A MODEL BASED ASSESSMENT OF REDISTRIBUTION DEPENDENT ELIMINATION AND BIOAVAILABILITY OF RIFABUTIN

The autoinduction characteristic of rifabutin (RIF) following multiple oral dosing was investigated via pharmacokinetic modeling. A two-compartment model with first-order absorption was fit to plasma RIF data obtained from a study conducted in healthy normal volunteers following both a single and multiple oral doses. Parameter estimates showed an elimination rate constant (k₁₀) of about 0·12--0·14 h⁻¹ which was independent of the single or multiple-dosing condition. The lower-than-expected drug accumulation following multiple dosing seems to suggest that prolonged dosing perturbs the linear kinetic system. However, this analysis has shown no significant changes (p>0·05) in the rate constants describing RIF absorption, tissue distribution/redistribution, and elimination. The mean rate of drug redistribution from the tissue compartment (k₂₁; 0·04--0·06 h⁻¹) was twofold to threefold lower than k₁₀, and, with a large steady-state distribution volume (V_ss/F after a single dose, 1630 L), RIF elimination appears to be dependent on drug redistribution. This hypothesis was further supported by a significant correlation (p<0·01) BETWEEN RIF TISSUE REDISTRIBUTION (k₂₁) and terminal disposition phase rate (λ_z) constants. The redistribution dependent elimination of RIF also helps explain the stability of the terminal half-life under both single and multiple-dosing paradigms. Urinary excretion of RIF and its 25-O-deacetyl metabolite totalled less than 7% of the oral dose following single dosing, and decreased to about 4% after multiple dosing. For individual patients, the decrease in urinary recovery of the 25-O-deacetyl metabolite was directly proportional to the decrease in urinary RIF recovery. In addition, both estimates of the model intercepts (A and B) were lower following multiple dosing. Further analyses revealed a linear relationship between A and B intercepts, and also between the urinary RIF recovery and the B intercept. These relationships, in conjunction with the lack of significant increase in the rate of elimination, indicate that induction of presystemic extrahepatic metabolism and/or decrease in the extent of oral absorption may be the primary causes for the lower-than-expected systemic RIF plasma levels after multiple oral dosing.     

Neurogenic orthostatic hypotension induced by tizanidine

Clinical Autonomic Research -     

Response to: Human papillomavirus (HPV) vaccine safety concerning POTS,CRPS and related conditions

Clinical Autonomic Research -     

Involvement of ryanodine receptors in neurotrophin-induced hippocampal synaptic plasticity and spatial memory formation

Ryanodine receptors (RyR) amplify activity-dependent calcium influx via calcium-induced calcium release. Calcium signals trigger postsynaptic pathways in hippocampal neurons that underlie synaptic plasticity, learning, and memory. Recent evidence supports a role of the RyR2 and RyR3 isoforms in these processes. Along with calcium signals, brain-derived neurotrophic factor (BDNF) is a key signaling molecule for hippocampal synaptic plasticity and spatial memory. Upon binding to specific TrkB receptors, BDNF initiates complex signaling pathways that modify synaptic structure and function. Here, we show that BDNF-induced remodeling of hippocampal dendritic spines required functional RyR. Additionally, incubation with BDNF enhanced the expression of RyR2, RyR3, and PKMζ, an atypical protein kinase C isoform with key roles in hippocampal memory consolidation. Consistent with their increased RyR protein content, BDNF-treated neurons generated larger RyR-mediated calcium signals than controls. Selective inhibition of RyR-mediated calcium release with inhibitory ryanodine concentrations prevented the PKMζ, RyR2, and RyR3 protein content enhancement induced by BDNF. Intrahippocampal injection of BDNF or training rats in a spatial memory task enhanced PKMζ, RyR2, RyR3, and BDNF hippocampal protein content, while injection of ryanodine at concentrations that stimulate RyR-mediated calcium release improved spatial memory learning and enhanced memory consolidation. We propose that RyR-generated calcium signals are key features of the complex neuronal plasticity processes induced by BDNF, which include increased expression of RyR2, RyR3, and PKMζ and the spine remodeling required for spatial memory formation.     

