Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/47—Quinolines; Isoquinolines
  • A61K31/4706—4-Aminoquinolines; 8-Aminoquinolines, e.g. chloroquine, primaquine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/47—Quinolines; Isoquinolines
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P33/00—Antiparasitic agents
  • A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
  • A61P33/06—Antimalarials
• • 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 a combination kit for use in the treatment of malaria and a method for producing such a kit.
• the invention relates to a combination kit comprising anti-malarial agents, 3-[l-[[4-[(6-methoxy-8-quinolinyl)amino]pentyl]amino]- ethyMene]-dihydro-2(3H)furanone and chloroquine.
• the present invention relates to the use of the combination kit containing an anti-malarial agent, 3-[l-[[4-[(6-metho ⁇ -8-quinolmyl)amino]pentyl]- amino]ethylidene]-dihydro-2(3H)-furanone and chloroquine against relapsing malaria caused by Plasmodium vivax for better patient compliance.
• the present invention further relates to a method for the treatment of malaria caused by P. vivax.
• Plasmodium malariae Malaria, caused by a parasitic protozoan called Plasmodium, is one of the most serious and complex tropical parasitic diseases. Generally human malaria is caused by four species of malarial parasites which are Plasmodium falciparwn, Plasmodium vivax, Plasmodium ovale and Plasmodium malariae. Of these P. falciparum and P. viv ⁇ x are most widespread and cause most of the mortality and morbidity associated with these types of infections.
• Chloroquine has been the effective treatment so far for the P. vivax malarial infections, however, some strains of P. vivax have shown resistance to this well known drug ⁇ Ann. Trop. Med. ParasitoL, 1999 Apr; 93(3): 225-230).
• drug resistant malaria has become one of the most serious problems in malaria control. Drug resistance necessitates the use of drugs which are more expensive and may have dangerous side effects.
• treatments comprising combinations of anti-malarial agents are on the rise. A number of anti-malarial combinations are already known in the malarial chemotherapy.
• a combination of amodiaquine and tetracycline, a combination of sulfadoxine and pyrimethamine known as fansidar, are known therapies for the treatment of P. fal ⁇ parum.
• fansidar a combination of mefloquine with sulfadoxine and pyrimetha min e is used against multidrug resistant strains of P. faldparum.
• United States Patent No. 5 998 449 describes a method for the treatment of malaria wherein combination of atovaquone and proguanil is used for the treatment of malaria.
• US Patent No. 5 834 505 combination of fenozan with another anti-malarial agent selected from artemisinin, sodium artesunate, chloroquine, mefloquine is described for the prophylactic and curative treatment of malaria.
• vivax malarial infection comprises of a sequential chloroquine-primaquine combination treatment regimen wherein primaquine is administered for 14 days following the 3 days course of chloroquine.
• WHO World Health Organisation
• primaquine is administered for 14 days following the 3 days course of chloroquine.
• WHO World Health Organisation
• primaquine is administered for 14 days following the 3 days course of chloroquine.
• a shorter duration of cMoroquine-primaquine treatment regimen was also tried out wherein primaquine was administered only for 5 days following the chloroquine course.
• the outcome of the treatment was not encouraging, since the percentage relapse was more than the standard 14 days primaquine treatment regimen (Trans. R. Soc. Trop. Med. Hyg., 93(6), 641-643).
• primaquine is known to cause hemolytic anemia in persons deficient in the enzyme glucose-6-phosphate dehydrogenase (G6PD) (Pharmacol Rev. 21: 73-103 (1969); Rev. Cubana Med trop, 1997; 49 (2): 136-8 ).
• G6PD glucose-6-phosphate dehydrogenase
• methemoglobin toxicity is another predictable dose-related adverse effect associated with primaquine. Needless to say that in the case of sequential combination therapy the patient may not complete the course once the symptoms of malaria are diminished, hence this may increase the chances of relapse.
