This invention relates to mutual prodrugs of amlodipine and atorvastatin and to pharmaceutical compositions thereof. This invention also relates to methods of treating angina pectoris, atherosclerosis, and hypertension and hyperlipidemia in a mammal using those prodrugs and compositions. This invention also relates to methods of managing cardiac risk in a mammal, including humans, presenting with symptoms of cardiac risk by administering those prodrugs and compositions.

This invention relates to mutual prodrugs of amlodipine and atorvastatin, pharmaceutically acceptable acid addition salts thereof, pharmaceutical compositions thereof and methods of using such prodrugs and compositions to treat subjects suffering from angina pectoris, atherosclerosis, combined hypertension and hyperlipidemia and to treat subjects presenting with symptoms of cardiac risk, including humans.
The conversion of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) to mevalonate is an early and rate-limiting step in the cholesterol biosynthetic pathway. This step is catalyzed by the enzyme HMG-CoA reductase. Statins inhibit HMG-CoA reductase from catalyzing this conversion. As such, statins are collectively potent lipid lowering agents.
Atorvastatin calcium, disclosed in U.S. Pat. No. 5,273,995, which is incorporated herein by reference, is currently sold as Lipitor(copyright) and has the formula
Atorvastatin calcium is a selective, competitive inhibitor of HMG-CoA. As such, atorvastatin calcium is a potent lipid lowering compound. The free carboxylic acid form of atorvastatin exists predominantly as the lactone of the formula
and is disclosed in U.S. Pat. No. 4,681,893, which is incorporated herein by reference.
Amlodipine and related dihydropyridine compounds are disclosed in commonly assigned U.S. Pat. No. 4,572,909, which is incorporated herein by reference, as potent anti-ischemic and antihypertensive agents. Commonly assigned U.S. Pat. No. 4,879,303, which is incorporated herein by reference, discloses amlodipine benzenesulfonate salt (also termed amlodipine besylate). Amlodipine and amlodipine besylate are potent and long lasting calcium channel blockers. As such, amlodipine, amlodipine besylate and other pharmaceutically acceptable acid addition salts of amlodipine have utility as antihypertensive agents and as antiischemic agents. Amlodipine and its pharmaceutically acceptable acid addition salts are also disclosed in commonly assigned U.S. Pat. No. 5,155,120 as having utility in the treatment of congestive heart failure. Amlodipine besylate is currently sold as Norvasc(copyright). Amlodipine has the formula
Atherosclerosis is a condition characterized by irregularly distributed lipid deposits in the intima of arteries, including coronary, carotid and peripheral arteries. Atherosclerotic coronary heart disease (hereinafter termed xe2x80x9cCHDxe2x80x9d) accounts for about 53% of all deaths attributable to a cardiovascular event. CHD accounts for nearly one-half (about $50-60 billion) of the total U.S. cardiovascular healthcare expenditures and about 6% of the overall national medical bill each year. Despite attempts to modify secondary risk factors such as, inter alia, smoking, obesity and lack of exercise, and treatment of dyslipidemia with dietary modification and drug therapy, CHD remains the most common cause of death in the United States.
High levels of blood cholesterol and blood lipids are conditions involved in the onset of atherosclerosis. It is well known that inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-COA reductase) are effective in lowering the level of blood plasma cholesterol, especially low density lipoprotein cholesterol (LDL-C), in man (Brown and Goldstein, New England Journal of Medicine, 1981, 305, No. 9, 515-517). It has now been established that lowering LDL-C levels affords protection from coronary heart disease (see, e.g., The Scandinavian Simvastatin Survival Study Group: Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S), Lancet, 1994, 344, 1383-89; and Shepherd, J. et al., Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia, New England Journal of Medicine, 1995, 333, 1301-07).
Angina pectoris is a severe constricting pain in the chest, often radiating from the precordium to the left shoulder and down the left arm. Often angina pectoris is due to ischemia of the heart and is usually caused by coronary disease.
Currently the treatment of symptomatic angina pectoris varies significantly from country to country. In the U.S., patients who present with symptomatic, stable angina pectoris are frequently treated with surgical procedures or PTCA. Patients who undergo PTCA or other surgical procedures designed to treat angina pectoris frequently experience complications such as restenosis. This restenosis may be manifested either as a short term proliferative response to angioplasty-induced trauma or as long term progression of the atherosclerotic process in both graft vessels and angioplastied segments.
The symptomatic management of angina pectoris involves the use of a number of drugs, frequently as a combination of two or more of the following classes: beta blockers, nitrates and calcium channel blockers. Most, if not all, of these patients require therapy with a lipid lowering agent as well. The National Cholesterol Education Program (NCEP) recognizes patients with existing coronary artery disease as a special class requiring aggressive management of raised LDL-C.
Amlodipine helps to prevent myocardial ischemia in patients with exertional angina pectoris by reducing Total Peripheral Resistance, or afterload, which reduces the rate pressure product and thus myocardial oxygen demand at any particular level of exercise. In patients with vasospastic angina pectoris, amlodipine has been demonstrated to block constriction and thus restore myocardial oxygen supply. Further, amlodipine has been shown to increase myocardial oxygen supply by dilating the coronary arteries.
Hypertension frequently coexists with hyperlipidemia and both are considered to be major risk factors for developing cardiac disease ultimately resulting in adverse cardiac events. This clustering of risk factors is potentially due to a common mechanism. Further, patient compliance with the management of hypertension is generally better than patient compliance with hyperlipidemia. It would therefore be advantageous for patients to have a single therapy which treats both of these conditions.
Coronary heart disease is a multifactorial disease in which the incidence and severity are affected by the lipid profile, the presence of diabetes and the sex of the subject. Incidence is also affected by smoking and left ventricular hypertrophy which is secondary to hypertension. To meaningfully reduce the risk of coronary heart disease, it is important to manage the entire risk spectrum. For example, hypertension intervention trials have failed to demonstrate full normalization in cardiovascular mortality due to coronary heart disease. Treatment with cholesterol synthesis inhibitors in patients with and without coronary artery disease reduces the risk of cardiovascular morbidity and mortality.
The Framingham Heart Study, an ongoing prospective study of adult men and women, has shown that certain risk factors can be used to predict the development of coronary heart disease. (see Wilson et al., Am. J. Cardiol. 1987, 59(14):91G-94G). These factors include age, gender, total cholesterol level, high density lipoprotein (HDL) level, systolic blood pressure, cigarette smoking, glucose intolerance and cardiac enlargement (left ventricular hypertrophy on electrocardiogram, echocardiogram or enlarged heart on chest X-ray). Calculators and computers can easily be programmed using a multivariate logistic function that allows calculation of the conditional probability of cardiovascular events. These determinations, based on experience with 5,209 men and women participating in the Framingham study, estimate coronary artery disease risk over variable periods of follow-up. Modeled incidence rates range from less than 1% to greater than 80% over an arbitrarily selected six year interval. However, these rates are typically less than 10% and rarely exceed 45% in men and 25% in women.
Kramsch et al., Journal of Human Hypertension (1995) (Suppl. 1), 53-59 disclose the use of calcium channel blockers, including amlodipine, to treat atherosclerosis. That reference further suggests that atherosclerosis can be treated with a combination of amlodipine and a lipid lowering agent. Human trials have shown that calcium channel blockers have beneficial effects in the treatment of early atherosclerotic lesions. (see, e.g., Lichtlen, P. R. et al., Retardation of angiographic progression of coronary artery disease by nifedipine, Lancet, 1990, 335, 1109-13; and Waters, D. et al., A controlled clinical trial to assess the effect of a calcium channel blocker on the progression of coronary atherosclerosis, Circulation, 1990, 82, 1940-53.) U.S. Pat. No. 4,681,893 discloses that certain statins, including atorvastatin, are hypolipidemic agents and as such are useful in treating atherosclerosis. Jukema et al., Circulation, 1995 (Suppl. 1), 1-197, disclose that there is evidence that calcium channel blockers act synergistically in combination with lipid lowering agents (e.g., HMG-CoA reductase inhibitors), specifically pravastatin. Orekhov et al., Cardiovascular Drugs and Therapy, 1997, 11, 350 disclose the use of amlodipine in combination with lovastatin for the treatment of atherosclerosis.
Commonly assigned International Patent Application Publication Number WO99/11259 discloses a combination of amlodipine and atorvastatin.
This invention is directed to compounds which are mutual prodrugs of amlodipine and atorvastatin and pharmaceutically acceptable salts thereof.
This invention is particularly directed to a mutual prodrug of amlodipine and atorvastatin having the formula I,
and pharmaceutically acceptable salts thereof.
This invention is more particularly directed to a compound of formula I wherein the carbon atom at the 4-position of the dihydropyridine ring has the (R)-configuration and pharmaceutically acceptable salts thereof.
This invention is also more particularly directed to a compound of formula I wherein the carbon atom at the 4-position of the dihydropyridine ring has the (S)-configuration and pharmaceutically acceptable salts thereof.
This invention is also directed to a mutual prodrug of amlodipine and atorvastatin which is a compound having the formula II,
wherein R1 and R2 are independently selected from H and (C1-C4)alkyl. It is particularly preferred that R1 and R2 are each H and pharmaceutically acceptable salts thereof.
This invention is more particularly directed to a compound of formula II wherein the carbon atom at the 4-position of the dihydropyridine ring has the (R)-configuration and pharmaceutically acceptable salts thereof.
This invention is also more particularly directed to a compound of formula II wherein the carbon atom at the 4-position of the dihydropyridine ring has the (S)-configuration and pharmaceutically acceptable salts thereof.
This invention is also directed to 4-(2-chloro-phenyl)-2-(2-[(5-{7-[2-(4-fluoro-phenyl)-5-isopropyl-3-phenyl-4-phenylcarbamoyl-pyrrol-1-yl]-3,5-dihydroxyheptanoyloxymethyl}-2-oxo-[1,3]dioxol-4-ylmethyl)-amino]-ethoxymethyl}-6-methyl-1,4-dihydro-pyridine-3,5-dicarboxylic acid 3-ethylester 5-methyl ester.
This invention is also directed to 4-(2-chloro-phenyl)-2-(2-{7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-phenylcarbamoyl-pyrrol-1-yl]-3,5-dihydroxyheptanoyloxymethoxycarbonylamino}-ethoxymethyl)-6-methyl-1,4-dihydro-pyridine-3,5-dicarboxylic acid 3-ethyl ester 5-methyl ester.
This invention is also directed to pharmaceutical compositions comprising a mutual prodrug of amlodipine and atorvastatin or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, vehicle or diluent. This invention is particularly directed to such a composition wherein the prodrug is 4-(2-chloro-phenyl)-2-(2-[(5-{7-[2-(4-fluoro-phenyl)-5-isopropyl-3-phenyl-4-phenylcarbamoyl-pyrrol-1-yl]-3,5-dihydroxy-heptanoyloxymethyl}-2-oxo-[1,3]dioxol-4-ylmethyl)-amino]-ethoxymethyl}-6-methyl-1,4-dihydro-pyridine-3,5-dicarboxylic acid 3-ethylester 5-methyl ester or is 4-(2-chloro-phenyl)-2-(2-{7-[2-(4-fluoro-phenyl)-5-isopropyl-3-phenyl-4-phenylcarbamoyl-pyrrol-1-yl]-3,5-dihydroxy-heptanoyloxymethoxycarbonylamino}-ethoxymethyl)-6-methyl-1,4-dihydro-pyridine-3,5-dicarboxylic acid 3-ethyl ester 5-methyl ester.
This invention is also directed to methods of treating angina pectoris in a mammal suffering from angina pectoris comprising administering to said mammal an angina pectoris treating effective amount of a mutual prodrug of amlodipine and atorvastatin or a pharmaceutically acceptable salt thereof.
This invention is also directed to methods of treating angina pectoris in a mammal suffering from angina pectoris comprising administering to said mammal an angina pectoris treating effective amount of a pharmaceutical composition comprising a mutual prodrug of amlodipine and atorvastatin or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, vehicle or diluent.
