Biomedical subjects
Publications and source records attributed to H Mucke.
TAK-147 is a CNS-specific acetylcholinesterase inhibitor under development by Takeda as a potential treatment for Alzheimer's disease. By November 1999, it had entered phase III trials in Japan [348496]. In August 1999, Lehman Brothers predicted product launch in 2002, with potential peak sales of $250 million in 2012 [349228].
Alosetron, a 5-HT(3)-receptor antagonist that is very closely related to ondansetron in terms of both chemistry and pharmacology, is the first compound of this type to be developed for irritable bowel syndrome. Clinical data for up to 3 months of treatment indicate that alosetron is orally bioavailable in tablet form, is well tolerated and is significantly superior to both placebo and the smooth muscle relaxant, mebeverine, in improving perception of visceral pain, spasms and diarrhea in female diarrhea-predominant irritable bowel syndrome. In males, symptoms were not alleviated to a statistically significant extent.
This meeting, which for the first time included BrainPET, was held in close cooperation with the International Society for Cerebral Blood Flow and Metabolism and was presided over by Dr Olaf B Paulson (Neuroscience Center, Rigshospitalet, Copenhagen, Denmark). It attracted approximately 750 registered participants from over 30 countries, with a particularly strong Japanese presence. More than 100 oral presentations were held and some 700 posters displayed.
Clomethiazole has been marketed for several years as a sedative/antiepileptic. Astra is now developing it for the potential treatment of stroke. An NDA is expected to be filed in 1999/2000. A North American phase III trial for large stroke has commenced. This will include 1200 patients. Two other smaller scale phase III studies with clomethiazole have also commenced in North America for intracerebral hemorrhage (n=200) and safety in combination with TPA (n=100 to 200) (Genentech). A large-scale phase III trial has been completed in which clomethiazole was evaluated for its ability to reduce nerve damage in acute cerebrovascular ischemia. The multicenter, international trial, called CLASS (Clomethiazole Acute Stroke Study), analyzed 1360 patients and found no significant treatment effect. However, a subgroup of patients who presented with large stroke, experienced a significant benefit. Of these (n=545), 41% treated patients were functionally independent after 90 days, compared to 30% patients on placebo. Clomethiazole reduced functional disability and brain damage in the marmoset permanent MCAO model. Clomethiazole is thought to act through a GABAergic pathway, whereby it augments GABA's depressive effect on the CNS, giving the drug both hypnotic and neuroprotectant properties.
In addition to a few disorders such as acute T-cell leukemia that are typically associated with the human T-cell leukemia virus (HTLV) 1 in endemic regions, this virus may also play a role in some other hematological diseases. Here, we examine the incidence of HTLV in hematological diseases from a nonendemic region in central Europe. Data obtained by PCR and/or serological techniques from a total of 730 cases showed that besides the expected presence of HTLV-1 in T-lymphoid diseases (2 of 27 cases), HTLV-1 was only detected in myelodysplastic syndrome (MDS), in which an incidence of 17% (11 of 65 cases) was found. A correlation with a history of multiple transfusions or treatment with blood products in the HTLV-1-positive MDS could not be ascertained. Cytogenetics detected the presence of del(5)(q) in six HTLV-positive cases (five MDS and one T-cell acute lymphocytic leukemia) but in only one HTLV-negative case. These data indicate that allelic deletions of a series of 5q-located genes that typically occur in MDS may be associated with HTLV infections in central Europe.
Serological evidence is presented for the fact that patients with the myelodysplastic syndrome exhibit a statistically significant reactivity in confirmatory assays for antibodies to human T-lymphotropic viruses types I and II (HTLV-I/II). This antibody reactivity, evident by indirect immunofluorescence and Western blot, was not confined to HTLV core antigens but extended to native and recombinant envelope glycoproteins. The effect was also observed in cases of acute myeloic leukemia, albeit to a lesser degree. It was essentially absent from patients with chronic myeloic leukemia or lymphocytic leukemias and healthy or multitransfused controls. No antibodies to human immunodeficiency viruses types 1 or 2 were detected in any of the specimens. The investigated clinical population had no known risk factor for retroviral infection other than a history of multiple platelet transfusions, and none of the specimens was seropositive for HTLV-I or HTLV-II according to recommended criteria. The cause of this cross-reactivity remains to be determined.