• the chloroquine- primaquine treatment regimen is not safe with respect to toxicity of primaquine and has a further limitation from the standpoint of patient compliance due to longer duration of treatment.
• the compound of formula (I) has been found to be safer and less toxic than the parent compound primaquine (Am. J. Trop. Med. Hyg, 1989 Dec; 41(6): 635-637). Its anti-relapse activity has been found to be comparable to primaquine.
• primaquine was the only drug used for the radical cure of malaria caused by P. vivax. Primaquine is associated with a number of severe adverse effects, therefore there is a need to develop agents which are more effective and/ or less toxic than primaquine.
• the compound I has been found to exhibit anti-relapse activity comparable to Primaquine (Am. J. Trop. Med. Hyg., 41(6): 633-637 (1989)). However, this compound has been shown to cause less methemoglobin formation (Am. J. Trop Hyg., 41(6): 638-642 (1989) ) and also has less effect on anti-oxidant defence enzymes than primaquine (Biochem Pharmacol. 46(10): 1859- 1860 (1993) ). Thus, this primaquine derivative (I) is found to be less toxic as compared to the parent drug, primaquine.
• the inventors have found that the longfelt need may be fulfilled by providing a treatment regimen consisting of regulated use of chloroquine and 3-[l-[[4-[(6-methoxy-8-quinolinyl)a ⁇ nino]pentyl]amino]ethylidene]- dihydro-2(3H)furanone of formula I over a period of between 5 to 8 days.
• the treatment regimen may be executed most effectively and in a user friendly manner by providing a combination kit which comprises two anti-malarial agents, namely chloroquine and 3-[l- [[4-[(6-meth.oxy-8-qumolmyl)am ⁇
• the present invention relates to a cornbination kit for the treatment of P. vivax malaria for a period of between 5 to 8 days which comprises
• the present invention also relates to a method for producing a combination kit for the treatment of P. vivax malaria for a period of between 5 to 8 days which comprises:
• second anti-malarial agent namely 3- [ 1 - [[4- [(6-methoxy-8-quinoJfeyl)amino]pentyl]- amino]ethylidene]-dihydro-2(3H)furanone;
• the present invention further relates to a method of treatment of malaria caused by P. vivax comprising administering a first anti-malarial agent, chloroquine and a second anti-malarial agent, 3-[l-[[4-[(6-methoxy-8- quinoHnyl)amino] ⁇ en1yl]ammo]et ⁇ ylidene]-dmydro-2(3H)furanone in predetermined doses and in a predetermined sequence for a period of between 5 to 8 days.
• a combination kit for the treatment of malaria caused by P. vivax for a period of between 5 to 8 days comprising:
• a combination kit for 6 days treatment of malaria caused by P. vivax comprising:
• a method for the treatment of malaria caused by P. vivax for a period of six days comprising:
• the kit used in the present invention may be one or more strips in which the anti-malarial agents are packed individually or in combination.
• the kit may further comprise an enclosure in the form of a small carton or otherwise.
• the instruction is in the form of printed instructions provided inside the carton.
• the instructions may also be printed on the carton and/or on the strip or strips themselves.
• the instructions may be in English and/or in any national or regional language.
• An illustration of an instruction material for a 6 days treatment regimen is shown in Table 1 below, although other forms of instruction materials are not excluded from the scope of the invention.
• the combination kit is prepared by packing the strip/ strips in a cardboard packaging on which the instructions for the administration of the anti-malarial agents are contained. TABLE 1
• the radical curative anti-malarial activity and toxicity of the compound I was evaluated and compared with that caused by primaquine.
• the curative activity of compound I was evaluated against P. cynomolgi (a Plasmodium species which closely resembles the human malarial parasite P. vivax), in rhesus monkeys for 7 days and the compound was found to be 100% curative in the dose range of 1.25 mg/kg to 4 mg/kg Also there was no relapse observed up to 100 days after stopping the treatment.
• the efficacy of the combination kit of the present invention containing compound I (25 mg) was clinically evaluated and compared with primaquine (15 mg) used in combination with chloroquine in a group of patients over a one year surveillance study.
