- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT01409837
The Effect and Safety of Lisinopril in Non-hypertensive Men With Infertility From Low Sperm Count
A 5-year Prospective, Placebo-controlled, Crossover Evaluation of the Efficacy and Tolerability of Low-dose Lisinopril in Normotensives With Idiopathic Oligospermic Infertility
Study Overview
Detailed Description
Introduction. Infertility constitutes the cause for about 16.6% of patients seeking consultations at the primary healthcare level. Male factor infertility accounts for about 50% of all infertility problems. Of this percentage seminal fluid abnormality of unknown cause is common, occurring in up to 60% of males with unexplained, this type of infertility. Although some subjects with seminal fluid defects have fathered children those with infertility have long posed a major therapeutic challenge. The rationale for using the various hormonal and non-hormonal drugs currently available is, at best, empirical as most of the efficacy trials conducted yielded conflicting results. Although assisted fertilization techniques have now increased the number of therapeutic options available to couples with infertility problems there is still a very serious limitation in the access to the new technology, especially in low-income countries. Besides, there are additional concerns regarding the possible untoward effects. These lingering problems underscore the need for continuing to search for other effective treatment options that will not only be cheaper and more accessible but also less complicated and non-invasive.
The current study was occasioned by our previous, independent observations (albeit fortuitous) of normalization of seminal fluid parameters as well as spouse pregnancies in two men with long-standing, idiopathic azoospermia. The common factor between the two men was treatment with low-dose (2.5mg per day) Lisinopril, an angiotensin converting enzyme inhibitor or ACEI prescribed for the concomitant hypertension. A review of the available literature on the efficacy studies of various types of angiotensin converting enzyme inhibitors on sperm count and quality revealed a near-consistent finding of improvement in animal studies. However, methodological flaws have rendered the results in the very scanty human studies extremely difficult to interpret. The current study design was intentionally rigorous; efforts having been consciously made to control for most known confounding factors as far as was possible.
Methods. The study was conducted at the University of Nigeria Teaching Hospital, Enugu. A prior approval of the detailed study protocol was obtained from the Ethics Committee of the same hospital. Each of the patients gave informed consent before enrollment into the study. The investigation was a longitudinal, randomized, double-blind and placebo-controlled clinical trial with a crossover design. The subjects for this investigation were selected from a volunteer pool of male patients attending the fertility clinic of University of Nigeria Teaching Hospital, Enugu. At the time of enrollment each subject was given explicit information about the study with respect to the intention, the expectations from him, the procedure, the planned duration of the investigation, and the potential adverse reactions that could occur from the intended medication. The recruitment of patients took place from March 1998 to September 2001 while the actual study lasted for five years, from January 2002 to December 2006. In strict compliance with the protocol requirement all the participants entered the study within 7 days of starting the onset and they were being followed up concurrently. Throughout the period of the clinical trial the patients mandated to continue their different "background" fertility medications in the same doses as they were being prescribed by their attending fertility physicians. The rationale for this was to avoid the unethical situation whereby a group taking placebo would be denied medication. Conceited efforts were made to exclude subjects with any background medication that had a documented interaction with lisinopril. The apparent superfluity of combining a crossover design (which provides for a within-subjects control) with a separate (between-subjects) control was deliberate. That was done in an effort to control, in one swoop, for two potentially confounding factors; viz., the possible effect on the study out-come of the concurrent background medications, and the possible event of a random, seasonal variation in human seminal fluid characteristics. Throughout the whole period of the study the investigators kept in close touch with the patients by phone calls in order to continually motivate them, remind them of scheduled appointment dates, monitor compliance and detect any possible incidence of adverse drug effect.
Assessment of compliance to the medications: Compliance to the medications was monitored by a combination of oral interviews and physical inspection of medication containers for pill counting. These were done at every scheduled visit, through sporadic phone calls and by unscheduled home visits. The level of compliance of each patient was expressed in percent (%) and calculated as the actual number of doses taken/the expected number of doses multiplied by 100 for the period under consideration.
