ACE Inhibitors with structure and nomenclature
1.1. Angiotensin-Converting Enzyme Inhibitors
In the 1950s, it was discovered that angiotensin exists as both an inactive decapeptide angiotensin I and an active octapeptide angiotensin II. Human angiotensin-converting enzyme contains 277 amino-acid residues and has two homologous domains, each with a catalytic site and a region for binding Zn+2 [1, 2]. The degradation of bradykinin to inactive peptides occurs via action of ACE; ACE thus not only produces a potent vasoconstriction but also inactivates a potent vasodilator. In 1965, Ferreira  studied the physiological effects of snake poisoning and discovered a specific component from the venom of the pit viper, Bothrops jararaca, which inhibits degradation of the peptide bradykinin and potentiate hypotensive action of bradykinin potentiating factors (BPFs), basically amino-acid-containing peptides. Bakhle  reported that these same peptides had an inhibitory activity on ACE of dog lung homogenate and inhibited the enzymatic conversion of angiotensin I to angiotensin II. Brunner and Laragh  administered them to hypertensive patients and found them to be extremely effective in lowering blood pressure. The structural requirements for substrates of angiotensin-converting enzyme to cleave a substrate are found to be similar to those observed with carboxypeptidase A of bovine pancreas [6, 7].
The molecule ACE is a zinc metallopeptidase and has a similar mode of action to carboxypeptidase . In 1970, the Bradykinin-potentiating pentapeptide BPP5a was isolated, which inhibited enzyme angiotensin and decreased blood pressure . The significance of ACE in the pathogenesis of hypertension was not fully appreciated until 1977, when Ondetti  first isolated and then synthesized the naturally occurring non-peptide, teprotide. He proposed a hypothetical model of the active site of ACE and used it to predict and design compounds that would occupy the carboxy-terminal binding site of the enzyme captopril, a specific potent inhibitor of ACE. Clinical trials showed excellent anti-hypertensive properties and these results had a major impact on the treatment of cardiovascular disease . The first demonstration of an orally active ACE inhibitor was made on 31 March 1975, when the succinyl group was replaced with a derivative of cysteine, increasing inhibitory potency about 2,000-fold because sulphhydryl of cysteine bound with zinc more tightly than the carboxyl of succinyl. This resulted in captopril, with a dramatic effect on renal function and on hypertension . Enalapril is basically a first derivative of ACE inhibitor, which was developed to overcome the limitations of captopril. Lisinopril is a lysine analogue of enalaprilat (the active metabolite of enalapril).
Angiotensin enzyme inhibitors are basically ester-containing drugs that show 100-1000 times less activity than their active form; these inhibitors are synthetic in nature and can be classified on the basis of their chemical structure. They can be grouped as sulphhydral-containing (fentiapril, pivalopril, zofenopril, alacepril, etc.), dicarboxyl-containing (lisinopril, benazepril, quinapirl, perindopril, indopril, pentopril, indalapril, alazapril, moexipril, romipril, spirapril, etc.), phosphorous-containing (fosinopril)  and naturally occurring lactokinins and casokinins. 
In general we can say that all ACE inhibitors differ by three properties: potency, conversion from pro-drug to active form, and pharmacokinetics (i.e., ADME). They also differ in terms of tissue distribution. All ACE inhibitors have a similar antihypertensive efficacy – they effectively block the conversion of angiotensin 1 to angiotensin II – and all have similar therapeutic indications, adverse effect profiles and contraindications.
1.1.3. Mechanism of action
These inhibitors block the converting enzyme of angiotensin, which is responsible for cleavage from angiotensin I, which is decapeptide, to angiotensin II, which is octapeptide [17, 18], and lower the BP by reducing PVR (peripheral vascular resistance). They also decrease aldosterone secretion and the resulting sodium and water retention.
The oral bioavailability of ACE inhibitors ranges from 13% to 95% [19, 20]. Most ACE inhibitors are administered as pro-drugs that remain inactive until esterified in the liver . Pharmakokinetic characteristics of different ACE inhibitors are given in Table 2
|Enalapril||60||<08||11||Partly converted enalaprilate||5-20|
1.1.5. Therapeutic use
ACE inhibitors are effective in patients with mild to moderately severe hypertension, normal or low plasma renin activity, collagen vascular disease and cardiovascular disease [22, 23]. They are also used in the prevention and treatment of myocardial infarction [24, 25] and in the management of cardiac arrhythmias . They can decrease the progression of atherosclerosis, microalbuminuria and diabetic retinopathy, and produce a beneficial effect in patients with Bartter’s syndrome .
