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PubMed1996

[Treatment of hyperandrogenemia].

Various kinds of non-hormonal or hormonal treatment of hirsutism with the description of medication effect spot, clinical effect and possible complications are described. The necessity for carrying out this therapy in combination with cosmetic interventions because of aesthetical reasons, as well as possible effect of androgenic hormones on subsequent fertility are emphasized. The effects of contraceptives, corticosteroides, spironolactones, ketoconazoles, GnRH agonists, flutamides, finasterides, somatostatine analogues, H2 receptors blockers, thyroid gland hormones and cyproterone acetates are shown.

Female↗

PubMed1996

[Current drug therapy of benign prostatic hyperplasia].

Almost 60% of elderly men suffer from symptoms of BPH, which have significant impact on their daily lives. Transurethral resection of the prostate (TURP) is currently the most effective therapy for relieve of obstruction and obstructive symptoms. Morbidity of TURP and disappointing results in patients with mild or moderate symptoms make surgery not suitable for all patients. 2 groups of drugs were currently developed, and showed efficacy in double-blinded placebo-controlled studies: alpha-blocking agents and 5 alpha-reductase inhibitors. Inhibition of alpha-adrenoreceptors significantly increases urinary flow rates and improves symptoms of BPH. Long-acting drugs, who selectively block alpha 1-adrenoreceptors (terazosin, doxazosin, tamsulosin) have the advantage, when compared with non-selective-alpha-blockers, that they have generally less adrenergic side effects. After intake alpha-adrenorceptor antagonists develop almost immediate action. 5 alpha-reductase inhibitors (finasteride) reduce prostatic size by 27%, they increase urinary flow rates and improve prostatic symptom scores, whilst adverse effects are extremely low. Full medical action is after 4 to 6 weeks. Both, alpha-Blockers and 5 alpha-reductase inhibitors need permanent administration for maintenance of action. Yet, synergistic effects, using their different modes of action have not been demonstrated after application of both drugs. Herbal products have not proved efficacious inspite of singular surprising results in clinical trials, their efficacy to treat BPH related symptoms was classified as placebo alike. Prior to therapy urological diagnosis and exclusion of prostate cancer is mandatory. Pharmacotherapy with alpha 1-adrenoreceptor antagonists and 5 alpha-reductase inhibitors have a place in the management of BPH patients with mild to moderate disease, who are bothered by their symptoms, or for those awaiting or wishing to delay surgery.

5-alpha Reductase Inhibitors↗

PubMed1996

Cancer risk factors for selecting cohorts for large-scale chemoprevention trials.

Many anticipate that application of findings in molecular genetics will help to achieve greater precision in defining high-risk populations that may benefit from chemopreventive interventions. We must recognize, however, that genetic susceptibility, environmental factors, and complex gene-environment interactions are all likely to be risk determinants for most cancers. Cohort studies of twins and cancer indicate that having "identical" genes is generally not a very accurate predictor of cancer incidence. Data from twin studies support the suggestion that environmental factors such as tobacco use significantly influence cancer risk. The complexities of the genetic contribution to disease risk are exemplified by the development of Duchenne muscular dystrophy in only one of monozygotic twin girls, hypothesized to be the result of X chromosome inactivation, with the distribution patterns of the X chromosome being skewed to the female X in the manifesting twin and to the male X in the normal twin. Evidence from transgenic and genetic-environmental studies in animals support the possibility of genetic-environmental interactions. Calorie restriction modifies tumor expression in p53 knockout mice; a high-fat, low-calcium, low-vitamin D diet increases prepolyp hyperplasia formation in Apc-mutated mice; and calorie restriction early in life influences development of obesity in the genetically obese Zucker rat (fafa). Such environmental modulation of gene expression suggests that chemoprevention has the potential to reduce risk for both environmentally and genetically determined cancers. In view of the growing research efforts in chemoprevention, the NCI has developed a Prevention Trials Decision Network (PTDN) to formalize the evaluation and approval process for large-scale chemoprevention trials. The PTDN addresses large trial prioritization and the associated issues of minority recruitment and retention; identification and validation of biomarkers as intermediate endpoints for cancer; and chemopreventive agent selection and development. A comprehensive database is being established to support the PTDN's decision-making process and will help to determine which agents investigated in preclinical and early phase clinical trials should move to large-scale testing. Cohorts for large-scale chemoprevention trials include individuals who are determined to be at high risk as a result of genetic predisposition, carcinogenic exposure, or the presence of biomarkers indicative of increased risk. Current large-scale trials in well-defined, high-risk populations include the Breast Cancer Prevention Trial (tamoxifen), the Prostate Cancer Prevention Trial (finasteride), and the N-(4-hydroxyphenyl) retinamide (4-HPR) breast cancer prevention study being conducted in Milan. Biomarker studies will provide valuable information for refining the design and facilitating the implementation of future large-scale trials. For example, potential biomarkers are being assessed at biopsy in women with ductal carcinoma in situ (DCIS). The women are then randomized to either placebo, tamoxifen, 4-HPR, or tamoxifen plus 4-HPR for 2-4 weeks, at which time surgery is performed and the biomarkers reassessed to determine biomarker modulation by the interventions. For prostate cancer, modulation of prostatic intraepithelial neoplasia (PIN) by 4-HPR and difluoromethylornithine is being investigated; similar studies are being planned for oltipraz, dehydroepiandrosterone, and vitamin E plus selenomethionine. The validation of biomarkers as surrogate endpoints for cancer incidence in high-risk cohorts will allow more agents to be evaluated in shorter studies that use fewer subjects to achieve the desired statistical power.