This invention is also directed to methods of treating hypertension and hyperlipidemia in a mammal suffering from hypertension and hyperlipidemia comprising administering to said mammal a hypertension and hyperlipidemia treating effective amount of a mutual prodrug of amlodipine and atorvastatin or a pharmaceutically acceptable salt thereof.
This invention is also directed to methods of treating hypertension and hyperlipidemia in a mammal suffering from hypertension and hyperlipidemia comprising administering to said mammal a hypertension and hyperlipidemia treating effective amount of a pharmaceutical composition comprising a mutual prodrug of amlodipine and atorvastatin or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, vehicle or diluent.
This invention is also directed to methods of treating atherosclerosis in a mammal suffering from atherosclerosis comprising administering to said mammal an antiatherosclerosis effective amount of a mutual prodrug of amlodipine and atorvastatin or a pharmaceutically acceptable salt thereof. This invention is particularly directed to those cases where said antiatherosclerotic effect is manifested by a slowing of the progression of atherosclerotic plaques, including wherein said atherosclerotic plaque formation is slowed in coronary arteries, carotid arteries or in the peripheral arterial system. This invention is also particularly directed to those cases where said antiatherosclerotic effect is manifested by a regression of atherosclerotic plaques, including wherein said regression occurs in the coronary arteries, in the carotid arteries and/or in the peripheral arterial system.
This invention is also directed to methods of treating atherosclerosis in a mammal suffering from atherosclerosis comprising administering to said mammal an antiatherosclerosis effective amount of a pharmaceutical composition comprising a mutual prodrug of amlodipine and atorvastatin or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, vehicle or diluent.
This invention is also directed to methods of managing cardiac risk in a mammal at risk of suffering an adverse cardiac event, comprising administering to said mammal a cardiac risk treating effective amount of a mutual prodrug of amlodipine and atorvastatin or a pharmaceutically acceptable salt thereof.
This invention is also directed to methods of managing cardiac risk in a mammal at risk of suffering an adverse cardiac event, comprising administering to said mammal a cardiac risk treating effective amount of a pharmaceutical composition comprising a mutual prodrug of amlodipine and atorvastatin or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, vehicle or diluent.
This invention is also directed to methods of preparing atorvastatin in vivo by administering to a mammal, e.g., a human, a mutual prodrug of amlodipine and atorvastatin of this invention or a pharmaceutically acceptable salt thereof.
This invention is also directed to methods of preparing amlodipine in vivo by administering to a mammal, e.g., a human, a mutual prodrug of amlodipine and atorvastatin of this invention or a pharmaceutically acceptable salt thereof.
This invention is also directed to methods of treating a mammal with amlodipine comprising administering to said mammal a mutual prodrug of amlodipine and atorvastatin of this invention or a pharmaceutically acceptable salt thereof.
This invention is also directed to methods of treating a mammal with atorvastatin comprising administering to said mammal a mutual prodrug of amlodipine and atorvastatin of this invention or a pharmaceutically acceptable salt thereof.
This invention is also directed to pharmaceutical compositions comprising an amount of a mutual prodrug of amlodipine and atorvastatin of this invention or a pharmaceutically acceptable salt thereof and an amount of amlodipine or a pharmaceutically acceptable salt thereof, e.g., amlodipine besylate.
This invention is also directed to pharmaceutical compositions comprising an amount of a mutual prodrug of amlodipine and atorvastatin of this invention or a pharmaceutically acceptable salt thereof and an amount of atorvastatin or a pharmaceutically acceptable salt thereof, e.g., the hemicalcium salt of atorvastatin.
This invention is also directed to methods of treating angina pectoris in a mammal comprising administering to said mammal an amount of a mutual prodrug of amlodipine and atorvastatin or a pharmaceutically acceptable salt thereof and an amount of amlodipine or a pharmaceutically acceptable salt thereof, e.g., amlodipine besylate.
This invention is also directed to methods of treating atherosclerosis in a mammal comprising administering to said mammal an amount of a mutual prodrug of amlodipine and atorvastatin or a pharmaceutically acceptable salt thereof and an amount of amlodipine or a pharmaceutically acceptable salt thereof, e.g., amlodipine besylate.
This invention is also directed to methods of managing cardiac risk in a mammal comprising administering to said mammal an amount of a mutual prodrug of amlodipine and atorvastatin or a pharmaceutically acceptable salt thereof and an amount of amlodipine or a pharmaceutically acceptable salt thereof, e.g., amlodipine besylate.
This invention is also directed to methods of treating hypertension and hyperlipidemia in a mammal suffering from hypertension and hyperlipidemia comprising administering to said mammal an amount of a mutual prodrug of amlodipine and atorvastatin or pharmaceutically acceptable salt thereof and an amount of amlodipine or a pharmaceutically acceptable salt thereof, e.g., amlodipine besylate.
This invention is also directed to methods of treating angina pectoris in a mammal comprising administering to said mammal an amount of a mutual prodrug of amlodipine and atorvastatin or a pharmaceutically acceptable salt thereof and an amount of atorvastatin or a pharmaceutically acceptable salt thereof, e.g., the hemicalcium salt of atorvastatin.
This invention is also directed to methods of treating atherosclerosis in a mammal comprising administering to said mammal an amount of a mutual prodrug of amlodipine and atorvastatin or a pharmaceutically acceptable salt thereof and an amount of atorvastatin or a pharmaceutically acceptable salt thereof, e.g., the hemicalcium salt of atorvastatin.
This invention is also directed to methods of managing cardiac risk in a mammal comprising administering to said mammal an amount of a mutual prodrug of amlodipine and atorvastatin or a pharmaceutically acceptable salt thereof and an amount of atorvastatin or a pharmaceutically acceptable salt thereof, e.g., the hemicalcium salt of atorvastatin.
This invention is also directed to methods of treating hypertension and hyperlipidemia in a mammal suffering from hypertension and hyperlipidemia comprising administering to said mammal an amount of a mutual prodrug of amlodipine and atorvastatin or pharmaceutically acceptable salt thereof and an amount of atorvastatin or a pharmaceutically acceptable salt thereof, e.g., the hemicalcium salt of atorvastatin.
This invention is also directed to methods of treating a mammal comprising administering to said mammal an amount of a mutual prodrug of amlodipine and atorvastatin or a pharmaceutically acceptable salt thereof and an amount of atorvastatin or a pharmaceutically acceptable salt thereof, e.g., the hemicalcium salt of atorvastatin.
Amlodipine is a racemic compound due to the chiral carbon atom at position 4 of the dihydropyridine ring. The R and S enantiomers may be prepared as described by Arrowsmith et al., J. Med. Chem., 1986, 29, 1696. The calcium channel blocking activity of amlodipine is substantially confined to the S(xe2x88x92) isomer and to the racemic mixture containing the R(+) and S(xe2x88x92) forms. (see International Patent Application No. PCT/EP94/02697). The R(+) isomer has little or no calcium channel blocking activity. However, the R(+) isomer is a potent inhibitor of smooth muscle cell migration. Thus, the R(+) isomer is useful in the treatment or prevention of atherosclerosis. (see International Patent Application No. PCT/EP95/00847). Based on the above, a skilled person could choose to prepare an isomer of the compounds of this invention wherein the amlodipine portion is the R(+) isomer, the S(xe2x88x92) isomer or the racemic mixture of the R(+) isomer and the S(xe2x88x92) isomer.
Where used herein and in the appendant claims, the term xe2x80x9ccardiac riskxe2x80x9d means the likelihood that a subject will suffer a future adverse cardiac event such as, e.g., myocardial infarction, cardiac arrest, cardiac failure or cardiac ischaemia. Cardiac risk is calculated using the Framingham Risk Equation as set forth above. The term xe2x80x9ccardiac risk managementxe2x80x9d means that the risk of future adverse cardiac events is substantially reduced.
The mutual prodrugs of this invention may be readily prepared as set forth in the following description and in the Examples below. Specifically, to prepare the mutual prodrug of amlodipine and atorvastatin having the structure of formula I, atorvastatin is reacted with a 1,3-dioxolone derivative, preferably 4,5-bis(bromomethyl)-1,3-dioxol-2-one, in a reaction inert solvent in the presence of a suitable base and optionally a catalyst such as sodium iodide. As used herein, the expressions xe2x80x9creaction inert solventxe2x80x9d and xe2x80x9cinert solventsxe2x80x9d refer to a solvent or mixture of solvents which does not interact with starting materials, reagents, intermediates or products in a manner which adversely affects the yield of the desired product. A particularly preferred such solvent is ethyl acetate. Suitable bases for this reaction include inorganic bases such as potassium and sodium carbonate. The reaction is conducted at 0xc2x0 C. to about ambient temperature for about four hours to about 16 hours. It is preferred to conduct the reaction at room temperature for about eight hours. The intermediate 2-oxo-1,3-dioxolane derivative of atorvastatin is isolated and reacted with amlodipine and a suitable base in a reaction inert solvent. A suitable such solvent is N,N-dimethylformamide. The reaction is conducted at 0xc2x0 C. to about ambient temperature for about four hours to about 16 hours. It is preferred to conduct this reaction at 0xc2x0 C. for about eight hours.
To prepare the mutual prodrug of amlodipine and atorvastatin having the structure of formula II, amlodipine is reacted with a chloromethyl chloroformate and a suitable organic base in a reaction inert solvent at a temperature of from xe2x88x9210xc2x0 C. to about room temperature. This reaction is preferably conducted at 0xc2x0 C. in chloroform. The preferred base for this reaction is pyridine. The reaction mixture is generally warmed to about ambient temperature to effect reaction. Usually the reaction is conducted for about two hours to about 24 hours and preferably for 16 hours. The residue is dissolved in a solution of the hemicalcium salt of atorvastatin in dimethylformamide. The reaction mixture is heated at about 80xc2x0 C. for about 22 hours.
Amlodipine may readily be prepared as described in U.S. Pat. No. 4,572,909 which is incorporated herein by reference. Amlodipine besylate, which is currently sold as Norvasc(copyright), may be prepared as described in U.S. Pat. No. 4,879,303, which is incorporated herein by reference. Amlodipine and amlodipine besylate are potent and long lasting calcium channel blockers.
The R and S enantiomers of amlodipine may be prepared as described by Arrowsmith et al., J. Med. Chem., 1986, 29, 1696.
Atorvastatin may readily be prepared as described in U.S. Pat. No. 4,681,893, which is incorporated herein by reference. The hemicalcium salt of atorvastatin, which is currently sold as Lipitor(copyright), may readily be prepared as described in U.S. Pat. No. 5,273,995, which is incorporated herein by reference.
The expression xe2x80x9cpharmaceutically acceptable acid addition saltsxe2x80x9d is intended to define but is not limited to such salts as the hydrochloride, hydrobromide, sulfate, hydrogen sulfate, phosphate, hydrogen phosphate, dihydrogenphosphate, acetate, besylate, succinate, citrate, methanesulfonate (mesylate) and p-toluenesulfonate (tosylate) salts.
The acid addition salts of the instant prodrugs of amlodipine and atorvastatin may be readily prepared by reacting the free base form thereof with the appropriate acid. When the salt is of a monobasic acid (e.g., the hydrochloride, the hydrobromide, the p-toluenesulfonate, the acetate), the hydrogen form of a dibasic acid (e.g., the hydrogen sulfate, the succinate) or the dihydrogen form of a tribasic acid (e.g., the dihydrogen phosphate, the citrate), at least one molar equivalent and usually a molar excess of the acid is employed. However when such salts as the sulfate, the hemisuccinate, the hydrogen phosphate or the phosphate are desired, the appropriate and exact chemical equivalents of acid will generally be used. The free base and the acid are usually combined in a co-solvent from which the desired salt precipitates, or can be otherwise isolated by concentration and/or addition of a non-solvent.
In addition, the mutual prodrugs of amlodipine and atorvastatin of this invention and pharmaceutically acceptable salts thereof may occur as hydrates or solvates. Said hydrates and solvates are also within the scope of the invention.