1.1.6. Adverse effects
ACE inhibitors have a relatively low incidence of side effects and are well tolerated; however, dry cough is common, appearing in 10-30% of patients. This appears to be related to the elevation in bradykinin [28-30]. Hypotension is seen especially in patients with heart failure , angiooedema (life-threatening airway swelling and obstruction; 0.1-0.2% of patients) and hyperkalaemia. ACE inhibitors are contraindicated in pregnancy, in the first trimester associated with a risk of major congenital malformations, particularly affecting the cardiovascular and central nervous systems . The most common (≥1% of patients) adverse effects include hypotension, fatigue, dizziness, headache, nausea and other gastrointestinal disturbances, dry cough, hyperkalaemia and renal impairment. Rash and taste disturbances are more prevalent with captopril and are attributed to its sulphhydryl moiety; eosinophilia has also been reported. Most of the adverse effects are reversible on withdrawing therapy . Treatment with ACE inhibitor has been associated with the development of anaphylactoid reaction .
1.1.7. Drug interactions
Hypotensive effect of ACE inhibitors decreased when given in combination with non-steroidal anti-inflammatory drugs , but this effect was enhanced with calcium-channel blockers and beta-blockers . Granulocytopaenia occurs after combined therapy of ACE inhibitors and interferones . ACE inhibitors interact with different drugs, like NSAIDs . Cytokines antagonize the hypotensive effect of ACE inhibitors ; severe hypokalaemia occurs with potassium-depleting diuretics  and potassium-sparing diuretics produce hyperkalaemia [41, 42]. ACE inhibitors were shown to increase potassium levels in the body . Alpha-blockers enhance the hypotensive effect of ACE inhibitors . Iron supplementation successfully decreases cough induced by ACE inhibitors  and can interfere with the absorption of ACE inhibitors . Hypoglycaemic effect is enhanced with anti-diabetics and insulin [47, 48]. Combination of azathioprine and ACE inhibitors is associated with anaemia . The risk of bone marrow depression is increased in patients taking concomitant therapy of ACE inhibitors and immunosuppressive agents.
1.2. HMG-CoA reductase inhibitors (statins)
3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) are the most effective among all hypolipidaemic agents . These lipid-lowering drugs are increasingly used for primary and secondary hindrance of cardiovascular disease ; they have only been recognized for treatment of hyperlipidaemia. In clinical studies, statins are highly effective in enhancing HDL levels while reducing total cholesterol, LDL cholesterol, apolipoprotein B and triglyceride levels.
The normal treatment regimen for these drugs involves daily exposure over a period of many years [52, 53]. They have also been examined in combination with cures of multiple sclerosis, osteoporosis, Alzheimer’s disease and dropping the superfluous increased occurrence in CHD in women on HRT treatment . They have anti-thrombogenic, anti-inflammatory and anticoagulant properties [55, 56]. These therapeutic properties are independent of lipid lowering , and the benefits of statins appear to be independent of baseline cholesterol . They can be classified into subclasses: the naturally or fungi-derived first generation, and the synthetic second generation. The first generation includes simvastatin, lovastatin and pravastatin, and the second atorvastatin and rosuvastatin. They can be further divided into the lipophilic group (simvastatin, lovastatin and atorvastatin) and the OH hydrophilic group (pravastatin and rosuvastatin) .
carbonyl]-1 H -
|Pravastatin||[1 S- [1alpha(beta S*, delta S*), 2,|
phthaleneheptanoic acid salt
Raw materials used were of pharmaceutical purity and were obtained from different pharmaceutical companies (Table 4). Tablets were purchased from a local pharmacy; each product was labelled with an expiry date not earlier than two years from the time of these studies.
|Captopril||Capoten||25||Bristol Meyers (Pvt.) Ltd.|
|Lisinopril||Lisinopril||5||Atco Laboratories Ltd.|
|Statins||Rosuvastatin||X-plended||20||Pharm Evo (Pvt.) Ltd.|
|Atorvastatin||Atopitar||10||Atco Pharma (Pvt.) Ltd.|
|Pravastatin||Pravachol||20||Bristol Meyers (Pvt.) Ltd.|
|Simvastatin||Atcol||10||Geofman Pharma (Pvt.) Ltd.|
Analytical-grade solutions were used for the performance of the experiment. Methanol and acetonitrile were of HPLC grade and other reagents included HCl, sodium hydroxide (NaOH), sodium chloride (NaCl), disodium hydrogen orthophosphate, potassium dihydrogen orthophosphate, ammonium chloride, NH3 solution (10%), phosphoric acid (8%) (Merck Germany). Organic solvents used were methanol, ethanol, ethyl acetate, chloroform, acetronitrile, triethylamine and DMSO (Merck HPLC Grade Germany).