An indirect immunofluorescence assay (IFA) was evaluated as a confirmatory test for antibody to human immunodeficiency virus type 1 in U.S. blood donor sera previously found to be repeatedly reactive by enzyme immunoassay. IFA results were 100% concordant with a licensed Western blot (immunoblot) for 53 negative and 49 positive samples. Four samples which exhibited antibody to viral proteins from more than one gene, yet were indeterminate by Western blot by the manufacturer's criteria, were also reactive by IFA, whereas 49 additional indeterminate samples were IFA negative.
In the GDR annually repeated indiscriminate mass miniature radiographies (MMR) of all persons in the age of 16 years and over were performed during 3 decades. The aim was, beside finding cases of pulmonary tuberculosis, the early detection of bronchogenic carcinoma. The decrease of tuberculosis incidence and the shift of nearly all new cases to higher age groups lead to a change of this policy. The new regulation, in force since 1986, provides mass X-ray examinations of all persons in the age of 40 years and over with 2 years interval, and X-ray examinations of the lung of persons in several risk groups with shorter, mainly annual intervals. The latter became a task of the chest clinics. The experience of 2 chest clinics with the organization of these examinations and the yield of new cases of pulmonary tuberculosis and bronchogenic carcinoma are reported. It is necessary to improve the organization and to reduce the number of risk-groups to those with an acceptable balance of input and result. Otherwise, the staff of the chest clinics is impeded to fulfill more rewarding tasks in the care of patients. The results of the attempts of early detection of bronchogenic carcinoma and improvement of life expectancy by X-ray examination of risk groups and early resection were disappointing. Thus, other ways must be found. A revision of the regulation of 1986, concerning risk groups, is proposed with the aim to rationalize their surveillance.
Cyanophora paradoxa, a unicellular flagellate, contains cyanelles which are supposed to be cyanobacterial origin. DNA was isolated from subcellular fractions and separated according to density components in CsC1 density gradients. The main DNA component, comprising more than 90% of the total DNA, has a buoyant density of 1.724 g X cm-3. Several subsfractions in the range from 1.718 g X cm-3 to 1.735 g X cm-3 are contained in this component. This DNA of high complexity was considered to be host nuclear DNA. The DNA from the endosymbiotic cyanelles, which were isolated, treated with DNase, and purified by sucrose density gradient centrifugation exhibited a buoyant density of 1.692 g X cm-3 in one strain and 1.695 g X cm-3 in a second strain. Both cyanelle DNAs (cyDNA) have a complexity of approximately 126 X 10(3) base pairs and comprise about 5% of the total cellular DNA content. Two additional DNA components of low complexity were isolated from crude cyanelle pellets obtained without DNase treatment. The larger of these, approximately 48 X 10(3) base pairs in size, had a density of approximately 1.688 g X cm-3. The second component, about 15 X 10(3) base pairs in size, banded in the density range between 1.710 g X cm-3 and 1.720 g X cm-3. The latter is associated with nuclear DNA. The 48 X 10(3)-base-pair component was located in the cytosol and could be obtained after CsC1/ethidium bromide density gradient centrifugation at the position of covalently closed circular DNA. Both these components amounted to approximately 0.5-1% of total DNA. A further DNA component with a complexity of more than 150 X 10(3) base pairs, enriched in fractions where mitochondria are expected, was not characterized further. The density was intermediate between cyDNA and nuclear DNA (1.710-1.720 g X cm-3) and it amounted to 1-2% of the total DNA. Our results indicate that the DNA from cyanelles, believed to be endosymbiotic cyanobacteria, is not more complex than higher plant chloroplast DNAs.
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