Efficacy of once-a-day terazosin in benign prostatic hyperplasia: a randomized, double-blind placebo-controlled clinical trial.

This randomized, placebo-controlled, double-blind study was performed to evaluate the efficacy and safety of once-a-day terazosin (10 mg/day) in ambulatory patients (n = 57) with benign prostatic hyperplasia (BPH). After a 4-week placebo lead-in and a 24-week treatment period with terazosin (both single-blind), 30 patients who responded to terazosin were randomly assigned to either the terazosin or placebo treatment group for 12 weeks. During the single-blind treatment period, the peak urine flow rate increased 54% from a baseline average of 7.76 ml/sec to 11.92 ml/sec after terazosin; the mean flow rate increased 55% from a baseline of 4.90 ml/sec to 7.59 ml/sec; and the residual volume decreased 56% from 93.1 ml to 40.7 ml. The mean obstructive symptom score, irritative symptom score and physician's global assessment score improved by 68%, 34% and 27%, respectively. All these changes were significant (P less than 0.05) when compared to baseline values. During the double-blind period, the improvement in all the variables was sustained in the terazosin group but not in the placebo group. Peak and mean urinary flow rates, and physician's global assessment showed significant (P less than or equal to 0.05) differences at the end of the double-blind period. Adverse events occurred only during the single-blind period. The most frequent were headache (n = 6), asthenia (n = 3), and hypotension (n = 3). In summary, terazosin administered once-a-day improved the obstructive and irritative symptoms of BPH, urine flow rates and residual volume. Terazosin was well tolerated.

Effects of terazosin in the treatment of benign prostatic hyperplasia. A pilot study.

Several reports in the literature suggest that alpha-receptor blockade may have therapeutic value in treating the symptoms of patients with benign prostatic hyperplasia (BPH). Terazosin (Heitrin, Hytrin) is a long acting, highly selective alpha 1-adrenergic blocking agent structurally similar to prazosin. The present study, which also can be regarded as a pilot study, was undertaken as part of a multicenter study to evaluate the safety and efficacy of terazosin in the treatment of patients with BPH. This article presents the results with terazosin in the first 15 patients who completed a dose-ranging, non-comparative single-blind study. These preliminary results confirm that terazosin significantly improved peak as well as mean urine flow rates and significantly reduced residual volume and significantly improved obstructive symptoms in patients with benign prostatic hyperplasia (p less than 0.001). The results of this study support the conclusion that terazosin is beneficial for treatment of symptoms in patients with BPH.

Clinical experience: symptomatic management of BPH with terazosin.

Several reports in the literature have suggested that alpha-receptor blockade may have therapeutic value in treating the symptoms of patients with benign prostatic hypertrophy (BPH). Terazosin is an alpha-1 adrenergic blocking agent currently marketed as an antihypertensive. A multicenter study to evaluate the safety and efficacy of terazosin in the treatment of patients with BPH was initiated. Preliminary results in 15 patients showed that terazosin significantly improved peak as well as mean flow rates, and improved obstructive symptoms in patients with BPH (P less than 0.001). The results at four months of a six-month study support the conclusion that terazosin is beneficial for treatment of symptoms in patients with benign prostatic hypertrophy.

[Drug therapy of metastasizing prostate carcinoma with special reference to the bioavailability of fosfestrol after oral administration]. / Medikamentöse Therapie des metastasierenden Prostatakarzinoms unter besonderer Berücksichtigung der Bioverfügbarkeit von Fosfestrol nach oraler Gabe.