A UV-visible spectrophotometer (Shimadzu Model 1601, Japan) with 10-mm path length was connected to a computer with UVPC version 3.9 software. A Stedec CSW-300 was used for deionization of water. Dissolution was accomplished using BP 2009 standards. Chromatographic studies were carried out by using two Shimadzu HPLC systems, one equipped with an LC-10 AT VP pump (SPD-10 A VP), and the second with an LC-20AT UV/VIS detector utilizing Hypersil, ODS, C18 (150×4.6 mm, 5 micron) and a Purospher® STAR RP-18 column. Chromatographic data peaks were analysed using Shimadzu Japan CBM-102, class GC 10 software.
Infrared studies were performed using Shimadzu FTIR Prestige-21. Spectral analysis was performed using Shimadzu software. The proton H1-NMR spectra were calculated on a Bruker (AMX 500 MHz) spectrometer using TMS as an internal standard. Melting points were recorded using Gallen kamp melting-point apparatus Minnesota Mining And Manufacturing Company.
2.2.1. Preparation of simulated gastric juice and buffers
0.1 N HCl was prepared by using 9 mL HCl (11 N) in a volumetric flask; the volume was made up with de-ionized water. Chloride buffer at pH 4 was prepared by dissolving 3.725 g of KCl (potassium chloride) in deionized water and 0.1N HCl was used for pH adjustment. For preparation of PO4 (phosphate buffer pH 7.4) 0.6 gm of potassium dihydrogen orthophosphate was used, plus 6.4 g of disodium hydrogen orthophosphate and 5.85 g of NaCl (sodium chloride), and the pH was adjusted. Preparation of NH3 ammonia buffer at pH 9 was done using 4.98 g of NH4Cl ammonium chloride and pH-adjusted with 10% ammonia.
2.2.2. Construction of the calibration curve of drugs
The above standard solutions of all drugs were scanned in the region 200-700 nm against the reagent blank, and absorbance maxima were recorded as shown in Table 5. Calibration curves were constructed between concentration and absorbance. Epsilon values and linear coefficients were calculated in each case at all the above-described pH values. Beer Lambert’s law was obeyed at all concentrations and pHs.
|ACE inhibitors||Enalapril||203, 206, 207, 208||1-9 x 10-5|
|Captopril||203, 204, 206||5 -14 x 10-7|
|Lisinopril||206||1-10 x 10-5|
|Statins||Atorvastatin||241||0.5-4.5 × 10-2|
|Rosuvastatin||240||1-5 × 10-5|
|Simvastatin||231, 238, 246||1-9 × 10-5|
|Pravastatin||235||1-9 × 10-5|
2.2.3. Monitoring of drug interactions of enalapril, captopril and lisinopril by high-performance liquid chromatography
HPLC methods for simultaneous determination of enalapril, captopril and lisinopril with statins in raw materials, pharmaceutical dosage forms or in human serum were developed and validated according to ICH guidelines. These methods were then applied to drug-drug, drug-metals and drug-antacid interaction studies.
2.2.4. Chromatographic conditions
Isocratic elution was performed at ambient temperature with two different types of column. Hypersil, ODS, C18 (150×4.6 mm, 5 micron) and Purospher® STAR RP-18, for assay of enalapril, captopril and lisinopril and simultaneous determination of these drugs with interacting drugs, respectively. The mobile phase, flow rate, wavelength and UV detection were varied as shown in Table 6. A sample volume of 20 μL was injected in triplicate onto the HPLC column and the elute was monitored at different wavelengths.
2.2.5. Preparation of standard solutions
Stock reference standard solutions of all drugs were prepared daily by dissolving appropriate amounts of each drug in mobile phase to yield final concentration of 300 μgmL-1. For the calibration standards, calibrators of each drug were prepared by making serial dilutions from stock solutions. All solutions were filtered through 0.45 μm filter and degassed using sonicator.
2.2.6. Preparation of pharmaceutical dosage from samples
Pharmaceutical formulations of the respective brands commercially available in Pakistan were evaluated. In each case, groups of 20 tablets were individually weighed and finely ground in a mortar. The portion of the powder equivalent to the amount of drug was transferred into a volumetric flask and completely dissolved in mobile phase, and then diluted with this solvent up to the mark. After filtration using a 0.45 micrometre μm filter this was then injected.
2.2.7. Preparation of standard plasma solutions
Samples of blood used were collected then centrifuged at 3000 rpm for at least ten minutes, Supernatant solution was stored at –20°C. The solution serum was deprotinated by using (ACN) acetonitrile, and this solution was spiked daily with working solutions for required concentrations of ACE inhibitors and interacting drugs (statins). 10 µL of sample was injected and chromatographed under the above conditions.
|Enalapril + statins||60||40||3||1.8||230|
|Captopril + statins||-||60||40||2.9||1.5||230|
|Lisinopril + statins||-||60||40||3||1||225|
2.2.8. Method development and optimization
HPLC methods were developed and optimized for certain parameters before method validation. The optimization of the analytical procedure was carried out by varying the mobile-phase composition, flow rate, pH of the mobile phase, diluent of solutions and wavelength of analytes in order to achieve symmetrical peaks with good resolution at reasonable retention time.