The mutual prodrugs, pharmaceutical compositions and methods of this invention are all adapted to therapeutic use as agents in the treatment of atherosclerosis, angina pectoris, and a condition characterized by the presence of both hypertension and hyperlipidemia in mammals, particularly humans. Further, since these diseases and conditions are closely related to the development of cardiac disease and adverse cardiac conditions, these compounds, compositions and methods, by virtue of their action as antiatherosclerotics, antianginals, antihypertensives and antihyperlipidemics, are useful in the management of cardiac risk.
The utility of the compounds and compositions of the present invention as medical agents in the treatment of atherosclerosis in mammals (e.g. humans) is demonstrated by the activity of the compounds and compositions of this invention in conventional assays and the clinical protocol described below.
This study is a prospective randomized evaluation of the effect of a mutual prodrug of amlodipine and atorvastatin on the progression/regression of coronary and carotid artery disease. The study is used to show that a mutual prodrug of amlodipine and atorvastatin is effective in slowing or arresting the progression or causing regression of existing coronary artery disease (CAD) as evidenced by changes in coronary angiography or carotid ultrasound, in subjects with established disease.
This study is an angiographic documentation of coronary artery disease carried out as a double-blind, placebo-controlled trial of a minimum of about 500 subjects and preferably of about 780 to about 1200 subjects. It is especially preferred to study about 1200 subjects in this study. Subjects are admitted into the study after satisfying certain entry criteria set forth below.
Entry criteria: Subjects accepted for entry into this trial must satisfy certain criteria. Thus, the subject must be an adult, either male or female, aged 18-80 years of age in whom coronary angiography is clinically indicated. Subjects will have angiographic presence of a significant focal lesion such as 30% to 50% on subsequent evaluation by quantitative coronary angiography (QCA) in a minimum of one segment (non-PTCA, non-bypassed or non-MI vessel) that is judged not likely to require intervention over the next 3 years. It is required that the segments undergoing analysis have not been interfered with. Since percutaneous transluminal cardiac angioplasty (PTCA) interferes with segments by the insertion of a balloon catheter, non-PTCA segments are required for analysis. It is also required that the segments to be analyzed have not suffered a thrombotic event, such as a myocardial infarct (MI). Thus, the requirement for non-MI vessels. Segments that will be analyzed include: left main, proximal, mid and distal left anterior descending, first and second diagonal branch, proximal and distal left circumflex, first or largest space obtuse marginal, proximal, mid and distal right coronary artery. Subjects will have an ejection fraction of greater than 30% determined by catheterization or radionuclide ventriculography or ECHO cardiogram at the time of the qualifying angiogram or within the previous three months of the acceptance of the qualifying angiogram provided no intervening event such as a thrombotic event or procedure such as PTCA has occurred.
Generally, due to the number of patients and the physical limitations of any one facility, the study is carried out at multiple sites. At entry into the study, subjects undergo quantitative coronary angiography as well as B-mode carotid artery ultrasonography and assessment of carotid arterial compliance at designated testing centers. This establishes baselines for each subject. Once admitted into the test, subjects are randomized to receive amlodipine besylate (10 mgs) and placebo or atorvastatin calcium (10 mgs) and placebo or a mutual prodrug of amlodipine and atorvastatin or a pharmaceutically acceptable salt thereof (about 5 to 160 mgs). All doses set forth in this protocol are per day doses. The amount of amlodipine besylate may be varied as required. Generally, a subject will begin taking 10 mg and the amount will be titrated down to as little as 5 mg as determined by the clinical physician.
The subjects are monitored for a one to three year period, generally three years being preferred. B-mode carotid ultrasound assessment of carotid artery atherosclerosis and compliance are performed at regular intervals throughout the study. Generally, six month intervals are suitable. Typically this assessment is performed using B-mode ultrasound equipment. However, a person skilled in the art may use other methods of performing this assessment.
Coronary angiography is performed at the conclusion of the one to three year treatment period. The baseline and post-treatment angiograms and the intervening carotid artery B-mode ultrasonograms are evaluated for new lesions or progression of existing atherosclerotic lesions. Arterial compliance measurements are assessed for changes from baseline and over the 6-month evaluation periods.
The primary objective of this study is to show that the mutual prodrug of amlodipine and atorvastatin or pharmaceutically acceptable salts thereof reduces the progression of atherosclerotic lesions as measured by quantitative coronary angiography (QCA) in subjects with clinical coronary artery disease. QCA measures the opening in the lumen of the arteries measured.
The primary endpoint of the study is the change in the average mean segment diameter of the coronary artery tree. Thus, the diameter of an arterial segment is measured at various portions along the length of that segment. The average diameter of that segment is then determined. After the average segment diameter of many segments has been determined, the average of all segment averages is determined to arrive at the average mean segment diameter. The mean segment diameter of subjects taking the mutual prodrug of amlodipine and atorvastatin or pharmaceutically acceptable salts thereof will decline more slowly, will be halted completely, or there will be an increase in the mean segment diameter. These results represent slowed progression of atherosclerosis, halted progression of atherosclerosis and regression of atherosclerosis, respectively.
The secondary objective of this study is to show that the mutual prodrug of amlodipine and atorvastatin or a pharmaceutically acceptable salt thereof reduces the rate of progression of atherosclerosis in the carotid arteries as measured by the slope of the maximum intimal-medial thickness measurements averaged over 12 separate wall segments (Mean Max) as a function of time. The intimal-medial thickness of subjects taking the mutual prodrug of amlodipine and atorvastatin or a pharmaceutically acceptable salt thereof will increase more slowly, will cease to increase or will decrease. These results represent slowed progression of atherosclerosis, halted progression of atherosclerosis and regression of atherosclerosis, respectively.
The utility of the compounds and compositions of the present invention as medical agents in the treatment of angina pectoris in mammals (e.g., humans) is demonstrated by the activity of the compounds and compositions of this invention in conventional assays and the clinical protocol described below.
This study is a double blind, parallel arm, randomized study to show the effectiveness of a mutual prodrug of amlodipine and atorvastatin or pharmaceutically acceptable salts thereof in the treatment of symptomatic angina.
Entry criteria: Subjects are males or females between 18 and 80 years of age with a history of typical chest pain associated with one of the following objective evidences of cardiac ischemia: (1) stress test segment elevation of about one millimeter or more from the ECG; (2) positive treadmill stress test; (3) new wall motion abnormality on ultrasound; or (4) coronary angiogram with a significant qualifying stenosis. Generally a stenosis of about 30-50% is considered to be significant.
Each subject is evaluated for about ten to thirty-two weeks. At least ten weeks are generally required to complete the study. Sufficient subjects are used in this screen to ensure that about 200 to 800 subjects and preferably about 400 subjects are evaluated to complete the study. Subjects are screened for compliance with the entry criteria, set forth above, during a four week run in phase. After the screening criteria are met, subjects are washed out from their current anti-anginal medication and stabilized on a long acting nitrate such as, for example, nitroglycerin, isosorbide-5-mononitrate or isosorbide dinitrate. The term xe2x80x9cwashed outxe2x80x9d, when used in connection with this screen, means the withdrawal of current anti-anginal medication so that substantially all of said medication is eliminated from the body of the subject. A period of eight weeks is preferably allowed for both the wash out period and for the establishment of the subject on stable doses of said nitrate. Subjects having one or two attacks of angina per week while on stable doses of long acting nitrate are generally permitted to skip the wash out phase. After subjects are stabilized on nitrates, the subjects enter the randomization phase provided the subjects continue to have either one or two angina attacks per week. In the randomization phase, the subjects are randomly placed into one of the four arms of the study set forth below. After completing the wash out phase, subjects in compliance with the entry criteria undergo twenty four hour ambulatory electrocardiogram (ECG) such as Holter monitoring, exercise stress testing such as a treadmill and evaluation of myocardial perfusion using PET (photon emission tomography) scanning to establish a baseline for each subject. When conducting a stress test, the speed of the treadmill and the gradient of the treadmill can be controlled by a technician. The speed of the treadmill and the angle of the gradient are generally increased during the test. The time intervals between each speed and gradient increase is generally determined using a modified Bruce Protocol.
After the baseline investigations have been completed, subjects are initiated on one of the following four arms of the study: (1) placebo; (2) atorvastatin calcium (about 2.5 mg to about 160 mg); (3) amlodipine besylate(about 2.5 mg to about 20 mg); or (4) a mutual prodrug of amlodipine and atorvastatin (about 5 to 160 mgs). The subjects are then monitored for two to twenty four weeks. It will be recognized by a person skilled in the art that a pharmaceutically acceptable salt of the mutual prodrug of amlodipine and atorvastatin may be used in the fourth arm of the study. Calculation of the dosage amount for these other forms of the mutual prodrug of amlodipine and atorvastatin is easily accomplished by performing a simple ratio relative to the molecular weights of the species involved.
After the monitoring period has ended, subjects will undergo the following investigations: (1) twenty four hour ambulatory ECG, such as Holter monitoring; (2) exercise stress testing (e.g. treadmill using said modified Bruce Protocol); and (3) evaluation of myocardial perfusion using PET scanning. Patients keep a diary of painful ischemic events and nitroglycerine consumption. It is generally desirable to have an accurate record of the number of anginal attacks suffered by the patient during the duration of the test. Since a patient generally takes nitroglycerin to ease the pain of an anginal attack, the number of times that the patient administers nitroglycerine provides a reasonably accurate record of the number of anginal attacks.
To demonstrate the effectiveness of the compounds and compositions of this invention, and to determine the dosage amounts of the mutual prodrug of this invention, the person conducting the test will evaluate the subject using the tests described. Successful treatment will yield fewer instances of ischemic events as detected by ECG, will allow the subject to exercise longer or at a higher intensity level on the treadmill, or to exercise without pain on the treadmill, or will yield better perfusion or fewer perfusion defects on photoemission tomography (PET).
The utility of the compounds and compositions of the present invention as medical agents in the treatment of hypertension and hyperlipidemia in mammals (e.g., humans) suffering from a combination of hypertension and hyperlipidemia is demonstrated by the activity of the compounds and compositions of this invention in conventional assays and the clinical protocol described below.
This study is a double blind, parallel arm, randomized study to show the effectiveness of a mutual prodrug of amlodipine and atorvastatin or pharmaceutically acceptable salts thereof in controlling both hypertension and hyperlipidemia in subjects who have mild, moderate, or severe hypertension and hyperlipidemia.
Each subject is evaluated for 10 to 20 weeks and preferably for 14 weeks. Sufficient subjects are used in this screen to ensure that about 400 to 800 subjects are evaluated to complete the study.
