DE10227148A1 - Use of ribavirin for the manufacture of a pharmaceutical composition against Bunyaviridae - Google Patents

Use of ribavirin for the manufacture of a pharmaceutical composition against Bunyaviridae Download PDF

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Publication number
DE10227148A1
DE10227148A1 DE2002127148 DE10227148A DE10227148A1 DE 10227148 A1 DE10227148 A1 DE 10227148A1 DE 2002127148 DE2002127148 DE 2002127148 DE 10227148 A DE10227148 A DE 10227148A DE 10227148 A1 DE10227148 A1 DE 10227148A1
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Prior art keywords
ribavirin
pharmaceutical composition
treatment
bunyaviridae
administration
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DE2002127148
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German (de)
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Cornelius Dr. Sobel
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BIOPARTNERS GmbH
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BIOPARTNERS GmbH
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Priority to DE2002127148 priority Critical patent/DE10227148A1/en
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole

Abstract

Use of ribavirin for the manufacture of a pharmaceutical composition for the treatment of a patient infected with Bunyaviridae, characterized in that the pharmaceutical composition is administered orally and / or rectally in compressed form and a consumer pack, characterized in that it contains information material on the use of Ribavirin and a pharmaceutical composition containing ribavirin in compressed form.

Description

  • For There are numerous ways and means of viral infections in humans the transfer. So will be a big one Group of viruses, which contains more than 400 species and consists exclusively of RNA viruses, mainly by Arthropod vectors transferred. These vectors include u. a. Mosquitoes, sand flies, ticks and lice. This large group of viruses was previously grouped under the name arboviruses. In the meantime, it has been divided into four virus families: Arenaviridae, Bunyaviridae, Flaviviridae and Togaviridae.
  • The family of the Bunyaviridae include the eponymous genus Bunyavirus also the genera Hantavirus, Nairovirus, Phlebovirus and Tospovirus. In connection with the The present invention includes both hantaviruses and nairoviruses really important.
  • Hantaviruses are from rodents transferred to humans. They call the hemorrhagic Fever with renal syndrome (HFRS) and the hantaviral pulmonale Syndrome (HPS). The latter shows a lethality of approximately 50% on. This is due to infection with the Hantavirus types circulating in Central Europe triggered The clinical picture is also referred to as Nephropathia epidemica. It is characterized in its full image by acute kidney failure. Antibodies against can be found in approx. 2% of the German population Hantaviruses, which indicate an expired infection, detected become.
  • Hantaviruses include one of the five genera of the Bunyaviridae family. They got their name from Hantaan River in South Korea, in the vicinity the prototype of the virus was isolated in 1978. Exists worldwide a larger number different types of Hantavirus with very different pathogenicity for humans. Hantaviruses are RNA viruses with a negative strand genome that consists of three Segments. These three segments code for the viral Nucleocapsid protein, the viral polymerase and the envelope glycoproteins G1 and G2. Your natural Hosts are rodents, with each virus type being relatively closely related to one is associated with certain rodent species. The persistently infected Animals do not usually get sick, but an illness can triggered in humans become. The viruses are transmitted through animal excretions containing viruses, which are absorbed by humans aerogenically or by os. But you can also directly above the saliva, i.e. by e.g. the bite of an infected animal become.
  • What genetic components of the Virus on one side and human on the other responsible for are whether a primary infection inapparent or clinically manifest is still largely unknown. It is believed that some Hantavirus types do not cause human diseases and other types in clinical Manifestation requires mild to weak courses with different lethalities. In particular, people who, by their profession or by their living and living conditions Contact with rodents and their excretions, an increased risk of infection exposed. These professional and risk groups include, for example Forest workers and soldiers in the field.
  • At that observed in Central Europe The course of the HFRS, the so-called Nephropathia epidemica, is the incubation period two to five weeks. First the patient shows unspecific flu-like general symptoms, which eventually too colic-like flank pain, abdominal pain, vomiting and ultimately lead to acute kidney failure.
  • Hämonhagisches Fever is an infection that causes an increased tendency to bleed. Most hämonhagischen Viruses cause fever. Basically, they come worldwide in the tropical and partly also subtropical regions, whereby the individual virus types occur regionally limited. The Fever can be caused by different groups, e.g. Togaviruses, flaviviruses, Arenaviruses, Filoviruses, Phleboviruses, Nairoviruses and Hantaviruses become.
  • The hantaviral pulmonary syndrome (HPS) is characterized by serious pulmonary disease with high mortality. It was first found in 1993 in the United States during an investigation a series of sudden and unexplainable deaths. With HPS there is an increased pulmonary capillary permeability that a first pulmonary edema to lead can. The pathogenicity of pulmonary edema HPS is not yet well understood, although an immunological one Mechanism seems to play an important role. It is believed that the Lymphoblasts and macrophages due to the high viral load penetrate the pulmonary tissue, a lymphokine-mediated activation of the vascular Cause endothelium, causing an increasing pulmonary permeability the capillaries comes.
