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Biomedical subjects

H Lepor

Publications and source records attributed to H Lepor.

At least 163 records · Page 9Linked to original sources
PubMed1989

Alpha adrenergic antagonists for the treatment of symptomatic BPH.

Benign prostatic hyperplasia (BPH) describes a benign enlargement of the prostate gland that develops in the aging male population. Approximately 50% of 60-year-old men have histologic evidence of BPH. The clinical manifestations of BPH are related entirely to the obstruction of urinary outflow. Benign prostatic hyperplasia produces obstruction to urinary flow by static and dynamic factors. The dynamic component of infravesical obstruction presumably is mediated by the tone of the prostate smooth muscle. Pharmacologic agents that cause relaxation of the prostate may represent an effective therapeutic approach for symptomatic BPH. Organ bath contractile studies have indicated that the contractile properties of prostate adenoma are mediated by alpha1 adrenoceptors. Ten clinical trials evaluating the efficacy of alpha adrenergic blockers for the treatment of symptomatic BPH have been performed in Europe during the past 11 years. Clinical efficacy was observed in 9 of the 10 clinical trials. Randomized, placebo controlled, multicenter clinical trials are currently in progress in the United States to evaluate the efficacy of alpha blockers for the treatment of BPH. Rationale and the clinical experience of alpha adrenergic blockers for the treatment of symtomatic BPH is reviewed in this article.

Adrenergic alpha-Antagonists↗
PubMed1989

The safety and efficacy of terazosin for the treatment of benign prostatic hyperplasia.

The efficacy and safety of terazosin was evaluated in 28 normotensive patients with symptomatic benign prostatic hyperplasia (BPH) ranging in age between 52-72 years. The parameters utilized to assess the efficacy of terazosin included peak and mean urinary flow rate, micturition symptom score and the patients' global assessment of symptomatic improvement. The dose of terazosin was titrated to 5 mg/day over a one-month interval, provided significant adverse drug reactions were not observed. Twenty-two (79%) of the 28 patients completed the terazosin dose-titration study, 5 (18%) were withdrawn owing to adverse drug reactions and 1 (3%) was withdrawn owing to poor compliance. Overall, the mean systolic blood pressure, increased 3 mmHg (3%) and the diastolic blood pressure decreased 1 mmHg (1%). The peak and mean urinary flow rates increased 63% and 61%, respectively. The obstructive and irritative symptom scores decreased 62% and 33%, respectively. The improvements in urinary flow rates and symptom scores were clinically and statistically significant. Overall, 61% of the patients indicated that their voiding symptoms were markedly improved on terazosin and 64% of the participants have elected to voluntarily continue on terazosin indefinitely. In conclusion, terazosin represents a safe and effective treatment for symptomatic BPH.

Adrenergic alpha-Antagonists↗
PubMed1988

The alpha adrenergic binding properties of terazosin in the human prostate adenoma and canine brain.

Clinical trials are currently underway to evaluate the efficacy of terazosin for the treatment of symptomatic benign prostatic hyperplasia (BPH). Terazosin is a potent and selective alpha 1 adrenergic blocking agent structurally similar to prazosin. The alpha adrenergic binding properties of terazosin were studied in human prostate adenomas and canine brains using radioligand receptor binding methods. Saturation analyses were performed at varying concentrations of [125I]-Heat and [3H]rauwolscine [( 3H]Ra) in human prostate adenomas and canine brains. The binding of [125I]-Heat and [3H]Ra in the human prostates and canine brains was consistently saturable and of high affinity. The equilibrium dissociation constant (Kd) for [125I]-Heat binding in the canine brains and human prostate adenomas was 84.4 +/- 4.3 pM and 65.4 +/- 19.2 pM, respectively (p greater than 0.05). The (Kd) for [3H]Ra binding in the human prostate adenomas and canine brains was 1.21 +/- 0.23 nM and 1.52 +/- 0.28 nM, respectively (p greater than 0.05). The density of alpha 1 (0.37 +/- 0.15 fmol/mg. wet wt.) and alpha 2 (0.29 +/- 0.09 fmol/mg. wet wt. adrenergic binding sites in the human adenomas were similar (p greater than 0.05). The IC50 corrected (IC50 corr) of terazosin for [125I]-Heat and [3H]Ra binding sites in the human prostate was 2.5 nM and 1.0 micron., respectively. The IC50 corr of terazosin for [125I]-Heat and [3H]Ra binding sites in the canine brain was 2.0 nM and 0.8 microM, respectively. The competitive binding assays indicate that terazosin binds selectively to alpha 1 adrenergic binding sites in the human prostate and canine brain.

