Influence of magnesium substitution on a collagen-apatite biomaterial on the production of a calcifying matrix by human osteoblasts

The induction of a calcifying matrix is of great interest in the restoration of bone defects. In a previous in vitro study we demonstrated that a collagen sponge constituted of type I collagen fibrils, chondroitin sulfates, and hydroxyapatite crystals induces an earlier and a more abundant synthesis of a new extracellular calcifying matrix than do other biomaterials such as collagen or hydroxyapatite alone. Bone mineral contains various amounts of magnesium ions, either adsorbed at the surface of apatite crystals or incorporated inside the crystal structure. Magnesium is known to reduce the degradation rate of tricalcium phosphate ceramics and to influence the crystallization of mineral substance. Thus we evaluated two sponges modified with different substituted apatites. The substituted low magnesium-containing apatite sample decreased the osteoinductive properties of the sponge whereas the substituted high magnesium-containing apatite sample had a toxic effect on bone cells and prevented the formation of any extracellular matrix. Such a toxic effect can be explained by the presence of large numbers of magnesium ions released into the culture medium even though at physiological level magnesium is able to promote bone mineralization and to control the growth of hydroxyapatite crystals. Thus collagen sponges containing hydroxyapatite remain one of the most appropriately evaluated biomaterials used for the restoration of periodontal pockets and bone defects.     

Rivastigmine. A review of its use in Alzheimer's disease

Rivastigmine (SDZ ENA 713) is a carbamylating, long-acting reversible and noncompetitive carbamate acetylcholinesterase inhibitor that is indicated as an oral treatment for patients with mild to moderately severe Alzheimer's disease. The drug has been evaluated for this use in 3 well designed, adequately powered, phase II/III, 26-week clinical trials that included a total of 1479 rivastigmine and 647 placebo recipients. Most of these patients had concomitant disorders that were being treated with numerous other drugs. Individual and pooled results of these trials indicate that rivastigmine 6 to 12 mg/day usually produces cognitive, global and functional changes that indicate significantly less deterioration than was observed with placebo in patients with mild to moderately severe Alzheimer's disease. Individual results of the 2 pivotal trials and pooled analysis also show that, compared with placebo recipients, significantly more rivastigmine 6 to 12 mg/day recipients respond to therapy. Indeed, after 26 weeks of therapy in the 2 pivotal trials, significantly more rivastigmine 6 to 12 mg/day than placebo recipients achieved clinically meaningful improvements as defined by 3 separate response criteria. The lower dosage range of 1 to 4 mg/day was not as effective as 6 to 12 mg/day, as measured using these criteria and other efficacy parameters. Rivastigmine causes adverse events that are generally those expected from an acetylcholinesterase inhibitor. They are usually mild to moderate, of short duration and responsive to dosage reduction. Unpublished data from 3989 patients indicate that rivastigmine and placebo were associated with similar incidences of serious adverse events and changes in laboratory parameters, ECG and cardiorespiratory vital signs. The most common events were gastrointestinal, central and peripheral nervous system and whole body adverse events. However, compared with placebo, rivastigmine more commonly caused adverse events resulting in treatment withdrawal. These events were most frequently gastrointestinal and were more common in women. CONCLUSION: Rivastigmine is a useful option for the treatment of patients with mild to moderately severe Alzheimer's disease. Although only short term (6- month) comparisons with placebo are available, given the lack of established treatment options it should be considered for first-line use in this population.     

Aristolochic acids, aristolactam alkaloids and amides from Aristolochia kankauensis

Fourteen aristolochic acid derivatives: ariskanins A-E, 3-hydroxy-4-methoxy-10-nitrophenanthrene-1-carboxylic acid methyl ester, aristolochic acid-II methyl ester, aristolochic acid-IV methyl ester, aristolochic acid-C, -I, -II, -III, -IV, -IVa; nine aristolactam alkaloids: aristolactam, aristolactam-AII, -BIII, -AIII, -III, cepharanone-A, 9-methoxy-aristolactam-I, aristolactam-N-beta-D-glucoside and aristolactam-C-N-beta-D-glucoside; a 4,5-dioxoaporphine alkaloid: cepharadione-A, together with 12 other compounds: methyl-p-coumarate, N-trans-feruloyltyramine, N-cis-feruloyltyramine, methyl vanillate, methyl paraben, allantoin, an octadecyl- and eicosyl ferulate mixture, cis- and trans-p-coumaric acid, N-p-coumaroyltyramine, N-p-cis-coumaroyltyramine, methyl ferulate and isorhamnetin-3-O-rutinoside were isolated and characterized from the fresh root and stem of Aristolochia kankauensis. Their structures were elucidated by spectral and chemical methods. Among them, ariskanins-A-E and N-p-cis-coumaroyltyramine are reported for the first time from a natural source. The cytotoxicity and antiplatelet activity of the compounds isolated are also discussed.     