Adverse events monitoring:
The patients were encouraged to report every event promptly by phone to one of the authors (NOG), no matter however minor and not minding whether related to lisinopril or not. Entries were promptly made and then one of the physicians in the team was detailed to make proper assessment of every reported case and make recommendations with respect to further management and/or the need or otherwise for withdrawal of the patient from the trial. Medical interventions, where needed, were given without any cost to the patients. In addition, the serum potassium concentrations and blood pressures (supine and erect) were measured in every patient at each of the scheduled visits in furtherance of the adverse events monitoring.
Clinical measurements:
Blood pressure measurements were done with mercury sphygmomanometers fitted with adult-size cuffs (Accoson, England) while korotcoffs I and V were used for systolic and diastolic blood pressures respectively. This was because these had given more concordant results among the team members than the traditional I and IV Korotcoffs. The mean arterial blood pressure (MAP) of each patient was calculated using the conventional formula; MAP = [(2 x diastolic) + systolic] divided by 3.
Laboratory measurements:
Seminal fluid for analysis was each time collected by self-masturbation in a room close to the laboratory and submitted promptly to the analysts. The collected semen specimens were incubated at 37 degrees Centigrade and allowed to stand for 1 hour in order to thaw. The pipette method was used for the ejaculate volume while microscopic methods were used for the total sperm cell count, the percentage of sperm cell motility and the percentage of abnormal sperm cell morphology in accordance with the World Health Organization (WHO) guidelines. Serum potassium levels were estimated using the flame photo-metric method as described by Davidson and Henry. The latter was a safeguard against hyperkalemia, a well documented, severe side effect of ACEI therapy.
Statistical analysis:
The statistical analysis was done with the Statistical Package for the Social Sciences version 16 (SPSS - 16) software. All the data analyses were performed on the basis of the intention-to-treat in which last observations after the baseline were carried forward to end point. Prior to the analysis all the parameter data were examined for distributional patterns using the Shapiro-Wilk Normality test. All the seminal fluid data as well as the serum potassium values were found to be skewed and so were normalized with logarithmic transformations. Two-group comparisons were performed using the unpaired Student's t-tests while proportions were compared using the Fisher's Exact tests. The data from longitudinally measured out-come parameters were analyzed using two-way repeated measures (mixed model) analysis of variance (mixed model ANOVA). Bonferroni's post-hoc multiple comparison tests were run wherever a statistically significant difference was found (at p < 0.05) in either the within-subjects means, the between-subjects means or the interaction. The post-hoc tests were done in order to explore further the patterns of within-subjects parameter changes with the duration of treatment in both groups. The unwanted events reported during treatment with lisinopril and during placebo treatment were compared for statistical significance with the Koch's adaptation of Wilcoxon-Mann-Whitney- rank-sum test.
Study Type
Enrollment (Actual)
Phase
- Phase 2
Contacts and Locations
Study Locations
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Enugu, Nigeria, 01129
- University of Nigeria Teaching Hospital, Ituku-Ozalla,
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Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
The subjects for this investigation were selected from a volunteer pool of male patients attending the fertility clinic of University of Nigeria Teaching Hospital, Enugu. The criteria for their selection were:
Inclusion criteria:
- regular attendance and on treatment for low sperm count or oligospermia in the fertility clinic for at least 2 years
- total sperm count at selection from 5 million/ml to 10 million/ml,
- white blood cell (WBC) count less than 1 million per ml of the ejaculate
- evidence of undergone comprehensive investigations to exclude secondary causes of low sperm count, (e) evidence of comprehensive investigations to exclude female factor infertility in the spouse
- an assurance of a personal commitment to continue participating in the study until the end-point was reached and (g) normal blood pressure.
Exclusion criteria:
- Patients who did not give their consent to participate
- did not meet the diagnostic criteria for oligospermia at the time of recruitment
- failed to fulfill any of the above inclusion criteria, even if the diagnostic criteria are fulfilled.
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: Randomized
- Interventional Model: Crossover Assignment
- Masking: Quadruple
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Placebo Comparator: Sugar pill
Started with Placebo until the crossover.
