US 2010O292280A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2010/0292280 A1 Zachar (43) Pub. Date: Nov. 18, 2010 (54) ANTI-PYRETIC VASODILATORS 2007, provisional application No. 61/012,934, filed on Dec. 12, 2007, provisional application No. 61/013, (76) Inventor: Oron Zachar, Tel Aviv (IL) 484, filed on Dec. 13, 2007. 5A Gr Address: Publication Classification aniel Feigelson Lev Hamada Building, Second Floor, 7 Oppenhe- (51) Int. Cl. imer St. A63L/455 (2006.01) Rehovot (IL) A6IP 29/00 (2006.01) (21) Appl. No.: 12/595,237 (52)52) U.S. Cl. ........................................................ S14/356 (22) PCT Filed: Apr. 14, 2008 (57) ABSTRACT The invention pprovides vasodilating9. medication as means for (86). PCT No.: PCT/ILO8/OOSO8 lowering fever when administered to humans in need of Such treatment. In particular,p the use of B3 vitamin substances and 7.St. Oct. 8, 2009 Nitric Oxide-donor ingredients in compositions intended for (2), (4) Date: ct. 8, use in reducing fever is introduced. The core composition O O substances can be used effectively on their own. Yet, in com Related U.S. Application Data bination with anti-pyretic Substances such as Aspirin, (60) Provisional application No. 60/911,894, filed on Apr. Acetaminophen, and Ibuprofen, the present invention enables 15, 2007, provisional application No. 60/911,900, the use of reduced dosage of composing Substances for filed on Apr. 15, 2007, provisional application No. achievement of desired fever reduction effect. In addition, an 60/914,369, filed on Apr. 27, 2007, provisional appli optional addition of Sweat inducing plant extracts in any of cation No. 60/946,157, filed on Jun. 26, 2007, provi the noted compositions leads to a synergistic effect of reduc sional application No. 60/980,849, filed on Oct. 18, ing fever by increase of both skin blood flow and perspiration. US 2010/0292280 A1 Nov. 18, 2010 ANT-PYRETIC VASODLATORS 0009. Thus, there is a need for safer methods of fever reduction. In particular, there is advantage for methods which FIELD OF THE INVENTION reduce fever without adverse effects on internal organs in general and without significantly affecting the levels of 0001. The invention relates generally to the field of anti COX-1 enzymes in particular. pyretic treatment. More specifically, the present invention 0010 Moreover, there is an advantage to novel anti relates to methods of reducing fever employing vasodilators, pyretic use of Substances that have already proven their rela optionally in combination with conventional anti-pyretics. tive safety in various dosages of administration for other BACKGROUND OF THE INVENTION indications. 0011. The anti-pyretic effect of the present medication is 0002 The white cells of the body produce a substance gradual and reaches maximum effect about 2 hours from time called interleukin-1 when they digest a germ. Interleukin-1 of administration. induces the formation of prostaglandins. Prostaglandins E2 0012. Therefore, there is absence of, and a need for a (PGE2) are substances that act on the hypothalamus resetting treatment that primarily acts to reduce fever without other the body thermostat to a higher level—resulting in a fever. broad systemic consequences. This is particularly relevant for PGE2 is the ultimate mediator of the febrile response. The use in children, where the anti-pyretic activity is the promi set-point temperature of the body will remain elevated until nent objective of medicinal use of the medicine of the present PGE2 is no longer present. invention by the consumer public. 0003 Fever is one of the body methods of fighting patho 0013 Moreover, due to side effects of the drugs currently gens. Hence, there is no substantial medical reason to treat available on the market, the medical recommendation is of a fever under 38 degrees Celsius (°C.), though personal sense minimum of 4 hours before repeated use of acetaminophen, of comfort may improved by reducing any fever. and 6 hours between administration of ibuprofen, and to avoid 0004. The present state of the art of anti-pyretic treatment use for more than 3 consecutive days. Hence, it would be is based on oral application of medicine. There are four basic advantageous to have a fever treatment which can be safely categories of medications: aspirin, ibuprofen, acetami used for longer periods and shorter intervals. nophen, and naproxen. These drugs have broad systemic activity and act as analgesic, anti-inflammatory, and anti 0014 For young hildren the oral administration of medi pyretic drugs (i.e., used to relieve pain, inflammation, Swell cine is frequently inconvenient due to lack of cooperation ing, and reduce fever). from the patients. Therefore, there is a need and an advantage 0005 Aspirin and other non-steroidal anti-inflammatory for topical anti-pyretic treatments applied to the skin. drugs (NSAID) target a group of enzymes called Cyclooxy 0015. When the present anti-pyretic medication is applied genases. These enzymes catalyze a key step in the synthesis of to patients with high fever, e.g., above 39°C., fever is com