Prostata cancer is one of the most dangerous tumours occurring in the older man. No general accepted therapy has existed up to now. In this study we were engaged on the pharmacokinetics of fosfestrol (Honvan) after oral administration. Its active principle is E-diethylstilbestrol (E-DES), the main metabolite. 250-1600 ng/ml E-DES are measurable after 60-110 min in the plasma of 11 patients suffering from metastatic prostata cancer who have been administered 360 mg fosfestrol orally. This range is equivalent to E-DES concentrations in plasma of 1-4 x 10(-6) mol/l. Thus that E-DES concentration range (5 x 10(-6) mol/l) is nearly attained for a short time to the concentration which hinders the mitosis of human breast cancer cells. Surprisingly similar but not higher concentration - time courses may be measured after a bolus infusion of 360 mg fosfestrol (lasting 45 min). Furthermore, E-DES-glucuronide, E-DES-sulphate and the mixed E-DES-glucuronide-sulphate could be observed in plasma after oral administration. In spite of the high sensitivity of the analytical method (limit of detection for fosfestrol 0.1 micrograms/ml and for E-DES and its mono-conjugates 2-5 ng/ml) neither fosfestrol nor E-DES-monophosphate are detectable in plasma due to the biotransformation of fosfestrol, which is already metabolized by the enzymes of the gut wall. Both phosphates only exist in plasma after intravenous infusion. Further investigations are linked with the question if phase II-conjugates of E-DES can eventually be prodrugs delivering E-DES by cleavage of the ester bonds.

[Lectin binding in immunohistologically AFP/HCG positive and negative testicular carcinoma]. / Lektinbindung bei immunhistologisch AFP/HCG-positiven und -negativen Hodenkarzinomen (Mit 1 Farbtafel).

The morphologic display of testicular cancer is a heterogenous cellular pattern. A biological heterogeneity is also true for the expression of tumor markers. The biosynthesis of tumor marker proteins alpha-fetoprotein (AFP), ferritin, Schwangerschaftsprotein (SP 1) glycoprotein, tissue polypeptide antigen and of hormones (beta-human chorionic gonadotropin (HCG) = significantly present in nonseminoma germ cell tumors--does, however, define only a small number of cancer cells. To better visualize the majority of cancer cells, lectin binding was studied. During the oncogenic transformation a distinct change of cell membrane glycoproteins has been observed. Reactions of WGA/PNA lectins which get attached to glycoproteins with cancer tissue sample from seminomas (n = 20) and nonseminomas (n = 20) were analyzed. The results were correlated to AFP/beta-HCG positive (negative) immunohistology to establish further subgroups of biological homogeneity. The binding of WGA lectin appears relatively more frequent in both seminoma and nonseminoma than that of PNA. Lectin binding of WGA and/or PNA can be stained in 3/11 AFP- and beta-HCG-negative nonseminoma tissues while lectin staining is positive in 7/18 beta-HCG-negative seminomas. The fact that lectin binding is dependent on the spermatozoogenesis and on androgens in normal testis tissues asks for more detailed studies in this field.

Quantification of alpha-fetoprotein and beta-HCG in testis tumor patients.

Patients with testis tumor were investigated for serum and tissue levels of alpha-fetoprotein and beta-human chorionic gonadotropin (beta-HCG). The tissue immune peroxidase-antiperoxidase staining for the tumor marker was quantitated by computer-assisted immunohistophotometry and immuno-gamma ray histospectrometry. The results supported the general view that mostly polynuclear giant cells produce beta-HCG in 66% of nonseminoma cancer. This finding qualifies beta-HCG as relatively unspecific in the absence of chorioepithelial cells in the tumor. Discrepancies of tissue and serum beta-HCG values may be caused by deglycolysation of beta-HCG while penetrating the perivascular tissues. Alpha-fetoprotein (AFP) appears helpfully to discriminate the true seminoma cancer, which is constantly negative. Histologically pure seminoma which reacts for AFP therefore suggests sclerotic teratoma compartments. A constant finding is the significantly reduced synthesis rate of tumor markers in metastasis compared to primary tumor.

[Plasma concentrations of fosfestrol as well as diethylstilbestrol on their conjugates following intravenous administration on prostatic carcinoma patients]. / Plasmakonzentrationen von Fosfestrol sowie von Diethylstilbestrol und seinen Konjugaten nach intravenöser Gabe an Prostatakarzinom-Patienten.