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Experimental: Lisinopril
Started with Lisinopril until the crossover
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The two groups of patients, A and B, were randomly allocated treatments in a double-blind fashion.
Group A was started on the coded drug "DY1" while group B was started on the coded drug "DZ2".
Both "DY1" and "DZ2" were very identical in appearance.
At week 96 the drugs were swopped between the groups such that group A changed to drug "DZ2" while group B changed to drug "DY1".
There was no intervening washout period.
The codes were concealed until after the data analysis.
Other Names:
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What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Changes From Baseline in the Seminal Fluid Characteristics Throughout the Study
Time Frame: Week 96.
|
The seminal fluid characteristics were assessed twice before the entry of each patient and both at least two-weeks apart.
The two values were averaged and recorded as baseline for week 0 while subsequent changes from the baseline were monitored during each of the scheduled visits at weeks 6, 12, 24, 48, 96, 102, 114, 138, 186 and 282.
The two groups swopped treatments at the 96th week.
The number of pregnancies achieved was also documented throughout the study period.
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Week 96.
|
Total Sperm Cell Count Per Milliliter of Seminal Fluid.
Time Frame: Week 96
|
the number of sperm cells counted per milliliter volume of seminal fluid
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Week 96
|
Proportion of Sperm Cells With Normal Motility (%)
Time Frame: Week 96
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This was determined as the proportion (percent) of the total sperm cells exhibiting both rhythmic and propulsive movements considered to be of normal intensity.
|
Week 96
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Proportion of Sperm Cells With Abnormal Morphology (%)
Time Frame: Week 96
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Proportion (per cent) of sperm cells with abnormal appearance
|
Week 96
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Ejaculate Volume
Time Frame: Week 282
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The volume in milliliters of seminal fluid produced per ejaculation.
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Week 282
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Total Sperm Cell Count
Time Frame: Week 282
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The total number of sperm cells found in each milliliter of seminal fluid.
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Week 282
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Proportion of Sperm Cells With Normal Motility (%)
Time Frame: Week 282
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The proportion (per cent) of the sperm cells exhibiting both rhythmic and propulsive movements considered to be of normal intensity.
|
Week 282
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Proportion of Sperm Cells With Abnormal Morphology (%)
Time Frame: Week 282
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The proportion (per cent) of the total number of sperm cell with abnormal appearance.
|
Week 282
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Adverse Events Monitoring
Time Frame: At weeks 6, 12, 24, 48, 96, 102, 114,138, 186 and 282
|
The patients were encouraged to report every event promptly by phone to one of the authors (NOG), no matter however minor.Blood pressure measurements were done with mercury sphygmomanometers fitted with adult-size cuffs (Accoson, England).
Serum potassium levels were estimated using the flame photometric method as described by Davidson and Henry
|
At weeks 6, 12, 24, 48, 96, 102, 114,138, 186 and 282
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Collaborators and Investigators
Investigators
- Principal Investigator: Anthony U Mbah, MD, FMCP, University of Nigeria Teaching Hospital, Ituku-Ozalla, Enugu
Publications and helpful links
General Publications
- Hassa H, Ayranci U, Unluoglu I, Metintas S, Unsal A. Attitudes to and management of fertility among primary health care physicians in Turkey: an epidemiological study. BMC Public Health. 2005 Apr 5;5:33. doi: 10.1186/1471-2458-5-33.
- Safarinejad MR. Infertility among couples in a population-based study in Iran: prevalence and associated risk factors. Int J Androl. 2008 Jun;31(3):303-14. doi: 10.1111/j.1365-2605.2007.00764.x. Epub 2007 May 7.
- Gianaroli L, Magli MC, Cavallini G, Crippa A, Nadalini M, Bernardini L, Menchini Fabris GF, Voliani S, Ferraretti AP. Frequency of aneuploidy in sperm from patients with extremely severe male factor infertility. Hum Reprod. 2005 Aug;20(8):2140-52. doi: 10.1093/humrep/dei033. Epub 2005 Apr 21.
