AU5969700A - Antilipemic combinations comprising hmg-coa reductase inhibitors and carnitines - Google Patents
Antilipemic combinations comprising hmg-coa reductase inhibitors and carnitines Download PDFInfo
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Description
WO 00/74675 PCT/EP00/05091 1 ANTILIPEMIC COMBINATIONS COMPRISING HMG-COA REDUCTASE INHIBITORS AND CARNITINES The invention described herein relates to a pharmaceutical composition for the treatment of diseases caused by lipid 5 metabolism disorders, and in particular a pharmaceutical composition comprising a statin and L-carnitine or one of its alkanoyl derivatives, useful for the prevention and treatment of statin-induced toxic or side effects. Cardiovascular diseases related to lipid metabolism disorders o10 are very frequent in the industrialised countries. In Italy, for instance, they account for more than 40% of the overall mortality (Capocaccia R., Farchi G., Prati S. et al.: La mortality' in Italia nell'anno 1989. Rapporto ISTISAN 1992/22). Our knowledge of the relationships between cholesterol and coronary heart disease stems 15is from epidemiological studies conducted in recent years. The conclusions of these studies indicate that the development of severe coronary atherosclerosis is closely related to serum cholesterol levels (McGill H.C. Jr. et al.: The International Atherosclerosis Project. Lab. Invest. 18: 463-653, 1968; Keys A.: Seven Countries: Death and 20 Coronary Heart Disease. Harvard University Press, Cambridge, 1980). Correction of eating habits through an appropriate diet is always the first measure to be adopted in cases of hyperlipidaemia. Good results, however, are not always achieved owing to widespread
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WO 00/74675 PCT/EP00/05091 2 intolerance of the strict dietary regimen, to the severity of the hypercholesterolaemia or to genetic-type resistance. In these cases, to achieve the desired results, that is to say to restore normal blood levels of triglycerides and cholesterol, it proves 5 necessary to resort to pharmacological treatment with lipid-lowering drugs. This category includes both drugs that prevalently reduce cholesterol levels and drugs that prevalently reduce triglyceride levels. The former group of drugs includes statins, probucol and io resins, and the latter group fibrates, nicotinic acid and omega-3 series fatty acids. The statins (simvastatin, lovastatin, pravastatin, fluvastatin and the like) are hydroxy-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors. By inhibiting this enzyme, they reduce the ~s hepatic synthesis of cholesterol (Lancet 1994; 334: 1383-1389). To compensate for the reduction in intracellular cholesterol, the liver cell produces more receptors for lipoproteins of the LDL and VLDL series, which in this way are removed from the bloodstream. In addition, the statins cause less absorption of cholesterol of 20 dietary origin in the intestine and a reduced output of apoprotein B present in low-density lipoproteins (LDL). The statins are better tolerated than the other cholesterol lowering agents, but present certain drawbacks: the most common
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WO 00/74675 PCT/EP00/05091 3 side effects caused by these drugs are gastrointestinal disorders, skin rashes and headache. A number of patients have complained of sleep disorders (EJ Schaffer, N Engl J Med, 319:1222,1988; Lancet, 339:547, 29 5 February 1992), while significant increases in transaminase activity (GOT and GPT) and in CK compared to basal values have been observed in patients taking statins in doses of 40 mg/kg (Schweiz Med Wochenschr 1991 Jun 29; 121 (26) : 977-83). Moreover, patients treated with simvastatin present side o10 effects related to myopathy, rhabdomyolysis, muscle pain and increases in serum CK and LDH activity [Dedlypere J.P. & Vermeulen A. (1991) Ann. Intern. Med. 114:342; Bizzarro N. et al. (1992) Clin. Chem. 38: 1504]. EP 0383432 describes the combination of an HMG-CoA 15 reductase inhibitor and coenzyme Q10 for the treatment of skeletal muscle myopathy caused by statins. It has been reported that statins cause a reduction in the number of deaths due to coronary heart disease, but, on the other hand, an increase in deaths due to other events such as tumours or 20 trauma has been noted in treated patients (Davey-Smith G., Song F., Sheldon T. A., Cholesterol lowering and mortality: the importance of considering initial level at risk. BMJ 1993; 306: 1367-1373; Ravnshov U.; Cholesterol lowering trials in coronary heart disease: frequency of citation and outcome. BMJ 1992; 305: 15-19). Young