2.2.9. Method validation
All validation parameters were established according to the guidelines given by ICH: system suitability, linearity, selectivity of drugs, specificity, (concentration-detector response relationship), accuracy or precision and sensitivity with systems, i.e., D and Q (detection and quantification) limit.
Specificity and linearity
The drugs were spiked with pharmaceutical formulations containing different excepients. The linearity of the proposed method was checked at different levels of concentration with different groups. Correlation coefficient was linear; intercept and slope values were also calculated.
Suitability of system
The system suitability of the method was evaluated by analysing five replicate analyses of the drug at a specific concentration for repeatability, (peaks) symmetry factor, theoretical plates for columns, resolution of peaks between interacting drugs, and relative retention of drugs.
Accuracy and precision
Accuracy was calculated at three different levels of concentration (80±20%) by spiking a known amount of the drug. Three or four injections of each drug were injected into the system and the percentage recovery was calculated.
For precision, six replicates of each level were injected into the system on two different non-consecutive days in each case, and the %RSD was calculated.
Limit of detection and quantification
The detection limit (LOD) of the method was calculated by the formula LOD = 3.3 SD/slope. The quantitation limit (LOQ) – the lowest level of analyte that is accurately measured – was set at ten times the noise level (LOQ = 10ơ/S, where ơ is the standard deviation of the lowest standard concentration and S is the slope of the standard curve).
Robustness was established by changing the concentration of mobile phase (water, methanol and acetonitrile), wave length, flow rate and pH. At least five repeated solutions were used with small variations of different parameters. Parameters that were changed mainly had a small deviation: ± 0.2% flow rate/pH, and ±5% for wave length.
Ruggedness was determined in different labs. Lab 1 was the (RIPS) Research Institute of Pharmaceutical Sciences, Faculty of Pharmacy, Karachi University, and the other at the same university in the Department of Chemistry. Two different instruments (LC 10/LC 20) and two different columns (Purospher STAR C18/Hypersil ODS) were used.
2.2.10. Interaction studies by HPLC
Enalapril solution was mixed with a solution of the interacting drug (statins), which gave a final concentration of 100 µgmL-1 for each constituent). These solutions were kept in a water bath at 37 °C for three hours. An aliquot of 5 mL was withdrawn at 30-minute intervals; after making appropriate dilutions it was filtered through 0.45 μ filter paper and three replicates were injected into the HPLC system. The concentration of each drug was determined and the percentage recovery was calculated; the same procedure was applied for captopril and lisinopril.
2.3. Synthesis of ACE inhibitors and interacting-drugs complexes
Complexes of enalapril, captopril and lisinopril with all interacting drugs were synthesized. Equimolar solutions of enalapril and interacting drugs were prepared in methanol. An equivolume solution of enalapril was mixed with each drug individually and the respective pH was adjusted either by 1-2 drops of ammonia or 0.1 N HCl. These mixtures were refluxed for three hours then filtered and left for crystallization at room temperature. Melting points and physical characteristics of these complexes were noted. Solubility of all these complexes was checked in different solvents: water, methanol, ethanol, chloroform and DMSO. A similar procedure was adopted for captopril and lisinoril.
2.3.1. Spectroscopic studies of complexes
22.214.171.124. Infrared studies
ACE inhibitors and their complexes were characterized by using a FT-IR spectrophotometer in the region 400-4000 cm-1. The infrared spectra were recorded using a potassium bromide disc. ATR (attenuated total reflection) or smart performer accessory was used for the sample (minimum amount).
126.96.36.199. Proton NMR analysis
Proton 1H NMR analysis was performed using a Bruker instrument in deuterated H2O, chloroform and methanol using (TMS) tetramethyl silane as an IS (internal standard).
3. Results and discussion
3.1. Method development/validation by HPLC
Simple, cheap and very precise, HPLC was used for the determination of ACE inhibitors (captopril, enalapril and lisinopril) in the presence of different statins: ROS (rosuvastatin), ATR (atorvastatin) and SMV(simvastatin) in active ingredients as well as in formulations. It was developed according to guidelines ICH. All inhibitors with statins separated out in less than 10 mins without interference from any ingredients. The recovery of drugs was within the desired range (99-102%). These methods were validated according to ICH and the criteria for acceptance (accuracy/linearity/precision/specificity) and for system suitability were met. The methods can easily be used for quantitative analysis of ACE inhibitors and statins as single drugs or in formulations.