- Cavallini G, Crippa A, Magli MC, Cavallini N, Ferraretti AP, Gianaroli L. A study to sustain the hypothesis of the multiple genesis of oligoasthenoteratospermia in human idiopathic infertile males. Biol Reprod. 2008 Oct;79(4):667-73. doi: 10.1095/biolreprod.107.067330. Epub 2008 Jun 18.
- Vandekerckhove P, Lilford R, Vail A, Hughes E. Clomiphene or tamoxifen for idiopathic oligo/asthenospermia. Cochrane Database Syst Rev. 2000;(2):CD000151. doi: 10.1002/14651858.CD000151.
- Barriere P, Roch M, L'Hermite A, Sagot P, Lopes P, Charbonnel B. [Evaluation of the probability of the occurrence of pregnancy during oligo-astheno-teratospermia]. Rev Fr Gynecol Obstet. 1989 Feb;84(2):101-5. French.
- Belaisch J. [Medical treatment of male infertility]. Rev Prat. 1993 Apr 15;43(8):965-9. French.
- Kumar R, Gautam G, Gupta NP. Drug therapy for idiopathic male infertility: rationale versus evidence. J Urol. 2006 Oct;176(4 Pt 1):1307-12. doi: 10.1016/j.juro.2006.06.006.
- Ghanem H, Shamloul R. An evidence-based perspective to the medical treatment of male infertility: a short review. Urol Int. 2009;82(2):125-9. doi: 10.1159/000200785. Epub 2009 Mar 19.
- Haidl G, Schuppe HC, Kohn FM, Leiber C. [Evidence-based drug therapy for male infertility]. Urologe A. 2008 Dec;47(12):1555-6, 1558-60. doi: 10.1007/s00120-008-1802-6. German.
- Aittomaki K, Wennerholm UB, Bergh C, Selbing A, Hazekamp J, Nygren KG. Safety issues in assisted reproduction technology: should ICSI patients have genetic testing before treatment? A practical proposition to help patient information. Hum Reprod. 2004 Mar;19(3):472-6. doi: 10.1093/humrep/deh100. Epub 2004 Jan 29.
- Dohle GR, Halley DJ, Van Hemel JO, van den Ouwel AM, Pieters MH, Weber RF, Govaerts LC. Genetic risk factors in infertile men with severe oligozoospermia and azoospermia. Hum Reprod. 2002 Jan;17(1):13-6. doi: 10.1093/humrep/17.1.13.
- Mbah AU. Normogonadotrophic, non-obstructive azoospermia: successful treatment of two cases using low-dose lisinopril (Abstract): 24th Annual Scientific Conference of the Association of Physicians of Nigeria. Port Harcourt, 1999.
- Saha L, Garg SK, Bhargava VK, Mazumdar S. Role of angiotensin-converting enzyme inhibitor, lisinopril, on spermatozoal functions in rats. Methods Find Exp Clin Pharmacol. 2000 Apr;22(3):159-62.
- Okeahialam BN, Amadi K, Ameh AS. Effect of lisnopril, an angiotensin converting enzyme (ACE) inhibitor on spermatogenesis in rats. Arch Androl. 2006 May-Jun;52(3):209-13. doi: 10.1080/01485010500398012.
- Somlev B, Subev M. Effect of kininase II inhibitors on bradykinin-stimulated bovine sperm motility. Theriogenology. 1998 Sep;50(4):651-7. doi: 10.1016/s0093-691x(98)00169-1.
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- Auger J, Jouannet P. Age and male fertility: biological factors. Rev Epidemiol Sante Publique. 2005 Nov;53 Spec No 2:2S25-35.
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- Liu M, Deng S, Ma C, Chen A, Jiang Y, Wen R, Wang Q, Tang L, Huang J, Yao X. [Comparison of sperm motion parameters in pre-freeze and post-thaw semen samples using computer-assisted sperm analysis]. Zhonghua Nan Ke Xue. 2004 Jun;10(6):431-3. Chinese.
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- World Health Organization, WHO Laboratory Manual for the Examination of Human Semen and Sperm-Cervical Mucus Interactions. 4th ed. Cambridge, United Kingdom: Cambridge University Press; 1999.
