Methods for lowering blood pressure with a dihydropyridine-type calcium channel blocker pharmaceutical composition

Abstract

A method is provided for lowering blood pressure in a subject in need thereof by administering a dihydropyridine-type calcium channel blocker pharmaceutical composition to a subject qualified for over-the-counter access to the dihydropyridine-type calcium channel blocker pharmaceutical composition. In some embodiments, the dihydropyridine-type calcium channel blocker pharmaceutical composition includes isradipine, nifedipine, or nisoldipine. In some embodiments, the dihydropyridine-type calcium channel blocker pharmaceutical composition includes 3-O-ethyl 5-O-methyl 2-(2-aminoethoxymethyl)-4-(2-chlorophenyl)-6-methyl-1,4-dihydropyridine-3,5-dicarboxylate or a pharmaceutically acceptable salt thereof.

What is claimed is: 
     
         1 . A computer system for qualifying a human subject for over-the-counter delivery of a dihydropyridine-type calcium channel blocker pharmaceutical composition for lowering blood pressure, the computer system comprising one or more processors and a memory, the memory comprising non-transitory instructions which, when executed by the one or more processor, perform a method comprising:
 a) conducting a first survey of the subject thereby obtaining a first plurality of survey results, wherein the first plurality of survey results comprises:
 whether the subject is pregnant or breastfeeding, 
 whether the subject is taking a dihydropyridine-type calcium channel blocker, 
 a systolic blood pressure of the subject, 
 a diastolic blood pressure of the subject, 
 whether the subject has ever had an atherosclerotic cardiovascular event or had a heart procedure, 
 a gender of the subject, 
 an age of the subject, 
 a race of the subject, 
 whether the subject is taking any blood pressure medications, 
 a diabetes status of the subject, 
 a smoking status of the subject, 
 a total cholesterol level of the subject, 
 a high-density lipoprotein (HDL) cholesterol level of the subject, 
 whether the subject has ever had a liver problem, and 
 whether the subject is taking a medication that interacts with the dihydropyridine-type calcium channel blocker pharmaceutical composition; 
   b) running all or a portion of the first plurality of survey results against a first plurality of filters of a first category class, wherein, when a respective filter in the first plurality of filters is fired, the subject is deemed not qualified for delivery of the dihydropyridine-type calcium channel blocker pharmaceutical composition and the method is terminated without delivery of the dihydropyridine-type calcium channel blocker pharmaceutical composition to the subject, wherein the first plurality of filters comprises:
 a first pregnancy filter that is fired at least when the first plurality of survey results indicates that the subject is pregnant or the subject is breastfeeding, 
 a dihydropyridine medication filter that is fired at least when the first plurality of survey results indicates that the subject is taking a dihydropyridine-type calcium channel blocker, 
 a first blood pressure filter that is fired at least when the first plurality of survey results indicates the subject has normal blood pressure or the subject has severe hypertension, 
 an age filter, and 
 a pooled cohort equation filter that incorporates characteristics of the subject to derive a risk for atherosclerotic cardiovascular disease; 
   c) running all or a portion of the first plurality of survey results against a second plurality of filters of a second category class, wherein, when a respective filter in the second plurality of filters is fired, the subject is provided with a warning corresponding to the respective filter, and wherein the second plurality of filters comprises:
 a first liver disease filter that is fired at least when the first plurality of survey results indicates that the subject has had a liver problem, and 
 a first drug interaction filter that is fired at least when the first plurality of survey results indicates that the subject is taking a medication that interacts with the dihydropyridine-type calcium channel blocker pharmaceutical composition; 
   d) obtaining acknowledgment from the subject for the warning issued to the subject by any filter in the second plurality of filters; and   e) proceeding with a fulfillment process when (i) no filter in the first plurality of filters has been fired and (ii) the subject has acknowledged each warning associated with each filter in the second plurality of filters that was fired, wherein the fulfillment process comprises:
 storing an indication in a subject profile of an initial order for the dihydropyridine-type calcium channel blocker pharmaceutical composition, 
 communicating an over the counter drug facts label for the dihydropyridine-type calcium channel blocker pharmaceutical composition to the subject, and 
 authorizing, upon confirmation from the subject that the over the counter drug facts label has been received and read, provision of the dihydropyridine-type calcium channel blocker pharmaceutical composition to the subject. 
   
