Varro E. Tyler

Tissue effects of saw palmetto and finasteride: use of biopsy cores for in situ quantification of prostatic androgens

OBJECTIVES To determine the effects of a saw palmetto herbal blend (SPHB) compared with finasteride on prostatic tissue androgen levels and to evaluate needle biopsies as a source of tissue for such determinations. METHODS Prostate levels of testosterone and dihydrotestosterone (DHT) were measured on 5 to 10-mg biopsy specimens (18-gauge needle cores) in three groups of men with symptomatic benign prostatic hyperplasia: 15 men receiving chronic finasteride therapy versus 7 untreated controls; 4 men undergoing prostate adenomectomy to determine sampling variability (10 specimens each); and 40 men participating in a 6-month randomized trial of SPHB versus placebo, before and after treatment. RESULTS Prostatic tissue DHT levels were found to be several times higher than the levels of testosterone (5.01 versus 1.51 ng/g), that ratio becoming reversed (1.05 versus 3.63 ng/g) with chronic finasteride therapy. The finasteride effect was statistically significant for both androgens (P <0.01), and little overlap of individual values between finasteride-treated and control patients was seen. In the randomized trial, tissue DHT levels were reduced by 32% from 6.49 to 4.40 ng/g in the SPHB group (P <0.005), with no significant change in the placebo group. CONCLUSIONS For control versus finasteride-treated men, the tissue androgen values obtained with needle biopsy specimens were similar-both for absolute values and the percentage of change-to those previously reported using surgically excised volumes of prostatic tissue. The quantification of prostatic androgens by assay of needle biopsies is thus feasible and offers the possibility of serial studies in individual patients. The SPHB-induced suppression of prostatic DHT levels, modest but significant in a randomized trial, lends an element of support to the hypothesis that inhibition of the enzyme 5-alpha reductase is a mechanism of action of this substance.

Plant drugs in the twenty-first century

Lack of effective cooperation among researchers in the applicable biological, physical, and clinical sciences has accounted, in large measure, for the lack of successful development in the United States of any significant number of new plant drugs during the latter part of the 20th century. Unrealistic federal regulations that tend to render unprofitable such research have also played an important role in hindering the development of new plant drugs. It is likely that both of these factors will change in the future as health-conscious consumers demand more accurate information and wider availability of natural drug products. Several anticipated developments will greatly facilitate research and production in this previously difficult area. These include the development of new, simplified bioassay procedures; improved, easily applied analytical methods; and innovative plant-cell-culture methodologies, possibly involving genetic manipulation. The kinds of drugs that need to be developed using such techniques are discussed. It is concluded that significant new plant drugs and new methods of producing them will be developed to serve mankind during the 21st century.

Herbal medicine: from the past to the future

A brief discussion of the history of the use of herbal medicines from prehistoric times to the mid-twentieth century precedes an explanation of why usage of such remedies in the United States declined in the 1940s but returned to popularity in the 1980s. The provisions of the Dietary Supplement Health and Education Act of 1994 are presented together with its perceived influence, both positive and negative, on the health of the American people. Possible futures of herbal medicines are considered. The negative viewpoint that they will ultimately be rejected is refuted, and the more optimistic prediction that herbs are ultimately destined to become a part of mainstream medicine is defended. Stumbling blocks to such acceptance are evaluated and methods of overcoming them suggested. The urgent need for the development of a sensible regulatory environment encouraging the approval of botanicals as drugs is emphasized. After predicting a bright future for rational phytomedicines, the author opines that many of them will eventually play significant roles in medicinal practice.

PC-SPES: herbal formulation for prostate cancer∗ ☆

PC-SPES is a potent eight-herb formulation sold directly to consumers; it has promising efficacy in the treatment of prostate cancer (CaP). The product induces a castrate status in most, if not all, men, resulting in a 50% or greater prostate-specific antigen reduction in the great majority of men with androgen-dependent CaP and in more than one half of the men with androgen-independent CaP. The duration of response is not yet clear. The efficacy of PC-SPES appears to exceed that of androgen ablation alone, but is not necessarily separate from an estrogenic effect. Common side effects include gynecomastia, nipple tenderness, loss of libido, and impotency; uncommon side effects include a 4% incidence of thromboembolic phenomena, but also two reports of bleeding diatheses. The mechanisms of action may involve downregulation of the androgen receptor, induction of apoptosis by way of inhibition of the bcl-2 gene, and increased expression of p53. Two marker compounds in PC-SPES are baicalin and oridonin, both of which exhibit antiproliferative effects in CaP cell lines. Thousands of men are currently obtaining this nonprescription medicine, and physicians should ask patients specifically about its use. PC-SPES is of great interest in men with androgen-independent CaP, an area in which future research should be primarily directed.

Isolation of 3,4′,5-trimethoxy-trans-stilbene, otobaene and hydroxyotobain from Virola cuspidata

Abstract Investigation of the petroleum ether extract of Virola cuspidata (Benth.) Warb. led to the isolation of 3,4′,5-trimethoxy- trans -stilbene and the lignans, otobaene and hydroxyotobain. The structure of 3,4′,5-trimethoxy- trans -stilbene was determined on the basis of its u.v. and NMR spectra. Otobaene and hydroxyotobain were identified by comparison of physical data with literature values.

Plight of plant-drug research in the United States today

Wild valerian is a medicine of great use in nervous disorders, and is particularly serviceable in epilepsies proceeding from a debility of the nervous system. Some recommend it as procuring sleep, particularly in fever, even when opium fails; but it is principally useful in affections of the hysterical kind.