- Clinical diagnosis by laboratory method. Davidson I, Henry JB (eds), ELBS, NewYork, 1979), pp. 340-500.
- SPSS Reference Guide. SPSS Inc. Chicago, IL, U.S.A. 1990
- Chen Y, Wang H, Qi N, Wu H, Xiong W, Ma J, Lu Q, Han D. Functions of TAM RTKs in regulating spermatogenesis and male fertility in mice. Reproduction. 2009 Oct;138(4):655-66. doi: 10.1530/REP-09-0101. Epub 2009 Jul 14.
- Toshimori K, Ito C, Maekawa M, Toyama Y, Suzuki-Toyota F, Saxena DK. Impairment of spermatogenesis leading to infertility. Anat Sci Int. 2004 Sep;79(3):101-11. doi: 10.1111/j.1447-073x.2004.00076.x.
- Mathur V, Murdia A, Hakim AA, Suhalka ML, Shaktawat GS, Kothari LK. Male infertility and the present status of its management by drugs. J Postgrad Med. 1979 Apr;25(2):90-6. No abstract available.
- Karande VC, Korn A, Morris R, Rao R, Balin M, Rinehart J, Dohn K, Gleicher N. Prospective randomized trial comparing the outcome and cost of in vitro fertilization with that of a traditional treatment algorithm as first-line therapy for couples with infertility. Fertil Steril. 1999 Mar;71(3):468-75. doi: 10.1016/s0015-0282(98)00490-7.
- Griffiths A, Dyer SM, Lord SJ, Pardy C, Fraser IS, Eckermann S. A cost-effectiveness analysis of in-vitro fertilization by maternal age and number of treatment attempts. Hum Reprod. 2010 Apr;25(4):924-31. doi: 10.1093/humrep/dep418. Epub 2010 Jan 26.
- Silverberg K, Daya S, Auray JP, Duru G, Ledger W, Wikland M, Bouzayen R, O'Brien M, Falk B, Beresniak A. Analysis of the cost effectiveness of recombinant versus urinary follicle-stimulating hormone in in vitro fertilization/intracytoplasmic sperm injection programs in the United States. Fertil Steril. 2002 Jan;77(1):107-13. doi: 10.1016/s0015-0282(01)02945-4.
- Lee KC. Fertility treatments and the cost of a healthy baby. Nurs Womens Health. 2011 Feb-Mar;15(1):15-8. doi: 10.1111/j.1751-486X.2011.01606.x. No abstract available.
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- Alatri A, Tribout B, Gencer B, Calanca L, Mazzolai L. [Thrombotic risk in assisted reproductive technology]. Rev Med Suisse. 2011 Feb 9;7(281):357-60. French.
- Chan WS. The 'ART' of thrombosis: a review of arterial and venous thrombosis in assisted reproductive technology. Curr Opin Obstet Gynecol. 2009 Jun;21(3):207-18. doi: 10.1097/GCO.0b013e328329c2b8.
- Budev MM, Arroliga AC, Falcone T. Ovarian hyperstimulation syndrome. Crit Care Med. 2005 Oct;33(10 Suppl):S301-6. doi: 10.1097/01.ccm.0000182795.31757.ce.
- Maxwell KN, Cholst IN, Rosenwaks Z. The incidence of both serious and minor complications in young women undergoing oocyte donation. Fertil Steril. 2008 Dec;90(6):2165-71. doi: 10.1016/j.fertnstert.2007.10.065. Epub 2008 Feb 4.
- McNaught J, Reid RL; SOGC/GOC JOINT AD HOC COMMITTEE ON BREAST CANCER. RETIRED: Progesterone-only and non-hormonal contraception in the breast cancer survivor: Joint Review and Committee Opinion of the Society of Obstetricians and Gynaecologists of Canada and the Society of Gynecologic Oncologists of Canada. J Obstet Gynaecol Can. 2006 Jul;28(7):616-626. doi: 10.1016/S1701-2163(16)32195-8. No abstract available. English, French.
