment of sepsis, severe sepsis or septic shock using alpha thymosin peptides according to the present invention.
• the present invention provides methods for determining a treatment regimen which include detecting an increase or decrease in the level of a sepsis, severe sepsis or septic shock biomarker in a biological sample from a subject treated with an alpha thymosin peptide and determining a treatment regimen of the alpha thymosin peptide based on an increase or decrease in the level of one or more one or more sepsis, severe sepsis or septic shock biomarkers in a biological sample.
• the sepsis, severe sepsis or septic shock biomarker is mHLA-DR.
• a decreased or reduced level of mHLA-DR is indicative of treatment response and/or treatment efficacy of treatment with alpha thymosin for sepsis, severe sepsis or septic shock.
• a decreased or reduced level of mHLA-DR which is enhanced or increased in response to alpha thymosin peptide treatment is indicative of treatment response and/or treatment efficacy of treatment with alpha thymosin peptide for sepsis, severe sepsis or septic shock.
• recovery of mHLA-DR levels to a predetermined standard level is indicative of better treatment prognosis (e.g., better survival rate) in treatment with an alpha thymosin peptide.
• larger increases in mHLA-DR levels is indicative of better treatment prognosis in treatment with an alpha thymosin peptide.
• the phrase "determining the treatment efficacy" and variants thereof can include any methods for determining that a treatment is providing a benefit to a subject.
• treatment efficacy and variants thereof are generally indicated by alleviation of one or more signs or symptoms associated with the disease and can be readily determined by one skilled in the art as the alleviation of one or more signs or symptoms of the indication or disease being treated.
• Treatment efficacy may also refer to the prevention or amelioration of signs and symptoms of toxicities typically associated with standard treatments of a disease, i.e. chemotherapy or radiation therapy for the treatment of cancer.
• Such methods are indication and disease specific and can include any methods well known in the art for determining that a treatment is providing a beneficial effect to a patient.
• evidence of prevention, treatment or reduction of sepsis, severe sepsis or septic shock, as well as determining treatment response can include decreased incidence of sepsis, severe sepsis or septic shock as well as reduced in-hospital mortality, ICU mortality, increased ICU-free days, reduced number of days in ICU, reduced ICU duration, reduced ICU frequency, beneficial or improved sequential organ failure assessment score (SOFA), reduced duration of ventilation, reduced frequency of ventilation.
• Treatment efficacy can include but is not limited to remission of the sepsis, severe sepsis or septic shock, including for example, a decrease or reduction in the underlying infection causing the sepsis, severe sepsis or septic shock.
• treatment efficacy can also include general improvements in the overall health of the subject, such as but not limited to enhancement of patient life quality, increase in predicted subject survival rate, decrease in depression or decrease in rate of recurrence of the indication (increase in remission time).
• treatment efficacy can also include general improvements in the overall health of the subject, such as but not limited to enhancement of patient life quality, increase in predicted subject survival rate, decrease in depression or decrease in rate of recurrence of the indication (increase in remission time).
• Predetermined standard levels of sepsis, severe sepsis or septic shock biomarkers can be defined using a variety of methods known to those of skill in the art.
• standard levels for a biomarker are determined by determining the level of a biomarker in a sufficiently large number of samples obtained from normal, healthy control subjects (e.g., subjects not exhibiting sepsis, severe sepsis or septic shock). Further, standard level information can be obtained from publically available databases, as well as other sources.
• standard level information can be obtained from publically available databases, as well as other sources.
• an increase or decrease of the level of one or more sepsis, severe sepsis or septic shock markers in a sample obtained from a subject treated with an alpha thymosin peptide is determined by comparing the level of one or more sepsis, severe sepsis or septic shock biomarkers to a predetermined standard level.
• Information regarding the increase or decrease in the level of one or more sepsis, severe sepsis or septic shock biomarkers can be used to determine the treatment efficacy of treatment with an alpha thymosin peptide, as well as to tailor treatment regimens for treatment with an alpha thymosin peptide.
• the treatment efficacy can be used to determine whether to continue treatment with an alpha thymosin peptide.