After the identification of E-diethylstilbestrol (DES)-glucuronide-sulphate-bis-conjugate in the plasma of patients suffering from metastatic prostatic cancer for the first time we have registered the plasma concentration-time curves of fosfestrol (Honvan) and its monophosphate as well as E-DES and its 3 conjugates over 8 h with a further 10 patients. Maximum concentrations fluctuate between 1 and 32 micrograms/ml plasma. Therefore the greatest amount of E-DES formed by hydrolysis and its conjugates are hidden in deeper compartments, probably in the lung. The oxidative metabolism of E-DES compared with its conjugation reactions is less important. Only E-DES monoglucuronide and small amounts of E-DES-glucuronide-sulphate-bis-conjugate are detectable in urine. Renal excretion of those metabolites which are in the enterohepatic circle in form of E-DES-glucuronide and E-DES-glucuronide-sulphate-bis-conjugate could be observed even over a period of 72 h.

[Direct determination of diethylstilbestrol and its monoconjugates in plasma]. / Direkte Bestimmung von Diethylstilbestrol und seinen Monokonjugaten im Plasma.

Direct Determination of Diethylstilbestrol and its Monoconjugates in Plasma After "homogeneous ion pair extraction" with CH3OH from plasma of patients suffering from metastatic prostate cancer and subsequent partitioning on a C18-phase diethylstilbestrol (E-DES) and its monoconjugates (glucuronide, sulfate) as well as its glucuronide-sulfate conjugate may be detected quantitatively by HPLC/UV (236 nm) or HPLC/ED (+1.0 V). Working electrode is a special home-made carbon paste electrode. The range of detection is in the low ng range (2-5 ng/ml plasma); standard deviation is less than 5%. It is the first time that plasma levels of these metabolites of fosfestrol (Honvan) could be measured directly without prior hydrolysis.

Some aspects of clearance of mitoguazone in cancer patients and experimental cancer models.

Mitoguazone (methylglyoxal-bis(guanyl-hydrazone), MGBG) was studied by its first-pass mechanism in both cancer patients and experimental cancer models. It appears from the study that 90% of MGBG is cleared from the plasma within minutes. 24-h recovery in the urine, however, did not exceed 16% so that 84% of the drug seems to be bound to subcellular compartments. Tissue levels of MGBG in the normal prostate ranged higher than in experimental prostate cancer type 3327 M/G, i.e. enhanced clearance from cancer tissues: polyamine biosynthetic enzymes ornithine decarboxylase as well as S-adenosylmethionine decarboxylase are contrarily affected by MGBG.

[Therapy with inhibitors of polyamine biosynthesis in refractory prostatic carcinoma. An experimental and clinical study]. / Therapie mit Inhibitoren der Polyaminbiosynthese beim refraktären Prostatakarzinom. Eine experimentelle und klinische Studie.

Transplantable prostate adenocarcinoma were treated with polyamine biosynthetic inhibitors. alpha-difluoromethylornithine (alpha-DFMO), an inhibitor of ornithine decarboxylase and by s-methylglyoxal-bisguanylhydrazone (MGBG), an inhibitor of s-adenosylmethionine decarboxylase. The therapeutic regimen of 0.8-1.11 g/kg DFMO reduced the tumor growth by 40% whilst the combination with 10.5 mg/kg MGBG completely destroyed the prostate adenocarcinomas in the tumor-bearing animals. The polyamine content of spermidine and spermine in the cancerous tissues is significantly lower whereas the putrescine levels remain unchanged. The MGBG therapy distinctly stimulates the activity of ornithine decarboxylase and increases the putrescine concentration up to toxic levels. The application of alpha-DFMO prevented the toxic accumulation of putrescine and allowed higher doses of MGBG. Clinical trials with polyamine antimetabolites appeared useful due to pathological polyamine excretion of patients with metastatic prostate cancer. The therapy with 0.2-0.3 g/kg DFMO in patients with hormone-resistent prostate cancer and metastasis displayed a moderate anti-tumor activity following 2 months additional treatment. High levels of side effects, however, were registered and were similar to those of other cytotoxic compounds. A combined therapy with DFMO/MGBG in a patient with metastatic anaplastic prostate cancer did not improve the survival rate but showed regressive effects of the histological pattern.