Animals↗

PubMed1997

Chemoprevention of cancer: review of the literature.

PURPOSE/OBJECTIVES: To explain the concept of cancer chemoprevention, describe chemoprevention trials, and discuss the agents currently under study to lower the incidence of oral premalignancy and head and neck, lung, breast, prostate, and colon cancers. DATA SOURCES: Published journal articles, books, bulletins, monographs, protocols, and professional experience. DATA SYNTHESIS: Chemoprevention is a promising approach to cancer control, and several key agents have been identified that may be able to block carcinogenesis. Phase III chemoprevention trials are being conducted to identify the role of agents (e.g., retinoids, tamoxifen, finasteride, aspirin) in cancer prevention. CONCLUSION: Knowledge of the genetic and hormonal changes that occur during carcinogenesis continues to increase. Agents are being identified that block the development of cancer by arresting carcinogenesis. As more agents are identified and investigated, their importance in chemoprevention is increasing. IMPLICATION FOR NURSING PRACTICE: The goal of nursing care for participants in prevention trials is to promote compliance with the study protocol while supporting optimum quality of life. Through proactive education of participants, family members, and the public and skillful management of side effects, nurses can play an integral part in the success of prevention trials.

Adult↗

PubMed1997

Peptide growth factors: clinical and therapeutic strategies.

The literature contains many accounts of studies in which tumour growth has been accelerated by administration of a particular mitogen and the response then inhibited by co-administration of the corresponding antagonist. Much effort has been focused on the development of cytokine or growth factor antagonists. Like most other cancer therapies, biological therapies will undoubtedly have undesirable toxicities because the proteins they target may not be unique to malignant cells. We reviewed the clinical and therapeutic potential of growth factor agonists and antagonists in some non urologic and urologic diseases. In a recent report we demonstrated that both androgen and antiandrogen treatments enhance the proliferation rate of the hormone-dependent prostate cancer cell line LNCaP, expressing a mutated androgen receptor. Simultaneous treatment with 1 nM R1881 and 100 nM OH-Flutamide, completely counteracted the androgen-induced increase of Epidermal Growth Factor (EGF) levels. Moreover we found that Testosterone, DHT and EGF are mainly concentrated in the periurethral zone in human BPH and long term treatment with Finasteride and with Flutamide modify the distribution and concentration of these factors. Some authors analyzed whether and addition of aurin tricarboxylic acid (ATA) can reduce the growth rate of basic FGF-dependent cells in a manner similar to suramin.

Animals↗

PubMed1997

Biomarker end-points in cancer chemoprevention trials.