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WO 00/74675 PCT/EP00/05091 4 rats treated with different cholesterol-lowering agents (simvastatin, lovastatin, and pravastatin) show signs of myopathy, when high doses of simvastatin are used (Reijneveld J. C. et al., 1976 Pediatr. Res. 39: 1028-1035). Moreover, Bhuiyan et al. (Bhuiyan J. & 5 Seccombe D.W. 1996 Lipids 31: 867-870) have demonstrated that the administration of lovastatin to rabbits causes a significant reduction in hepatic, cardiac and skeletal muscle L-carnitine. The results of experiments in animals and in human subjects have suggested that, to reduce cholesterol levels, pharmacological i0 treatment with statins should be used only in patients at high risk of coronary disease in the short term (JAMA, 1996; 275: 55-60). Equally well known are the triglyceride- and cholesterol lowering effects of a number of alkanoyl carnitines, in particular of acetyl L-carnitine. US Patent 4,268,524 describes a therapeutic !5 method for increasing the level of high-density lipoproteins (HDL) so as to selectively reduce the LDL + VLDL:HDL ratio in the plasma of patients at risk of cardiovascular disease, in whom this ratio is abnormally high. This method includes the daily administration of 5-50 mg/kg of alkanoyl carnitine or of one of its pharmacologically 20 acceptable salts. The international patent application WO99/01126 filed in the name of the applicant describes the use of alkanoyl L-carnitine in combination with statins for the treatment of diseases related to lipid metabolism disorders. WO99/01126 does not describe or
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WO 00/74675 PCT/EP00/05091 5 suggest that L-carnitine or the alkanoyl L-carnitines exert a protective action on statin-induced toxic or side effects. It has now unexpectedly been found that the co-ordinated use - this term will be defined precisely here below - of L-carnitine or an 5 alkanoyl L-carnitine, in which the linear or branched alkanoyl has 2-6 carbon atoms, or one of their pharmacologically acceptable salts and a statin affords a protective action against statin-induced toxic or side effects. The well-known lack of toxic and side effects of L-carnitine o10 and of the alkanoyl L-carnitines and the protective action exerted by these compounds on statin-induced toxic or side effects allow the statins to be used at doses higher than those usually administered (10-20 mg/day). The co-ordinated use according to the invention is 15 particularly useful and safe for the treatment of both hypercholesterolaemic and/or hyper-triglyceridaemic patients at high risk for cardiovascular disease in the short, medium or long term. Thanks to the protective effect exerted by L-carnitine or by the 20 alkanoyl L-carnitines, it has been found, in fact, that it is possible to use higher doses of statin than those normally used in human therapy, while the dose of L-carnitine or alkanoyl L-carnitines may be 100-3000 mg/day.
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WO 00/74675 PCT/EP00/05091 6 In the context of the invention described herein, what is meant by "co-ordinated use" of the above-mentioned compounds is, indifferently, either (i) co-administration, i.e. the substantially simultaneous administra-tion of L-carnitine or one of the aforesaid 5 alkanoyl L-carnitines or one of their pharmacologically acceptable salts and of a statin, or (ii) the administration of a composition comprising the aforesaid active ingredients in combination and in a mixture, in addition to possible excipients. What is meant by co administration is also a pack or manufactured article, comprising 10 distinct administration forms of L-carnitine or one of the aforesaid alkanoyl L-carnitines, or one of their pharmacologically acceptable salts and a statin, accompanied by instructions for the co-ordinated simultaneous intake of the active ingredients according to a dosage regimen established by the primary care physician on the basis of 1s the patient's condition. The invention described herein therefore covers both the co administration of L-carnitine or one of the aforesaid alkanoyl L carnitines, or one of their pharmacologically acceptable salts and a statin, and pharmaceutical compositions which can be administered 20 orally or parenterally, comprising a mixture of the two active ingredients. The subject matter of the invention described herein also includes the use of a therapeutically effective amount of a statin and a detoxifying amount of L-carnitine or an alkanoyl L-carnitine in .1.