Intraoral Luting: Modified Prosthetic Design to Achieve Passivity,Precision of Fit,and Esthetics for a Cement‐Retained,Implant‐Supported Metal‐Resin‐Fixed Complete Denture

An intraoral luting technique between electroformed gold copings and a metallic framework for a cement‐retained, implant‐supported metal‐resin‐fixed complete‐denture is presented. The peculiarity is the different prosthetic design with the metallic framework that was 1.5 mm shorter than the margin of the electroformed copings. As a consequence, the conventional thick prosthesis margin (electroformed copings, cement for the luting phase, framework) was modified into a thin electroformed prosthesis seal (0.3 mm) just beyond the apical limit of the esthetic material. Passive fit between the framework and the electroformed gold copings was achieved during the intraoral luting phase. The procedure was efficient and standardized and enhanced esthetics.     

Release of naltrexone on buccal mucosa: permeation studies, histological aspects and matrix system design.

Transbuccal drug delivery has got several well-known advantages especially with respect to peroral way. Since a major limitation in buccal drug delivery could be the low permeability of the epithelium, the aptitude of NLX to penetrate the mucosal barrier was assessed. Ex vivo permeation across porcine buccal mucosa 800 microm thick was investigated using Franz type diffusion cells and compared with in vitro data previously obtained by reconstituted human oral epithelium 100 microm thick. Both fluxes (Js) and permeability coefficients (K(p)) are in accordance, using either buffer solution simulating saliva or natural human saliva. Permeation was evaluated also in presence of chemical enhancers or iontophoresis. No significant differences in penetration rate were observed using chemical enhancers; in contrast, Js and K(p) were extensively affected by application of electric fields. Tablets, designed for Naltrexone hydrochloride (NLX) administration on buccal mucosa, were developed and prepared by direct compression of drug loaded (56%) poly-octylcyanocrylate (poly-OCA) matrices. NLX is slowly discharged from buccal tablets following Higuchian kinetic. Histologically, no signs of flogosis ascribable to NLX and/or poly-OCA were observed, while cytoarchitectural changes due to iontophoresis were detected. Buccal tablets containing NLX may represent a potential alternative dosage form in addiction management.     

Quantitative detection of molecular markers ProEx C (minichromosome maintenance protein 2 and topoisomerase IIa) and MIB‐1 in liquid‐based cervical squamous cell cytology

BACKGROUND.

In this study, the authors conducted a comparative quantitative evaluation of the proliferation markers ProEx C (an aberrant S‐phase induction marker, human papillomavirus E6‐E7 correlated) and MIB‐1 in squamous intraepithelial lesions (SIL) to identify a biomolecular profile informative for the diagnosis of high‐grade SIL/cervical intraepithelial neoplasia 3 or greater that was complementary to the morphologic Papanicolaou (Pap) test (“biomolecular Pap test”).

METHODS.

After the cytologic diagnosis, reflex immunocytochemistry was carried out on 76 unstained SurePath cell samples (20 routine samples that were negative for intraepithelial lesion or malignancy and 56 positive samples that were selected with matching histology). Both a morphometric analysis with a software imaging analysis system and a quantitative analysis of atypical squamous clusters were performed.

RESULTS.

The quantitative evaluation revealed an excellent, direct correlation between the 2 markers, although ProEx C was more selective and more informative for the progression of low‐ and moderate‐grade lesions, because it only revealed cells in aberrant S‐phase cell cycle. The quantitative morphometric analysis revealed the increased presence of atypical, positive clusters and the percentage of positive cells within, both paralleling the severity of the lesions. The threshold of a 3% ProEx C‐positive nuclear area was useful for splitting lesions into groups with a low risk or high risk of progression.

CONCLUSIONS.

Both ProEx C and MIB‐1 were valid proliferation markers in cytologic preparations, and nuclear positivity was quantified successfully by using computer‐assisted analysis. The analysis of atypical clusters may be a valuable tool in the diagnosis of SIL. The presence of atypical clusters and their positivity for proliferation markers are good first‐glance indicators of lesion grade. Cancer (Cancer Cytopathol) 2008. © 2008 American Cancer Society.