Trade Herbal Products and Induction of CYP2C19 and CYP2E1 in Cultured Human Hepatocytes

Abstract: The aim of this study was to evaluate in vitro the dose‐dependent induction potential of six commonly used trade herbal products on CYP2C19 and CYP2E1 metabolic activities in cultured human hepatocytes. S‐mephenytoin and chlorzoxazone were used as specific CYP substrates, respectively, and rifampicin was used as a positive induction control for both enzymes. The hepatocytes were exposed to herbal extracts in increasing and biological relevant concentrations for 72 hrs and CYP substrate metabolites were quantified by validated HPLC methodologies. The major findings were that St John's wort was the most potent CYP‐modulating herb, showing a dose‐dependent induction/inhibition of both CYP2C19 and CYP2E1, with induction at low dosages and inhibition at higher. Ginkgo biloba showed an induction/inhibition profile towards CYP2C19 which was similar but weaker than that observed for St John's wort. If cooperative mechanisms are involved is still an open question. Common sage induced CYP2C19 in a log‐linear dose‐dependent manner with increasing concentrations. Common valerian was a weak inducer of CYP2C19, while horse chestnut and cone flower were characterized as non‐inducers of CYP2C19. Only St John's wort showed an inductive effect towards CYP2E1. In addition to St John's wort, Gingko biloba and common sage should be considered as possible candidates for clinically relevant drug‐herb interactions with selected CYP2C19 substrates.     

Clinical characteristics of severe peripheral neuropathy induced by docetaxel (Taxotere)

Background: Docetaxel, a semi-synthetic taxane may cause a usuallymild sensory neuropathy. We describe the clinical characteristics of fivepatients who developed a more severe neuropathy following treatment withdocetaxel.Patients and methods: All patients were treated in phase II studieswith 100 mg/m² docetaxel in three weekly cycles, withoutsteroid administration.Results: The clinical picture in these patients was dominated by asensory neuropathy, but in one case severe weakness was present. Anotherpatient developed Lhermitte's sign. Signs and symptoms are usually reversibleafter discontinuation of docetaxel administration, but in three patientssymptoms worsened for some time after the end of treatment before improvementoccurred.Conclusion: Severe docetaxel neuropathy may especially occurfollowing treatment with cumulative dosage over 600 mg/m²; inpatients treated with this dosage a moderate or severe neuropathy may not berare.     

An investigation of the potential for laser nerve welding.

Suture repair of a severed peripheral nerve is cumbersome, presents a focus for infection and neuroma formation, and does not always produce adequate stump alignment. An alternative form of repair is laser nerve welding, which is attractive because it does not introduce foreign material into the anastomotic site, it forms a circumferential seal, and it can be performed in difficult-to-reach areas. Laser repair has not been widely accepted both because the effect of laser irradiation on intact nerves is not well documented, and the anastomotic strength of the weld has been inferior to suture repair. In the first part of the present study, rat sciatic nerves were exposed and irradiated with increasing intensities from a Sharplan CO2 and KTP laser to document nerve damage as recorded by decreases in the peak compound action potential. A new technique of laser repair (S-Q weld) was then developed that involved harvesting subcutaneous tissue from the adjacent dermis, wrapping it around the two opposed nerve stumps, and lasering it to the epineurium to effect a weld. The strength of the S-Q weld (6.1 grams) was considerably greater than that produced by laser welding alone. The third phase of the study compared regeneration at 2 months in severed rat sciatic nerves repaired by either microsuture or S-Q weld. Analysis of the compound action potential values indicated that the number of regenerating fibers after laser repair was greater than that after suture repair, although a significant difference could not be demonstrated.(ABSTRACT TRUNCATED AT 250 WORDS)     

Erythropoietic protoporphyria and pretransplantation treatment with nonbiological liver assist devices.

Erythropoietic protoporphyria (EPP) is a disease of the heme metabolism due to a deficiency of ferrochelatase, leading to accumulation of protoporphyrin (PPIX) in the erythrocyte (red blood cell [RBC]). The major clinical manifestation in EPP is photosensitivity; however, in a small number of patients liver failure is a significant complication and liver transplantation is the only treatment option. Damage to both abdominal skin and organs occurs when exposed to operating light; however, this problem can be ameliorated by the use of filters that block the transmission of light with wavelength below 470 nm. A more unusual but very serious complication postoperatively is severe motor neuropathy, with few or no known acute available precautions. An effective treatment option is needed to manage EPP crises and to prevent complications after liver transplantation. We successfully treated a patient with EPP-induced liver failure with the molecular adsorbents recirculating system (MARS) and Prometheus in independent sessions. Following treatment with MARS we found a 9.1% reduction of the RBC-PPIX concentration and a 5.9% reduction after treatment with the Prometheus system. Plasmapheresis made a reduction in RBC-PPIX concentration of 0.8%. Following treatment sessions with MARS and Prometheus, the clinical condition was markedly improved and orthotopic liver transplantation was performed without further complications. In conclusion, extracorporeal therapy with MARS or Prometheus seems to be efficient in reducing RBC-PPIX concentration in comparison to plasma exchange.     