Medicinal Plants, Phytomedicines, and Phytotherapy

From a historical perspective, the production of medicines and the pharmacologic treatment of diseases began with the use of herbs. Methods of folk healing practiced by the peoples of the Mediterranean region and the Orient found expression in the first European herbal, De Materia Medica, written by the Greek physician Pedanios Dioscorides in the first century AD. During the Renaissance, this classical text was revised to bring it more in line with humanistic doctrines. The plants named by Dioscorides were identified and illustrated with woodcuts, and some locally grown medicinal herbs were added. Herbals were still based on classical humoral pathology, which taught that health and disease were determined by the four bodily humors - blood, phlegm, black bile, and yellow bile. The humors, in turn, were associated with the elemental principles of antiquity: air, water, earth, and fire. The elements could be mixed in varying ratios and proportions to produce the qualities of cold, moist, dry, or warm - properties that also were associated with various proportions of the four bodily humors. Thus, if a particular disease was classified as moist, warm, or dry, it was treated by administering an herb having the opposite property (Juttner, 1983). Plant medicines were categorized by stating their property and grading their potency on a four-point scale as “imperceptible,” “perceptible,” “powerful,” or “very powerful.” Opium, for example, was classified as grade 4/cold. A line of association that linked sedation with “cooling” allowed the empirically known sedative and narcotic actions of opium to be fitted into the humoral system. Pepper was classified as grade 4/dry and warming. The goal of all treatment, according to Hippocrates, was to balance the humors by removing that which is excessive and augmenting that which is deficient” (H.Haas, 1956). Humoral pathology obviously developed into one of the basic principles of conventional medicine.

Gynecologic Indications for Herbal Remedies

Herbal remedies cover a small but very important range of indications in the treatment of gynecologic diseases and functional disorders. They are used principally in the treatment of premenstrual syndrome (PMS), dysmenorrhea, and menopausal complaints in cases where stronger-acting drugs are not indicated or are declined by the patient. Two medicinal plants stand out in the frequency with which they are prescribed for gynecologic complaints: chasteberries (used chiefly for PMS) and black cohosh rhizome (used principally for menopausal complaints) (Schwabe and Rabe, 1995). Table 7.1 also lists four other herbs recommended by Commission E as having gynecologic indications. It can be seen that the range of recommended dosages (column 3 in Table 7.1) is greater for gynecologic herbal remedies than for any other class of phytomedicines. Some of the dosages are many times lower than the traditional single dose of about 1–4 g of crude drug taken in a cup of medicinal tea. There is an urgent need for pharmacologic and clinical studies to investigate the dose-dependency of the actions and efficacy of these drugs.

The Future of Botanical Drugs and the Rainforest

The importance of the rainforest as a source of botanical drugs is discussed. The future of botanical medicines is focused on pure compounds and plant extracts. Further efforts need to be devoted to isolation of active components with structural descriptions. The author states that only 90,000 natural compounds have been so studied representing only 40% of total possible new drugs while several million synthetics comprise the remaining 60%. It is estimated that 35,000 to 50,000 plant species are found in the Amazon rainforest hence it is a valuable source of new compounds.

“Pharmacognosy”! What’s that? you spell it how?

In this autobiographical sketch, the author discusses the development of his interest in the biological sciences, crediting his father, his first employer, his high school science teacher, and his college pharmacognosy professor with initially shaping his career. His early work on ergot alkaloid biosynthesis and subsequently, together with students and colleagues, on the toxic constituents of basidiomycetes is detailed. This is followed by comments on his developing interest in the therapeutic utility of herbs and phytomedicinals. A concern with the beneficial use of such products stemmed largely from observations made during sabbatical leaves and frequent travel in Germany. The importance of such botanicals (not currently recognized as drugs in the United States) in our developing health-care system is emphasized. The author concludes his comments by thanking his wife, his teachers, his students, and his many colleagues and friends for their unstinting assistance and support during his entire career.ResumenIn dieser autobiographischen Skizze spricht der Autor über die Entfaltung seines Interesses an den biologischen Wissenschaften: sein Vater, sodann sein erster Arbeitgeber, sein Naturwissenschaftslehrer auf der höheren Schule, sowie—während seiner Studienjahre—sein Professor in Pharmakognosie seien die Mentoren, denen er diese berufliche Ausrichtung ursprünglich verdanke. Es folgen detaillierte Ausführungen betreffs seiner frühen Forschungsarbeiten über Mutterkorn-alkaloide Biosynthese und—in Zusammenarbeit mit Studenten und Kollegen—die toxischen Bestandteile von Basidiomyzeten. Im AnschluB daran beschreibt der Autor, wie sein Augenmerk allmahlich auf die Frage der therapeutischen Verwertung Heilpflanzen und Phytopharmaka gelenkt wurde. Das Interesse an einer niitzlichen Verwendung solcher Produkte sei in erster Linie durch Beobachtungen angeregt worden, die er im Verlaufe verschiedentlicher Forschungsaufenthalte in Deutschland angestellt habe. Er betont die Bedeutung dieser (zu diesem Zeitpunkt in den USA nicht als Drogen geltenden) Pflanzen für unser Gesundheitswesen, das ständig nach neuen Wegen und Lösungen suche. Abschlieβend spricht der Autor seiner Frau, seinen Lehrern, Studenten, sowie seinen zahlreichen Kollegen und Freunden seine Anerkennung und seinen Dank für deren unermüdlichen Beistand auf sämtlichen Stufen seiner langjährigen Laufbahn aus.