     
     
         2 . The computer system of  claim 1 , wherein the dihydropyridine-type calcium channel blocker pharmaceutical composition comprises an active ingredient having the structure: 
       
         
           
           
               
               
           
         
         wherein:
 Y is —(CH 2 ) 2 —, —(CH 2 ) 3 —, —CH 2 CH(CH 3 )—, or —CH 2 C(CH 3 ) 2 — 
 R is aryl; 
 R 1  and R 2  are each independently C 1 -C 4  alkyl or 2-methoxyethyl; and 
 R 3  is hydrogen, C 1 -C 4  alkyl, 2-(C 1 -C 4  alkoxy)ethyl, cyclopropylmethyl, benzyl, or —(CH 2 ) m COR 4  where m is 1, 2 or 3 and R 4  is hydroxy, C 1 -C 4  alkoxy or —NR 5 R 6  where R 5  and R 6  are each independently hydrogen or C 1 -C 4  alkyl; wherein aryl is phenyl; phenyl substituted by one or two of nitro, halo, C 1 -C 4  alkyl, C 1 -C 4  alkoxy, hydroxy, trifluoromethyl or cyano; 1-naphthyl; or 2-naphthyl. 
 
       
     
     
         3 . The computer system of  claim 1 , wherein the dihydropyridine-type calcium channel blocker pharmaceutical composition comprises amlodipine, or a pharmaceutically acceptable salt thereof, as an active ingredient. 
     
     
         4 . The computer system of  claim 1 , wherein the dihydropyridine-type calcium channel blocker pharmaceutical composition comprises amlodipine besylate, as an active ingredient. 
     
     
         5 . The computer system according to any one of  claims 2 - 4 , wherein, upon confirmation from the subject that the over the counter drug facts label has been received and read, the subject is authorized for provision of a dosage of from 1 mg to 10 mg per day of the active ingredient. 
     
     
         6 . The computer system according to any one of  claims 2 - 4 , wherein, upon confirmation from the subject that the over the counter drug facts label has been received and read, the subject is authorized for provision of a dosage of from 2.5 mg to 5 mg per day of the active ingredient. 
     
     
         7 . The computer system according to  claim 1 , wherein the dihydropyridine-type calcium channel blocker pharmaceutical composition is selected from the group consisting of isradipine, nifedipine, and nisoldipine. 
     
     
         8 . The computer system according to  claim 7 , wherein, upon confirmation from the subject that the over the counter drug facts label has been received and read, the subject is authorized for provision of a dosage of from 15 mg to 60 mg of nifedipine per day. 
     
     
         9 . The computer system according to  claim 7 , wherein, upon confirmation from the subject that the over the counter drug facts label has been received and read, the subject is authorized for provision of a dosage of from 1 mg to 10 mg of isradipine per day. 
     
     
         10 . The computer system according to  claim 7 , wherein, upon confirmation from the subject that the over the counter drug facts label has been received and read, the subject is authorized for provision of a dosage of from 8.5 mg to 17 mg of nisoldipine per day. 
     
     
         11 . The computer system according to any one of  claims 1 - 10 , wherein the first pregnancy filter is also fired when the first plurality of survey results indicates that the subject is planning to become pregnant. 
     
     
         12 . The computer system according to any one of  claims 1 - 11 , wherein the dihydropyridine medication filter is fired when the first plurality of survey results indicates that the subject is already taking amlodipine, isradipine, nifedipine, and nisoldipine. 
     
     
         13 . The computer system according to any one of  claims 1 - 12 , wherein the first blood pressure filter is fired when the first plurality of survey results indicates that:
 A) the systolic blood pressure of the subject is greater than a ceiling systolic pressure;   B) the diastolic blood pressure of the subject is greater than a ceiling diastolic pressure; or   C) the systolic blood pressure of the subject is less than a baseline systolic pressure and the diastolic blood pressure of the subject is less than a baseline diastolic pressure.   
     