WO 00/74675 PCT/EP00/05091 7 which the linear or branched alkanoyl has 2-6 carbon atoms, or of one of their pharmacologically acceptable salts for the preparation of a medicinal agent useful for the treatment of diseases caused by lipid metabolism disorders, characterised in that said medicinal 5 agent presents reduced statin-induced toxic or side effects. A further subject of the invention described herein is the use of a detoxifying amount of L-carnitine or an alkanoyl L-carnitine, in which the linear of branched alkanoyl has 2-6 carbon atoms, or one of their pharmacologically acceptable salts, for the preparation of a o10 medicinal agent useful for the treatment of statin-induced toxic or side effects. The invention described herein also comprises the use of L carnitine or an alkanoyl L-carnitine, in which the linear or branched alkanoyl has 2-6 carbon atoms, or of one of their pharmacologically 15 acceptable salts, for the preparation of a medicinal agent useful for the treatment of statin-induced toxic or side effects. The statin is preferably selected from the group consisting of lovastatin, simvastatin, pravastatin and fluvastatin, while the alkanoyl L-carnitine is preferably selected from the group consisting 20 of acetyl L-carnitine, propionyl L-carnitine, butyryl L-carnitine, valeryl L-carnitine and isovaleryl L-carnitine or one of their pharmacologically acceptable salts.
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WO 00/74675 PCT/EP00/05091 8 More preferably, the statin is simvastatin and the alkanoyl L carnitine is propionyl L-carnitine or one of its pharmacologically acceptable salts. Even more preferably, the statin is simvastatin and the 5 carnitine is L-carnitine or one of its pharmacologically acceptable salts. What is meant by a pharmacologically acceptable salt of an alkanoyl L-carnitine is any salt of this with an acid which does not give rise to toxic or side effects. These acids are well known to 10 pharmacologists and to experts in pharmaceutical technology. Examples of pharmaceutically acceptable salts of alkanoyl L carnitines, though not exclusively these, are chloride, bromide, orotate, acid aspartate, acid citrate, acid phosphate, fumarate and acid fumarate, maleate and acid maleate, mucate, acid oxalate, acid 15 sulphate, glucose phosphate, tartrate and acid tartrate. By favouring the use of larger doses of statins, the combination according to the invention allows better treatment of diseases related to lipid metabolism disorders, thus achieving greater therapeutic success. 20 The combination according to the invention also contributes to the healing and to prolonging the lives of the patients treated, amongst other things thanks to the increase in therapeutic success rates due to the possibility of maintaining the scheduled treatment
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WO 00/74675 PCT/EP00/05091 9 protocols for longer periods, without having to discontinue the treatment owing to the toxic or side effects of the statins. The protective action of L-carnitine or of an alkanoyl L carnitine on the toxic or side effects of statins has been confirmed by 5 the results of experimental studies, which are reported here below. Though reference is made in these examples only to L carnitine, it must, however, be understood that such protection is also afforded by the above-mentioned alkanoyl L-carnitines and by their pharmacologically acceptable salts. io Example 1 Male Wister rats aged 23 days and weighing 45-50 g were used. The animals were housed in polycarbonate cages, 5 animals per cage, maintained at a constant temperature of 22 ± 2oC and at 55 ± 15% relative humidity, with a light-darkness cycle of 12 hours, 15 fed on 4RF21 pellet feed (Mucedola), with tap water to drink ad libitum. The control group consisted of 14 animals, whereas the groups treated with simvastatin at various doses and with simvastatin plus L-carnitine consisted of 10 animals each, according 20 to the following experimental design: - Control (no treatment); - Simvastatin 70 mg/kg; - Simvastatin 140 mg/kg; - Simvastatin 210 mg/kg;
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WO 00/74675 PCT/EP00/05091 10 - Simvastatin 70 mg/kg + L-carnitine 400 mg/kg. - Simvastatin 140 mg/kg + L-carnitine 400 mg/kg. - Simvastatin 210 mg/kg + L-carnitine 400 mg/kg. L-carnitine was given by oral administration via a gastric 5 tube, twice daily (2 x 200 mg/kg) suspended in 0.5% carboxymethylcellulose (CMC) to the groups treated with statin, or in water when administered alone. Simvastatin was administered orally suspended in 0.5% carboxy-methylcellulose (CMC) (10 mL/kg). o10 The duration of the treatment was 9 days. 24 hours after the last treatment, the animals were anaesthetised and blood samples were taken from the sublingual vein. The blood was centrifuged at 400 rpm for 30 min and the 15 serum thus obtained was used to evaluate plasma levels of CK, GOT, GPT and cholesterol. The CK, GOT, GPT and cholesterol analyses were carried out using a Cobas Mira S (Roche) automatic analyser and Roche diagnostic kits. 20 Since the plasma enzyme activity showed a highly skewed distribution, it was decided to analyse the data using the non parametric Mann-Whitney U test; the test data are shown as median values together with the associated ranges. The results obtained are reported in Table 1.