Adrenergic alpha-Antagonists↗
PubMed1988

The effect of electrocautery on neurotransmitter receptor binding assays in the canine prostate.

The purpose of this study was to determine whether resection of the prostate with electrocautery alters the binding properties of various neurotransmitter ligands. Prostate glands were removed from four adult male dogs. The prostates were divided in the midsaggital plane and one half of the prostate was resected using a resectoscope. Saturation experiments were performed on the resected and control prostatic tissue using 3H-NMS, 125I-Heat, and 3H-rauwolscine. The mean equilibrium dissociation constants (Kd) and the mean densities of 3H-NMS, 125I-Heat, and 3H-Rauwolscine binding sites were similar in tissue homogenates obtained from control and resected portions of the prostate (p greater than 0.05). Resection of the prostate using electrocautery did not alter the binding properties of various neurotransmitter ligands for characterizing and quantifying muscarinic cholinergic, alpha 1 adrenergic, and alpha 2 adrenergic binding sites in the canine prostate. Approximately 90% of prostatectomies for symptomatic BPH (benign prostatic hyperplasia) are performed transurethrally. The ability to accurately measure neurotransmitter receptor densities in prostate tissues obtained following transurethral resection is imperative for our future studies designed to elucidate the role of alpha adrenergic receptors in the development of bladder outlet obstruction in men with BPH.

Animals↗
PubMed1988

Transrectal ultrasonography in the diagnosis and staging of carcinoma of the prostate.

Transrectal prostatic ultrasonography is a potentially valuable means to evaluate the prostate of men with suspected carcinoma. We studied 118 patients with this modality before histological evaluation of the prostate (20 underwent radical prostatectomy, 75 core needle biopsy and aspiration cytology, and 23 transurethral resection of the prostate). Transrectal ultrasonography was more efficient than digital rectal examination in the staging of carcinoma of the prostate before radical prostatectomy. The value of transrectal ultrasonography in the diagnosis of prostatic cancer in men with an abnormal-feeling prostate on digital rectal examination is less certain, since 10 of 75 patients (13 per cent) in this group had a falsely positive scan. The predictive value of a scan positive for malignancy was 37 per cent. Further refinements in the technique of transrectal prostatic ultrasonography are needed to realize fully the diagnostic potential of this imaging modality.

Carcinoma↗
PubMed1988

The stereospecificity of LY253352 for alpha 1-adrenoceptor binding sites in the brain and prostate.

1. The stereospecificity of the enantiomers of LY253352, a potent and selective alpha 1-adrenoceptor antagonist, were studied in the human prostate and canine brain using radioligand receptor binding methods. 2. The mean equilibrium dissociation constant (KD) in the canine brain and human prostatic adenoma was 84.4 pM and 65.4 pM, respectively. 3. The alpha 1-adrenoceptor density in the canine brain was approximately eight fold greater than in the human prostatic adenoma. 4. The mean Ki values of (-)-LY253352 and (+)-LY253352 in the prostate were 0.19 nM and 5.79 nM, respectively. 5. The mean Ki values of (-)-LY253352 and (+)-LY253352 in the brain were 0.29 nM and 34.7 nM, respectively. 6. This study indicates that the stereochemical specificity of the optical isomers of LY253352 is a manifestation of differential affinities of the enantiomers for alpha 1-adrenoceptor binding sites. 7. The differential affinities of (+)-LY253352 in the brain and prostate are suggestive of subtle unique properties of adrenoceptor binding sites in these tissues.

Animals↗
PubMed1988

Laboratory assessment of terazosin and alpha-1 blockade in prostatic hyperplasia.

The alpha-1 adrenergic innervation of the human prostate has been studied using radioligand receptor binding methods and in vitro contractile experiments. The density of alpha-1 adrenergic binding sites is of the same order of magnitude as alpha-2 adrenergic and muscarinic-cholinergic (MCh) receptors in the human prostate adenoma. The contractile response of human prostate adenomas to selective alpha-1, alpha-2, and MCh agonists indicated that smooth muscle contraction of the human prostate is mediated by alpha-1 adrenoceptors. The selective affinities of terazosin for alpha-1 and alpha-2 binding sites were determined using competitive displacement assays. Terazosin was shown to have a four hundred-fold greater affinity for alpha-1 binding sites. The concentration of terazosin-inhibiting phenylephrine-induced contractions suggested that terazosin inhibits prostate smooth muscle contraction via alpha-1 adrenoceptors.

Adrenergic alpha-Antagonists↗
PubMed1988

Long-term results of radical prostatectomy in clinically localized prostate cancer: experience at the Johns Hopkins Hospital.