prostaglandins. Prostaglandins are hormones that carry local monly not restored fully back to normal but instead levels off messages to neighbouring cells (most other hormones carry at lower fever (e.g., at 38°C.). This situation inclines many messages throughout the body). There are two cyclooxyge parents to infer that the fever medication was not fully effec nase genes in humans; the enzymes they make are called tive, and may induce them to administer additional doses of COX-1 and COX-2. Put simply, present anti-pyretic medica medications counter to the prescribed safety instructions. tions work as enzyme inhibitors. They interfere with the Therefore, there is need and advantage to fever medication activity COX-1 and COX-2 enzymes. with increased effectiveness to reduce fever more down to 0006 COX-1 makes prostaglandins that are necessary for normal from high levels. the synthesis of protective gastric mucus in the stomach and 0016 Over 40% of pediatric OTC acetaminophen sales for proper blood flow in the kidneys. It also makes a prostag are within Cold&Cough combination formulas; which con landin necessary for platelet cell functioning. So by inacti tain multiple Substances including a decongestant, cough Vating this enzyme Such medications have a negative effect on Suppressant, antihistamine, with the anti-pyretic/analgesic the stomach and kidneys but a beneficial effect on the circu acetaminophen component. latory system. 0017. A survey of pediatricians, conducted at the recent 0007 COX-2 makes prostaglandins that are involved in Annual Meeting of the American Academy of Pediatrics inflammation, pain, and fever. By inhibiting this enzyme, American Academy of Pediatrics Convention Study, Oct. 31, medication can reduce each of these three responses within 2000, Prepared by Wirthlin Worldwide, shows that 61% of our bodies. respondents are very concerned that, by combining common 0008. From the above description it would seem that a over-the-counter cold and fever medications, parents may better pain-killer than aspirin would be one that inhibited unwittingly give their children an overdose of medication, COX-2 but did not inhibit COX-1. Indeed, drugs with these putting children's health at risk. The pediatricians' chief con properties have been developed and are referred to as selec cern was that children may be getting an overdose of fever tive COX-2 inhibitors. COX-2 inhibitors such as Celebrex reducers, which can affect the liver or the kidney. Often, (celecoxib, made by Pfizer) and Vioxx (rofecoxib, made by parents who are unaware of these ingredients may give their Merck & Co.) were introduced in 1999. They decrease pain, children an additional fever-reducing medication. Therefore, fever, and inflammation with no negative effects on the stom when recommending an over-the-counter cold remedy for ach. Its world-wide sales were $2.5 billion (US) in 2003. their patients, 73% of pediatricians surveyed considered it Unfortunately, patients who were on Vioxx for more than. 18 very important to eliminate the anti-pyretic component from months began to show an increased frequency of serious recommended present pediatric cold medication. cardiovascular problems. Vioxx was withdrawn from the 0018. Therefore, there is a need and advantage to intro market. It is not clear why Vioxx causes cardiovascular prob duce combination cold&cough medicinal formulas that do lems. not contain NSAID elements (such as acetaminophen oribu US 2010/0292280 A1 Nov. 18, 2010 profen), but still do contain an anti-pyretic component ele February 1994, The FASEB Journal), shows that NO can ment with lesser overdose risks. increase human skin microvascular blood flow in vivo. How 0019 Known anti-pyretic NSAID include, but are not lim ever, the NO donorsodium nitroprusside was 10,000-fold less ited to ibuprofen, flurbiprofen, ketoprofen, aclofenac, potent than PG when injected intradermally. This suggests diclofenac, aloxiprin, aproxen, aspirin, diflunisal, fenopro that on a molar basis endogenous NO has less influence on fen, indomethacin, mefenamic acid, naproxen, phenylbuta microvascular flow than PG, the predominant prostaglandin Zone, piroXicam, Salicylamide, Salicylic acid, Sulindac, des of the microcirculation. oxysulindac, tenoxicam, tramadol, ketoralac, flufenisal, 0028 B3 vitamins have been described in multiple thera Salsalate, triethanolamine Salicylate, aminopyrine, antipy peutic uses. Niacin (but not niacinamide) can significantly rine, oxyphenbutaZone, apaZone, cintaZone, flufenamic acid, improve cholesterol profile, reducing levels of total and LDL clonixeril, clonixin, meclofenamic acid, flunixin, colchicine, (“bad”) cholesterol and raising HDL (“good') cholesterol. demecolcine, allopurinol, oxypurinol, benzydamine hydro Therapeutic dosages for Such indication are high-around chloride, dimefadane, indoxole, intrazole, mimbane hydro 3000 mg per day continuously over a period of 4 weeks or chloride, paranylene, hydrochloride, tetrydamine, benzin more. However, unpleasant flushing reactions as well as a risk dopyrine hydrochloride, fluprofen, ibufenac, naproXol.