  • This pathogen is particularly explosive also by the fact that hantaviruses from the "US Centers for Disease Control and Prevention "(CDC) in the list of potential Bioweapons have been classified. Furthermore, it is expected that in particular new hantavirus types will appear from the tropical regions, the too life-threatening manifestations of different clinical pictures in humans. For example, worldwide yearly about 200,000 to 300,000 HFRS cases observed, but it is considered certain that many more HFRS cases even cannot be recognized because acute kidney failure either fails this infectious Cause is thought or the technical requirements for a corresponding Virus diagnostics are missing.
  • Before going into therapy and / or pro phylaxis of Hantavirus diseases, another genus of the Bunyaviridae family, which also causes hemorrhagic fever, is described. The sero group of viruses belongs to the genus of nairoviruses, which causes Crimean-Congo fever in humans.
  • Crimean-Congo Hemorrhagic Fever (CCHF) is transmitted by nairoviruses and is found mainly in Asia, Africa, Southeast Europe and the Middle East. A transfer the virus mainly takes place held by hyaloma ticks, which are also an important pathogen reservoir represent. These ticks come only in warmer regions south of the Balkans before. But also domesticated animals such as cows, sheep, goats and camels an important reservoir. A pathogen transmission can also occur on contact with infectious animal Blood, such as B. when inhaling infected blood when slaughtering, or through muscle meat. There are also infections in hospitals (nosocominal infections) instead. The incubation of the disease is upon transmission by ticks for 2 to 5 days and 5 to for nosocominal infections 9 days.
  • The disease begins with typical ones flu-like symptoms such as fever, chills, severe head, muscle and joint pain and a pronounced feeling of illness. It is coming relatively early to conjunctivitis and bleeding into the chest and abdomen and organs. With nausea with nausea, abdominal pain, and diarrhea, it can last up to three fifth Day of illness leads to the appearance of bleeding from the skin and organs (so-called hemorrhages). With slight gradients bleeding from the nose and gums are observed. In severe cases there is bleeding from all orifices come and the appearance of puncture sites is common. Finally, can the disease to liver cell damage lead to liver failure. The lethality is in dependence from the virus strain approx. 10 to 50%, the lethality in secondary and tertiary illness decreases. The relationship between hemorrhagic and non-hemorrhagic make is used in the states of the former USSR to 1: 5 estimated.
  • Prophylaxis and Therapy of Hantavirus and CCHF diseases
  • To combat Hantavirus diseases the development of vaccines plays an important role. vaccine are especially for infection prophylaxis for members of risk groups makes sense. While Hantavirus vaccine in some Asian countries in the form of whole virus vaccines are used in Europe and America developments in particular to recombinant Creating vaccines. Hantavirus live vaccines based on recombinant Smallpox viruses do not show that in clinical trials in the United States hoped for vaccination success. In animal experiments, the incubation of one protected immunity shown by the administration of naked hantavirus protein-encoding DNA become. But since developing a vaccine is very time consuming and has no effect on already infected individuals, there is an obvious interest in hantavirus infections through a drug Combat treatment.
  • It has already been shown in the literature been that ribavirin shows a therapeutic effect in hantavirus infections.
  • The virustatic called ribavirin is 1-β-D-ribafuranosyl-1,2,4-triazole-3-carboxamide and is approved for therapy in humans with limited indication. Due to its chemically modified ribose unit, ribavirin the typical feature of an antimetabolite or its precursor molecule. An inhibition of the synthesis of guanosine nucleosides has been described by ribavirin, an inhibition of RNA polymerase and an indirect Inhibition of protein biosysthesis. The exact mechanism of action of Ribavirins has not yet been resolved.
  • In Germany, ribavirin was initially only approved for aerosol therapy for the most severe bronchopulmonary infections caused by the Respiratory Syncytial Virus (RSV). A ribavirin-containing dry substance for the preparation of inhalation solutions has been available under the trade name "Virazole ® " since 1993. Ribavirin is now approved as "Rebetol ® " in oral form for the treatment of chronic hepatitis C in combination with interferon α.
  • The only oral dosage form so far of ribavirin, namely Rebetol®, are hard capsules based on gelatin.