Entry criteria: Subjects are male or female adults between 18 and 80 years of age having both hyperlipidemia and hypertension. The presence of hyperlipidemia is evidenced by evaluation of the low density lipoprotein (LDL) level of the subject relative to certain positive risk factors. If the subject has no coronary heart disease (CHD) and has less than two positive risk factors, then the subject is considered to have hyperlipidemia if the LDL of the subject is greater than or equal to 190. If the subject has no CHD and has two or more positive risk factors, then the subject is considered to have hyperlipidemia if the LDL of the subject is greater than or equal to 160. If the subject has CHD, then the subject is considered to have hyperlipidemia if the LDL of the subject is greater than or equal to 130.
Positive risk factors include (1) male over 45, (2) female over 55 wherein said female is not undergoing hormone replacement therapy (HRT), (3) family history of premature cardiovascular disease, (4) the subject is a current smoker, (5) the subject has diabetes, (6) an HDL of less than 45, and (7) the subject has hypertension. An HDL of greater than 60 is considered a negative risk factor and will offset one of the above mentioned positive risk factors.
The presence of hypertension is evidenced by a sitting diastolic blood pressure (BP) of greater than 90 or sitting systolic BP of greater than 140. All blood pressures are generally determined as the average of three measurements taken five minutes apart.
Subjects are screened for compliance with the entry criteria set forth above. After all screening criteria are met, subjects are washed out from their current antihypertensive and lipid lowering medication and are placed on the NCEP ATP II Step 1 diet. The NCEP ATP II (adult treatment panel, 2nd revision) Step 1 diet sets forth the amount of saturated and unsaturated fat which can be consumed as a proportion of the total caloric intake. The term xe2x80x9cwashed outxe2x80x9d where used in connection with this protocol, means the withdrawal of current antihypertensive and lipid lowering medication so that substantially all of said medication is eliminated from the body of the subject. Newly diagnosed subjects generally remain untreated until the test begins. These subjects are also placed on the NCEP Step 1 diet. After the four week wash out and diet stabilization period, subjects undergo the following baseline investigations: (1) blood pressure and (2) fasting lipid screen. The fasting lipid screen determines baseline lipid levels in the fasting state of a subject. Generally, the subject abstains from food for twelve hours, at which time lipid levels are measured.
After the baseline investigations are performed subjects are started on one of the following: (1) a fixed dose of amlodipine besylate, generally about 2.5 to 10 mg; (2) a fixed dose of atorvastatin calcium, generally about 10 to 80 mg; or (3) a mutual prodrug of amlodipine and atorvastatin (about 5 to 160 mgs). Subjects remain on these doses for a minimum of six weeks, and generally for no more than eight weeks. It will be recognized by a skilled person that a pharmaceutically acceptable salt of the mutual prodrug of amlodipine and atorvastatin may be used in the third arm of this investigation. Calculation of the dosage amount for these forms of the mutual prodrug of amlodipine and atorvastatin is easily accomplished by performing a simple ratio relative to the molecular weights of the species involved. The subjects return to the testing center at the conclusion of the six to eight weeks so that the baseline evaluations can be repeated. The blood pressure of the subject at the conclusion of the study is compared with the blood pressure of the subject upon entry. The lipid screen measures the total cholesterol, LDL-cholesterol, HDL-cholesterol, triglycerides, apoB, VLDL (very low density lipoprotein) and other components of the lipid profile of the subject. Improvements in the values obtained after treatment relative to pretreatment values indicate the utility of the test compound.
The utility of the compounds and compositions of the present invention as medical agents in the management of cardiac risk in mammals (e.g., humans) at risk for an adverse cardiac event is demonstrated by the activity of the compounds and compositions of this invention in conventional assays and the clinical protocol described below.
This study is a double blind, parallel arm, randomized study to show the effectiveness of a mutual prodrug of amlodipine and atorvastatin or pharmaceutically acceptable salts thereof in reducing the overall calculated risk of future events in subjects who are at risk for having future cardiovascular events. This risk is calculated by using the Framingham Risk Equation. A subject is considered to be at risk of having a future cardiovascular event if that subject is more than one standard deviation above the mean as calculated by the Framingham Risk Equation. The study is used to evaluate the efficacy of a mutual prodrug of amlodipine and atorvastatin in controlling cardiovascular risk by controlling both hypertension and hyperlipidemia in patients who have both mild to moderate hypertension and hyperlipidemia.
Each subject is evaluated for 10 to 20 weeks and preferably for 14 weeks. Sufficient subjects are recruited to ensure that about 400 to 800 subjects are evaluated to complete the study.
Entry criteria: Subjects included in the study are male or female adult subjects between 18 and 80 years of age with a baseline five year risk which risk is above the median for said subject""s age and sex, as defined by the Framingham Heart Study, which is an ongoing prospective study of adult men and women showing that certain risk factors can be used to predict the development of coronary heart disease. The age, sex, systolic and diastolic blood pressure, smoking habit, presence or absence of carbohydrate intolerance, presence or absence of left ventricular hypertrophy, serum cholesterol and high density lipoprotein (HDL) of more than one standard deviation above the norm for the Framingham Population are all evaluated in determining whether a patient is at risk for adverse cardiac event. The values for the risk factors are inserted into the Framingham Risk equation and calculated to determine whether a subject is at risk for a future cardiovascular event.
Subjects are screened for compliance with the entry criteria set forth above. After all screening criteria are met, patients are washed out from their current antihypertensive and lipid lowering medication and any other medication which will impact the results of the screen. The patients are then placed on the NCEP ATP II Step 1 diet, as described in the hypertension and hyperlipidemia section above. Newly diagnosed subjects generally remain untreated until the test begins. These subjects are also placed on the NCEP ATP II Step 1 diet. After the four week wash out and diet stabilization period, subjects undergo the following baseline investigations: (1) blood pressure; (2) fasting; (3) lipid screen; (4) glucose tolerance test; (5) ECG; and (6) cardiac ultrasound. These tests are carried out using standard procedures well known to persons skilled in the art. The ECG and the cardiac ultrasound are generally used to measure the presence or absence of left ventricular hypertrophy.
After the baseline investigations are performed patients will be started on one of the following: (1) a fixed dose of amlodipine (about 2.5 to 10 mg); (2) a fixed dose of atorvastatin (about 10 to 80 mg); or (3) a mutual prodrug of amlodipine and atorvastatin (about 5 to 160 mgs). It will be recognized by a skilled person that a pharmaceutically acceptable salt of a mutual prodrug of amlodipine and atorvastatin may be used in this invention. Calculation of the dosage amount for these other forms of a mutual prodrug of amlodipine and atorvastatin is easily accomplished by performing a simple ratio relative to the molecular weights of the species involved. Patients are kept on these doses and are asked to return in six to eight weeks so that the baseline evaluations can be repeated. At this time the new values are entered into the Framingham Risk equation to determine whether the subject has a lower, greater or no change in the risk of future cardiovascular event.
The above assays demonstrating the effectiveness of a mutual prodrug of amlodipine and atorvastatin or pharmaceutically acceptable salts thereof in the treatment of angina pectoris, atherosclerosis, hypertension and hyperlipidemia together, and the management of cardiac risk, also provide a means whereby the activities of the compounds of this invention can be compared between themselves and with the activities of other known compounds. The results of these comparisons are useful for determining dosage levels in mammals, including humans, for the treatment of such diseases.
The following dosage amounts and other dosage amounts set forth elsewhere in the specification and in the appendant claims are for an average human subject having a weight of about 65 kg to about 70 kg. The skilled practitioner will readily be able to determine the dosage amount required for a subject whose weight falls outside the 65 kg to 70 kg range, based upon the medical history of the subject and the presence of diseases, e.g., diabetes, in the subject. All doses set forth herein, and in the appendant claims, are daily doses.
In general, in accordance with this invention, a mutual prodrug of amlodipine and atorvastatin is generally administered in a dosage of about 2.5 mg to about 20 mg. It will be recognized by a skilled person that the free base form or other salt forms of the mutual prodrug of amlodipine and atorvastatin may be used in this invention. Calculation of the dosage amount for these other forms of the mutual prodrug of amlodipine and atorvastatin is easily accomplished by performing a simple ratio relative to the molecular weights of the species involved.
The compounds of the present invention are generally administered in the form of a pharmaceutical composition comprising a compound of this invention together with a pharmaceutically acceptable carrier, vehicle or diluent. Thus, the compounds of this invention can be administered either individually or together in any conventional oral, parenteral or transdermal dosage form.
For oral administration a pharmaceutical composition can take the form of solutions, suspensions, tablets, pills, capsules, powders, and the like. Tablets containing various excipients such as sodium citrate, calcium carbonate and calcium phosphate are employed along with various disintegrants such as starch and preferably potato or tapioca starch and certain complex silicates, together with binding agents such as polyvinylpyrrolidone, sucrose, gelatin and acacia. Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often very useful for tabletting purposes. Solid compositions of a similar type are also employed as fillers in soft and hard-filled gelatin capsules; preferred materials in this connection also include lactose or milk sugar as well as high molecular weight polyethylene glycols. When aqueous suspensions and/or elixirs are desired for oral administration, the compounds of this invention can be combined with various sweetening agents, flavoring agents, coloring agents, emulsifying agents and/or suspending agents, as well as such diluents as water, ethanol, propylene glycol, glycerin and various like combinations thereof.
The compositions of this invention may also be administered in a controlled release formulation such as a slow release or a fast release formulation. Such controlled release dosage formulations of the compounds of this invention may be prepared using methods well known to those skilled in the art. The method of preferred administration will be determined by the attendant physician or other person skilled in the art after an evaluation of the subject""s condition and requirements.
For purposes of parenteral administration, solutions in sesame or peanut oil or in aqueous propylene glycol can be employed, as well as sterile aqueous solutions of the corresponding water-soluble salts. Such aqueous solutions may be suitably buffered, if necessary, and the liquid diluent first rendered isotonic with sufficient saline or glucose. These aqueous solutions are especially suitable for intravenous, intramuscular, subcutaneous and intraperitoneal injection purposes. In this connection, the sterile aqueous media employed are all readily obtainable by standard techniques well-known to those skilled in the art.
Methods of preparing various pharmaceutical compositions with a certain amount of active ingredient are known, or will be apparent in light of this disclosure, to those skilled in this art. For examples, see Remington""s Pharmaceutical Sciences, Mack Publishing Company, Easton, Pa., 19th Edition (1995).
Pharmaceutical compositions according to the invention may contain 0.1%-95% of the compound(s) of this invention, preferably 1%-70%. In any event, the composition to be administered will contain a quantity of a compound(s) according to the invention in an amount effective to treat the condition or disease of the subject being treated.