     
         14 . The computer system of  claim 13 , wherein:
 the ceiling systolic pressure is 139 mm Hg;   the ceiling diastolic pressure is 89 mm Hg;   the baseline systolic pressure is 130 mm Hg; and   the baseline diastolic pressure is 80 mm Hg.   
     
     
         15 . The computer system according to any one of  claims 1 - 14 , comprising, when the first plurality of survey results indicate that the subject has elevated blood pressure but is not hypertensive:
 firing the first blood pressure filter; and   transmitting, to the subject, advice to manage their blood pressure by eating healthy and exercising.   
     
     
         16 . The computer system according to any one of  claims 1 - 15 , comprising, when the first plurality of survey results indicate that the subject has stage two hypertension:
 firing the first blood pressure filter; and   transmitting, to the subject, advice to visit a doctor to discuss taking a prescription-strength blood pressure medication.   
     
     
         17 . The computer system according to any one of  claims 1 - 16 , comprising, when the first plurality of survey results indicate that the subject is in hypertension crisis:
 firing the first blood pressure filter; and   transmitting, to the subject, advice to seek emergency medical attention.   
     
     
         18 . The computer system according to any one of  claims 1 - 17 , wherein the age filter is fired when the first plurality of survey results indicates that the subject is less than eighteen years old. 
     
     
         19 . The computer system according to any one of  claims 1 - 18 , wherein the pooled cohort equation filter is fired when the first plurality of survey results indicates:
 A) the subject is younger than forty years old; or   B) the subject has a 10-year risk for atherosclerotic cardiovascular disease, as determined using the pooled cohort equation, that is less than 10%.   
     
     
         20 . The computer system according to any one of  claims 1 - 19 , wherein the pooled cohort equation is implemented as a multivariable Cox proportional hazard regression. 
     
     
         21 . The computer system according to any one of  claims 1 - 20 , comprising, when the first plurality of survey results indicate that the subject is at least 80 years old, that the subject has had an atherosclerotic cardiovascular event, or that the subject has had a heart procedure, bypassing the pooled cohort equation filter. 
     
     
         22 . The computer system according to any one of  claims 1 - 21 , wherein the drug interaction filter is fired when the first plurality of survey results indicates that the subject is taking a medication selected from the group consisting of simvastatin, cyclosporine, tacrolimus, sildenafil, and a CYP3A inhibitor. 
     
     
         23 . The computer system according to any one of  claims 1 - 22 , wherein:
 the first plurality of survey results further comprises whether the subject is allergic to the dihydropyridine-type calcium channel blocker pharmaceutical composition, and   the first plurality of filters includes an adverse reaction filter that is fired when the first plurality of survey results indicates that the subject is allergic to the dihydropyridine-type calcium channel blocker pharmaceutical composition.   
     
     
         24 . The computer system according to any one of  claims 1 - 23 , wherein:
 the warning corresponding to a respective filter in the second plurality of filters comprises a prompt for the subject to indicate whether they have discussed the risk factor underlying the respective filter in the second plurality of filters that was fired with a health care provider; and   acknowledgement is obtained from the subject when the subject indicates that they have discussed the risk factor underlying the respective filter in the second plurality of filters that was fired with a health care provider.   
     
     
         25 . The computer system according to any one of  claims 1 - 24 , wherein the fulfillment process further comprises:
 storing a destination associated with the subject in the subject profile.   
     
     
         26 . The computer system according to any one of  claims 1 - 25 , wherein the fulfillment process further comprises:
 coordinating shipping of the dihydropyridine-type calcium channel blocker pharmaceutical composition to a physical address associated with the subject.   
     
     
         27 . The computer system according to any one of  claims 1 - 26 , wherein the method further comprises:
 f) responsive to receiving a re-order request from the subject for the dihydropyridine-type calcium channel blocker pharmaceutical composition, performing a re-fulfillment procedure comprising:
 (i) conducting a second survey of the subject thereby obtaining a second plurality of survey results, wherein the second plurality of survey results comprises:
 whether the subject is pregnant or breastfeeding, 
 whether the subject has experienced an atherosclerotic cardiovascular event or had a heart procedure since receiving their last provision of the dihydropyridine-type calcium channel blocker pharmaceutical composition, 
 whether the subject has started taking a medication that interacts with the dihydropyridine-type calcium channel blocker pharmaceutical composition since receiving their last provision of the dihydropyridine-type calcium channel blocker pharmaceutical composition, and 
 whether the subject has developed a liver problem since receiving their last provision of the dihydropyridine-type calcium channel blocker pharmaceutical composition; 
 