- Marmor D, Taillemite JL, Van den Akker J, Portnoi MF, le Porrier N, Joye N, Delafontaine D, Roux C. Semen analysis in subfertile balanced-translocation carriers. Fertil Steril. 1980 Nov;34(5):496-502. doi: 10.1016/s0015-0282(16)45144-7.
- Bourrouillou G, Mansat A, Calvas P, Pontonnier F, Colombies P. [Chromosome anomalies and male infertility. A study of 1,444 subjects]. Bull Assoc Anat (Nancy). 1987 Dec;71(215):29-31. French.
- Miharu N. Chromosome abnormalities in sperm from infertile men with normal somatic karyotypes: oligozoospermia. Cytogenet Genome Res. 2005;111(3-4):347-51. doi: 10.1159/000086909.
- Schill WB, Miska W. Possible effects of the kallikrein-kinin system on male reproductive functions. Andrologia. 1992 Mar-Apr;24(2):69-75. doi: 10.1111/j.1439-0272.1992.tb02613.x.
- Vandekerckhove P, Lilford R, Vail A, Hughes E. Kinin-enhancing drugs for unexplained subfertility in men. Cochrane Database Syst Rev. 2000;(2):CD000153. doi: 10.1002/14651858.CD000153.
- Agusti A, Bonet S, Arnau JM, Vidal X, Laporte JR. Adverse effects of ACE inhibitors in patients with chronic heart failure and/or ventricular dysfunction : meta-analysis of randomised clinical trials. Drug Saf. 2003;26(12):895-908. doi: 10.2165/00002018-200326120-00004.
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- Joshi N, Kodwany G, Balaiah D, Parikh M, Parikh F. The importance of computer-assisted semen analysis and sperm function testing in an IVF program. Int J Fertil Menopausal Stud. 1996 Jan-Feb;41(1):46-52.
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- Roberts M, Jarvi K. Steps in the investigation and management of low semen volume in the infertile man. Can Urol Assoc J. 2009 Dec;3(6):479-85. doi: 10.5489/cuaj.1180.
- Hagaman JR, Moyer JS, Bachman ES, Sibony M, Magyar PL, Welch JE, Smithies O, Krege JH, O'Brien DA. Angiotensin-converting enzyme and male fertility. Proc Natl Acad Sci U S A. 1998 Mar 3;95(5):2552-7. doi: 10.1073/pnas.95.5.2552.
- Esther CR, Marino EM, Howard TE, Machaud A, Corvol P, Capecchi MR, Bernstein KE. The critical role of tissue angiotensin-converting enzyme as revealed by gene targeting in mice. J Clin Invest. 1997 May 15;99(10):2375-85. doi: 10.1172/JCI119419.
- Fuchs S, Frenzel K, Hubert C, Lyng R, Muller L, Michaud A, Xiao HD, Adams JW, Capecchi MR, Corvol P, Shur BD, Bernstein KE. Male fertility is dependent on dipeptidase activity of testis ACE. Nat Med. 2005 Nov;11(11):1140-2; author reply 1142-3. doi: 10.1038/nm1105-1140. No abstract available.
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- Ghanem H, Shaeer O, El-Segini A. Combination clomiphene citrate and antioxidant therapy for idiopathic male infertility: a randomized controlled trial. Fertil Steril. 2010 May 1;93(7):2232-5. doi: 10.1016/j.fertnstert.2009.01.117. Epub 2009 Mar 6.
- Pribylov SA. [Pulmonary hypertension, endothelial dysfunction, and their correction with lisinopril in patients with heart failure in combination of ischemic heart disease and chronic obstructive pulmonary disease]. Kardiologiia. 2006;46(9):36-40. Russian.
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- Lacourciere Y. The incidence of cough: a comparison of lisinopril, placebo and telmisartan, a novel angiotensin II antagonist. Telmisartan Cough Study Group. Int J Clin Pract. 1999 Mar;53(2):99-103.
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Study record dates
Study Major Dates
Study Start
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Estimate)
Study Record Updates
Last Update Posted (Estimate)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Keywords
Additional Relevant MeSH Terms
Other Study ID Numbers
- GHF/GrS/99/S.3
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