Molecular structure of captopril
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Captopril

Captopril is an Angiotensin-Converting Enzyme inhibitor (ACE inhibitor) used for the treatment of hypertension and some types of chronic heart failure. Captopril was the first ACE inhibitor developed and was considered a breakthrough both because of its novel mechanism of action and also because of the revolutionary development process. The original innovator drug Bristol-Myers Squibb's Capoten®. more...

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Clinical Use

Development of captopril

Captopril was invented in 1975 by three researchers at the American drug company Squibb (now Bristol-Myers Squibb) , Miguel Ondetti, Bernard Rubin and David Cushman. Squibb filed for American patent protection on the drug in February 1976 and U.S. Patent was 4,046,889 was granted in September 1977.

The development of captopril was amongst the earliest successes of the revolutionary concept of structure-based drug design. The renin-angiontensin-aldosterone system had been extensively studied in the mid-20th century and it had been decided that this system presented several opportune targets in the development of novel treatments for hypertension. The first two targets that were attempted were renin and ACE. Captopril was the culmination of efforts by Squibb's laboratories to develop an ACE inhibitor.

Ondetti, Cushman and colleagues built on work that had been done in the 1960s by the British Nobel laureate Sir John Vane when he was a researcher at the Royal College of Surgeons. Working with a Brazilian colleage, SĂ©rgio Ferreira, Vane discovered a peptide in Brazilian viper venom which was a 'collected-product inhibitor' of angiotensin II. Captopril was developed from this peptide after it was found via QSAR-based modification that the terminal sulfhydryl-moiety of the peptide provided a high potency of ACE inhibition.

Capoten gained FDA approval in June 1981. The drug went generic in the U.S. in February 1996 as a result of the end of market exclusivity for Bristol-Myers Squibb.

Shortcomings

During Phase III/IV trials of captopril, it was found that captopril had some undesirable adverse effects. The most predominant of which included cough, rash and taste disturbances (metallic or loss of taste). Cough is an adverse effect common to all of the ACE inhibitors, but the rash and taste disturbances were attributed to the very sulfhydryl moiety which granted captopril its potency. An additional shortcoming of captopril is the short half-life, necessitating 2-3 times daily dosing.

The development of longer-acting ACE inhibitors lacking the sulfhydryl-moiety such as enalapril proved to be the downfall of captopril and, whilst it is still used, it is no longer amongst the more widely used ACE inhibitors.

Reference

  • Smith CG, Vane JR. The discovery of captopril. FASEB J 2003;17:788-9. Fulltext. PMID 12724335.

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Randomised controlled trial of long term efficacy of captopril on preservation of kidney function in normotensive patients with insulin dependent diabetes
From British Medical Journal, 7/3/99 by Elisabeth R Mathiesen

In patients with insulin dependent diabetes, angiotensin converting enzyme inhibition delays the progression from microalbuminuria to diabetic nephropathy, but previous studies have been too short to show a preservation of kidney function.[1-3] We assessed the effectiveness of angiotensin converting enzyme inhibition on preservation of kidney function in an 8 year prospective, randomised controlled trial.

Patients, methods, and results

Forty four normotensive patients with insulin dependent (type I) diabetes and persistent microalbuminuria (30-300 rog/24 h) were enrolled as previously described in detail.[1] The treatment group (n = 21) was given captopril (100 mg/24 h) and bendrofluazide (2.5 mg/24 h). The 23 remaining patients were left untreated. Diabetic nephropathy was defined as albuminuria persistently [is greater than] 300 mg/24 h. Glomerular filtration rate was measured annually with Crom EDTA plasma clearance over 4 hours.[1]

After 4 years two patients in each group were excluded because they did not attend follow up sessions. Four of the patients in the control group started antihypertensive treatment with diuretics, [Beta] blockers, or a calcium channel blocker. Three patients in the treatment group were changed from bendrofluazide to frusemide because of oedema or diastolic blood pressure [is greater than] 95 mm Hg. After 8 years 16 of the 21 patients in the treatment group and two patients from the control group were subsequently investigated after a treatment pause of 2 months.

The proportion of patients who progressed to diabetic nephropathy was 40% (9/23) in the control group and 10% (2/21) in the captopril group (survival analysis P = 0.019). In the captopril group there was a significant increase in urinary albumin excretion (P [is less than] 0.001) during the treatment pause. In six (38%) of the 16 patients albuminuria exceeded 300 mg/24 h.