  • Huggins JW et al. (J. Infect. Dis., 1986; 153 (3): 489-97) describe ribavirin therapy for hantavirus infections in mouse juveniles. Intravenous administration of ribavirin as a therapy for hemorrhagic fever in people with renal syndrome is described by Huggins JW (J. Infect. Dis., 1999; 164 (6): 1119-27). This is an intravenous administration of ribavirin according to the following scheme: starting dose of 33 mg / kg, 16 mg / kg every 6 hours for 4 days and 8 mg / kg every 8 hours for 3 days. It was shown that the administration of ribavirin according to the scheme outlined above could significantly reduce mortality. The only ribavirin side effect observed was marked, fully reversible anemia after treatment was discontinued. In addition to the treatment of HFRS, intravenous ribavirin therapy for pulmonary hantavirus syndrome (HPS) has also been described. Chapman LE et al. (Antivir. Ther., 1999; 4 (4): 211-219) describe the treatment of HPS patients with ribavirin. Due to the structure of the therapy study, which included a placebo control during the development phase of the sick was lacking, the drug could not be shown to be sufficiently effective. Further studies on the treatment of hantavirus infections with ribavirin were carried out by Murphy ME et al. and are described in J. Vet. Med. Sci., 2001; 63 (6): 637-645. Experiments with mouse juveniles showed that ribavirin concentrations of 25 and 50 mg / kg led to survival rates of 68% and 80%, in contrast to 7% otherwise.
  • Recently (February 21, 2002) has the European Office too Medical Device Evaluation (EMEA) in collaboration with a policy document to its Scientific Committee (CPMP) for the use of medical products for treatment and prophylaxis biological agents that are released as biological weapons could be used by tenors. This is under point 6 on the viral hemonhagic Fever entered. In addition to the usual treatment for adults, those under hemonhagic Suffer from fever, which is caused, among other things, by hantaviruses can be with an intravenous Administration of ribavirin is also based on oral administration received. In particular, a therapy scheme is shown in which 2 g of ribavirin are administered orally as the starting dose, followed from 4 g / day in 4 divided doses for 4 days, followed by 2 g / day for 6 days. The administration of ribavirin as a therapeutic agent to patients, who are infected with hantaviruses either find in the prior art, and currently preferred, intravenously or about the administration of ribavirin with the help of capsules instead.
  • In the fight against CCHF diseases the development and administration of vaccines plays a subordinate role Role. For prophylaxis, vaccines from infected are in Bulgaria mouse Brain for laboratory staff has been developed. This is intended to attempt nosocominal transmissions avoid. Obtain important control measures focus on fighting vectors and on compliance with general hygiene conditions.
  • As already described for the fight against hantaviruses, the use of ribavirin can also be found in the prior art for the treatment of CCHF diseases.
  • Watts D.M. et al. (Am. J. Trop. Med. Hyg. 1989; 41 (5): 581-585) describe the use of ribavirin as a potential therapeutic for Crimea-Congo Hämmorhagisches Fever (CCHF) Here for studies by "African green monkey kidney "cells carried out. Even relatively low doses of ribavirin (5 μg / ml) lead to a transient reduction in viral load. This can happen with higher Concentrations until there is no viral replication fueren. Tignor G.H. and Hanham C.A. describe in antiviral. Res., 1993; 22 (4): 309-325 the use of ribavirin in intraperitoneally with CCHF virus infected young mice. It could be shown that the Ribavirin treatment significantly increased mortality in young mice reduced and also virus growth in the liver and training viremia decreased significantly. The use of ribavirin for the treatment of CCHF was published in Lancet, 1995; 346 (8973): 472-475 by Fisher-Hoch S.P. et al. described. This involves oral administration of ribavirin to hospital staff in Pakistan. Oral administration includes 4 g / day for 4 days, then 2.4 g / day for 6 days. In this case, ribavirin was administered orally selected there intravenously Ribavirin to be administered was not available. It has been observed that the Patients within 48 hours of ribavirin treatment IgG and IgM antibodies against the CCHF virus and recovered completely. However, the results presented in this article refer to only on a small group of three patients, with oral administration of ribavirin for the treatment of CCHF infections very promising seems to be.
  • The previously known dosage forms of Ribavirin has several disadvantages.
  • The intravenous administration of a drug via a longer Period can cause that itself inflame the veins and thereby further e.g. bacterial infections strain the body can, that the permanent cannula clogs or breaks the flexibility and well-being of the Patients suffering from the treatment or the drug in its liquid Form not available stands or only stored and transported under complex conditions can be.
  • As previously used and in the state Process known in the art for the oral administration of ribavirin can Capsules are used. Capsules have a number of disadvantages on. For example, the accuracy with which an active ingredient doses capsules can be lower than, for example, tablets. Is accordingly the most legally permitted Mass variance per dose unit ± 7.5% for capsules and ± 5% for tablets. Add to that capsules frequently are relatively large and is difficult to take by seriously ill people or children can be. Another critical trait that has been increasing lately What has gained in importance is that capsules are animal components Origin, such as gelatin, and thus pose the risk e.g. to transmit the BSE pathogen.
  • In the animal experiment it was shown that ribavirin acts teratogenically, especially within the first six weeks of embryonic development. This has u. a. as a result that female Treatment staff and family members before exposure protected Need to become.