• the overall study conftrmed that the combination kit of the present invention can be used effectively in P. vivax malarial infection and that the compound I is as effective as primaquine with respect to radical curative activity.
• the invention thus includes the use of this safer anti-relapse agent, compound I with chloroquine in the form of a combination kit for the radical cure of P. vivax malaria.
• this safer anti-relapse agent compound I with chloroquine in the form of a combination kit for the radical cure of P. vivax malaria.
• the total course of treatment wherein compound I is administered concurrently with chloroquine lasts for 6 days only whereas in the chloroquine-primaquine treatment regimen, the total course of the effective treatment is 17 days.
• novel combination therapy of the present invention comprising the use of compound I in combination with chloroquine has distinct advantages in terms of safety and improved patient compliance due to shorter duration of treatment.
• the use of the combination kit of the present invention containing chloroquine and the compound I becomes a very useful treatment from the standpoint of low toxicity.
• concurrent administration of the drugs and shorter duration of the treatment may also improve patient compliance.
• the chloroquine tablets and capsules of compound I may be obtained commercially or prepared by conventional methods.
• the capsules containing compound I may be prepared by first mixing appropriate quantities of compound I along with the excipients lactose, colloidal silicon dioxide and magnesium stearate in an octagonal blender to obtain a powdered mixture and further filling hard gelatine capsule shells with the resulting mixture.
• the capsules are blister packed using approved PVC film and aluminium foil.
• the dosage of the drugs depends on the need of an individual and the dosages described herein are adult doses. However, this invention is not limited to the dosage of the combination regimen described herein and may be varied according to medical advice. Accordingly the specific dosage described in the typical embodiment is only illustrative and non- limiting combination kits for other dosage forms are also included in the scope of this invention.
• relapse is used herein to indicate that the symptoms of malaria recur.
• Each tablet contains 500 mg of chloroquine phosphate equivalent to 300 mg chloroquine base.
• the tablet containing chloroquine may be prepared by conventional techniques.
• Each capsule contains 25 mg of 3-[l-[[4-[(6-methoxy-8- quinolinyl)amino]pentyl]ajnino]ethylidene]-dihydro-2(3H)furanone (I) .
• the capsule containing compound I may be prepared according to the following formulation by the procedure as described:
• Compound I 25 mg
• lactose 250 mg
• colloidal silicon dioxide (2 mg) are separately sifted through an S. S. screen no. 40 fitted on a vibratory sifter and transferred to a octagonal blender and the contents are mixed for 40-45 minutes.
• magnesium stearate (10 mg) is sifted through a S. S. screen no. 40 fitted on a vibratory sifter and transferred to the octagonal blender.
• the contents are further mixed for 10-15 minutes.
• the resulting powdered mixture is then filled in size '2' double locking gelatine capsule shells which are further polished using a capsule polishing machine.
• the patients may be given the following treatment over a period of six days.
• Day 3 One tablet of chloroquine phosphate 500 mg (equivalent to 300 mg base) and one capsule containing 25 mg of compound I.
• Day 4 One capsule containing 25 mg of compound I.
• Day 5 One capsule containing 25 mg of compound I.
• Day 6 One capsule containing 25 mg of compound I.
• Example 2
• 2(3H)furanone (I) was evaluated vis-a-vis primaquine for toxicity related to methemoglobin formation in human.
• the methemoglobin toxicity of compound I was evaluated vis-a-vis that of primaquine in normal human volunteers. It was found that when the human subjects were administered with 25 mg daily dose of compound I for 7 days the methemoglobin level rose from 2.29 % to 3.02 % and in case of 15 mg daily dose of primaquine for 7 days the methemoglobin level rose from 3.97 % to 16.23 %.