3.2. Interaction of ACE inhibitors with statins
Hyperlipidaemia and hypertension correlate with each other. They can effect coronary heart disease (CHD), because cardiovascular disease (CVD) is closely related to different factors, such as hypertension (HT) or high cholesterol levels. Factors include family history, age, sex, and diabetes [60-66]. Co-administration of antihypertensive, lipid-lowering and antidiabetic drugs is used in the treatment [67-72]. The most commonly used combinations of diuretic (chlorthalidone, hydrochloroth-iazide, etc.) and an angiotensin II receptor antagonist to control hypertension, as well as with a statin (fluvastatin, simvastatin, etc.) to reduce the cholesterol . Co-administration of an antihypertensive agent with statin is an effective therapeutic option for treatment of multiple cardiovascular risk factors, and especially for high blood pressure (BP) and LDL-C [74-78]. In addition, statins may improve the vasodilatation capacity of large arteries and may thus contribute to BP-lowering in patients treated with both an anti-hypertensive and a statin . Hypercholesterolaemia is often accompanied by hypertension, an associated risk factor for coronary-artery disease (CAD) [80-82]. ACE inhibitors are effective for the management of hypertension, supraventricular arrhythmias and angina pectoris. Other antihypertensive drugs such as propranolol  and atenolol  also interact with HMG-CoA reductase inhibitor. In the light of the above results, ACE inhibitors may interact and effect a change in each other’s availabilities. Methods were developed by HPLC for both ACE inhibitors and statins before starting interaction studies [85-88].
3.2.1. Interaction of enalapril with statins using HPLC
3.2.2. Interaction of captopril with statins using HPLC
3.2.3. Interaction of lisinopril with statins using HPLC
Interaction studies suggest that enalapril and lisinopril are not affected by statins but captopril changes the availability of drugs.
Bernstein KE, Martin BM, Edwards AS and Bernstein EA (1989) Mouse angiotensin-converting enzyme is a protein composed of two homologous domains, J. Biol. Chem., 264, 11945-11951.
Soubrier F, Alhene-Gelas F, Hubert C, Allegrini J, John M, Tregear G and Corvol P (1988) Two putative active centres in human angiotensin I-converting enzyme revealed by molecular cloning, Proc. Natl. Acad. Sci., 85, 9386-9390.
Ferreira SH (1965) A bradykinin-potentiating factor present in the venom of Bothrops jararaca, Brit. J. Pharmacol., 24, 163-169.
Bakhle YS (1968) Conversion of angiotensin I to angiotensin II by cell free extracts of dog lung, Nature, 220, 919-21.
Brunner HR, Laragh JH, Sealey JE, Gavras I and Vukovich RA (1974) An angiotensin converting enzyme inhibitor to identify and treat vasoconstrictor and volume factors in hypertensive patients, New Eng. J. Med., 291, 817-821.
Hartsuck JA and Lipscomb WN (1971) Carboxypeptidase A, In the Enzymes, Vol 3, ed. P.D. Boyer., pp l-56, New York, Academic Press.
Hofmann K and Bergmann M (1946) The specificity of carboxypeptidase, J. Biol. Chem., 134, 225-235.
Quiocho F and Lipscomb WN (1971) Carboxypeptidase A, A protein and an enzyme, Adv. Protein. Chem., 25, l-78.
Ferreira SH, Bartelt DC and Greene LJ (1970) Isolation of bradykinin potentiating peptides from Bothrops jararaca venom, Biochemistry, 9, 2583- 2593.
Ondetti MA, Rubin B and Cushman DW (1977) Science, 196, 441-444.
Maxwell RA and Eckhadt SB (1990) Captopril Drug Discovery, 19, 34.
Cushman DW, Ondetti MA, Gordon EM, Natarajan S, Karanewsky DS, Krapcho J and Petrillo EW (1980) Rational Design and Biochemical utility of specific inhibitors, Journal of Cardiovascular Pharmacology: 7, S17-30.
G a G(1996) The Pharmacological Basis of Therapeutic, 9th edition McGraw-Hill Press, New York p. 744.
Fitz Gerald RJ, Murray BA and Walsh DJ (2004) Hypotensive peptides from milk proteins, J Nutr., 134, 980S-8S.
Aloysius TN, Kelly C, Pierre R and Edward DS (2006) Synthesis and molecular modeling of a lisinopril-tryptophan analogue inhibitor of angiotensin I-converting enzyme. Bioorganic and Medicinal Chemistry Letters, 17(1), 4616-4619.
Sweetman SC and M (2005) The Complete Drug Reference,Pharmaceutical Press, London & Chicago, 34th Ed., 900-901.