  • When capsules are put together, it is inevitable that ribavirin powder will stick to their outer surface. Unlike tablets gelatin capsules cannot be coated with an aqueous coating suitable for firmly binding the powder. Not only when packaging the capsules, but also when administered by e.g. B. Nurses or family members are therefore very likely to come into contact with ribavirin.
  • Therefore, in addition to the general disadvantages another capsule, especially in the case of ribavirin desirable.
  • The invention is therefore the object underlying a use of ribavirin for the treatment of viruses the Bunyaviridae to provide, which eliminates the disadvantages of the prior art.
  • According to the invention we use the task of ribavirin for the manufacture of a pharmaceutical composition used to treat a patient infected with Bunyavirdae, thereby characterized that the pharmaceutical composition orally and / or rectally in compressed Form is administered.
  • The use of pharmaceutical composition held in tablet form.
  • In a particularly preferred embodiment, the use in tablet form takes place by the administration of Ravanex ® .
  • Alternatively, it is used the pharmaceutical composition in the form of a suppository.
  • In a preferred embodiment is the use of ribavirin administration according to the following scheme carried out: a) Day 1: 1-3 times 500 to 2000 mg ribavirin b) day 2 to 20: 1-3 times 400-1500 mg Ribavirin.
  • In a particularly preferred embodiment finds the use of ribavirin administration according to the following scheme instead of: a) Day 1: 3 times 800 mg ribavirin, b) Day 2 to 11: 3 times 600 mg ribavirin.
  • A preferred embodiment includes one Consumer pack, the information material on the use of ribavirin and a pharmaceutical composition containing ribavirin in compressed form Form includes.
  • A particularly preferred embodiment comprises a consumer pack containing information material about the Use of ribavirin and a pharmaceutical composition, which contains ribavirin, in tablet form.
  • An alternative embodiment includes one Consumer pack, the information material on the use of ribavirin and a pharmaceutical composition containing ribavirin in suppository form includes.
  • The use of ribavirin in tablets or suppository form according to the present scheme, rapid symptom control causes a Infection with hantaviruses and CCHF viruses and can take until complete healing lead to the disease. The Dosage form of tablets enables direct absorption of the active ingredient in the upper area of the gastrointestinal tract and thus a rapid circulation of ribavirin in the blood and one immediate combat of viruses. The tablets can easily taken and precisely dosed and a ribavirin contamination of nursing staff and family members during treatment at home is excluded.
  • Another dosage form relates on the administration of suppositories. The dissolution of the suppository in the lower area of the intestinal tract also leads to a rapid Absorption, especially in the area of the rectum, and a rapid Circulation of ribavirin in the bloodstream. This dosage form is particularly common in patients who are already severely affected by the infection weakened or older ones People or children who have problems swallowing the drug in tablet form. Especially useful and this dosage form has proven effective in infants.
  • Since ribavirin is known to be teratogenic recommended that the Drug is not taken by pregnant women. Furthermore care should be taken that the patient is not within the following six months after taking the drug pregnant will to malformations of the fetus submissions.
  • The present invention is disclosed in the following examples executed.
  • example 1
  • When administered orally Tablet ribavirin to a patient infected with bunya viruses (for example hantaviruses or CCHF viruses) is the first Daily dose of 3 times 800 mg of ribavirin administered. This treatment is given on days 2 to 11 Amount of 3 times 600 mg of ribavirin continued, and then ended. The state of infection of the treated patient can be examined both symptomatically and at the RNA level. The usage of ribavirin according to the therapy scheme shown leads to a rapid improvement in the state of health of the infected patient, lowers mortality after virus infection and ultimately leads complete healing in a high percentage of sick patients illness.
  • Example 2
  • One tablet contains 200 mg ± 3% ribavirin and additives according to the recipe: ribavirin 200.00 mg Polyvidon K25 16.00 mg Microcrystalline cellulose 77.00 mg crospovidone 3.50 mg silica 2.00 mg magnesium stearate 1.50 mg all in all 300.00 mg
  • Example 3
  • The tablet of the formulation described in Example 2 is additionally coated with a water-soluble film ("coating", "coating"), composed of: hydroxypropyl methylcellulose 4.00 mg Titanium dioxide 2.00 mg 6.00 mg
    or alternatively composed of: hydroxypropyl methylcellulose 4.00 mg Titanium dioxide 2.00 mg Polyethylene glycol 6000 (Macrogol 6000) 1.00 mg 7.00 mg
  • Example 4
  • Ribavirin can also help with suppositories Patients infected with bunya viruses (e.g. hantaviruses or CCHF viruses). This is essentially the Maintain the dose recommendation of Example 1. Even in the case of therapy with suppositories there is a rapid improvement in the symptoms of the virus infection and at a large percentage the patient to a complete Healing the disease.
  • The set out in Examples 1 and 4 Ribavirin therapy can accordingly with a lower body weight, such as. in children or infants, be carried out with a smaller amount. The goes Therapy shown in Examples 1 and 4 of an average weight of the patient from 75 kg and a corresponding reduction in administered ribavirin amount at a lower body weight is for obvious to the expert.