[Polyamines, polyamine antimetabolites and urogenital tumors. State of research and clinical results]. / Polyamine, Polyaminantimetaboliten und urogenitale Tumoren. Stand der Forschung und klinische Ergebnisse.

The polyamine metabolism is pathologically changed in tumor tissues, and especially putrescine and spermidine demonstrate abnormally high values in kidney, bladder, and prostate cancer. The inductive processes which activate the biosynthetic polyamine enzymes in cancer are completely unknown. Of therapeutic interest is the fact that increased enzyme activities through irreversible inhibitors become significantly reduced, which consequently slows the tumor growth. Experimental therapy, especially in transplantable bladder and prostate cancer, displayed a 50% tumor destruction. In clinical studies using inhibitors of the polyamine biosynthesis, the dose had to be significantly reduced because of expressed toxicity. Additional investigations which tried a combination of reversible and irreversible inhibitors proved a similar antitumor activity, but less severe side effects.

Chemotherapy and trace element levels in blood and tissue of rats implanted with prostate tumor cells.

Male Copenhagen rats with transplanted prostatic adeno-carcinoma were treated with different polyamine synthesis inhibitors, such as methylglyoxal-bis-guanylhydrazone (MGBG), erythro-9-(2-hydroxy-3-nonyl) adenine (EHNA) combined with 9-ß-D-arabin-ofuranosyl-adenine (ARA-A), α-difluoromethyl-ornithine (DFMO), and some of their combinations. Levels of the essential trace elements-copper, zinc, magnesium, iron, selenium, and manganese -have been determined in blood, tumor, kidney, and liver of these animals and are discussed in terms of efficiency of the treatment. MGBG had the strongest effect on trace element levels in tissues of treated animals. MGBG combined with DFMO exhibited the highest antitumor activity of all treatment protocols. Selenium given as selenite with drinking water was used as an adjuvant with the most toxic combination, (ARA-A/EHNA, MGBG). Selenite reduced the toxicity of these therapeutic agents.

[Plasma levels of fosfestrol and its monophosphate, of diethylstilbestrol and its monoglucuronide following intravenous administration in patients with metastatic prostatic carcinoma]. / Plasmaspiegel von Fosfestrol und seinem Monophosphat, von Diethylstilbestrol und seinem Monoglucuronid nach intravenöser Gabe bei Patienten mit metastasierendem Prostatakarzinom.

A homogeneous ion pair extraction technique enables the nearly quantitative isolation of fosfestrol (1) (Honvan) and up till now of three of its metabolites from the plasma of patients suffering from metastatic prostata cancer. The detection occurs by HPLC with UV-detector. The range of detection is in the lower microgram range. It is the first time that plasma levels of 1 and its monophosphate (2) can be measured.

Some effects of inhibitors of polyamine synthesis on experimental prostatic cancer.

Difluoromethylornithine (DFMO) and methylglyoxal-bis(guanyl-hydrazone) (MGBG), inhibitors of ornithine decarboxylase (ODC) and S-adenosylmethionine decarboxylase (AMDC), respectively, were tested in two experimental prostatic cancer models. DFMO resulted in a reduction in tumor size in both the rapidly growing R-3327 rat prostatic adenocarcinoma (30.5 +/- 15 versus 61 +/- 9.5 in control animals) and the human DU-145 adenocarcinomas (1.7 ml versus 3.3 ml in control animals) in nude mice. MGBG was tested only in the rat tumor, where it induced a reduction of 22.9 +/- 9.5 ml versus 61 +/- 9.5 in control animals in tumor size but was highly toxic. Flutamide or 9-B-D-arabinofuranosyladenine (Ara-A) proved ineffective per se in reducing tumor growth of the human DU-145 or of the R-3327-G strain, respectively, but increased the efficacy of DFMO against the DU-145 tumor had a high level of ODC which was reduced by DFMO of by Ara-A; the R-3327 tumor had a low level of ODC which was too low to be decreased by DFMO.