 (ii) running all or a portion of the second plurality of survey results against a third plurality of filters of the first category class, wherein, when a respective filter in the third plurality of filters is fired, the subject is deemed not qualified for the dihydropyridine-type calcium channel blocker pharmaceutical composition and the re-fulfillment process is terminated without delivery of the dihydropyridine-type calcium channel blocker pharmaceutical composition to the subject, wherein the third plurality of filters comprise:
 a second pregnancy filter that is fired at least when the second plurality of survey results indicates that the subject is pregnant or the subject is breastfeeding; and 
 
 (iii) running all or a portion of the second plurality of survey results against a fourth plurality of filters of the second category class, wherein, when a respective filter in the fourth plurality of filters is fired, the subject is provided with a warning corresponding to the respective filter, and wherein the fourth plurality of filters comprises:
 an atherosclerotic cardiovascular event filter that is fired at least when the second plurality of survey results indicates that the subject has experienced an atherosclerotic cardiovascular event or the subject has had a heart procedure since receiving their last provision of the dihydropyridine-type calcium channel blocker pharmaceutical composition, 
 a second drug interaction filter that is fired at least when the second plurality of survey results indicates that the subject has started taking a medication that interacts with the dihydropyridine-type calcium channel blocker pharmaceutical composition since receiving their last provision of the dihydropyridine-type calcium channel blocker pharmaceutical composition, and 
 a second liver disease filter that is fired at least when the second plurality of survey results indicates that the subject has developed symptoms of liver disease since receiving their last provision of the dihydropyridine-type calcium channel blocker pharmaceutical composition; 
 
 (iv) obtaining acknowledgment from the subject for the warning issued to the subject by any filter in the fourth plurality of filters; 
 (v) proceeding with the re-fulfillment process when (a) the re-fulfillment process is not already terminated by the firing of a filter in the third plurality of filters and (b) the subject has acknowledged each warning associated with each filter in the fourth plurality of filters that was fired, wherein the re-fulfillment process further comprises:
 storing an indication in the subject profile of a re-order for the dihydropyridine-type calcium channel blocker pharmaceutical composition, 
 communicating the over the counter drug facts label for the dihydropyridine-type calcium channel blocker pharmaceutical composition to the subject, and 
 authorizing, upon confirmation from the subject that the over the counter drug facts label has been received and read, a re-order provision of the dihydropyridine-type calcium channel blocker pharmaceutical composition to the subject. 
 
   
     
     
         28 . The computer system of  claim 27 , wherein the re-fulfillment procedure further comprises, when the subject profile for the subject does not include a recent blood pressure for the subject:
 obtaining, in the second plurality of survey results, a blood pressure status of the subject; and   including, in the third plurality of filters of the first category class, a second blood pressure filter that is fired at least when the second plurality of survey results indicates that the subject has hypertension.   
     
     
         29 . The computer system of  claim 27 , wherein the re-fulfillment procedure further comprises:
 obtaining, in the second plurality of survey results, blood pressure status of the subject; and   including, in the third plurality of filters of the first category class, a second blood pressure filter that is fired at least when the second plurality of survey results indicates that the subject has hypertension.   
     
     
         30 . The computer system according to  claim 28  or  29 , wherein the second blood pressure filter is fired when the second plurality of survey results indicates that:
 A) the systolic blood pressure of the subject is above 130 mm Hg, or 
 B) the diastolic blood pressure of the subject is above 80 mm Hg. 
 
     
     
         31 . The computer system according to any one of  claims 27 - 30 , comprising, when the second plurality of survey results indicate that the subject has hypertension:
 firing the second blood pressure filter; and   transmitting, to the subject, advice to visit a doctor to discuss taking a prescription-strength blood pressure medication.   
     