Claims (9)

  1. Use of ribavirin for the manufacture of a pharmaceutical composition for treating a patient who is infected with Bunyaviridae, characterized in that the pharmaceutical composition is administered orally and / or rectally in compressed form.
  2. Use according to claim 1, characterized in that the pharmaceutical Composition is administered in tablet form.
  3. Use according to claim 2, characterized in that the tablet form is Ravanex ® .
  4. Use according to claim 1, characterized in that the pharmaceutical Suppository form is administered.
  5. Use according to one of the preceding claims, characterized characterized that the Ribavirin administration is carried out according to the following scheme: a) Day 1: 1-3 times 500 to 2000 mg of ribavirin b) Day 2 to 20: 1-3 times 400 up to 1500 mg ribavirin
  6. Use according to claim 5, characterized in that the ribavirin administration according to the following Scheme done becomes: a) Day 1: 3 times 800 mg ribavirin b) Day 2 to 11: 3 times 600 mg of ribavirin
  7. Consumer pack, characterized in that it contains information material on the Use of ribavirin according to claims 1 to 6 and a pharmaceutical Composition containing ribavirin in compressed form.
  8. Consumer pack according to claim 7, characterized in that that she Information material about the use of ribavirin according to any one of claims 1 to 6 and a pharmaceutical composition containing ribavirin in tablet form.
  9. Consumer pack according to claim 7, characterized in that that she Information material about the use of ribavirin according to any one of claims 1 to 6 and a pharmaceutical composition containing ribavirin in suppository form.
DE2002127148 2002-06-18 2002-06-18 Use of ribavirin for the manufacture of a pharmaceutical composition against Bunyaviridae Ceased DE10227148A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
DE2002127148 DE10227148A1 (en) 2002-06-18 2002-06-18 Use of ribavirin for the manufacture of a pharmaceutical composition against Bunyaviridae

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE2002127148 DE10227148A1 (en) 2002-06-18 2002-06-18 Use of ribavirin for the manufacture of a pharmaceutical composition against Bunyaviridae
PCT/EP2003/006392 WO2003105839A1 (en) 2002-06-18 2003-06-17 Use of ribavirin for producing a pharmaceutical composition directed against bunyaviridae
AU2003276994A AU2003276994A1 (en) 2002-06-18 2003-06-17 Use of ribavirin for producing a pharmaceutical composition directed against bunyaviridae

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DE10227148A1 true DE10227148A1 (en) 2004-01-08

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103977319A (en) * 2014-05-17 2014-08-13 王平 Traditional Chinese medicine composition for treating lower-limb phlebitis formation
CN103961617A (en) * 2014-05-30 2014-08-06 济南高达信息技术有限公司 External ointment for treating venous inflammation
CN104083592B (en) * 2014-07-28 2017-07-14 河南中医学院 A kind of Externally applied Chinese medicine liquid for treating phlebitis caused by chemotherapeutic medicines

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* Cited by examiner, † Cited by third party
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WO1999032128A1 (en) * 1997-12-22 1999-07-01 Schering Corporation Orally administrable solid ribavirin dosage forms and process for making them

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WO2003105839A1 (en) 2003-12-24

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