Na-tartrate in the treatment of chronic nonbacterial prostatitis.

In an open investigation 20 patients with a history of chronic abacterial prostatitis (24 month duration) and of multiple therapies were treated by 0.07-0.15/kg Na-tartrate. Na-tartrate, a known inhibitor of the prostatic fraction of acid phosphatase in laboratory studies, was given orally for 12 weeks after dissolution in fluids and well tolerated. 13 patients completed the study and 3 spermiograms at 6 weeks interval were performed. 11/13 patients demonstrated increased sperm count (44.5 +/- 26.4 leads to 55.06 +/- 34.7) elevated seminal prostatic phosphatase (727 +/- 114.7 leads to 810.8 +/- 55.7) and improved seminal testosterone (2.86 +/- 1.6 leads to 4 +/- 1.4) while seminal y-GT was not significantly changed. Polyamine excretion showed a distinct elevation for putrescine 17.7 +/- 5.3 leads to 28.5 +/- 6.8. Clinically the 11 from 13 patients presented with marked improvement in a 4 months follow-up.

Antigrowth effect of some inhibitors of polyamine synthesis on transplantable prostate cancer.

Inhibitors of polyamine synthesis were tested for therapeutic effectiveness on transplantable prostate cancer. Inhibition of either ornithine decarboxylase or S-adenosyl-L-methionine decarboxylase (AMDC) by alpha-difluormethylornithine (DFMO) or methylglyoxal-bis[guanylhydrazone] (MGBG), respectively, was associated with significant antitumor effect. The combination of DFMO with MGBG was not only more effective but no more toxic than MGBG alone. Combination of MGBG with 9-B-D-arabinofuranosyladenine, an indirect effector of SAMDC, failed to increase therapeutic effectiveness of MGBG.

Experimental chemotherapy in a transplantable renal adenocarcinoma. I: Effects of some inhibitors of polyamine synthesis.

Difluoromethylornithine (DFMO) and methylglyoxal bis (guanylhydrazone) (MGBG), inhibitors of ornithine decarboxylase (ODC) and S-adenosylmethionine decarboxylase (AMDC), respectively, were tested for antitumor activity in the BALB/C mouse renal adenocarcinoma model, wherein ODC and AMDC activity are elevated compared to the normal kidney. Additionally, an indirect effector of AMDC synthesis, arabinofuranosyladenine and an inhibitor of AMDC synthesis, cycloleucin (CL), were tested in this model. Simultaneous administration of both DFMO and MGBG affected the growth of renal adenocarcinoma less than did administration of DFMO or MGBG alone. Combinations of inhibitors of polyamine synthesis demonstrated a high toxicity with low therapeutic activity. The most effective tumor suppression was observed with CL alone but associated toxicity was severe. Suramin, an ODC stimulator, may have enhanced tumor growth.

[Thyroid hormones in metastasizing prostate cancer treated with polyestradiol phosphate]. / Schilddrüsenhormone beim metastasierenden Prostatakarzinom unter Polyoestradiolphosphat.

Patients with prostate cancer demonstrate a significant change in thyroid hormones when treated with estrogens after orchiectomy. Low-dose estrogen treatment for more than six months stimulates the synthesis of thyroxine-binding globulin. As a consequence, serum level of thyroxine is also increased. Serum free thyroxine is distinctly lowered by estrogen treatment while the linear ratio of thyroxine and free thyroxine is disturbed.