Biochemische Aspekte der l-DOPA-Wirkung bei Parkinsonpatienten

Zusammenfassung Es wurde bei 19 Patienten mit Paralysis agitans die Wirkung einer Langzeitbehandlung mit 2500–5000 mg l-DOPA/die untersucht: a) mit Hilfe von klinischen Tests, b) durch Messung der Aminosäurezusammensetzung des Liquor cerebrospinalis. Krankheitsdauer und Ausprägung der Symptome waren verschieden. Der Beobachtungszeitraum betrug 3 Monate bis 2 Jahre.1. Bei 9 Patienten war vor Beginn der Behandlung mit l-DOPA die Aminosäurezusammensetzung im Liquor cerebrospinalis so verändert, wie es bei einer Parkinsonsymptomatik zu erwarten war: Die Konzentrationen von Glycin, Serin, Threonin, Cystein + Cystin und Methionin waren erhöht, die von Glutaminsäure vermindert. Diese Patienten sprachen auf eine Behandlung mit l-DOPA sehr gut bis gut an; das Aminosäurespektrum im Liquor cerebrospinalis normalisierte sich.2. Bei 5 Patienten wich vor Beginn der Behandlung mit l-DOPA die Aminosäurezusammensetzung des Liquors nur wenig vom normalen Durchschnitt ab, der Erfolg der l-DOPA-Therapie war nicht zufriedenstellend.3. Eine Normalisierung der Aminosäurewerte ohne wesentlichen Therapieerfolg wurde nicht beobachtet.4. Von 5 weiteren Patienten sprachen 4 auf l-DOPA gut an; eine Einordnung in die vorgenannten Gruppen erscheint aus verschiedenen Gründen nicht sinnvoll.Die Analyse der Liquoraminosäuren scheint somit eine Prognose zu erlauben, ob eine l-DOPA-Therapie sinnvoll ist oder nicht. Aus den vorgelegten Ergebnissen ist weiters zu folgern, daß das klinische Krankheitsbild Paralysis agitans keine einheitliche Krankheit ist, sondern sich einzelne Formen hinsichtlich der Störung des Stoffwechsels im ZNS voneinander unterscheiden.

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Biochemical aspects of the effect of l-DOPA in patients with Parkinson's disease

Summary We tested the effect of a prolonged l-DOPA therapy in 19 patients suffering from Parkinson's disease, by a) applying medical tests and b) measuring concentrations of free amino acids of cerebrospinal fluid. The period of observation ranged from 3 months up to two years, with doses from 2500 to 5000 mg l-DOPA per day.1. In 9 patients the pattern of free amino acids of CSF was altered according to what we are used to find in Parkinson's disease: the concentrations of glycine, serine, thereonine, cysteine + cystine as well as methionine were increased, that of glutamic acid decreased. The clinical success was very good along with a restoration to normal of the pathological amino acid pattern.2. In 5 patients the amino acid pattern was similar to that of normal controls. Clinically, these cases showed an unsatisfactory response to therapy, the amino acid pattern of CSF also remaining unchanged.3. In no case we did find a normalization of amino acid levels without an improvement of the clinical symptoms.4. Of another 5 patients 4 responded favourably to l-DOPA, one did not. These patients were not considered to belong to the above mentioned groups because of several complicating factors.The estimation of the pattern of free amino acids in CSF seems to be of prognostic value in yielding a biochemical parameter that seems to indicate whether or not a prolonged treatment with l-DOPA might be successful. Patients with a pathological pattern of CSF amino acids run a better chance of therapeutic improvement. We could not find any correlation between levels of amino acids in CSF and the duration of the disease or the severity of symptoms. We conclude that Parkinson's disease is not caused by a single type of disturbed cerebral metabolism.