Richard AH and Pamela CC (1977) Illustrated Review Pharmacology, Lippincott-Raven Publishers, Philadelphia, Revised ed., 151-162.
Bertam GK (1998) Basic and Clinical Pharmacology, Appleton and Lange, Revised ed., 197-213 Stamford.
Riley TN and De Ruiter J (1992) New drugs, U.S. Pharmacist., 17(3), 42-46.
Riley TN and DeRuiter (1997) New Drugs, U.S. Pharmacist, 22(3)175-176.
Leonetti G and Cuspidi C (1995) Choosing the right ACE inhibitor: A guide to selection, Drugs, 49, 516-535.
Burris JF (1995) the expanding role of angiotensin-converting enzyme inhibitors in the management of hypertension, J. Clin. Pharmacol., 35, 337-342.
The 1998 report of the Joint National Committee on the Detection, Evaluation and. Treatment of High Blood Pressure, Arch. Intern. Med., 1998; 148, 1023-1038.
Borghi C and Ambrosioni E (1996) A risk-benefit arrestment of ACE inhibitor therapy post-myocardial infarction, Drug Safety, 14, 277-87.
Murdoch DR and McMurray JJV (1998) ACE inhibitors in acute myocardial infarction, Hosp. Med., 59, 111-15.
Deedwania PC (1990) Angiotensin converting enzyme inhibitors in congestive heart failure, Arch. Intern. Med., 150, 1798-1805.
Jest P (1991) Angiotensin-converting enzyme inhibitors as a therapeutic potential in Bartter’s syndrome, Eur. J. Clin. Pharmacol., 41, 303-5.
28 Okumura H, Nishimura E and Kariya S (2001) Angiotensin-converting enzyme (ACE), 121(3), 253-7.
Anonymous (1994) Cough caused by ACE inhibitors, Drug Ther. Bull., 32(28)55-56.
Ravid D (1994) ACE-inhibitors and cough: a prospective evaluation in hypertension and congestive heart failure, J. Clin. Pharmacol., 34, 1116-1120.
Parish RC and Miller IJ (1992) Adverse effects of angiotensin-converting enzyme inhibitors: an update, Drug Safety, 7, 14-31.
Cooper WO, Hernandez-Diaz S, Arbogast PG, Dudley JA, Dyer S and Gideon PS (2006) Major congenital malformations after first-trimester exposure to ACE inhibitors, N. 33 Engl. J. Med., 354(23), 2443-51.
Molinaro G, Cugno M and Perez M (2002) Angiotensin-converting enzyme inhibitor- associated angioedema is characterized by a slower degradation of des-arginine(9)- bradykinin, J. Pharmacol. Exp. Ther., 303, 232-7.
Verresen L (1990) Angiotensin-converting-enzyme inhibitors anaphylactoid reactions to high-flux membrane dialysis, Lan., 336, 1360-1362.
Koopman PP, Van Megan T, Thien I and Gribrav FWJ (1989) The interaction between indomethacine and captopril or enalepril in normal volunteers, Journal of Internal Medicine, 226, 139-142.
Bainbridge AD, MacFadyen RJ, Lees KR and Reid JL (1991) A study of the acute pharmacodynamic interaction of ramipril and felodipine in normotensive subjects, Br. J. Clin. Pharmacol., 31, 148-53.
Casato M (1995) Granulocytopenia after combined therapy with interferone and angiotensin-converting enzyme inhibitors: evidence for a synergistic hematologic toxicity, Am. J. Med., 99, 386-91.
Shionoiri H (1993) Pharmacokinetic drug interactions with ACE inhibitors, Clin. Pharmacokinet., 25(1), 20-58.
Shionoiri H, Naruse M, Minamisawa K, Ueda S, Himeno H, Hiroto S, Takasaki I (1997) Fosinopril clinical pharmacokinetics and clinical potential, Clin. Pharmacokinet., 32(6), 460-80.
D’Costa DF, Basu SK and Gunasekera NPR (1990) ACE inhibitors and Diuretics causing hypokalemia, B.J.C.P., 44, 26-7.
Shionoiri H (1993) Pharmacokinetic drug interactions with ACE inhibitors, Clin. Pharmacokinet., 25(1), 20-58.
42 Mignat C and Unger T (1995) ACE-inhibitors: Drug interaction of clinical significance, Drug Safety, 12, 334-7.
Good CB, McDermott L and McCloskey B (1995) Diet and serum potassium in patients on ACE inhibitors, JAMA, 274, 538.
Baba T, Tomiyama T and Takebe K (1990) Enhancement by ACE inhibitors of first dose hypotension caused by an alpha1-blocker, N. Eng. J. Med., 322, 1237.
Lee SC, Park SW and Kim DK (2001) Iron supplementation inhibits cough associated with ACE inhibitors, Hypertension, 38, 166-170.