WO 00/74675 PCT/EP00/05091 11 Table 1 GOT GPT CK Cholesterol U/L U/L U/L mg/dl Control Median 140.73 45.94 1056.12 73.18 Range 96.4-196.4 40.3-57.4 477.7-1616.4 60.3-80.7 Simvastatin Median 125.68 50.65 971.51 71.35 70 mg/kg Range 98.8-237.1 41.1-73.6 396.8-1754.2 44.6-87.1 Simvastatin Median 189.97*** 69.18*** 1308.92 56.72 140 mg/kg Range 139.0-293.8 40.7-98.7 417.8-1836.1 44.2-81.3 Simvastatin Mediana 686.69*** 93.71** 1784.32* 46.54*** 210 mg/kg Range 172.3-5288.8 35.5-494.9 8808-4887.0 35.9-66.1 Simvastatin Mediana 123.14 50.42 709.29 74.95 70 mg/kg + L-carnitine Range 100.4-204.4 37.8-76.6 442.0-1840.1 56.7-119.4 200 mg/kg Simvastatin Median 209.45 57.49 762.53* 57.21 140 mg/kg + L-carnitinE Range 112.3-373.6 42.3-138.0 350.2-1455.7 33.2-75.3 200 mg/kg Simvastatin Median 435.11 77.80 741.65* 40.06 210 mg/kg + L-carnitine Range 134.0-2422.7 51.8-494.9 535.2-2425.0 31.3-66.5 200 mg/kg Mann-Whitney U test: - significance: *** = p<0.002; ** = p<0.0 2 ; * = p<0.
0 5 ; 5 - the significance of the groups treated with statin (alone) was calculated versus the control group;
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WO 00/74675 PCT/EP00/05091 12 - the significance of the groups treated with statin in combination with L-carnitine was calculated versus the group treated with statin alone The results presented in Table 1 indicate that the 5 administration of simvastatin at the highest dose (210 mg/kg) caused a substantial and significant increase in plasma GOT (p<0.002), GPT (p<0.002) and CK (p<0.05) compared to controls. At a lower dose (140 mg/kg), simvastatin treatment caused an increase in all the enzyme activities tested, with GOT (p<0.002) and GPT 10 (p<0.0 2 ). Simvastatin treatment at the lowest dose (70 mg/kg) did not significantly increase the enzyme activity tested. The cholesterol level was significantly lowered only at the highest simvastatin dose used. 15 The administration of L-carnitine to the groups treated with simvastatin showed lower plasma CK activity compared to the group treated with simvastatin alone. Statistically, L-carnitine administration was significantly effective in counterbalancing the plasma CK elevation at the simvastatin doses of 140 and 210 mg/kg 20 (Table 1). Simvastatin treatment at the lowest dose (70 mg/kg) in combination with L-carnitine reduced plasma CK activity as compared to simvastatin alone at the same dose, though not to a statistically significant extent.
WO 00/74675 PCT/EP00/05091 13 The results of these studies furnish substantial evidence of the protective action of L-carnitine and of the alkanoyl L-carnitines on the toxic and side effects of statins which constitutes the basis for the invention described herein. 5 In a second experiment conducted in the same way as the first, the only difference being that L-carnitine was administered in the animals' drinking water, comparable results were obtained. Therefore, a further realisation of the invention described herein comprises the co-ordinated use of L-carnitine or one of its o10 alkanoyl derivatives or one of their pharmacologically acceptable salts and of a statin according to the above definitions, in the treatment of animals, such as, for example, livestock and, particularly, pets. In this particular realisation, L-carnitine, or one of its derivatives, may be in solid form, such as, for example, fumarate, 15 tartrate or mucate, to be dissolved in drinking water, or in metered dose liquid form, to be diluted.
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Claims (20)
1. Pharmaceutical composition comprising a detoxifying amount of L-carnitine or of an alkanoyl L-carnitine in which the linear or branched alkanoyl has 2-6 carbon atoms, or one of their 5 pharmacologically acceptable salts, and a therapeutically effective amount of a statin;
2. Pharmaceutical composition comprising a detoxifying amount of L-carnitine in which the linear or branched alkanoyl has 2-6 carbon atoms, or one of their pharmacologically acceptable 10 salts, and a statin, characterised in that the statin is present at a greater dose than the one normally used in therapy which leads to the occurrence of side effects related to its use.
3. Composition according to Claim 1 or 2, in which the statin is selected from the group consisting of lovastatin, simvastatin, 15 pravastatin and fluvastatin, the one preferred being simvastatin.
