Pharmacodynamic modeling of the electroencephalographic effects of flumazenil in healthy volunteers sedated with midazolam

The purpose of this study was to model pharmacodynamically the reversal of midazolam sedation with flumazenil. Ten human volunteers underwent four different sessions. In session 1, individual midazolam pharmacokinetics and electroencephalographic pharmacodynamics were determined. In sessions 2 and 3, a computer-controlled infusion of midazolam with individual volunteer pharmacokinetic data was administered, targeting a plasma concentration corresponding to a light or deep level of sedation (20% or 80% of the maximal midazolam electroencephalographic effect) for a period of 210 minutes. After obtaining a stable electroencephalographic effect and constant midazolam plasma concentrations, a zero-order infusion of flumazenil was started until complete reversal of midazolam electroencephalographic effect was obtained. The flumazenil infusion was then stopped and the volunteer was allowed to resedate because of the constant midazolam drug effect. The electroencephalographic response was measured during a 180-minute period and analyzed by aperiodic analysis and fast-Fourier transforms. In session 4, a midazolam plasma concentration corresponding to a deep level of sedation was targeted for 210 minutes to examine for the possible development of acute tolerance. No flumazenil was given in session 4. For a light sedation level, with a mean midazolam plasma concentration of 160 +/- 64 ng/ml, the mean half-life of the equilibration rate constant of flumazenil reversal is 5.0 +/- 2.5 minutes, and the mean effect site concentration causing 50% of Emax is 13.7 +/- 5.8 ng/ml. For a deep level of sedation, with a mean midazolam plasma concentration of 551 +/- 196 ng/ml, the mean half-life of the equilibration rate constant is 3.9 +/- 1.5 minutes, and the mean effect site concentration causing 50% of Emax is 20.6 +/- 6.8 ng/ml. This study provides an estimate of the magnitude of the blood/central nervous system equilibration delay for flumazenil antagonism of midazolam sedation and further defines the usefulness of the electroencephalogram as a measure of midazolam pharmacodynamic effect.     

Hyperdynamic circulation of cirrhotic rats: role of substance P and its relationship to nitric oxide

BACKGROUND: It has been suggested that excessive formation of nitric oxide (NO) is responsible for the hyperdynamic circulation observed in portal hypertension. Substance P is a neuropeptide partly cleared by the liver and causes vasodilatation through the activation of the endothelial NO pathway. However, there are no previously published data concerning the plasma level of substance P in cirrhotic rats and its relationship to NO. METHODS: Plasma concentrations of substance P and nitrate/nitrite (an index of NO production) were determined in control rats and cirrhotic rats with or without ascites using an enzyme-linked immununosorbent assay and a colorimetric assay, respectively. In addition, systemic and portal hemodynamics were evaluated by a thermodilution technique and catheterization. RESULTS: Cirrhotic rats with and without ascites had a lower systemic vascular resistance (2.6 +/- 0.2 and 3.9 +/- 0.4 mmHg ml(-1) x min x 100 g body weight, respectively) and higher portal pressure (14.6 +/- 0.6 and 11.3 +/- 1.8 mmHg) than control rats (6.5 +/- 0.3 mmHg x ml(-1) x min x 100 g BW and 6.8 +/- 0.2 mmHg, respectively, P < 0.05), and cirrhotic rats with ascites had the lowest systemic vascular resistance. Plasma levels of nitrate/nitrite progressively increased in relation to the severity of liver dysfunction (control rats, 2.7 +/- 0.5 nmol/ml; cirrhotic rats without ascites, 5.6 +/- 1.3 nmol/ml; cirrhotic rats with ascites, 8.3 +/- 2.2 nmol/ml; P < 0.05). Cirrhotic rats with ascites displayed higher plasma values of substance P (57.7 +/- 5.9 pg/ml) than cirrhotic rats without ascites (37.9 +/- 3.1 pg/ml, P < 0.05) and control rats (30.1 +/- 1.0 pg/ml, P < 0.05). There was no significant difference in plasma substance P values between control rats and cirrhotic rats without ascites (P > 0.05). No correlation was found between plasma levels of substance P and nitrate/nitrite (r = 0.318, P > 0.05). CONCLUSIONS: Excessive formation of NO may be responsible, at least partly, for the hemodynamic derangements in cirrhosis. Although substance P may not participate in the initiation of a hyperdynamic circulation in cirrhosis, it may contribute to the maintenance of the hyperdynamic circulation observed in cirrhotic rats with ascites.     