Campbell NR and Hasinoff BB (1991) Iron supplements, a common cause of drug interactions, Br. J. Clin. Pharmacol., 31, 251-255.
Herings RMC (1995) Hypoglycemia associated with use of inhibitors angiogenesin converting enzyme, Lancet, 345, 1195-8.
Morris AD (1997) ACE inhibitors’ use is associated with hospitalization for severe hypoglycemia in patients with diabetes, Diabetes Care, 20, 1363-7.
Gossmann J, Kachel HG, Schoeppe W and Scheuermann EH (1993) Anemia in renal transplant recipients caused by concomitant therapy with azathioprine angiotensin- converting enzyme inhibitors, Transplantation, 56, 585-9.
Goldstein JL and Brown MS (1990) Regulation of the mevalonate pathway, Nature, 343, 425-430.
Chester BG (2002) Polypharmacy in Elderly Patients with Diabetes, Diabetes Spectrum, 15, 240-248.
Jones PH, Davidson MH, Stein EA, Bays HE, McKenney JM, Miller E, Cain VA and Blasetto JW (2003) Comparison of the efficacy and safety of rosuvastatin versus atorvastatin, simvastatin, and pravastatin across doses, Am. J. Cardiol., 92, 152-160.
Caslake MJ, Stewart G, Day SP, Daly E, McTaggart F, Chapman MJ, Durrington P, Laggner P, Mackness M, Pears J and Packard CJ (2003) Phenotype-dependent and independent actions of rosuvastatin on atherogenic lipoprotein subfractions in hyperlipidaemia, Atherosclerosis,171, 245-253.
54 Engstrom G, Lind P, Hedblad B, Stavenow L, Janzon L and Lindgarde F (2002) Effects of cholesterol and inflammation-sensitive plasma proteins on incidence of myocardial infarction and stroke in men, Circulation, 105, 2632-2637.
Dangas G, Smith DA, Unger AH, Shao JH, Meraj P, Fier C, Cohen AM, Fallon JT, Badimon JJ and Ambrose JA (2000) Pravastatin: an antithrombotic effect independent of the cholesterol lowering effect, Thromb Haemost., 83, 688-692.
Honjo M, Tanihara H, Nishijima K, Kiryu J, Honda Y, Yue BY and Sawamura T (2002) Statin inhibits leukocyte-endothelial interaction and prevents neuronal death induced by ischemia-reperfusion injury in the rat retina, Arch. Ophthalmol., 120, 1707-1713.
67 Delanty N, Vaughan CJ and Sheehy N (2001) Statins and neuroprotection, Expert Opin. Investig. Drugs, 10, 1847-1853.
Heart Protection Study Collaborative Group (2002) MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial, Lancet, 360, 7-22.
Chong PH (2002) Lack of Therapeutic Interchangeability of HMG-CoA Reductase Inhibitors, Ann. Pharmacother., 36, 1907-1917.
Poulter N (1999) Coronary heart disease is a multifactorial disease. Am. J. Hypertens., 12, 92S-95S.
Lloyd-Jones DM, Evans JC and Larson MG (1999) Cross-classification of JNC VI blood pressure stages and risk groups in the Framingham Heart Study, Arch. Intern. Med., 159, 2206-2212.
Wilson PW, Kannel WB, Silbershatz H and D’Agostino RB (1999) Clustering of metabolic factors and coronary heart disease, Arch. Intern. Med., 159, 1104-1109.
Thomas F, Bean K and Guize L (2002) Combined effects of systolic blood pressure and serum cholesterol on cardiovascular mortality in young (<55 years) men and women, Eur. Heart J., 23, 528-535.
Wood D, Durrington P and McInnes G (1998) Joint British recommendations on prevention of coronary heart disease in clinical practice, Heart, 80(Suppl. 2), S1-S29.
Kannel WB (2000) Risk stratification in hypertension: New insights from the Framingham Study. Am. J. Hypertens., 13, 3S-10S.
Grundy SM, Brewer HB, Cleeman JI, Smith SC and Lenfant C (2004) Definition of metabolic syndrome: Report of the National Heart, Lung, and Blood Institute/American Heart Association conference on scientific issues related to definition, Circulation, 109,433-438.
Lars-Christian R, Elena B, Boguslaw O, Marianne W, Albert K and Philippe F (2008) Coadministration of Valsartan 160 and 320 mg and Simvastatin 20 and 40 mg in Patients with Hypertension and Hypercholesterolemia: A Multicenter, 12-Week, Double-Blind, Double-Dummy Parallel Group Study, Clinical Therapeutics, 30, 10.