4. Composition according to Claim 3, in which the statin is simvastatin.
5. Composition according to Claim 1 or 2, in which the alkanoyl L carnitine is selected from the group consisting of acetyl L 20 carnitine, propionyl L-carnitine, butyryl L-carnitine, valeryl L carnitine, and isovaleryl L-carnitine.
6. Composition according to Claim 5, in which the alkanoyl L carnitine is propionyl L-carnitine. ./. WO 00/74675 PCT/EP00/05091 15
7. Composition according to Claim 1 or 2 and either of Claims 3 or 4, in which L-carnitine is present.
8. Composition according to Claim 1 or 2, in which the pharmacologically acceptable salt of L-carnitine or of the 5 alkanoyl L-carnitines is selected from the group consisting of chloride, bromide, orotate, acid aspartate, acid citrate, acid phosphate, fumarate and acid fumarate, maleate and acid maleate, mucate, acid oxalate, acid sulphate, glucose phosphate, tartrate and acid tartrate. 10
9. Use of a therapeutically effective amount of a statin and of a detoxifying amount of L-carnitine or an alkanoyl L-carnitine, in which the linear or branched alkanoyl has 2-6 carbon atoms, or of one of their pharmacologically acceptable salts, for the preparation of a medicinal agent useful for the treatment of 15 diseases caused by lipid metabolism disorders, characterised in that said medicinal agent presents reduced statin-induced toxic or side effects.
10. Use of a therapeutically effective amount of a statin and of a detoxifying amount of L-carnitine or an alkanoyl L-carnitine, in 20 which the linear or branched alkanoyl has 2-6 carbon atoms, or one of their pharmacologically acceptable salts, for the preparation of a medicinal agent useful for the treatment of statin-induced toxic or side effects. ./. WO 00/74675 PCT/EP00/05091 16
11. Use of L-carnitine or an alkanoyl L-carnitine, in which the linear or branched alkanoyl has 2-6 carbon atoms, or of one of their pharmacologically acceptable salts, for the preparation of a medicinal agent useful for the treatment of statin-induced toxic 5 or side effects.
12. Use according to Claim 9, or 10, or 11, in which the statin is selected from the group consisting of lovastatin, simvastatin, pravastatin and fluvastatin, the one preferred being simvastatin.
13. Use according to Claim 9, or 10, or 11, in which the alkanoyl L 10 carnitine is selected from the group consisting of acetyl L carnitine, propionyl L-carnitine, butyryl L-carnitine, valeryl L carnitine, and isovaleryl L-carnitine, the preferred one being propionyl L-carnitine.
14. Use according to Claim 9, or 10 or 11, in which the alkanoyl L 15 carnitine is propionyl L-carnitine.
15. Use according to Claim 9, or 10, or 11, in which L-carnitine is present.
16. Use according to Claim 9, or 10 or 11, in which the pharmacologically acceptable salt of L-carnitine or of the 20 alkanoyl L-carnitines is selected from the group consisting of chloride, bromide, orotate, acid aspartate, acid citrate, acid phosphate, fumarate and acid fumarate, maleate and acid maleate, mucate, acid oxalate, acid sulphate, glucose phosphate, tartrate and acid tartrate. ./. WO 00/74675 PCT/EP00/05091 17
17. Co-ordinated use of a therapeutically effective amount of a statin selected from the group consisting of lovastatin, simvastatin, pravastatin and fluvastatin, and of a detoxifying amount of L-carnitine or an alkanoyl L-carnitine, in which the 5 linear or branched alkanoyl has 2-6 carbon atoms, or one of their pharmacologically acceptable salts, for reducing statin induced toxicity, while conserving the therapeutic efficacy of the statin.
18. Use according to Claim 16, in which the administration is 10 sequential.
19. Use according to Claim 16, in which the administration is substantially simultaneous.
20. A manufactured article comprising a pharmaceutical composition according to Claim 1 or 2, accompanied by 15 instructions for the co-ordinated, simultaneous intake of the drugs or for their intake according to a predetermined dosage regimen. ./.