The objectives of our retrospective long-term analysis of radical prostatectomy at The Johns Hopkins Hospital are to determine the efficacy of radical prostatectomy and the optimal statistical method for ascertaining survival following therapeutic intervention for men with clinically localized prostate cancer. The duration of survival and the cause of death were ascertained for 57 men with clinical stage B1 prostate cancer who had radical prostatectomies at The Johns Hopkins Hospital between 1951 and 1963. The absence of metastatic disease was determined by radiographic survey of the bones only. The survival curve determined by the direct method was virtually identical to the projected survival curve for a 62-year-old man in 1960. The cause-specific actuarial survival analysis indicated that only 14% of the men with stage B1 disease and a 15-year life expectancy will develop metastatic prostate cancer following radical prostatectomy. The cause-specific survival curve plateaued after 10 years, which indicated that the majority of men surviving 10 years free of disease are cured of the disease. Survival analysis was also determined by the direct method for 48 men with clinical stage B2 prostate cancer who had undergone radical prostatectomy between 1951 and 1963. Overall, the survival rates for these men were considerably lower than those for similarly treated men with clinical stage B1 disease. The survival curves following radical prostatectomy for men with stage B1 disease and clinical stage B2 disease pathologically confined to the prostate were similar. Radical prostatectomy for stage B1 disease was performed with minimal morbidity, and potency was preserved in most patients with the use of nerve-sparing modifications.(ABSTRACT TRUNCATED AT 250 WORDS)

Humans↗
PubMed1987

The role of radical prostatectomy in the management of prostatic cancer.

The indications for radical prostatectomy must reflect the following: an understanding of the natural history of the disease, the projected life span of the patient, the stage of the disease, and the relative morbidity and efficacy of alternative therapeutic regimens. The integration of clinical stage, histologic grade, and pelvic lymph node evaluation has improved the selection of the ideal candidate for radical prostatectomy. In men with localized disease, there is no evidence that any treatment other than radical prostatectomy produces better control of the primary lesion and of distant metastases than does total surgical excision of the prostate. Recently the morbidity of radical prostatectomy has been reduced by improvements in surgical technique. Intraoperative identification and preservation of the branches of the pelvic plexus that innervate the corpora cavernosa has resulted in long-term postoperative potency rates of 70% without compromising complete excision of the tumor. Thus it appears possible today to preserve sexual function in a majority of patients undergoing radical prostatectomy without compromising the cancer operation, an observation that may encourage more physicians to take greater interest in diagnosing prostatic cancer in young men at a stage when it is still curable.

Adenocarcinoma↗
PubMed1987

Alpha 1 adrenergic receptors in canine lower genitourinary tissues: insight into development and function.

Radioligand receptor binding methods were used to characterize the alpha 1-adrenergic receptor in the bladder body, bladder base, prostate and urethra of the male dog. Saturation experiments were performed in tissue homogenates using [125iodine]-Heat, an alpha 1-adrenergic antagonist of high specific activity (2,200 Ci. per mmol.). The equilibrium dissociation constant Kd for [125iodine]-Heat binding in the bladder body (0.56 pM.), bladder base (0.81 +/- 0.11 pM.), prostate (0.86 +/- 0.19 pM.) and urethra (0.55 pM.) was similar, suggesting homogeneity of alpha 1-adrenergic binding sites in lower genitourinary tissues. The receptor density in the bladder body, bladder base, prostate and urethra, expressed as fmol. per mg. wet weight, was 0.22 +/- 0.02, 0.82 +/- 0.09, 0.55 +/- 0.06 and 0.27 +/- 0.06, respectively (mean +/- standard error of mean). Competitive binding experiments with [125iodine]-Heat and unlabeled prazosin and clonidine confirmed the selectivity of Heat for alpha 1-adrenergic binding sites. Anatomical dissections have revealed that a major component of the smooth muscle of the bladder base and prostate originates from the ureter, whereas a major component of the smooth muscle of the urethra originates from the bladder. The measured alpha 1-adrenergic receptor densities support these developmental theories.

Animals↗
PubMed1987

Identification and characterization of alpha 1 adrenergic receptors in the canine prostate using [125I]-Heat.