Sphingosine 1 phosphate induces the chemotaxis of human natural killer cells. Role for heterotrimeric G proteins and phosphoinositide 3 kinases

We have examined the effect of sphingolipids on the chemotaxis of human natural killer (NK) cells. Messenger RNA for Edg-1, Edg-6 and Edg-8 but not Edg-3, are expressed in these cells. Sphingosine 1 phosphate (SPP), dihydro SPP (DHSPP) or the CC chemokine RANTES (CCL5), but not sphingosine induces the chemotaxis of these cells. Pertussis toxin inhibits the chemotaxis induced by these ligands. Permeabilization of NK cells with streptolysin O (SLO) and introduction of blocking antibodies to the heterotrimeric G proteins, showed that Galpha(i2), Galpha(s), Galpha(q/11) or Galpha(13) mediate the chemotaxis of SPP, whereas Galpha(i2), Galpha(o) or Galpha(q/11) mediate the chemotaxis of DHSPP. Galpha(i2), Galpha(o), Galpha(s), Galpha(q/11), Galpha(z) or Galpha(12 )mediates RANTES-induced NK cell chemotaxis. Further analysis showed that phosphoinositide 3 kinase (PI3K) inhibitors wortmannin and LY294002 inhibit NK cell chemotaxis induced by SPP, DHSPP or RANTES. Blocking antibody to PI3Kgamma inhibits the chemotaxis induced by the three ligands, whereas anti-PI3Kbeta was without effect. In contrast, SPP and DHSPP recruit PI3Kbeta isozyme into NK cell membranes, suggesting that although this isoform is not involved in chemotaxis, it is activated by these phospholipids.     

Simultaneous quantitation of diphtheria and tetanus antibodies by double antigen, time-resolved fluorescence immunoassay

A dual, double antigen, time-resolved fluorescence immunoassay (DELFIA) for the simultaneous detection and quantitation of diphtheria (D) and tetanus (T) antibodies in sera has been developed. In the double antigen format one arm of the antibody binds to antigen coated microtitre wells and the other arm binds to labelled antigen to provide a fluorescent signal. This assay was found to be functionally specific for IgG antibodies and showed a good correlation with established toxin neutralization assays. Furthermore, the double antigen set-up was species independent, permitting the direct use of existing international references of animal origin to measure protective antibody levels in humans in international units (IU/ml). The detection limit corresponded to 0.0003 IU/ml with Eu³⁺-labelled toxoids and to 0.0035 IU/ml using Sm³⁺-labelled toxoids. The assay was fast with a high capacity making it a suitable method for serological surveillance studies.     

Detection and identification of group B streptococci by use of pigment production

Pigment production by group B streptococci (GBS) is a useful test for identification of the organisms. The test is positive in 99.5% of beta-haemolytic strains. No false-positives are noted. Non-haemolytic strains do not produce pigment. Islam's media less agar can be used as a one-step broth detector of GBS in mixed cultures. This may have application for the detection of GBS in women in labour. When used as an identification system for GBS, serum-starch broth can be further modified by reduction of serum and starch concentrations by at least 80%.     

Polycystin-1, the product of the polycystic kidney disease 1 gene, co-localizes with desmosomes in MDCK cells

Polycystin-1 is a novel protein predicted to be a large membrane-spanning glycoprotein with an extracellular N-terminus and an intracellular C-terminus, harboring several structural motifs. To study the subcellular localization, antibodies raised against various domains of polycystin-1 and against specific adhesion complex proteins were used for two-color immunofluorescence staining. In Madine Darby canine kidney (MDCK) cells, polycystin-1 was detected in the cytoplasm as well as co-localizing with desmosomes, but not with tight or adherens junctions. Using confocal laser scanning and immunoelectron microscopy we confirmed the desmosomal localization. By performing a calcium switch experiment, we demonstrated the sequential reassembly of tight junctions, subsequently adherens junctions and finally desmosomes. Polycystin-1 only stained the membrane after incorporation of desmoplakin into the desmosomes, suggesting that membrane-bound polycystin-1 may be important for cellular signaling or cell adhesion, but not for the assembly of adhesion complexes.     

Terbutaline Depot Tablets in Asthma

A sustained release preparation of terbutaline sulphate has been formulated (Bricanyl® depot tablets) in order to extend the duration and accordingly change the dosage regimen to twice a day. This presentation gives a summary of a clinical trial performed in order to study effect and side effects of terbutaline depot tablets 7.5 mg twice a day compared to terbutaline tablets 5 mg three times a day.
Patients suffering from perennial asthma and with daily requirement of asthma medicine were accepted for the study. The trial was a double-blind cross-over, double dummy and randomized. The tablets were given in two consecutive periods of 7 day's duration each. The effect of terbutaline depot tablets was equal to the effect of the ordinary terbutaline tablets. The indication for using depot tablets in the basic treatment of bronchial asthma is a better patient compliance due to medication twice a day. Furthermore in patients with unstable bronchial asthma and in patients with morning dips in PEF the more stable plasma concentration may perhaps keep the patients in a more steady state.