Identification of extractable growth factors from small intestinal submucosa

When implanted as a biomaterial for tissue replacement, selected submucosal layers of porcine small intestine induce site-specific tissue remodeling. Small intestinal submucosa (SIS), as isolated, is primarily an acellular extracellular matrix material. In an attempt to discover the components of small intestinal submucosa which are able to induce this tissue remodeling, the material was extracted and extracts were tested for the ability to stimulate Swiss 3T3 fibroblasts to synthesize DNA and proliferate. Each of the four different extracts of small intestinal submucosa had measurable cell-stimulating activity when analyzed in both a whole cell proliferation assay (alamarBlue dye reduction) and a DNA synthesis assay ([3H]-thymidine incorporation). Proteins extracted from SIS with 2 M urea induced activity profiles in the two assays which were very similar to the activity profiles of basic fibroblast growth factor (FGF-2) in the assays. As well, the changes in cell morphology in response to the extracted proteins mimicked the changes induced by FGF-2. Neutralization experiments with specific antibodies to this growth factor confirmed the presence of FGF-2 and indicated that it was responsible for 60% of the fibroblast-stimulating activity of the urea extract of small intestinal submucosa. Western blot analysis with a monoclonal antibody specific for FGF-2 detected a reactive doublet at approximately 19 kDa and further confirmed the presence of FGF-2. Cell stimulating activity of proteins extracted from SIS with 4 M guanidine was neutralized by an antibody specific for transforming growth factor beta (TGF beta). Changes in the morphology of the fibroblasts exposed to this extract were nearly identical to changes induced by TGF beta. Although no reactive protein band was detected at 25 kDa in nonreduced western blot analysis, several bands were reactive at higher molecular weight. The identity of this TGF beta-related component of small intestinal submucosa is unknown. Identification of FGF-2 and TGF beta-related activities in SIS, two growth factors known to significantly affect critical processes of tissue development and differentiation, provides the opportunity to further elucidate the mechanisms by which this extracellular matrix biomaterial modulates wound healing and tissue remodeling.     

The most frequently prescribed medications in the elderly and their impact on dental treatment

The high prevalence of multiple chronic medical conditions in the elderly and the likelihood of multiple drug therapies dramatically increase the chance of drug-specific adverse effects and drug-drug interactions. This article reviews the age-associated alterations in pharmacokinetics and pharmacodynamics along with the most frequently prescribed medications for the elderly. Adverse drug reactions, drug-drug interactions and oral side effects are reviewed along with the impact these medications may have on dental treatment planning and management.     

An experimental investigation of triboelectrification in cohesive and non-cohesive pharmaceutical powders

A detailed experimental investigation has been undertaken of the triboelectrification process of the pharmaceutical excipient alpha-lactose monohydrate and selected drugs. Particle charge studies involved the design and construction of an apparatus to incorporate pneumatic powder feed, triboelectric charging via a cyclone separator and simultaneous powder charge (Q) and mass (M) measurements using a modified Faraday well. Preliminary studies showed the charging of the selected materials to be unaffected by relative humidity up to 84%, due to the very low hygroscopicity of the powders. Experiments using lactose size fractions with brass, steel and cellulose contact charging surfaces conducted at different feeder gas pressures, gave net electronegative specific charge values (Q/M) for the metal surfaces, and electropositive values for cellulose. Specific charge increased linearly with gas pressure for the metals, and non-linearly for cellulose. Samples of micronised lactose and beclomethasone dipropionate (BDP) showed more tendency than unmicronised samples to adhere to the contact surface which resulted in more complex charging processes. A novel system to analyse the charge and mass data in further detail was developed, giving relative Q/M values at unit time intervals. It is proposed that this will overcome the limitations of reliance on the final net specific charge value. Preliminary results indicated differences in the charging mechanism for lactose in contact with the two metal surfaces.     

Analysis of simian hemorrhagic fever virus (SHFV) subgenomic RNAs, junction sequences, and 5' leader

Full-length simian hemorrhagic fever virus (SHFV) genome RNA (about 15 kb in length) and six subgenomic RNAs, ranging in size from 0.65 to 4.7 kb, were detected by Northern blot hybridization in MA104 cytoplasmic extracts with a 3' genomic antisense probe. The 5' regions of the two smallest subgenomic RNAs (RNAs 6 and 7) were cloned and sequenced. Sequence analysis indicated that these two RNAs contained a common 5' leader sequence joined to the subgenomic RNA bodies via a highly conserved junction sequence; the junction sequence of RNA 7 was 5'-TTAACC-3', while that of RNA 6 was 5'-TCAACC-3'. The complete 5' leader sequence (208 nt) was obtained from genomic RNA. The genomic 5' junction sequence is identical to that of RNA 7. Northern blot hybridization with an antisense 5' leader probe confirmed the presence of the complete leader sequence in all six species of subgenomic RNA. In its virion morphology, genome size, gene order, and replication strategy, SHFV is most similar to viruses such as equine arteritis virus, lactate dehydrogenase-elevating virus, and Lelystad virus/porcine respiratory and reproductive syndrome virus.