We have recently utilized radioligand receptor binding methods to characterize muscarinic cholinergic and alpha adrenergic receptors in human prostate adenomas. The primary advantages of radioligand receptor binding methods are that neurotransmitter receptor density is quantitated, the affinity of unlabelled drugs for receptor sites is determined, and receptors can be localized using autoradiography on slide-mounted tissue sections. Recently, [125I]-Heat, a selective and high affinity ligand with high specific activity (2200 Ci/mmole) has been used to characterize alpha 1 adrenergic receptors in the brain. In this study alpha 1 adrenergic receptors in the dog prostate were characterized using [125I]-Heat. The Scatchard plots were linear indicating homogeneity of [125I]-Heat binding sites. The mean alpha 1 adrenergic receptor density determined from these Scatchard plots was 0.61 +/- 0.07 fmol/mg. wet wt. +/- S.E.M. The binding of [125I]-Heat to canine prostate alpha 1 adrenergic binding sites was of high affinity (Kd = 86 +/- 19 pM). Steady state conditions were reached following an incubation interval of 30 minutes and specific binding and tissue concentration were linear within the range of tissue concentrations assayed. The specificity of [125I]-Heat for alpha 1 adrenergic binding sites was confirmed by competitive displacement assays using unlabelled clonidine and prazosin. Retrospective analysis of the saturation experiments demonstrated that Bmax can be accurately calculated by determining specific [125I]-Heat binding at a single ligand concentration. [125I]-Heat is an ideal ligand for studying alpha 1 adrenergic receptors in the prostate and its favorable properties should facilitate the autoradiographic localization of alpha 1 adrenergic receptors in the prostate.

Animals↗
PubMed1987

Alpha 2 adrenergic receptors in canine prostate: biochemical and functional correlations.

The sympathetic innervation of human prostate adenomas has been previously demonstrated using fluorescence microscopy and in vitro isometric studies. A clinical implication of these observations is that bladder outlet obstruction in men with benign prostatic hypertrophy may be subject to pharmacologic manipulation using adrenergic drugs. Randomized clinical trials have demonstrated the efficacy of alpha adrenergic antagonists for symptomatic BPH. We have previously characterized the alpha1 and alpha2 adrenergic receptors in the human prostate using [3H]prazosin and [3H]rauwolscine, respectively. The mean alpha1 and alpha2 receptor densities in the adenomas studied were equivalent. The effect of alpha2 adrenergic drugs on prostatic urethral pressure has not been examined in the human or in an animal model. In this study a canine model was used to define the effect of alpha2 drugs on prostatic urethral pressure. Intravenous administration of clonidine, a selective alpha2 agonist, resulted in a dose dependent increase in prostatic urethral pressure. The maximal increase in urethral pressure ranged between 18 to 30 cm. H2O. The maximal response to clonidine was approximately 50% less than the response to epinephrine, indicating that clonidine acts as a partial agonist. Pretreatment with yohimbine, a selective alpha2 adrenergic antagonist, abolished the effects of clonidine and epinephrine. The alpha2 adrenergic receptors were then studied in the canine prostates using [3H]rauwolscine. The equilibrium dissociation constant, Kd, ranged between 0.68 to 1.80 nM and the receptor density ranged between 14.8 to 69.3 fmol./mg. protein. The receptor density was homogeneous in specimens obtained from the proximal, midportion, and distal canine prostate suggesting that the effect of alpha2 drugs is not sphincter mediated. These in vitro and in vivo studies provide the basis for investigating the effects of alpha2 antagonists in men with symptomatic BPH.

Adrenergic alpha-Agonists↗
PubMed1986

Alpha 2 adrenergic receptors in hyperplastic human prostate: identification and characterization using [3H] rauwolscine.

[3H]Rauwolscine ([3H]Ra), a selective ligand for the alpha 2 adrenergic receptor, was used to identify and characterize alpha 2 adrenergic receptors in prostate glands of men with benign prostatic hyperplasia. Specific binding of [3H]Ra to prostatic tissue homogenates was rapid and readily reversible by addition of excess unlabelled phentolamine. Scatchard analysis of saturation experiments demonstrates a single, saturable class of high affinity binding sites (Bmax = 0.31 +/- 0.04 fmol./microgram. DNA, Kd = 0.9 +/- 0.11 nM.). The relative potency of alpha adrenergic drugs (clonidine, alpha-methylnorepinephrine and prazosin) in competing for [3H]Ra binding sites was consistent with the order predicted for an alpha 2 subtype. The role of alpha 2 adrenergic receptors in normal prostatic function and in men with bladder outlet obstruction secondary to BPH requires further investigation.

Binding, Competitive↗
PubMed1985

Down regulation of the muscarinic cholinergic receptor of the rat prostate following castration.