Mutual prodrugs of amlodipine and atorvastatin


The disclosure relates to an optical terminator device suitable for terminating high energy optical signals. The device includes a heat sink cap having an internal surface. An optical absorbing layer is positioned on the internal surface of the heat sink cap. A scattering core having a fiber or waveguide connection is positioned within the heat sink cap such that a thermal barrier is maintained between the optical absorbing layer and the scattering core.

It is not unusual for optical systems (such as fiber lasers, fiber optic communications, and medical, industrial and remote sensing applications which utilize light delivery means) to handle high optical power signals. For example, it is common for such systems to utilize optical signals in a single fiber or waveguide having optical signal power of up to several Watts. These fibers and waveguides support a large variety of operating modes, for example, single-mode, multi-mode and polarization maintaining mode.
These optical systems suffer from noise which is commonly caused by optical reflections resulting from discontinuities. As an example, the end of an optical fiber may cause an optical signal to reflect and travel back towards the source. This reflected signal may interfere with the source operation. Additionally, the generated noise may limit the ability of system components to detect transmitted signals. It is known in the art to control reflection through the use of optical terminators which possess low reflection characteristics. These optical terminators typically utilize thin film coatings, optical absorbing polymers and adhesives, and optical black coatings. However, when the specific intensity or power per unit area of the terminated optical signal is relatively high, these prior art terminators are exposed to light fluxes beyond their damage thresholds and eventually fail. A need accordingly exists for an optical terminator that is capable of terminating or dumping optical signals having high intensities or powers. There would be an advantage if such an optical terminator could be placed at the end of the fiber line or integrated within an optical device.
It is further recognized that many optical systems are being designed to carry optical signals over a relatively broad spectral range. Unfortunately, many prior art optical terminators, in addition to being limited in terms of power, are further restricted to providing effective termination to a limited range of wavelengths. There is accordingly a need for an optical terminator that is capable of terminating a wide range of wavelengths (for example, from the visible at about 400 nm to the infared at about 2000 nm).
It is further recognized that transmitted optical signals can utilize any one of a number of selected transverse modes. The variety of mode choices include, for example, single-mode of various numerical apertures, multi-modes of various numerical apertures and polarization maintaining waveguides of various geometries. It would be an advantage if the optical terminator were configured to be capable of terminating a wide range of numerical apertures and mode structures.
There exist a number of known ways for realizing an optical terminator.
In accordance with one method, one or more highly absorbing materials are attached to the end of a fiber or a waveguide thus creating a spot of high temperature at the point of optical signal impingement. This solution puts the maximal limit of operation at the damage threshold of the chosen absorbing material. The damage threshold is limited since heat transfer times are slow, and in many cases not sufficiently fast to cool down the hot spot before damage, like melting or phase change, occurs to the absorbing media.
In another method, a higher power optical terminator is realized by using long volume absorbers in the core (for example, core absorbing fibers ATN-FB by CorActive Inc. Quebec, Canada). This solution is relatively expensive, and undesirably leaves the heat in the core volume which is generally small compared to the clad and cover cap volume. Additionally, these fibers usually can perform an absorbing function within a limited wavelength region.
Yet another method performs the absorbing function in a tight clad coated with polymer. Here, the core is non-absorbing core, with absorption occurring in a tight clad coated with polymer solutions. Undesirably, the core can nonetheless become heated by heat conduction from the absorbing tight clad, thus limiting the useful power range of the terminator to low powers. This solution requires a very precise matching of the core indexes (so as to prevent back reflection at the interface). Matching in this manner is a difficult task at a wide range of temperatures of operation since different materials used possess different dn/dT values (index change with temperature).
In summary, optical terminators which are better at handling higher power signals without damage, are capable of handling wider spectral ranges and further support many mode structures simultaneously, are needed. The present invention addresses these and other needs in the art.