• the treatment efficacy can be used to determine whether to discontinue treatment with an alpha thymosin peptide.
• the treatment efficacy can be used to determine whether to modify treatment with an alpha thymosin peptide.
• the treatment efficacy can be used to determine whether to increase or decrease the dosage of alpha thymosin peptide that is administered. In other embodiments the treatment efficacy can be used to determine whether to change the dosing frequency. In further embodiments, the treatment efficacy can be used to determine whether to change the number of dosage per day, per week, times per day. In yet further embodiments the treatment efficacy can be used to determine whether to change the dosage amount.
• Methods for obtaining biological samples are well known in the art and any standard methods for obtaining biological samples can be employed.
• Biological samples that find use with the methods of the present invention include but are not limited to serum, blood, plasma, whole blood and derivatives thereof, skin, hair, hair follicles, saliva, oral mucous, vaginal mucous, sweat, tears, epithelial tissues, urine, semen, seminal fluid, seminal plasma, prostatic fluid, pre-ejaculatory fluid (Cowper's fluid), excreta, biopsy, ascites, cerebrospinal fluid, lymph, and tissue extract sample or biopsy.
• Clinical Proteomics Methods and Protocols, Vol. 428 in Methods in Molecular Biology, Ed. Antonia Vlahou (2008).
• ABSTRACT Severe sepsis is associated with a high mortality rate despite implementation of guideline recommendations. Adjunctive treatment may be efficient and require further investigation. In light of the crucial role of immunologic derangement in severe sepsis, thymosin alpha 1 (Talphal ) is considered as a promising beneficial immunomodulatory drug. The trial is to evaluate whether Talphal improves 28-day all-cause mortality rates and immunofunction in patients with severe sepsis. Methods We performed a multicenter randomized controlled trial in 6 tertiary, teaching hospitals in China between May 12, 2008 and Dec 22, 2010.
• SOFA Sequential Organ Failure Assessment
• mHLA-DR monoocyte human leukocyte antigen-DR
• Severe sepsis is an important cause of admission to intensive care units (ICUs) throughout the world and is characterized by high mortality in adults [1 -3]. Severe sepsis is diagnosed in more than 750,000 people annually in the United States, of whom 215,000 will die [3]. Reported mortality rates of severe sepsis ranged from 28% to 35.5% [3-7]. In spite of the adoption of therapeutic bundles based on Surviving Sepsis Campaign (SSC) guidelines, mortality is reported to be about 30% [4]. The key role of immunologic derangement in the course and the poor outcome has led to an increased interest in immunotherapy [8,9].
• SSC Surviving Sepsis Campaign
• Thymosin alpha 1 is a naturally occurring thymic peptide first described and characterized by Goldstein et al. [10]. It acts as an endogenous regulator of both the innate and adaptive immune systems [1 1 ]. It is used worldwide for treating diseases associated with immune dysfunction including viral infections such as hepatitis B and C, certain cancers, and for vaccine enhancement [12,13]. Notably, recent development in immunomodulatory research has indicated the beneficial effect of Ta1 treatment in septic patients. However, the results of these studies should be viewed with caution due to their small sample sizes and use of more than one drug as therapeutic intervention [14-16]. This multicenter randomized controlled trial was implemented to determine the efficacy of Ta1 in treating severe sepsis.
• Ta1 In the Ta1 group, patients received subcutaneous injections of 1 .6 mg Ta1 (ZADAXINTM, SciClone Pharmaceuticals, Foster City, CA, USA) twice per day for five consecutive days, then once per day for two consecutive days. Prior to administration, the lyophilized powder is to be reconstituted with 1 ml of the provided diluent (sterile water for injection). After reconstitution, the final concentration of Ta1 is 1 .6 mg/mL. In the control group, patients received subcutaneous injections of 1 ml_ normal saline twice per day for five consecutive days, then once per day for two consecutive days. According to trial protocol, therapy had to be started within 4 hrs after enrollment.
