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Integrins α4β1/ α9β1 are important in the pathogenesis and progression of inflammatory and autoimmune diseases by their roles in leukocyte activation and trafficking. Natalizumab, a monoclonal antibody selectively targeting α4β1 integrin and blocking leukocyte trafficking to the central nervous system, is an immunotherapy for multiple sclerosis (MS). However, due to its adverse effects associated with chronic treatment, alternative strategies using small peptide mimetic inhibitors are being sought. In the present study, we synthesized and characterized visabron c (4–4), a backbone cyclic octapeptide based on the sequence TMLD, a non-RGD unique α4β1 integrin recognition sequence motif derived from visabres, a proteinous disintegrin from the viper venom. Visabron c (4–4) was selected from a minilibrary with conformational diversity based on its potency and selectivity in functional adhesion cellular assays. Visabron c (4–4)’s serum stability, pharmacokinetics, and therapeutic effects following ip injection were assessed in an experimental autoimmune encephalomyelitis (EAE) animal model. Furthermore, visabron c (4–4)’s lack of toxic effects in mice was verified by blood analysis, tissue pathology, immunogenicity, and “off-target” effects, indicating its significant tolerability and lack of immunogenicity. Visabron c (4–4) can be delivered systemically. The in vitro and in vivo data justify visabron c (4–4) as a safe alternative peptidomimetic lead compound/drug to monoclonal anti-α4 integrin antibodies, steroids, and other immunosuppressant drugs. Moreover, visabron c (4–4) design may pave the way for developing new therapies for a variety of other inflammatory and/or autoimmune diseases.

Apomorphine (APO), a potent treatment for Parkinson's disease, is only administered parenterally either as intermittent injections or as an infusion. This is due to extensive hepatic “first pass” metabolism. Prolonged delivery through buccal mucosa may be potential substitute for parenteral infusions. To investigate this concept of buccal mucosal delivery, permeability ex vivo studies were performed through excised porcine buccal mucosa by utilizing Ussing diffusion chamber. Permeability rates were assessed for APO from simulated saliva medium at pH 7.4 as well as with utilization of different permeability modifying methods. Lowering the pH to 5.9 decreased permeability rate six-fold, while addition of ethanol : propylene glycol solution elevated it four-fold. Addition of nano-scale lipospheres to the donor compartment delayed the accumulation of APO at the receiver side, prolongating the lag-time from one to approx. three hours. These findings were strengthened by results obtained with co-administration of permeability markers (standards) atenolol and metoprolol. Simulation of the obtained permeability rates to in vivo setup in human showed therapeutically relevant plasma levels when using the outcomes of the current study. These findings verify the novel concept of APO prolonged release buccal administration as a noninvasive substitute for parenteral infusions in treating Parkinson's disease.

Contrary to human, porcine mucosa of the inner side of the lip is parakeratinized. Thus, although desirable due to its large surface area, it does not closely resemble human buccal mucosa to be considered a suitable model for systemic drug delivery research. Nevertheless, it can be utilized for comparative screening of topical or systemic delivery of bioactive agents, mostly lipophilic such as cannabinoids.

Delivery of drugs through oral mucosa enables bypass of the gastrointestinal tract and “first pass“ metabolism in the liver and the gut. Thus, a higher and less variable bioavailability can be obtained. Mechanisms of this administration route for cannabidiol were investigated in the current research in pigs. Results show that cannabidiol has substantially low permeability rate over 8 h through oral mucosa and accumulates significantly within it. Furthermore, following the removal of the delivery device, residual prolongation of release from the oral mucosa into systemic blood circulation continues for several hours. This method of delivery enabled acquisition of clinically relevant plasma levels of cannabidiol. The absorption profile indicates that cannabidiol, as well as other lipophilic molecules, should be delivered through oral mucosa for systemic absorption from a device that conceals the drug and prevents its washout by the saliva flow and subsequent ingestion into gastrointestinal tract.