Over the last decade, the Chemoprevention Branch, Division of Cancer Prevention and Control, National Cancer Institute, USA, has been developing drugs that will slow or stop the progression to invasive cancer of precancerous (pre-invasive) lesions generally termed 'intraepithelial dysplasia' or 'dysplasia'. Over 40 short-term clinical trials are in progress, testing the following classes of agents on precancerous lesions in the different major organ systems: antimutagens (N-acetylcysteine, oltipraz), antiproliferatives (difluoromethylornithine, dehydroepiandrosterone, selenomethionine), antioxidants (vitamin E, curcumin), anti-inflammatories (aspirin, piroxicam, ibuprofen, sulindac sulfone) and hormonally active agents (tamoxifen in breast ductal carcinoma in situ and finasteride in prostatic intraepithelial neoplasia). Because of the strong practical need to keep so many clinical trials as short-term as possible, certain tissue changes known to be associated with high cancer risk were selected for use as biomarker end-points in the trials, such changes being quantitatively assayed by computer-assisted image analysis. These 'surrogate end-point biomarkers' (SEBs) are based on the individual cellular morphological and functional changes universally used by histopathologists to diagnose the lesion of intraepithelial neoplasia (Riddell, 1984; Boone et al., 1992; Wright et al., 1994). High grades of this lesion precede invasive cancer in the great majority of cases, and therefore SEBs based on them are linked to high cancer risk. Table 1 summarizes some of the short-term clinical trials now being monitored by the Chemoprevention Branch. The SEBs abbreviated 'PPNN' in the figure are: proliferative index (P); ploidy (DNA histogram) (P); nuclear morphometry and chromatin texture (N); and nucleolar size and frequency (N). Computer-assisted image analysis is used to assay these features quantitatively, which gives the SEBs increased objectivity, reproducibility and sensitivity. Further details concerned with cancer chemoprevention trials using SEBs, and their relation to the field of cancer epidemiology, are given below.

Biomarkers, Tumor↗

PubMed1998

Benign prostatic hyperplasia: use of drug therapy in primary care.

Age and normal male androgenic function are the two most well-established risk factors for benign prostatic hyperplasia. Clinical manifestations of BPH may range from minimally bothersome symptoms to urinary retention and renal failure. Digital rectal examination, serum PSA, urinalysis, serum creatinine, and the AUA symptom score are recommended for the initial evaluation. For mild symptoms, watchful waiting may be all that is needed. For severe symptoms, surgical therapy is the most appropriate option. For men with mild to moderate symptoms, less invasive procedures and several pharmacologic therapies have proved to be effective for treating BPH. The pharmacologic therapies include a 5 alpha-reductase inhibitor (finasteride) and three selective alpha-1 blockers (terazosin, doxasozin, and tamsulosin).

5-alpha Reductase Inhibitors↗

PubMed1998

Benign prostatic hyperplasia in older men.

Urinary tract symptoms secondary to benign prostatic hyperplasia (BPH) may adversely affect quality of life in many older men. Evaluation of patients with BPH should be focused on excluding complicating factors such as urinary tract infection, renal dysfunction, and malignancy. Watchful waiting is an appropriate option for men in whom such complicating conditions have been excluded. For those men who elect to be treated, therapy using alpha blockers (terazosin, doxazosin) or 5-alpha reductase inhibitors (finasteride) should be offered initially. Surgical treatment is generally reserved for patients who do not have a sufficient response to medical therapy and those with absolute indications for intervention, such as complete retention, recurrent infection or hematuria, renal insufficiency, and bladder stones.

5-alpha Reductase Inhibitors↗

PubMed1998

Biotransformation of tirilazad in human: 3. tirilazad A-ring reduction by human liver microsomal 5alpha-reductase type 1 and type 2.

Tirilazad mesylate (FREEDOX), a potent inhibitor of membrane lipid peroxidation in vitro, is under clinical development for the treatment of subarachnoid hemorrhage. In humans, tirilazad is cleared almost exclusively via hepatic elimination with a medium-to-high extraction ratio. In human liver microsomal preparations, tirilazad is biotransformed to multiple oxidative products and one reduced, pharmacologically active metabolite, U-89678. Characterization of the reduced metabolite by mass spectrometry and cochromatography with an authentic standard demonstrated that U-89678 was formed via stereoselective reduction of the Delta4 bond in the steroid A-ring. Kinetic analysis of tirilazad reduction in human liver microsomes revealed that kinetically distinct type 1 and type 2 5alpha-reductase enzymes were responsible for U-89678 formation; the apparent KM values for type 2 and type 1 were approximately 15 and approximately 0.5 microM, respectively. Based on pH dependence and finasteride inhibition studies, it was inferred that 5alpha-reductase type 1 was the high affinity/low capacity microsomal reductase that contributed to tirilazad clearance in vivo. In addition, a role for CYP3A4 in the metabolism of U-89678 was established using cDNA expressed CYP3A4 and correlation studies comparing U-89678 consumption with cytochrome P450 activities across a population of human liver microsomes. Collectively, these data suggest that formation of U-89678, a circulating pharmacologically active metabolite, contributes to the total metabolic elimination of tirilazad in humans and that clearance of U-89678 is mediated primarily via CYP3A4 metabolism. Therefore, concurrent administration of therapeutic agents that modulate 5alpha-reductase type 1 or CYP3A activity are anticipated to affect the pharmacokinetics of PNU-89678.