• Empirical antibiotic therapy was considered adequate when at least one effective drug was included in the empirical antibiotic treatment within the first 24 hrs of the admission to the ICU and the optimal dose and the correct route of administration were in accordance with medical standards and in ICU survivors without microbiologically detected microorganism in bloodstream or focus.
• the empirical antibiotic therapy had to be changed after microbiological detection of microorganism, it was considered inadequate, whereas in non-survivors without microbiologically detected microorganism in bloodstream or focus it was considered not evaluable [18-20].
• the primary efficacy end point was death from any cause and was assessed 28 days after the initiation of treatment assignment. Secondary outcomes included dynamic changes of Sequential Organ Failure Assessment (SOFA), CD 4+/CD8+ and monocyte human leukocyte antigen-DR (mHLA-DR) expression measured on day 0 (the day of enrollment), 3 and 7 in both groups. All mHLA-DR measurements were done in the center laboratory of the First affiliated Hospital of Sun Yat-sen University. 1 ml unprocessed EDTA whole blood was stored on ice at once after drawing and was transferred to the center laboratory as soon as possible to guarantee measurement within 3 hrs after blood drawing. The method of measuring mHLA-DR was mentioned in our previous paper [21].
• SOFA Sequential Organ Failure Assessment
• CD 4+/CD8+ CD 4+/CD8+
• mHLA-DR monocyte human leukocyte antigen-DR
• the pulmonary and cardiovascular systems were the most commonly affected organ systems with an incidence of 94.7% and 65.7% respectively. The most common sites of infection were lung and abdomen, with an incidence of 74.5 and 27.4%, with mixed pathogens or gram-negative organisms accounting for the majority of cases. There was no difference in adequate antibiotic treatment (refer to Table 2).
• Table 1 Baseline characteristics in both study groups.
• Cardiovascular 1 13 (62.8%) 124 (68.5%) 0.25
• Nervous system 1.3 + 1.4 1.4 + 1.4 0.69
• Patients may have had more than one site of infection; Other sites of infection included skin, central nervous system, bones and joints; *patients may have had more than one organism cultured. ⁇ 1 , thymosin alpha 1 .
• Table 3 Baseline levels of laboratory values.
• Lymphocyte %WBC
• CD cluster of differentiation
• CI confidence interval
• mHLA-DR monocyte human leukocyte antigen-DR
• SOFA Sequential Organ Failure Assessment
• thymosin alpha 1 thymosin alpha 1 .
• the average SOFA score changes on day 3 and day 7 were -1.3 (95% CI -1.7 to -0.8, P ⁇ 0.001 ) and - 1.8 (95% CI -2.4 to -1.3, P ⁇ 0.001 ) in the control group, and -1.8 (95% CI -2.3 to - 1.4, P ⁇ 0.001 ) and -2.5 (95% CI -3.1 to -2.0, P ⁇ 0.001 ) in the Ta1 group.
• the decreasing tendency within 7 days in SOFA score seemed to favor the Ta1 group.
• the ratio of CD4+/CD8+ remained unchanged during the 7 days in both groups.
• CD 4 7DC 8+ Measures Control Group Ta1 group Between groups difference
• ADay 3 and ADay 7 were defined as the value changes on day 3 and day 7 compared with that on day 0. a P ⁇ 0.05; b P ⁇ 0.01 .
• CD cluster of differentiation; CI, confidence interval; mHLA-DR, monocyte human leukocyte antigen-DR; SOFA, Sequential Organ Failure Assessment; Ta1 , thymosin alpha 1 .
• Safety and tolerability assessment of Ta1 was based on the comparison of all available information obtained from the two groups with respect to detected outliers in laboratory safety data, drug-related serious adverse events (assessed by the investigator) and deterioration of organ and system function (assessed by the individual SOFA component scoring for respiratory, cardiovascular, hepatic, coagulation, renal and nervous systems that arose during the treatment).
• Table 6 Frequency of patients with outlying values of laboratory safety assays and all-cause organ and system impairment.