     
         32 . The computer system according to any one of  claims 27 - 31 , wherein:
 the second plurality of survey results further comprises whether the subject has experienced a side effect associated with the dihydropyridine-type calcium channel blocker pharmaceutical composition since receiving their last provision of the dihydropyridine-type calcium channel blocker pharmaceutical composition, and   the fourth plurality of filters further comprises a side effect filter that is fired at least when the second plurality of survey results indicates that the subject has experienced, since receiving their last provision of the dihydropyridine-type calcium channel blocker pharmaceutical composition, a side effect selected from the group consisting of swelling of the legs, swelling of the ankles, tiredness, extreme sleepiness, stomach pain, nausea, dizziness, flushing, arrhythmia, heart palpitations, muscle rigidity, tremors, and abnormal muscle movement.   
     
     
         33 . The computer system according to any one of  claims 27 - 32 , wherein the re-fulfillment process further comprises, when a respective filter in the third plurality of filters or fourth plurality of filters is fired, storing a record associated with the firing of the respective filter in an adverse event profile comprising records of filter firing events associated with a plurality of subjects. 
     
     
         34 . The computer system according to any one of  claims 35 - 33 , wherein the lowering blood pressure is to treat or prevent a heart disease. 
     
     
         35 . A method for lowering blood pressure in a subject in need thereof, the method comprising:
 administering a dihydropyridine-type calcium channel blocker pharmaceutical composition to a subject qualified for over-the-counter access to the dihydropyridine-type calcium channel blocker pharmaceutical composition.   
     
     
         36 . The method of  claim 35 , wherein the dihydropyridine-type calcium channel blocker pharmaceutical composition comprises 3-O-ethyl 5-O-methyl 2-(2-aminoethoxymethyl)-4-(2-chlorophenyl)-6-methyl-1,4-dihydropyridine-3,5-dicarboxylate, or a pharmaceutically acceptable salt thereof, as an active ingredient. 
     
     
         37 . The method of  claim 35 , wherein the dihydropyridine-type calcium channel blocker pharmaceutical composition comprises an active ingredient having the structure: 
       
         
           
           
               
               
           
         
         wherein:
 Y is —(CH 2 ) 2 —, —(CH 2 ) 3 —, —CH 2 CH(CH 3 )—, or —CH 2 C(CH 3 ) 2 — 
 R is aryl; 
 R 1  and R 2  are each independently C 1 -C 4  alkyl or 2-methoxyethyl; and 
 R 3  is hydrogen, C 1 -C 4  alkyl, 2-(C 1 -C 4  alkoxy)ethyl, cyclopropylmethyl, benzyl, or —(CH 2 ) m COR 4  where m is 1, 2 or 3 and R 4  is hydroxy, C 1 -C 4  alkoxy or —NR 5 R 6  where R 5  and R 6  are each independently hydrogen or C 1 -C 4  alkyl; wherein aryl is phenyl; phenyl substituted by one or two of nitro, halo, C 1 -C 4  alkyl, C 1 -C 4  alkoxy, hydroxy, trifluoromethyl or cyano; 1-naphthyl; or 2-naphthyl. 
 
       
     
     
         38 . The method of  claim 35 , wherein the dihydropyridine-type calcium channel blocker pharmaceutical composition comprises amlodipine, or a pharmaceutically acceptable salt thereof, as an active ingredient. 
     
     
         39 . The method of  claim 35 , wherein the dihydropyridine-type calcium channel blocker pharmaceutical composition includes amlodipine besylate, as an active ingredient. 
     
     
         40 . The method according to any one of  claims 36 - 39 , wherein the subject is administered from 1 mg to 10 mg of the active ingredient per day. 
     
     
         41 . The method according to any one of  claims 36 - 39 , wherein the subject is administered 2.5 mg of the active ingredient per day. 
     
     
         42 . The method of  claim 35 , wherein the dihydropyridine-type calcium channel blocker pharmaceutical composition includes a composition selected from the group consisting of isradipine, nifedipine, and nisoldipine. 
     
     
         43 . The method of  claim 42 , wherein the subject is administered from 15 mg to 60 mg of nifedipine per day. 
     
     
         44 . The method of  claim 42 , wherein the subject is administered from 1 mg to 10 mg of isradipine per day. 
     
     
         45 . The method of  claim 42 , wherein the subject is administered from 8.5 mg to 17 mg of nisoldipine per day.