Biotransformation↗

PubMed1998

Cancer chemoprevention. Part 1: Retinoids and carotenoids and other classic antioxidants.

Cancer chemoprevention is the use of specific natural or synthetic substances with the objective of reversing, suppressing, or preventing carcinogenic progression to invasive cancer. Currently, numerous chemopreventive agents are in various stages of development and testing. Part 1 of this two-part series provides an overview of issues unique to chemoprevention trials, including the use of surrogate biomarkers as end points. This is followed by a discussion of the retinoids, such as all-trans-retinoic acid (ATRA [Vesanoid]), 9-cis-retinoic acid (9cRA), and isotretinoin (Accutane), and the carotenoids (e.g., beta-carotene and lycopene) and other "classic" antioxidants (e.g., vitamins E and C and selenium). Research on these agents will be delineated by disease site when applicable. Part 2, which will appear in next month's issue, will focus on hormonally mediated chemopreventive agents, such as tamoxifen (Nolvadex), finasteride (Proscar), oral contraceptives, and dehydroepiandrosterone (DHEA). Part 2 also will cover nonantioxidant natural agents, such as calcium, the polyphenols, the isothiocyanates, and genistein; nonsteroidal anti-inflammatory drugs (NSAIDS), such as celecoxib, sulindac sulfone, and aspirin; difluromethylornithine (DFMO [Eflornithine]); oltipraz; and N-acetylcysteine.

Antineoplastic Agents↗

PubMed1998

Factors related to delayed treatment and posttreatment symptom severity in Taiwanese patients with benign prostatic hyperplasia.

We evaluated the sociodemographic and clinical factors of delayed treatment and posttreatment symptom severity in outpatients with benign prostatic hyperplasia (BPH). The study included 146 BPH patients treated at the National Taiwan University Hospital in early 1997. All patients were treated with alpha-adrenergic antagonists or finasteride for at least 2 weeks. A questionnaire based on Andersen's Health Behavior Model was used to assess various sociodemographic features, while the pre- and posttreatment symptoms severity was rated according to the International Prostate Symptom Score (IPSS). Multiple logistic regression was used to assess the associations of these factors with delayed treatment and posttreatment symptom severity. Subjects who had recently quit smoking or were blue-collar workers tended to delay treatment, while those who chose a medical center as the care provider for chronic diseases tended to be less likely to delay treatment. However, none of these associations were statistically significant. No enabling factors (income, insurance) or need factors (symptom scores) evaluated were associated with delayed treatment. Predisposing factors associated with higher posttreatment symptom severity were delayed treatment (over 12 months) (adjusted odds ratio [OR]: 2.67, 95% confidence interval [CI]: 1.16-6.16), quitting smoking (adjusted OR: 4.47, 95% CI: 1.34-14.94), and having never smoked (adjusted OR: 3.73, 95% CI: 1.15-12.11). Subjects with severe pretreatment symptoms were far more likely than subjects with mild pretreatment symptoms to have severe symptoms after treatment (adjusted OR: 52.69, 95% CI: 54.46-621.90). Our findings, though based on a limited number of subjects, suggest sociodemographic factors rather than objective clinical attributes (prostate specific antigen level, prostate volume, and urodynamic results) are associated with delayed treatment in Taiwanese men with BPH. Both pretreatment symptom severity and sociodemographic factors are related to posttreatment symptom severity.

Adult↗

PubMed1998

Cancer chemoprevention. Part 2: Hormones, nonclassic antioxidant natural agents, NSAIDs, and other agents.

This two-part series provides an up-to-date summary of the various chemopreventive agents currently in development and testing. Part 1, published in last month's issue, focused on the retinoids, such as all-trans-retinoic acid (ATRA [Vesanoid]), 9-cis-retinoic acid (9cRA), and isotretinoin (Accutane), and the carotenoids, such as beta-carotene and lycopene, and other "classic" antioxidants, such as vitamins E and C and selenium. This second part centers on hormonally mediated chemopreventives, such as tamoxifen (Nolvadex), finasteride (Proscar), oral contraceptives, and dehydroepiandrosterone (DHEA). A number of these agents have site-specific mechanisms of action and will be discussed as such. Also discussed in part 2 are various nonclassic antioxidant natural agents, including calcium, the polyphenols, the isothiocyanates, and genistein; nonsteroidal anti-inflammatory drugs (NSAIDS), such as aspirin and sulindac; difluoromethylornithine (DFMO [Eflornithine]); oltipraz; and N-acetylcysteine.

Animals↗

PubMed1999