Landscapes

• Health & Medical Sciences (AREA)
• Veterinary Medicine (AREA)
• Animal Behavior & Ethology (AREA)
• Chemical & Material Sciences (AREA)
• Medicinal Chemistry (AREA)
• Public Health (AREA)
• General Health & Medical Sciences (AREA)
• Pharmacology & Pharmacy (AREA)
• Life Sciences & Earth Sciences (AREA)
• Epidemiology (AREA)
• Tropical Medicine & Parasitology (AREA)
• General Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Medicinal Preparation (AREA)
• Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
• Medicines Containing Plant Substances (AREA)

Priority Applications (13)

Applications Claiming Priority (2)

Publications (3)

Family

ID=11097250

Family Applications (1)

Country Status (28)

Cited By (1)

Families Citing this family (2)

Family Cites Families (5)

• 2000
  • 2000-08-30 US US10/296,215 patent/US7404962B1/en not_active Expired - Fee Related
  • 2000-08-30 AU AU2879001A patent/AU2879001A/xx active Pending
  • 2000-08-30 DE DE60025403T patent/DE60025403T2/de not_active Expired - Lifetime
  • 2000-08-30 EP EP00993875A patent/EP1292306B1/en not_active Expired - Lifetime
  • 2000-08-30 AU AU2001228790A patent/AU2001228790B2/en not_active Ceased
  • 2000-08-30 PL PL372718A patent/PL200748B1/pl not_active IP Right Cessation
  • 2000-08-30 AT AT00993875T patent/ATE314848T1/de active
  • 2000-08-30 JP JP2001587559A patent/JP2004505017A/ja active Pending
  • 2000-08-30 HK HK03104811.6A patent/HK1052467B/en not_active IP Right Cessation
  • 2000-08-30 CZ CZ20024071A patent/CZ296875B6/cs not_active IP Right Cessation
  • 2000-08-30 MX MXPA02011883A patent/MXPA02011883A/es active IP Right Grant
  • 2000-08-30 DE DE0001292306T patent/DE00993875T1/de active Pending
  • 2000-08-30 KR KR1020027016169A patent/KR20030025926A/ko not_active Ceased
  • 2000-08-30 CA CA002413775A patent/CA2413775C/en not_active Expired - Fee Related
  • 2000-08-30 HU HU0301925A patent/HUP0301925A3/hu unknown
  • 2000-08-30 AP APAP/P/2002/002672A patent/AP1435A/en active
  • 2000-08-30 OA OA1200200359A patent/OA12276A/en unknown
  • 2000-08-30 ES ES00993875T patent/ES2200729T3/es not_active Expired - Lifetime
  • 2000-08-30 DK DK00993875T patent/DK1292306T3/da active
  • 2000-08-30 WO PCT/IN2000/000081 patent/WO2001091535A2/en not_active Ceased
  • 2000-10-05 EC EC2000003694A patent/ECSP003694A/es unknown
  • 2000-10-13 SV SV2000000201A patent/SV2002000201A/es unknown
  • 2000-10-25 GT GT200000187A patent/GT200000187A/es unknown
  • 2000-11-06 BR BR0005247-7A patent/BR0005247A/pt not_active Application Discontinuation
• 2001
  • 2001-05-14 AR ARP010102288A patent/AR028458A1/es unknown
  • 2001-05-23 PE PE2001000469A patent/PE20011319A1/es not_active Application Discontinuation
  • 2001-05-30 HN HN2001000118A patent/HN2001000118A/es unknown
• 2002
  • 2002-11-28 CR CR6835A patent/CR6835A/es not_active Application Discontinuation
  • 2002-11-29 NO NO20025765A patent/NO324774B1/no not_active IP Right Cessation
  • 2002-11-29 ZA ZA200209726A patent/ZA200209726B/en unknown

Non-Patent Citations (8)

Also Published As

Similar Documents

Legal Events