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US13800899P | 1999-06-08 | 1999-06-08 | |
US60/138008 | 1999-06-08 | ||
EP99830415A EP1064943B1 (en) | 1999-06-30 | 1999-06-30 | Combination having antilipemic activity substantially free from toxic or side effects due to antilipemic drugs |
EP99830415 | 1999-06-30 | ||
PCT/EP2000/005091 WO2000074675A1 (en) | 1999-06-08 | 2000-06-05 | Antilipemic combinations comprising hmg-coa reductase inhibitors and carnitines |
Publications (2)
Publication Number | Publication Date |
---|---|
AU5969700A true AU5969700A (en) | 2000-12-28 |
AU782188B2 AU782188B2 (en) | 2005-07-07 |
Family
ID=26153794
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
AU59697/00A Ceased AU782188B2 (en) | 1999-06-08 | 2000-06-05 | Antilipemic combinations comprising HMG-COA reductase inhibitors and carnitines |
Country Status (10)
Country | Link |
---|---|
JP (1) | JP2003501385A (en) |
KR (1) | KR100725263B1 (en) |
AU (1) | AU782188B2 (en) |
CA (1) | CA2375378C (en) |
CZ (1) | CZ20014218A3 (en) |
HU (1) | HUP0201597A3 (en) |
MX (1) | MXPA01012644A (en) |
PL (1) | PL197899B1 (en) |
SK (1) | SK285900B6 (en) |
WO (1) | WO2000074675A1 (en) |
Families Citing this family (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
AU2007348123B2 (en) * | 2007-02-27 | 2013-01-17 | Alfasigma S.P.A. | Composition useful for the treatment of type 2 diabetes |
CA2681185C (en) | 2007-03-21 | 2018-05-01 | Sigma-Tau Industrie Farmaceutiche Riunite S.P.A. | Composition useful for the prevention of type 2 diabetes and its complications in pre-diabetic patients with insulin resistance |
JP5677856B2 (en) * | 2008-02-29 | 2015-02-25 | バイオラブ・サヌス・ファーマセウティカ・エルティーディーエー. | Pharmaceutical composition |
US20120130202A1 (en) * | 2010-11-24 | 2012-05-24 | Fujitsu Limited | Diagnosis and Monitoring of Musculoskeletal Pathologies |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH0667833B2 (en) * | 1985-11-28 | 1994-08-31 | 雪印乳業株式会社 | Enteral nutrition |
DE69001146T2 (en) * | 1989-01-18 | 1993-10-07 | Merck & Co Inc | Coenzyme Q10 with HMG-COA reductase inhibitors. |
IT1293067B1 (en) * | 1997-07-01 | 1999-02-11 | Sigma Tau Ind Farmaceuti | PHARMACEUTICAL COMPOSITION FOR THE TREATMENT OF PATHOLOGIES CAUSED BY ALTERED LIPID METABOLISM |
-
2000
- 2000-06-05 WO PCT/EP2000/005091 patent/WO2000074675A1/en not_active Application Discontinuation
- 2000-06-05 MX MXPA01012644A patent/MXPA01012644A/en active IP Right Grant
- 2000-06-05 KR KR1020017015675A patent/KR100725263B1/en not_active IP Right Cessation
- 2000-06-05 JP JP2001501212A patent/JP2003501385A/en active Pending
- 2000-06-05 SK SK1715-2001A patent/SK285900B6/en not_active IP Right Cessation
- 2000-06-05 HU HU0201597A patent/HUP0201597A3/en unknown
- 2000-06-05 CZ CZ20014218A patent/CZ20014218A3/en unknown
- 2000-06-05 CA CA002375378A patent/CA2375378C/en not_active Expired - Fee Related
- 2000-06-05 AU AU59697/00A patent/AU782188B2/en not_active Ceased
- 2000-06-05 PL PL352106A patent/PL197899B1/en unknown
Also Published As
Publication number | Publication date |
---|---|
PL197899B1 (en) | 2008-05-30 |
HUP0201597A2 (en) | 2002-09-28 |
CA2375378A1 (en) | 2000-12-14 |
JP2003501385A (en) | 2003-01-14 |
CZ20014218A3 (en) | 2002-04-17 |
WO2000074675A1 (en) | 2000-12-14 |
HUP0201597A3 (en) | 2003-04-28 |
KR100725263B1 (en) | 2007-06-07 |
AU782188B2 (en) | 2005-07-07 |
SK17152001A3 (en) | 2002-03-05 |
KR20020025066A (en) | 2002-04-03 |
SK285900B6 (en) | 2007-10-04 |
MXPA01012644A (en) | 2002-07-22 |
CA2375378C (en) | 2009-08-11 |
PL352106A1 (en) | 2003-07-28 |
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Legal Events
Date | Code | Title | Description |
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DA3 | Amendments made section 104 |
Free format text: THE NATURE OF THE AMENDMENT IS: AMEND THE APPLICANT TO READ: SIGMA-TAU INDUSTRIE FARMACEUTICHE RIUNITE S.P.A. |