Systems and methods to obtain an ultrasonic image of a large detection area are disclosed. A system includes a source of ultrasound generating ultrasonic energy and projecting the ultrasonic energy from a projecting end and an adapter interfaced to the projecting end and ultrasonically coupling the source of ultrasound to a first surface of the structure to be imaged at an adjustable angle of incidence. A method includes ultrasonically coupling a source of ultrasonic energy to a first surface of a structure to be imaged with an adapter, the adapter adjustable to a select a first angle of incidence and a second angle of incidence, projecting ultrasonic energy into the structure, and detecting a reflected acoustic energy from the structure with an ultrasound camera. A first angle of incidence is selected to introduce a longitudinal wave into the structure, and a second angle of incidence is selected to introduce a shear wave into the structure.

A common application of ultrasound is for the detection of cracks, corrosion and other similar flaws in metals and welded structures. A particular need is to detect flaws in welded structures. These flaws include such things as lack of fusion planes, porosity, inclusions, and other similar flaws that may compromise the structural integrity of the welded part. The majority of contact testing employs longitudinal waves propagating normal to the test object surface. However, there is often a need for employing shear waves propagating at an angle, for example, for imaging surfaces substantially parallel to the test object surface, discontinuities in weld bevels, e.g., welds with countersinks, or other uneven top surfaces.
Many ultrasound imaging studies have been carried out on welds. A particularly good set of images have been presented in Chapter 4 of Nondestructive Testing Handbook, Second Edition, Volume Seven on Ultrasonic Testing, the disclosure of which is incorporated herein by reference. Images are shown of welds that have regions with a lack of fusion, regions of welds with porosity, and welds showing regions of discontinuities as well as regions of intergranular stress corrosion cracks.
Fatigue failures occur in those locations that are subjected to repeated high stress loadings and are usually associated with areas having stress concentrations, e.g., around fasteners. For example, in the areas around a flat head rivet, the base material features a countersunk hole to accept the rivet head. This countersink leads to several "knife edges" (e.g., the rivet opening with walls normal to the structure surface) that serve to further increase the normal stress concentration caused by the hole alone and thus are particularly prone to fatigue failures. These failures typically begin as a crack that is initiated at one of the knife-edges that then progresses with repeated loading
The prediction of any fatigue crack is an extremely complex combination of stress history and material properties with a large statistical variation expected even under perfect laboratory conditions. Thus, one way to ensure that no cracks are present is to perform an inspection of fasteners in the highly stressed areas, e.g., in highly stressed areas of the airframe.
Present inspection methods employ an ultrasonic testing (UT) transducer. For example, typical portable ultrasound devices allow the operator to make determinations about internal defects by sending out an ultrasound pulse and studying the amplitude and time of returned pulses. In another example, an ultrasonic testing (UT) transducer that is slowly rotated around a fastener can develop a map of the full 360° region. Since a focused beam transducer is used, only a single pencil-point region is checked at a time, and consequently the whole process takes on the order of minutes per fastener. Further, the direct test results (before any post-processing) are signal responses that require an experienced operator to interpret correctly. The combination of long inspection times and high operator skill requirements can limit the overall probability of detection of any cracks or flaws.


A diaphragm bellows device comprises a diaphragm bellows with a plurality of successive diaphragms which are welded together alternately at the outer and inner edges, wherein the length of the diaphragm bellows can be adjusted between an expanded state and a contracted state, and a plurality of sleeve parts which surround the successive diaphragms and which, together, enclose the successive diaphragms also in the expanded state of the diaphragm bellows over its entire longitudinal extension and overlap to a greater or lesser extent in axial direction of the diaphragm bellows depending on the adjusted length of the diaphragm bellows, wherein at least one of the sleeve parts is held on the welded outer edges of two adjoining diaphragms by a snap connection.

a) Field of the invention
The invention is directed to a diaphragm bellows device comprising a diaphragm bellows with a plurality of successive diaphragms which are welded together at the outer and inner edges, wherein the diaphragm bellows can be adjusted in length between an expanded state and a contracted state, and comprising a protective device surrounding the successive diaphragms.
b) Description of the Related Art
Diaphragm bellows of the type mentioned above, which are used particularly as vacuum leadthroughs, are known in various embodiment forms. For example, these diaphragm bellows are used for sealing actuating stems or spindles inside a housing of a vacuum valve. Diaphragm bellows are adjustable in length between a contracted state and an expanded state. Normally, the device in connection with which the diaphragm bellows is used has a limit for the expansion of the diaphragm bellows which predetermines the completely expanded state of the diaphragm bellows. The maximum length of the diaphragm bellows in its fully expanded state is usually also specified by the manufacturer.
In diaphragm bellows of this kind, when foreign bodies fall into the intermediate spaces located between two adjacent diaphragms at the outer side of the diaphragm bellows and are trapped there, this could damage the diaphragm bellows when contracted, possibly after repeated expansion and contraction processes, so that the diaphragm bellows are no longer tight. Diaphragm bellows are used, for example, in transfer valves arranged between two vacuum chambers and frequently lie below the valve opening in the installed state. When a wafer breaks while moving through the valve opening, splinters or fragment s of this wafer can fall between the diaphragms and be trapped in the gaps between the diaphragms.
For this reason, it has already been suggested to protect the diaphragm bellows by surrounding it with a self-supporting, telescoping sleeve. This is disadvantageous particularly in that particles are generated and released in to the vacuum when the telescoping parts of the sleeve are displaced relative to one another. Also, these telescoping sleeves have a relatively large installed length which can increase space requirements.
An important object of the invention is to provide a diaphragm bellows device in which the diaphragm bellows is protected against the penetration of parts into the gaps between two adjacent diaphragms so that additional particles are prevented as far as possible from being released into the vacuum when the diaphragm bellows are adjusted. Another object of the invention is to provide a diaphragm bellows device which is simple to produce and assemble and in which the diaphragm bellows are protected against penetration and release of foreign bodies between the adjacent diaphragms.
According to the invention, this object is met by a diaphragm bellows device which comprises:
a diaphragm bellows with a plurality of successive diaphragms which are alternately welded together at the outer and inner edges, wherein the length of the diaphragm bellows can be adjusted between an expanded state and a contracted state, and
a plurality of sleeve parts which surround the successive diaphragms and which, together, enclose the successive diaphragms in the expanded state of the diaphragm bellows over its entire longitudinal extension and overlap to a greater or lesser extent in axial direction of the diaphragm bellows depending on the adjusted length of the diaphragm bellows,
wherein at least one of the sleeve parts is held on the welded outer edges of two adjoining diaphragms by means of a snap connection.
No other separate guide device is required for the at least one sleeve part that is held on the outer edges of two adjacent diaphragms. During the length adjustment of the diaphragm bellows, this sleeve part is carried along by the movement of the diaphragms themselves.
In an advantageous embodiment form of the invention, the diaphragms at the ends are welded to end pieces by which the diaphragm bellows can be connected to other parts. In this way, for example, a vacuum-tight connection with a vacuum chamber or a part of a vacuum valve can be produced. Insofar as end pieces of this kind are provided, diaphragm bellows is understood in the present Application to mean the unit comprising the successive diaphragms with the end pieces welded to both ends. In principle, it would also be conceivable and possible to connect, particularly to weld, the end diaphragms on one or both sides directly to a part of the vacuum device, for example, to a part of a vacuum valve.
In a preferred embodiment form of the invention, an end piece sleeve part is fastened to the two end pieces of the diaphragm bellows and extends from this end piece in the direction of the other end piece. The end piece sleeve parts and the one or more sleeve parts fastened to the outer edges of two adjacent diaphragms also overlap somewhat in axial direction in the expanded state of the diaphragm bellows. The sleeve parts that are individually fastened to the end pieces and to the diaphragms are advantageously spaced apart somewhat in radial direction and therefore do not contact one another. Due to this fact that the individual sleeve parts are arranged without contacting and, accordingly, without friction, practically no additional particles are generated during the contraction and expansion of the diaphragm bellows.
In an advantageous embodiment form of the invention, each of the one or more sleeve parts held at the outer edges of two adjoining diaphragms has a jacket and a web which projects inward therefrom and which is provided with a groove-shaped recess at its inner end side in order to clip the sleeve part to the outer edges of the two adjoining diaphragms.
The various features and constructions according to the invention are set forth in the claims.


A video classification method is provided for a computer device. The method includes obtaining a to-be-processed video, where the to-be-processed video has a plurality of video frames, and each video frame corresponds to one time feature; and sampling the to-be-processed video according to a time-feature sampling rule, and obtaining at least one video frame feature sequence. The time-feature sampling rule is a correspondence between time features and video frame feature sequences. The method also includes processing the video frame feature sequence by using a first neural network model, to obtain a feature representation result corresponding to the video frame feature sequence, where the first neural network model is a recurrent neural network model; and processing the feature representation result by using a second neural network model, to obtain a prediction result corresponding to the video frame feature sequence.

With the rapid development of network multimedia technologies, various multimedia information constantly emerges. A growing number of users are used to watching videos on the network. To enable the users to select, from a large number of videos, content that the users want to watch, a server usually classifies the videos, and video classification has great significance for implementing video management and interest recommendation.
A currently used video classification method mainly includes: first performing feature extraction on each video frame in a to-be-marked video, and then converting, by using an average feature method, a frame-level feature into a video-level feature, and finally, transmitting the video-level feature into a classification network for classification.
However, in the current video classification method, converting the frame-level feature only by using the average feature method is relatively simple and, during the video classification process, the impact of changes in other dimensions on video frame feature conversion is often ignored, and the accuracy of video classification is undesired.