Cefalu WT (2008) Diabetic dyslipidemia and the metabolic syndrome, Diab. Metab. Synd. Clin. Res. Rev., 2, 208-222.
Marcus AO (2000) Safety of drugs commonly used to treat hypertension, dyslipidemia, and type 2 diabetes (The Metabolic Syndrome): Part 1, Diabetes Technol. Ther., 2, 101-110.
Grundy SM, Cleeman JI, Daniels SR, Donato KA, R Eckel H, Franklin BA, Gordon DJ, Krauss RM, Savage PJ, Smith SC, Spertus JA and Costa F (2005) Diagnosis and Management of the Metabolic Syndrome, Circulation, 112, 2735-2752.
Plosker GL and Robinson DM (2008) Amlodipine/valsartan, fixed-dose combination in hypertension, Drugs, 68, 373.
Jacobson TA (2004) Comparative pharmacokinetic interaction profiles of pravastatin, simvastatin, and atorvastatin when coadministered with cytochrome P450 inhibitors, Am. J. Cardiol., 94(9), 1140-6.
Markham A and Goa KL (1997) Valsartan: A review of its pharmacology and therapeutic use in essential hypertension, Drugs, 54, 299-311.
Pool JL, Glazer R, Chiang YT and Gatlin M (1999) Dose-response efficacy of valsartan, a new angiotensin II receptor blocker, J. Hum. Hypertens., 13, 275-281.
Burnier M and Brunner HR (2000) Angiotensin II receptor antagonists, Lancet, 355, 637-645.
Weir MR, Crikelair N and Levy D (2007) Evaluation of the dose response with valsartan and valsartan/hydrocholorothia- zide in patients with essential hypertension. J. Clin. Hypertens., 9, 103-112.
Dorval JF, Anderson T and Buithieu J (2005) Reaching recommended lipid and blood pressure targets with amlodipine/atorvastatin combination in patients with coronary heart disease, Am. J. Cardiol., 95, S249-S253.
Koh KK, Quon MJ and Han SH (2004) Additive beneficial effects of losartan combined with simvastatin in the treatment of hypercholesterol-emic, hypertensive patients, Circulation, 110, 3687-3692.
Borghi C, Dormi A and Veronesi M (2002) Use of lipid-lowering drugs and blood pressure control in patients with arterial hypertension, J. Clin. Hypertens., 4, 277-285.
Gotto Jr. AM (1998) Risk factor modification: rationale for management of dyslipidemia, American Journal of Medicine, 104, 6S-8S.
Gould KL, Casscells SW, Buja LM and Goff DC (1995) Non-invasive management of coronary artery disease: Report of a meeting at the University of Texas Medical School at Houston, Lancet, 346, 750-753.
Wood D (2001) Asymptomatic individuals’ risk stratification in the prevention of coronary heart disease, British Medical Bulletin, 59, 3-16.
Pan HY, Triscari J and DeVault AR (1991) Pharmacokinetic interaction between propranolol and HMG-CoA reductase inhibitor pravstatin and lovastatin, Br. J. Clin. Pharmacol., 31, 665-670.
O’Riordan M (2005) ASCOT-LLA: Lower coronary event rates in patients treated with amlodipine and atorvastatin, Hypertension, Medscape, Medical News.
Sultana N, Arayne MS and Safila Naveed (2010) Simultaneous Determination of Captopril and Statins in API, Pharmaceutical Formulations and in Human Serum by RP-HPLC, J. Chin. Chem. Soc., 57, 378-383. [online] Available at: http://onlinelibrary.wiley.com/doi/10.1002/jccs.201000056/abstract
Sultana N, Arayne MS and Safila N. (2011) Simultaneous Determination of Enalapril and Statins in Pharmaceutical Formulations by RP- HPLC, Chilean Chemical Society, 56(3), 734-737. [online] Available at:. http://www.scielo.cl/scielo.php?script=sci_arttext&pid=S0717-97072011000300003
Sultana N, Arayne MS, Shah SN and Safila N. (2010) Simultaneous Determination of Prazosin, Atorvastatin, Rosuvastatin and Simvastatin in API, Dosage Formulations and Human Serum by RP-HPLC, Journal of the Chinese Chemical Society, 57(6), 1286-1292. [online] Available at: http://onlinelibrary.wiley.com/doi/10.1002/jccs.201000190/abstract
Sultana N, Arayne MS and Safila N. (2011) Validated Method for the Simultaneous Determination of Lisinopril, Pravastatin, Atorvastatin and Rosuvastatin in API, Formulations and Human Serum by RP-HPLC, Chinese Journal of Chemistry, 29, 1216-1220. DOI: 10.1002/cjoc.201190226. [online] Available at: http://onlinelibrary.wiley.com/doi/10.1002/cjoc.201190226/abstract