• Cardiovascular system 21 (1 1 .7) 28 (15.5) 0.29
• ALT alanine aminotransferase
• Immune system dysregulation plays a significant role in the course of sepsis. Previously, it was believed that the exaggerated pro-inflammatory response and its associated inflammation-induced organ injury were the major factors leading to deaths in sepsis. However, recent studies indicate that heterogeneity exists in septic patients' immune response, with some appearing immunostimulated, whereas in others appearing sup-pressed [23]. Although both pro-inflammatory and antiinflammatory drugs have been evaluated, few have yet been found to significantly reduce the mortality [24-26]. Ta1 is thought to have immunomodulating effects primarily affecting the augmentation of T-cell function [27,28].
• Ta1 has also shown actions beyond its effect on T lymphocytes by acting as an endogenous regulator of both the innate and adaptive immune systems [1 1 ,29]. Ta1 plays a unique role in balancing pro- and anti-inflammatory cytokine production through the involvement of distinct Toll-like receptors (TLRs) acting on different dendritic cells (DC) subsets and involving the MyD88-dependent signaling pathway. Ta1 can increase IL-12, IL-2, IFN-a and IFN- ⁇ secretion to present antimicrobial effect and increase IL-10 and percentage of regulatory T cells (Tregs) to control inflammation [1 1 ,30-32]. Therefore, is an appropriate immunoregulator for treating severe sepsis that is characterized by the large heterogeneity in immune function.
• TLRs Toll-like receptors
• DC dendritic cells
• the ratio of CD4+/CD8+ is another parameter to evaluate immunological status in sepsis. Decreased CD4+/CD8+ ratio was related to the development of severe sepsis and multiple organ failure (MOF) in trauma patients [39]. Some studies showed that thymosin alpha 1 can increase CD4+/CD8+ ratio [40,41 ]. On the other side, one research study has indicated that mHLA-DR, not CD4+, CD8+ or ratio of CD4+/CD8+, can predict the prognosis of severe sepsis [42]. In our research, we did not find statistically significant difference in the CD4+/CD8+ ratio between the two groups.
• the median time from the first organ dysfunction detected to enrollment was more than 24 hrs in both groups, but longer in the Ta1 group.
• objective data such as blood gas analysis
• those patients without indicative objective data could also have suffered from severe sepsis and the delay in laboratory tests could substantially underestimate the time after onset.
• the time after onset determined by laboratory tests in non-ICU departments was out of our control and subject to errors, especially when the estimation was based on hours instead of days.
• Types of pathogen and empirical antibiotic therapy are very important factors that affect the outcome of severe sepsis. It is noted that the origins of microorganisms are substantially diverse in different areas and even in different hospitals in the same area. So is empirical therapy. In the present study, there was a high isolation rate of gram-negative bacteria (pseudomonas, acinetobacter) compared with some other epidemiology study of infection in ICU [44]. In fact, the relatively higher incidence of pseudomonas and acinetobacter infections is not unusual in China [33] so that the adequate empirical therapy is adjusted accordingly.
• Thymosin alpha 1 has been shown to be a safe and well-tolerated agent in other studies [12,13]. Serious adverse events were not observed in our trial. Outlying laboratory values and all-cause organ and system impairment were similar in both groups. However, subjective sensations such as irritation or burning, general or gastrointestinal disorders were difficult to assess due to the severity of disease, sedation or analgesia in severe sepsis patients.
• mHLA-DR granulocyte-macrophage colony-stimulating factor
• immunotherapy may be an important adjunctive treatment.
• Goldstein AL From lab to bedside: emerging clinical applications of thymosin alpha 1 . Expert Opin Biol Ther 2009, 9:593-608.
• Lin HY [Clinical trial with a new immunomodulatory strategy: treatment of severe sepsis with Ulinastatin and Maipuxin]. Zhonghua Yi Xue Za Zhi 2007, 87:451 - 457.
• Degoricija V, Sharma M, Legac A, Gradiser M, Sefer S, Vucicevic Z Survival analysis of 314 episodes of sepsis in medical intensive care unit in university hospital: impact of intensive care unit performance and antimicrobial therapy. Croat Med J 2006, 47:385-397.
• Remick DG Pathophysiology of sepsis. Am J Pathol 2007, 170:1435-1444.

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