Video classification method, information processing method, and server

TENCENT TECHNOLOGY (SHENZHEN) COMPANY LIMITED


A serving tray having multiple levels includes a lower tray, a tapered collar, a cylindrical extension and an upper tray. The lower tray has a receiving cup having a ribbed exterior surface for alignment to one end of the tapered collar in a non-rotatable manner. The cylindrical extension is sized to fit through the other end of the collar and into the receiving cup such that rotatable movement of the extension is permitted. The upper tray has a centrally located cup with a vertical wall that extends below the planar surface of the upper tray and fits within the upper end of the extension so that the upper tray rotates with the extension.

Trays having a tiered formation are well known in the art. Multi-tiered trays provide a means for serving a number of food products by using minimal table space. Storage space is also kept to a minimum in a refrigerator compartment when using a tiered tray apparatus. Another advantage of the multi-tiered tray includes handling and delivery of delicatessen trays for carryout purposes. For use in deli handling, it is preferred that the tiers, although may be releasibly stacked upon each other, they are secured when connected together. This is especially necessary for carryout deli trays when being handled by customers or the general public. It is further desirable to have trays that may be either stacked or used as well individually.


A positively chargeable toner includes at least a binder resin, and toner particles of which surfaces are modified by a polyvinylamine compound.

1. Technical Field
The present invention relates to a positively chargeable toner, a liquid developer, a developer, a developer cartridge, a process cartridge, and an image forming method.
2. Related Art
A method of visualizing image information though an electrostatic charge image such as an electrophotography method is currently used in many fields. In the electrophotography method, a latent image (electrostatic latent image) is formed on an image holding member in charging and exposure steps (latent image forming step), and the latent image is visualized by developing an electrostatic latent image with an electrostatic charge image developer (hereinafter, simply referred to as a "developer" in some cases) including an electrostatic charge image developing toner (hereinafter, simply referred to as a "toner" in some cases) (development step), and performing a transfer step and a fixation step. As a developer used in a dry development method, a two-component developer made with a toner and a carrier, and a single component developer in which a magnetic toner or a non-magnetic toner is singly used are included.
Meanwhile, a liquid developer used in a wet development method is obtained by dispersing toner particles in an insulating carrier liquid. A type in which toner particles including a thermoplastic resin are dispersed in a volatile carrier liquid, a type in which toner particles including a thermoplastic resin are dispersed in a hardly volatile carrier liquid, and the like are known.

Positively chargeable toner, liquid developer, developer, developer cartridge, process cartridge, and image forming method


A method for detecting species in a target plant genus comprises the steps of conducting PCR using at least one member selected from the group consisting of primers (A) and (B), which can hybridize under stringent conditions to a nucleic acid molecule having a common nucleotide sequence for all species in the target plant genus in 45S rRNA precursor gene sequence thereof, wherein 3′ end of primer (A) can complementarily bind to a base in ITS-1 sequence of the target plant genus when the primer hybridizes to the nucleic acid molecule while 3′ end of primer (B) can complementarily bind to a base in ITS-2 sequence of the target plant genus when the primer hybridizes to the nucleic acid molecule, and identifying the presence of the resulting amplification product from PCR containing at least a part of ITS-1 or ITS-2 sequence of the target plant genus.

The 45S rRNA precursor gene sequence (Small Subunit ribosomal RNA (SSU rRNA) gene˜Internal Transcribed Spacer-1 (ITS-1)˜5.8S ribosomal RNA (5.8S rRNA) gene˜Internal Transcribed Spacer-2 (ITS-2)˜Large Subunit ribosomal RNA (LSU rRNA) gene) has been used for the classification of species. For example, according to the method developed by Shin J H, et al. (J. Clin. Microbiol., 37: 165-170(1999)), 5 candida species (fungi) of the genus Candida can be detected and identified using two primers hybridized to the 5.8S rRNA and 28S rRNA (LSU rRNA) gene sequences common to fungi and 5 separate probes each of which can specifically hybridize to the ITS-2 sequence of its corresponding species. The method is different from the present invention as described below. Firstly, the method is aimed at fungi, specifically candida (fungi). Secondly, the method does not use the primers, which hybridize to ITS-1 or ITS-2 sequence. Consequently, these primer pairs do not assure the specificity to the genus Candida, whereas each of five probes can independently recognize its corresponding candida species (fungi) of the genus Candida. In other words, only one species of the genus Candida can be detected and identified when a single set of the primer pair and a probe is used. Thirdly, the above publication does not describe about the sensitivity of the detection, which is very important for the detection methods of allergenic plants in food. Lastly, the method needs expensive reagents and instruments due to the use of probes.
According to the method developed by Proft J, et al. (Parasitol. Res., 85: 837-843(1999)), a certain anopheles mosquito can be classified into one of 6 species of the genus Anopheles using 6 primer pairs. The method uses a primer that can hybridize to the 5.8 rRNA gene sequence common to the six anopheles mosquito species of the genus Anopheles in combination with 6 primer pairs each of which can specifically hybridize to the ITS-2 sequence of its corresponding anopheles mosquito species of the genus Anopheles. Based on the size of the amplification product obtained by PCR method, the anopheles mosquito of interest can be classified into one of the 6 species of the genus Anopheles. The method is different from the present invention as described below. Firstly, the method is aimed at mosquitoes, specifically the anopheles mosquitoes. Secondly, due to the properties of designed primer pairs, only one species of the genus Anopheles can be detectable when a single primer pair is used. Thirdly, an object of the method is to identify a specimen exclusively derived from a single species of mosquitoes. Consequently, the object of the method is not to analyze anopheles mosquitoes in a mixture. Lastly, the above publication does not describe about the sensitivity of the detection, which is very important for the detection methods of allergenic plants in food.
Thus, the conventional methods mentioned above are to detect one specific species in a mixture and to identify a bio specimen exclusively derived from a single species of the genus, and therefore, the methods do not relate to a method for detecting the target genus broadly in cases where even one kind of the target genus is contained in a mixture. In addition, the primer sequences common to several species are located on SSU rRNA, 5.8S rRNA and LSU rRNA gene sequence, and therefore, primer sequences common to several species are not found in ITS-1 or ITS-2 sequence.
On the other hand, regarding detection of allergenic plants in food, a method for detecting whether some wheat is contained in a food sample of interest is disclosed by Allmann M, et al. (Z Lebensm Unters Forsch, 196: 248-251(1993)). The method uses primers which specifically hybridize to a IGS sequence between 25S rRNA (LSU rRNA) and 18S rRNA (SSU rRNA) gene sequences of wheat. However, it is hard to evaluate the specificity of the primers by simulation and the like because the primers have to be designed based on little information about the IGS sequence in the method. Therefore, it would be difficult to judge the reliability of the analysis.

Abstract: The method for detecting species in a target plant genus, particularly an allergenic plant genus such as the genus Fagopyrum, can make it possible to detect with high sensitivity, for example, about 1 ppm of the plant(s) in cases where the plant(s) is contained in a food ingredient or food product.


According to an aspect of the present invention, medical devices are provided which comprise: (a) a substrate and (b) bioerodable polymeric layer over the substrate that contains (i) one or more biodegradable polymers, (ii) one or more therapeutic agents, and (iii) one or more plasticizers.

Numerous polymer-based medical devices have been developed for implantation or insertion into the body. For example, in recent years, drug eluting coronary stents, which are commercially available from Boston Scientific Corp. (TAXUS and PROMUS), Johnson & Johnson (CYPHER) and others, have become the standard of care for maintaining vessel patency. These existing products are based on metallic balloon expandable stents with biostable polymer coatings, which release antiproliferative drugs at a controlled rate and total dose.
Specific examples of biostable polymers for biostable drug eluting polymer coatings include homopolymers and copolymers, such as poly(ethylene-co-vinyl acetate), poly(vinylidene fluoride-co-hexafluoropropylene) and poly(isobutylene-co-styrene), for example, poly(styrene-b-isobutylene-b-styrene triblock copolymers (SIBS), which are described in U.S. Pat. No. 6,545,097 to Pinchuk et al. FIG. 1, which is taken from Pub. No. US 2006/0171981 to Richard et al., illustrates a release profile of a stent coating that contains 25 wt % paclitaxel and 75 wt % SIBS.
Biodegradable polymers may have certain advantages over biostable polymers. For example, because they erode over time, biodegradable polymers may reduce or eliminate long term effects that may be associated with non-biodegradable polymers (e.g., foreign body effects, late stent thrombosis, etc.).

Medical devices having bioerodable layers for the release of therapeutic agents


A air-powered dental tool (20) for animals such as the equine species includes a dental rasp (34) which reciprocates at at least 3,000 oscillations per minute, and has a stroke of approximately 10 millimeters. In a preferred embodiment, dental tool (20) further includes a noise abatement system which routes the exhaust compressed air to a remote location away from the animal and using veterinarian.