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Abkürzungen AS Aminosäuren - Arg Arginin - Ala Alanin - Asp Asparaginsäure - Asp-NH₂ Asparagin - Cys Cystein + Cystin - l-DOPA l-Dihydroxyphenylalanin - Glu Glutaminsäure - Glu-NH₂ Glutamin - Gly Glycin - His Histidin - Ileu Isoleucin - Leu Leucin - Lys Lysin - Met Methionin - Phe Phenylalanin - Ser Serin - Thr Threonin - Tyr Tyrosin - Val Valin - ZNS Zentralnervensystem - BTS Brenztraubensäure - GOT Glutamat-Oxalacetat-Transaminase - GPT Glutamat-Pyruvat-Transaminase. Für das Forschungsstipendium, das uns die Durchführung dieser Arbeit ermöglichte, sind wir der Fa. Hoffmann-La Roche, Basel, zu Dank verpflichtet.     

Ectopic expression of VAV1 reveals an unexpected role in pancreatic cancer tumorigenesis

Herein, we show that the hematopoietic-specific GEF VAV1 is ectopically expressed in primary pancreatic adenocarcinomas due to demethylation of the gene promoter. Interestingly, VAV1-positive tumors had a worse survival rate compared to VAV1-negative tumors. Surprisingly, even in the presence of oncogenic KRAS, VAV1 RNAi abrogates neoplastic cellular proliferation in vitro and in vivo, thus identifying Vav1 as a growth-stimulatory protein in this disease. Vav1 acts synergistically with the EGF receptor to stimulate pancreatic tumor cell proliferation. Mechanistically, the effects of Vav1 require its GEF activity and the activation of Rac1, PAK1, and NF-kappaB and involve cyclin D1 upregulation. Thus, the discovery of prooncogenic pathways regulated by Vav1 makes it an attractive target for therapeutic intervention.     

Comparison of intense pulsed light to 595-nm long-pulsed pulsed dye laser for treatment of hypertrophic surgical scars: a pilot study

BACKGROUND: The short-pulsed pulsed dye laser (PDL) has been previously reported to improve the appearance of hypertrophic scars. Prolonged purpura following treatment led to the development of the newer long-pulsed pulsed dye laser (LPDL). Intense pulsed light (IPL) has been extensively used to improve the various components of photo damage and to reduce the incidence of purpura, but its effect on scars has not been analyzed. The objective of this pilot study was to prospectively determine and compare the safety and efficacy of LPDL and IPL on surgically induced scars. METHODS: Breast reduction scars (N = 10 scars) and abdominoplasty scars (N=5 scars) were treated using both LPDL and IPL. For breast reduction scars, one side was treated with each technique. For abdominoplasty scars, one half of the scar was treated with each device. Two treatments were performed 2 months apart. Physician global assessment scores of improvement were determined by side-by-side comparison of preoperative and randomly presented postoperative photographs. Patient pain scores during treatment were also obtained and the presence of post, treatment purpura was assessed. RESULTS: Mean improvement on a 0 to 3 point scale was 2.2 (55%) after the first LPDL treatment and 3.2 (80%) after the second. Mean improvement was 1.8 (45%) after the first IPL treatment and 2.6 (65%) after the second. Differences in improvement between the LPDL and IPL sides were not statistically significant. Patients rated IPL as more painful than LPDL. The incidence of post-treatment purpura was lower with IPL. CONCLUSIONS: This pilot study suggests that LPDL and IPL are equally effective in improving the appearance of hypertrophic surgical scars. IPL offers a novel method of treating scars that minimizes the risk of purpura.     

A large 12-month extension study of an 8-week trial to evaluate the safety and efficacy of triple combination (TC) cream in melasma patients previously treated with TC cream or one of its dyads

This was a 12-month extension of a randomized, investigator-blinded, multicenter, 8-week trial with triple combination (TC) cream in facial melasma. A total of 585 patients were enrolled in the study and 569 patients received study medication. Three hundred eighty-nine patients completed 6 months of treatment and 327 patients completed 12 months of treatment. TC cream demonstrated a favorable safety profile: only 14 patients (2.5%) discontinued the study due to treatment-related adverse events (AEs). The 2 cases of skin atrophy were mild and did not lead to withdrawal. From the 23 cases of mild telangiectasia, only 2 resulted in discontinuation. All others were transient. Results confirmed those of a previous smaller study, with both physicians and patients reporting clinically significant improvements in melasma. By month 12, 80% of patients had lesions completely cleared or nearly cleared. Once daily application of TC cream applied intermittently over a long period is a safe, tolerable, and effective treatment for moderate to severe melasma of the face.