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Beans, roots and leaves: a brief history of the pharmacological therapy of parkinsonism.

Foley P.

Prince of Wales Medical Research Institute

It is not clear whether parkinsonism as it is now defined - a progressive neurodegenerative disorder of the basal ganglia characterized by sharply reduced striatal dopamine levels - has always affected a significant minority of aged persons, but suggestive evidence to this effect is reviewed. THe major discussion commences, however, with the administration of various plant alkaloids to parkinsonism patients in the second half of the 19th century. Antiparkinsonian therapy since this time can be divided into a number of phases: 1. Employment of alkaloids derived from solanaceous plants: initially hyoscyamine, then hyoscien/scopolamine. 2. With the outbreak of encephalitis lethargica during the First World War, parkinsonian patient numbers increased dramatically, leading to a multiplicity of new directions, including high dose atropine and harmala alkaloid therapies. 3. The "Bulgarian treatment", popularized in western Europe in the mid-1930s, was also a belladona alkaloid-based therapy, but associated with greater efficacy and few side effects. This approach, whether as actual plant extracts or as defined combinations of belladona alkaloids, remained internationally dominant until the end of the 1940s. 4. Following the Second World War, synthetic antiparkinsonism agents were developed with the aim of overcoming the deficiencies of belladonna alkaloid therapy. These agents fell into two major classes: synthetic anticholinergic agents, such as benzhexol, and antihistaminergic drugs, including diphenhydramine. 5. A complete change in direction was heralded by the discovery in 1960 of the striatal dopamine deficit in parkinsonism. This led to the introduction of L-DOPA therapy, the first approach directed against an identified physiological abnormality in the disorder. 6. Subsequent developments have thus far refined of supplemented the L-DOPA effect. Recent attempts to develop neuroprotective or -restorative approaches are also briefly discussed.The history of antiparkinsonian therapy illustrates the fact that the nature of experimental clinical pharmacology has markedly changed during the 20th century: No longer the preserve of individual physicians, it is now based firmly on fundamental laboratory research, the clinical relevance of which is not always immediately apparent, and which is only later examined in clinical trials. It is nonetheless concluded that antiparkinsonian therapy was never 'irrational', but has always been necessarily rooted in current knowledge regarding neural and muscular function. The achievements of L-DOPA therapy, the first successful pharmacological treatment for a neurodegenerative disorder, derived from the fruitful union of hte skills and contributions of different types by laboratory scientists, pharmacologists and clinicians.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15641199&dopt=Abstract hyoscyamine Levbid SL



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Overexpression of tropinone reductases alters alkaloid composition in Atropa belladonna root cultures.

Richter U, Rothe G, Fabian AK, Rahfeld B, Drager B.

Institute of Pharmaceutical Biology, Martin-Luther-University Halle-Wittenberg, Hoher Weg 8, D-06120 Halle/Saale, Germany.

The medicinally applied tropane alkaloids hyoscyamine and scopolamine are produced in Atropa belladonna L. and in a small number of other Solanaceae. Calystegines are nortropane alkaloids that derive from a branching point in the tropane alkaloid biosynthetic pathway. In A. belladonna root cultures, calystegine molar concentration is 2-fold higher than that of hyoscyamine and scopolamine. In this study, two tropinone reductases forming a branching point in the tropane alkaloid biosynthesis were overexpressed in A. belladonna. Root culture lines with strong overexpression of the transcripts contained more enzyme activity of the respective reductase and enhanced enzyme products, tropine or pseudotropine. High pseudotropine led to an increased accumulation of calystegines in the roots. Strong expression of the tropine-forming reductase was accompanied by 3-fold more hyoscyamine and 5-fold more scopolamine compared with control roots, and calystegine levels were decreased by 30-90% of control. In some of the transformed root cultures, an increase of total tropane alkaloids was observed. Thus, transformation with cDNA of tropinone reductases successfully altered the ratio of tropine-derived alkaloids versus pseudotropine-derived alkaloids.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15642710&dopt=Abstract hyoscyamine Levbid SL



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Induction of tropane alkaloid formation in transformed root cultures of Brugmansia suaveolens (Solanaceae).

Zayed R, Wink M.

Institut fur Pharmazie und Molekulare Biotechnologie, Universitat Heidelberg, INF 364, D-69120 Heidelberg, Germany.