The teeth of the equine species continuously grow, and as such it is necessary to periodically file off overgrown surfaces and sharp projecting edges. The filing process is also known as rasping or "floating". Absent this periodic treatment, the animal's teeth will grow to a point where it can experience difficulty in chewing, or can develop tooth induced ulcerations of the soft mouth tissue and tongue. Devices to file a horse's teeth are well known in the art. They range from hand-held floats and rasps, to rasps mounted upon both reciprocating and rotary power tools. For example, U.S. Pat. No. 579,966 shows a veterinary file holder. Two lips or flanges are secured to a wire member, forming salient edges which overlap the edges of a file. U.S. Pat. No. 5,533,894 defines an equine dental float which includes a handle with a head at one end. The head has a trough-like structure with a plurality of individual teeth mounted in the trough. A pin mounted through an aperture in each of the plurality of teeth aligns the teeth and removably connects the teeth within the trough. Each tooth is polygon in shape and has a plurality of cutting edges, with one of the cutting edges of each tooth projecting upwardly out of the trough to form a filing surface. German Patent 26 37 915 depicts a tool for filing horse teeth having a reciprocating rasp in a U/rail supported by a rod connected to a drive housing. The joint between the rod and the housing is formed by a plate attached to the end of the rod and covering the housing interior and the drive mechanism. The tool can be handled more safely and allows rapid filing down of teeth without insertion of a lock in the horse's mouth. German Patent 30 02 386 comprises a teeth grinding instrument intended for the molars of horses having a motordriven grindstone. The grindstone is coupled by a chuck to a compressed air motor. The device also has one or more air outlet ports, together with a water pipe spraying onto the grinding area, and one or more fiber optic light sources. French Patent 1.052.653 describes 15 a rotary grinding device for animal dentistry. Mikita Model 4399D and 4399DW discloses a Cordless Equine Rasp. This device operates an 2,700 strokes per minute, has a 5/32 inch stroke, and weighs 5.3 lbs. Rotary motion provided by an electric is mechanically converted to reciprocating motion. The tool is marketed by the Mikita Corp. 3-11-8, Sumiyoshi-cho, Anjo, Aichi 446 Japan. EQUI-DENT Technologies, Inc., P.O. Box 5877, Sparks Nev. 89432-5877 (702) 358-6695, also markets an electrically powered reciprocating rasp for horses which operates at 1,200 oscillations per minute, has a 1 and 3/16 inch stroke, and weighs approximately 7.4 lbs. Mikita Model TR 3000V reciprocating saw forms the basis for the EQUI-DENT rasp.
None of the aforementioned prior art equine dentistry devices utilize compressed air to directly drive a rasp in a reciprocating fashion. Further, the aforementioned electricallydriven devices operate at no load speeds of no more than 2,700 oscillations per minute. When loaded down with the weight of a rasp and shaft, the speed of these devices is reduced substantially.

Air-powered dental tool for animals and method of use


Disclosed is a toner composition for electrophotography which comprises, as a principal component, a urethane-modified polyester resin whose loss tangent (tan .delta.) has a maximum and a minimum both falling within the range of from 0.7 to 2.5, the loss tangent being determined at 150.degree. C. and a frequency ranging from 10.sup.-2 to 10 Hz. The toner composition has excellent low temperature fixing ability and offset resistance as well as a wide range of permitted fixing temperature.

The present invention relates to a toner composition for electrophotography and more specifically to a toner composition for electrophotography being excellent in both low-temperature fixing ability and offset resistance.
In electrophotography, images are obtained by forming electric latent images on a photosensitive substance by a variety of means utilizing photoconductive materials, then, the latent images are developed with a toner, followed by transferring the images onto an image support such as paper according to demand and then fixing the images with, for instance, a heating roll for fixing. A variety of resins have been investigated for use in such toners. In particular, polyester resins have been used as resins for toners which can be fixed to a transfer paper with a heating roll for fixing, because of their excellent properties such as ability for wetting the transfer paper, good compatibility with a coloring agent such as carbon black, and excellent fixing ability, when it is molten.
It is required in electrophotography that clear images be provided in a stable condition from the viewpoint of transfer of information. Recently, because the quantity of information to be handled has increased, a correspondingly faster rate of reproduction has been required. As the rate of reproduction increases, however, a great deal of heat is consumed by copying paper. Therefore, the surface temperature of the heating roll for fixing is greatly lowered in proportion to the increase in the number of copied paper. Thus, a toner is needed which does not exhibit an offset phenomenon and insufficient fixing, which has a wide range of permitted fixing temperature and which makes it possible to perform stable fixing, even when the surface temperature of the heating roll for fixing varies.
In conventional toners where a polyester resin is employed, additions such as a low molecular weight polyolefin or a partially incorporated a gel component have been used to eliminate the foregoing problems. However, the foregoing problems still have yet to be fundamentally solved, since the surface temperature of the heating roll for fixing is beyond the lower limit (low temperature fixing ability) and/or the upper limit (offset resistance) of the permitted fixing temperature of the toner.

Toner composition for electrophotography


Generating weights for biometric tokens in probabilistic matching systems is disclosed, where these weights are generated from computations performed on matched sets and unmatched sets of a reference data set. In an embodiment, scores from a similarity scoring function are distributed among bins, and a weight is computed for each bin as the log of (the matched set ratio/the unmatched set ratio), where the ratios are computed as the number of scores in a particular bin as compared to the total size of the set. The weights may then be used subsequently with scores computed by the scoring function to assess confidence of a computed similarity score, and are directed toward making the output of the probabilistic matching system more data-driven and more accurate.

The present invention relates to matching processes that use biometric tokens (such as facial images, fingerprints, iris scans, palm scans, and so forth), and generating weights for use in probabilistic matching systems for such biometric tokens.
Identifying a person by biographic data or demographic data (such as the person's name, address, date of birth, and so forth) has commonly been performed using a probabilistic matching system. A probabilistic matching system is one in which there are multiple possible outcomes, where each outcome may have a different degree of certainty (or uncertainty)—that is, a different probability of being true.

INTERNATIONAL BUSINESS MACHINES CORPORATION


A device receives a software program, performs a dynamic malware analysis of the software program to generate dynamic malware analysis results, and generates a call graph based on the dynamic malware analysis of the software program. The device utilizes, during the dynamic malware analysis of the software program, the call graph to identify an exit of the software program and/or a forced kill of the software program, and performs a static malware analysis of the software program based on identifying the exit of the software program and/or the forced kill of the software program. The device generates static malware analysis results based on performing the static malware analysis of the software program, and combines the dynamic malware analysis results and the static malware analysis results to generate combined malware analysis results. The device performs one or more actions based on the combined malware analysis results.

A software program (e.g., a binary software program) executed inside a sandbox may identify all application programming interfaces (APIs) used by the software program if the software program does not exhibit armoring during execution. Logging API traces used by a software program is important to understand the behavior of the software program and to help determine whether the software program is malicious (e.g., is malware or includes malware). However, malware uses different kinds of armoring to prevent dynamic malware analysis of a software program in a sandbox, which prevents logging of the API traces. For example, malware may detect that the software program is executing within a sandbox and may exit the software program to prevent identification of API traces indicating malicious behavior.

Extending dynamic detection of malware using static and dynamic malware analyses


A strip test method includes the following steps. First, an assembly strip is provided, wherein the assembly strip includes a plurality of semiconductor devices, each having a plurality of leads. A test socket and a base are provided, wherein the test socket has a plurality of probe sets. The assembly strip is loaded to the base. The probe sets electrically contacts the leads of the semiconductor devices simultaneously and respectively so as to process an electrical test. When one of the semiconductor devices is failed in the electrical test, one of the base and the test socket are relatively moved in such a manner that the failed one of the semiconductor devices is corresponding to one of the probe sets which is successful in the electrical test and is the nearest to the failed one of semiconductor device. Finally, the successful and nearest one of probe sets simultaneously and electrically contacts the leads of the failed one of the semiconductor devices so as to process another electrical test again.

1. Field of the Invention
The present invention generally relates to a strip test method, and more particularly to a strip test method, wherein the semiconductor devices which are failed in the first electrical test can be electrically tested again by the probe set in which the electrical test is successful in the first electrical test.
2. Description of the Related Art
U.S. Pat. No. 6,720,786, entitled "Lead Formation, Assembly Strip Test and Singulation System" discloses an integral system for testing semiconductor devices. Referring to FIG. 1, a functional test device includes a test module 20 and a base 24. The test module 20 has a plurality of probes 22. Generally, a plurality of molded semiconductor devices 12 are assembled (packaged) on matrix-type lead frame structures in which the semiconductor devices 12 are arranged in multiple rows and columns. Before being singulated (separated) into individual molded semiconductor devices 12, the molded semiconductor devices 12 are loaded to the base 24, and then are tested while the probes 22 simultaneously, respectively and electrically contact the leads 14 of the molded semiconductor devices 12 so as to process an electrical test, thereby reducing manufacturing time and costs. The term "assembly strip 10" is adapted to describe the integral structure formed by such a matrix-type lead frame structure with the molded semiconductor devices 12 packaged thereon. The term "strip test" is adapted to describe the electrical test before the molded semiconductor devices 12 are singulated.
In addition, referring to FIG. 2, it depicts a conventional strip test method. The strip test method includes the following steps. In step 48, an assembly strip 10 is inputted in a test area. In step 50, the assembly strip 10 is loaded to the base 24. In step 52, the probes 22 of the test module 20 simultaneously, respectively and electrically contact the leads 14 of the semiconductor devices 12 of the assembly strip 10, so as to process an electrical test. In step 54, the assembly strip 10 is unloaded from the base 24. In step 56, it is judged whether any semiconductor device 12 is failed in the electrical test or not. If the answer is "No", the strip test method goes to step 58; and if the answer is "Yes", the strip test method returns to step 50. In step 58, the assembly strip 10 is outputted from the test area.
However, according to the conventional strip test method, the assembly strip will be unloaded from the base after an electrical test of the assembly strip is finished. If some semiconductor devices are failed in the electrical test, the original assembly strip must be loaded to the base again and then another electrical test of the assembly strip is processed, such that the conventional strip test method will increase manufacturing time and decrease the production output. Furthermore, when another electrical test of the assembly strip is processed again, the semiconductor devices which are failed in the first electrical test will be still corresponding to the same probes in the first electrical test. If these probes malfunction, the test result of the second electrical test of the semiconductor devices which are failed in the first electrical test may be still wrong.
Accordingly, there exists a need for a strip test method and a functional test device capable of solving the above-mentioned problems.