Glomerular filtration rate in the captopril group declined from 126 (24) at baseline to 114 (23) ml/min after 8 years but rose again to 126 (21) during the pause in treatment (table). Follow up values of glomerular filtration rate measured during the treatment pause were therefore used whenever available. The decline in mean glomerular filtration rate (ml/min) was 11.8 (95% confidence interval 1.2 to 22.0; t test P value 0.03) and 1.4 (-4.9 to 7.7; P = 0.65) in the control and captopril group, respectively (P = 0.09 between the groups). The fall in glomerular filtration rate during the 8 year study period in the eight control patients who developed nephropathy was 27.3 (3.7 to 51.0; P = 0.03) while glomerular filtration rate increased by 3.8 ( - 3.5 to 11.0) in the six patients treated with captopril with urinary albumin excretion [is greater than] 300 mg/24 h during the treatment pause (P = 0.02 between the groups). Haemoglobin [A.sub.1c] and blood pressure did not differ between the two groups at any time during the study.

Mean glomerular filtration rates (ml/min)in normotensive patients with insulin dependent diabetes at baseline, after 8 years' follow up, and during pause in treatment in captopril and control groups

(*) Patient developed diabetic nephropathy during 8 years of follow up or during treatment pause.

([dagger]) Difference from baseline significant at P = 0.03.

Comment

Our study has shown that the beneficial effect of angiotensin converting enzyme inhibition in the prevention of diabetic nephropathy is long lasting and associated with preservation of normal glomerular filtration rate. To obtain a valid determination of the rate of decline in glomerular filtration rate the applied glomerular filtration rate method should have a good accuracy and precision and the observation period should exceed 2 years.[4] These requirements have been fulfilled in our study in contrast with previous studies.[2 3] The second part of the study showed a return in glomerular filtration rate to the values before treatment after 2 months of withdrawal of antihypertensive treatment. The temporary fall in glomerular filtration rate in the intervention group was therefore regarded as a reversible haemodynamic phenomenon. Patients with persistent microalbuminuria at follow up had a stable normal glomerular filtration rate.[5] The clinically significant effect of angiotensin converting enzyme inhibition on preservation of normal glomerular filtration rate was related to prevention of progression from micro-albuminuria to diabetic nephropathy in patients with insulin dependent diabetes.

Contributors: HHP had the original idea for the study. ERM and HHP were responsible for conducting the study and interpreting the results and are guarantors. ERM and EH conducted the clinical evaluation during the 8 years of study. HPH and ERM conducted the clinical evaluation during the treatment pause. UMS performed the assessments of glomerular filtration rate. All authors participated in the interpretation of the results and reporting.

Funding: ERM was funded by a senior research fellowship from the University of Copenhagen. Steno Diabetes Center supplied us with equipment for glomerular filtration analysis and laboratory tests. Squibb donated the tablets and a 1 month research fellowship for ERM.

Competing interests: None declared.

[1] Mathiesen ER, Hommel E, Giese J, Parving H-H. Efficacy of captopril in postponing nephropathy in normotensive insulin dependent diabetic patients with microalbuminuria. BMJ 1991;303:210-6.

[2] Viberti G, Mogensen CE, Groop LC, Pauls JF. Effect of captopril on progression to clinical proteinuria in patients with insulin dependent diabetes mellitus and microalbuminuria. JAMA 1994;271:275-9.

[3] Laffel LMB, McGill JB, Cans DJ. The beneficial effect of angiotensin-converting enzyme inhibition with captopril on diabetic nephropathy in normotensive IDDM patients with microalbuminuria. Am J Med 1995;99:497-504.

[4] Levey AS, GassmanJ, Hall PM, Walker WG. Assessing the progression of renal disease in clinical studies: effects of duration of follow-up and regression to the mean. J Am Soc Nephrol 1991;1:1087-94.

[5] Mathiesen ER, Feldt-Rasmussen B, Hommel E, Deckert T, Parving H-H. Stable glomerular filtration rate in normotensive IDDM patients with stable microalbuminuria: a 5 year prospective study. Diabetes Care 1997;20:286-9.

Steno Diabetes Center, DK 2860 Gentofte, Copenhagen, Denmark

Elisabeth R Mathiesen, consultant

Eva Hommel, chief physician

Henrik P Hansen, research fellow

Ulla M Smidt, laboratory technician

Hans-Henrik Parving, professor

Correspondence to: Dr E R Mathiesen, Medical Endocrine Department, University Hospital of Copenhagen, Rigshospitalet, 2100 Copenhagen O, Denmark em@rh.dk

COPYRIGHT 1999 British Medical Association
COPYRIGHT 2000 Gale Group

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