Luminance contrast and spatial-frequency tuning of the transient-vergence system

Vergence has transient components that are stimulated by brief presentations of stimuli at large disparities (up to several degrees). The question that we have addressed is what stimulus features are encoded by this system. A competition paradigm [Jones & Kerr, (1972)]. Vision Research, 12, 1425-1430) was used in which three gabors were presented. A single Gabor was presented to the fovea of one eye and two gabors, 2.5 deg to either side of the fovea, to the other; one of which, when paired with the single Gabor defined a convergent direction, the other a divergent direction. First we determined if increasing the luminance contrast of the Gabor pair whose disparity was opposite to the observer's response-bias direction (variable-contrast pair) relative to the remaining Gabor (reference) could alter the observer's response direction. Secondly, we determined if the contrast required for such a change in response was affected by the relative spatial frequency of the convergent and divergent Gabors. The reference Gabor was held at 2 cpd and the variable Gabor pair was varied between 5.6 and 0 (a gaussian) cpd. Results demonstrated that increasing the luminance contrast of the variable pair relative to the reference Gabor could alter the observer's response direction, even when the contrast of only one of the variable-pair Gabors was increased. The luminance contrast required for this change to occur was directly related to the spatial frequency of the variable pair over the entire frequency range tested. Vergence responses were preferentially made to lower spatial frequencies, even when a low spatial frequency was pared with a high one. We conclude that transient-vergence responses are not reduced by mixed contrasts (i.e. no contrast-paradox effect) and appear to be mediated by a system that employs a single lowpass sensitive channel.     

The characterization of a subgenomic RNA and in vitro translation products of oat chlorotic stunt virus

Apoptosis has classically been viewed as a process not involving mitochondria, whereas the implication of mitochondrial dysfunction in necrosis has been recognized for several decades. Recently, it has become clear that apoptosis implies a disruption of mitochondrial membrane intregrity that is decisive for the cell death process. Cytofluorometric methods assessing the mitochondrial membrane function and structure can be employed to demonstrate that, at least in most models of apoptosis, mitochondrial changes precede caspase and nuclease activation. Moreover, pharmacological and genetic experiments suggest that the loss of mitochondrial membrane integrity is a critical event of the apoptotic process, beyond or at the point of no return of programmed cell death. Inhibitors of the mitochondrial megachannel (= permeability transition pore) can prevent both the mitochondrial and the post-mitochondrial manifestations of apoptosis.     

Pharmacotherapeutic compass 1998

The Central Medical Pharmaceutical Committee of the Health Insurance Council informs the medical profession annually about the effects of drugs through the Pharmacotherapeutical Compass. The 1998 edition now contains a chapter on pharmacokinetics as well. Compared with previous editions the main alterations of the contents concern an introduction and advice on the antidepressants, two protocols with respect to the medical treatment of patients suffering from epilepsy, advice with respect to oral drugs for the treatment of inflammatory bowel disease, an introduction and advice regarding the treatment of allergic rhinitis, the treatment of patients suffering from AIDS with antiretroviral drugs, the treatment of genital herpes, the taking of insulin lispro by patients with diabetes and the taking of bisphosphonates to prevent or to treat osteoporosis. Two corrections to the 1998 edition are given.     

Synergistic anticancer effects of ganciclovir/thymidine kinase and 5-fluorocytosine/cytosine deaminase gene therapies

BACKGROUND: A bacterial enzyme, Escherichia coli cytosine deaminase, which converts the prodrug 5-fluorocytosine into the toxic drug 5-fluorouracil, and a viral enzyme, herpes simplex virus thymidine kinase, which converts ganciclovir from an inactive prodrug to a cytotoxic agent by phosphorylation, are being actively investigated for use in gene therapy for cancer. The purpose of this study was to determine whether combining these prodrug-activating gene therapies might result in enhanced anticancer effects. METHODS: Rat 9L gliosarcoma cells were transfected with plasmids containing the E. coli cytosine deaminase gene (9L/CD cells), with plasmids containing the herpes simplex virus thymidine kinase gene (9L/TK cells), or with both expression plasmids (9L/CD-TK cells). The drug sensitivities of the cell lines were evaluated; in addition, the sensitivities of 9L and 9L/CD-TK cells mixed in varied proportions were measured. The effects of prodrug treatment on 9L/CD-TK tumor growth (i.e., size and volume) in nude mice were monitored. The isobologram method of Loewe and the multiple drug-effect analysis method of Chou-Talalay were used to measure the interaction between the two prodrug-activating gene therapies. To elucidate the mechanism of interaction, the phosphorylation of ganciclovir in 9L/CD-TK cells after varying prodrug treatments was studied. RESULTS AND CONCLUSIONS: The presence of transfected cytosine deaminase and thymidine kinase genes in 9L gliosarcoma cells reduced cell survival, both in vitro and in vivo, following treatment with the relevant prodrugs; the effects of the two components appeared to be synergistic and related mechanistically to the enhancement of ganciclovir phosphorylation by thymidine kinase following 5-fluorouracil treatment.