Hairy root cultures of Brugmansia suaveolens were set up by infection of root tips with Agrobacterium rhizogenes. The successful transformation was confirmed by analysing rolC and virC genes using polymerase chain reaction (PCR). Hairy root cultures were employed to study the formation of tropane alkaloids, such as hyoscyamine. The transformed cultures were incubated with potential elicitors, such as methyljasmonate, quercetin and salicylic acid in order to stimulate the biosynthesis of tropane alkaloids. Profile and amounts of tropane alkaloids were analysed using capillary GLC-MS. At least 18 different tropane alkaloids could be identified. Treatment of the cultures with 200 microM methyljasmonate increased the alkaloid accumulation 25-fold up to a level of 1 mg/g fresh weight as compared to untreated controls. Quercetin enhanced the alkaloid production 10 fold (0.4 mg/g fresh weight) within 24 h. In contrast 100 microM salicylic acid decreased alkaloids to a level of 1 microg/g fresh weight.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15666547&dopt=Abstract hyoscyamine Levbid SL



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Potentially inappropriate medication use by elderly persons in u.s. Health maintenance organizations, 2000-2001.

Simon SR, Chan KA, Soumerai SB, Wagner AK, Andrade SE, Feldstein AC, Lafata JE, Davis RL, Gurwitz JH.

HMO Research Network, Center for Education and Research on Therapeutics, Harvard Pilgrim Health Care and Harvard Medical School, Boston, Massachusetts.

Objectives: To determine rates of potentially inappropriate medication use in elderly persons in managed care plans in the United States in 2000-2001. Design: Cross-sectional study using automated medication-dispensing data. Setting: Ten geographically distributed health maintenance organizations (HMOs). Participants. One hundred fifty-seven thousand five hundred seventeen members aged 65 years and older enrolled in one of the HMOs. Measurements: Prevalence of use of 33 potentially inappropriate medications from January 1, 2000 through June 30, 2001. Results: In 2000-2001, 28.8% (95% confidence interval=28.6-29.1) of elderly individuals received at least one of 33 potentially inappropriate medications. This rate ranged from 23.0% to 36.5% across the 10 HMOs. Approximately 5% of elderly patients received at least one of the 11 medications classified by an expert panel as "always avoid," 13% received at least one of the eight medications that would rarely be considered appropriate, and 17% received at least one of the 14 medications that have some indications but are often misused. Overall, rates of use of these medications were greater in women (32.4%) than in men (24.2%). At least 1% of elderly members received belladonna alkaloids (2.3%), dicyclomine (1.1%), or hyoscyamine (1.2%), each of which multiple expert panels have classified as always inappropriate in patients aged 65 years and older. Seven percent of elderly members received propoxyphene, an analgesic medication considered rarely appropriate in the elderly and a drug that has a long history of limited efficacy and potential for toxicity. Conclusion: Recent rates of potentially inappropriate medication use by elderly HMO members were at least as great as in a 1996 national sample. This study highlights the need to understand more fully the rationale behind the continued use of these medications.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15673345&dopt=Abstract hyoscyamine Levbid SL



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Expression of Vitreoscilla hemoglobin enhances growth of Hyoscyamus muticus hairy root cultures.

Wilhelmson A, Kallio PT, Oksman-Caldentey KM, Nuutila AM.

VTT Biotechnology, Espoo, Finland.

The Vitreoscilla hemoglobin gene (vhb) was introduced into Hyoscyamus muticus with the aim of investigating its effect on growth and alkaloid production of Agrobacterium rhizogenes-induced hairy root cultures. We were able to generate several VHb-expressing hairy root lines with different integration patterns. Substantial somaclonal variation was observed in growth and hyoscyamine production amongst both VHb-expressing lines and controls. Despite this variation, the growth properties of single lines remained stable over time. Expression of VHb was found to improve growth of H. muticus hairy roots in shake-flask cultures. The dry weights of the root cultures expressing Vitreoscilla hemoglobin were on average 18 % higher than those of the controls. VHb expression also increased the volumetric hyoscyamine production, mainly due to the improved growth properties. However, this difference was not statistically significant due to the wide somaclonal variation and fluctuations over time in both VHb and control hairy root lines.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15678373&dopt=Abstract hyoscyamine Levbid SL