Prostatic secretion is dependent upon the integrity of the endocrine and autonomic nervous systems and is dramatically influenced by muscarinic cholinergic analogs. In this study, we have used radioligand receptor binding methods on whole tissue homogenates and slide mounted tissue sections of rat prostate to determine whether androgens regulate the density of muscarinic cholinergic receptors in the prostate. The muscarinic cholinergic receptor binding affinities (Kd) of [3H] N-methylscopolamine in prostatic homogenates obtained from intact, castrate, and castrate rats receiving testosterone replacement (castrate + T) were similar (0.07 to 0.10 nM). The muscarinic cholinergic receptor binding capacity decreased 73 per cent following castration. Testosterone administration restored the density of muscarinic cholinergic receptors in castrate rats to intact levels. In order to ensure that the loss of receptor density was not due to a decrease in the epithelial: stromal cell ratio, the number of muscarinic cholinergic receptors per unit area of epithelium was determined in the 3 treatment groups using autoradiography on slide mounted tissue sections. The density of muscarinic cholinergic receptors in a unit area of epithelium was decreased 91 per cent following castration. Testosterone administration restored the density of muscarinic cholinergic receptors in the castrate rats to intact levels. The modulation of neurotransmitter receptors by steroid hormones may be a mechanism by which sex steroids regulate biological responsiveness of target tissues.

Androgens↗
PubMed1985

Muscarinic cholinergic receptors in bladder exstrophy: insights into surgical management.

The surgical management of classical bladder exstrophy (functional bladder closure or urinary diversion) should be influenced by the inherent detrusor function of the exstrophied bladder. Cystometrograms performed previously on individuals with successful exstrophy closures demonstrate normal bladder function. The biochemical and neurophysiological properties of the exstrophied bladder have otherwise not been investigated. In this study radioligand receptor binding techniques were used to compare the density and equilibrium dissociation constant of muscarinic cholinergic receptors in control and exstrophy bladders. The density of muscarinic cholinergic receptors in the control and exstrophy groups was 1.97 plus or minus 0.29 and 1.44 plus or minus 0.21 fmol. per microgram deoxyribonucleic acid (mean plus or minus standard error of mean), respectively. The dissociation constant of the control and exstrophy groups was 0.15 plus or minus 0.02 and 0.14 plus or minus 0.02 nM. (mean plus or minus standard error of mean), respectively. These data show that the muscarinic receptor density and binding affinity in control and exstrophy bladders are similar. Therefore, the neurophysiological composition of the exstrophied bladder is not grossly altered during the anomalous development.

Bladder Exstrophy↗
PubMed1985

Precise localization of the autonomic nerves from the pelvic plexus to the corpora cavernosa: a detailed anatomical study of the adult male pelvis.

The anatomical location of the branches of the pelvic plexus that innervate the corpora cavernosa has been identified previously in stillborn male neonates and fetuses. Based upon these observations, the techniques of radical retropubic prostatectomy and cystectomy have been modified to avoid injury to the autonomic innervation of the corpora cavernosa. However, the exact anatomical relationships of these nerves to the prostate, urethra and other pelvic structures in adults are unclear, since the initial anatomical studies of the pelvic plexus were performed in stillborn neonates in whom the accompanying vessels and fascia had been removed. Because these nerves are microscopic in size and can only be identified by their association with other pelvic structures, it was believed that a more refined understanding of the anatomy was necessary. In an effort to identify precisely the relationship of the cavernous branches of the pelvic plexus to the lateral pelvic fascia and the branches of the prostatovesicular arteries and veins, the following study was performed. Shortly after death a 60-year-old man was perfused completely with Bouin's fixative solution. The entire bladder, prostate, urethra, penis, corpora cavernosa, rectum, and pelvic sidewall fascia and musculature were removed en bloc. The specimen was serially sectioned transversely at 10 mu thickness, and every tenth section was stained with hematoxylin and eosin. An anatomical reconstruction in 3 dimensions was performed and illustrated. Thus, the specific location of the nerves that innervate the corpora cavernosa and their important relationships to the urethra, prostatic capsule, Denonvilliers' fascia and pelvic floor vasculature have been identified.

Autonomic Nervous System↗
PubMed1984

The inheritance of the exstrophy-epispadias complex.

The inheritance pattern of the exstrophy-epispadias complex was investigated by a combined literature review and a survey of the personal experience of pediatric urologists in North and South America, and Europe. Bladder exstrophy recurred in only 9 of approximately 2,500 families (1 in 275) with bladder exstrophy or complete epispadias. The recurrence of the exstrophy-epispadias complex in offspring of parents with bladder exstrophy or complete epispadias has never been described previously. We identified 215 offspring produced by parents with bladder exstrophy or epispadias, and bladder exstrophy was inherited in 3 of the offspring (1 in 70 live births). The recurrence of bladder exstrophy in offspring of parents with the exstrophy-epispadias complex is greater than previously assumed.

Abnormalities, Multiple↗