Insulin-dependent type-1 diabetes (T1D) is driven by autoimmune β-cell failure, whereas systemic resistance to insulin is considered the hallmark of insulin-independent type-2 diabetes (T2D). In contrast to this canonical dichotomy, insulin resistance appears to precede the overt diabetic stage of T1D and predict its progression, implying that insulin sensitizers may change the course of T1D. However, previous attempts to ameliorate T1D in animal models or patients by insulin sensitizers have largely failed. Sensitization to insulin by MEthyl-substituted long-chain DICArboxylic acid (MEDICA) analogs in T2D animal models surpasses that of current insulin sensitizers, thus prompting our interest in probing MEDICA in the T1D context. MEDICA efficacy in modulating the course of T1D was verified in streptozotocin (STZ) diabetic rats and autoimmune nonobese diabetic (NOD) mice. MEDICA treatment normalizes overt diabetes in STZ diabetic rats when added on to subtherapeutic insulin, and prevents/delays autoimmune T1D in NOD mice. MEDICA treatment does not improve β-cell insulin content or insulitis score, but its efficacy is accounted for by pronounced total body sensitization to insulin. In conclusion, potent insulin sensitizers may counteract genetic predisposition to autoimmune T1D and amplify subtherapeutic insulin into an effective therapeutic measure for the treatment of overt T1D.

Piperine is an alkaloid naturally found in black pepper with a myriad of pharmacological attributes. Piperine's most far reaching indication is drug absorption enhancment, with supportive data regarding its ability to inhibit first pass effect mechanisms. However, alongside these findings, the role of piperine as an absorption enhancer is undermined with publications stating an apparent effect of a metabolic inducer. The aim of this work is to investigate the effect of repeated administration of piperine in a lipid-based formulation ,on oral absorption of cannabidiol (CBD), compared to acute piperine dosing. The effect of piperine on CBD absorption was determined pre-clinically in the freely moving rat model. Results of this work demonstrated that there was no significant difference in piperine's effect, when given chronically or in a single dose regimen. Both groups resulted in approximate 2.5-fold increase in oral bioavailability of CBD compared to control group without piperine.

Introduction: Sativex® spray is clinically utilized to deliver delta9-tetrahydrocannabinol and cannabidiol to oral mucosa for systemic absorption. We challenge the consensus that the mechanism of absorption following the oro-mucosal application occurs via the buccal tissue. Areas covered: Correctness of the consensus of this absorption pathway arose when reviewing publications regarding the influence fed versus fasting states have on pharmacokinetics of these cannabinoids administered to the oral mucosa. This finding is more suitable for peroral administration, where stomach content affects the absorption profile. We hypothesize that these cannabinoids are ingested and absorbed in the gastrointestinal tract. Expert opinion: Although clinical importance of Sativex® is not disputed, the wide acceptance of its being a successful example of drug delivery through oral mucosa is questionable. Sativex® acts as an example for other drugs delivered to oral mucosa for systemic absorption and unintentionally washed by the saliva flow into the gastrointestinal tract. Delivery of each medicine through oral mucosa should be validated in-vivo to ensure this route to be the predominant one. Revealing the underlying absorption mechanisms would enable predicting the impact of different physiological parameters such as saliva flow and fed/fasting states on the pharmacokinetics of the delivered medication.

There is a growing clinical interest in developing and commercializing pharmaceutical-grade cannabinoid products, containing primarily tetrahydrocannabinol (THC) and cannabidiol (CBD). The oral bioavailability of THC and CBD is very low due to extensive "first-pass" metabolism. A novel oral THC and CBD formulation, PTL401, utilizing an advanced self-emulsifying oral drug delivery system, was designed to circumvent the "first-pass" effect. In this study, the bioavailability of THC and CBD from the PTL401 capsule was compared with similar doses from a marketed reference oromucosal spray (Sativex ® ). Fourteen healthy male volunteers received, on separate treatment days, either a single dose of PTL401 or an equivalent dose of the oromucosal spray. Blood samples for pharmacokinetic analyses were collected, and safety and tolerability were assessed. PTL401 yielded 1.6-fold higher plasma C max than the equivalent dose of the oromucosal spray, for both THC and CBD. Their relative bioavailability was also higher (131% and 116% for CBD and THC, respectively). Values of T max were significantly shorter for both CBD and THC (median of 1.3 h for PTL401 vs. 3.5 h for the spray). The pharmacokinetic profiles of the active 11-OH-THC metabolite followed the same pattern as THC for both routes of delivery. No outstanding safety concerns were noted following either administration. We conclude that PTL401 is a safe and effective delivery platform for both CBD and THC. The relatively faster absorption and improved bioavailability, compared to the oromucosal spray, justifies further, larger scale clinical studies with this formulation.

Background Amphotericin-B (AMB) is associated with toxicity such as renal impairment, hypokalemia and infusion-related events (IRE). With the advent of AMB lipid formulations and newer antifungal drugs, presenting improved safety profiles, it was suggested that using the conventional deoxycholate (AMB-D) formulation should no longer be regarded acceptable. Objectives Evaluation of real-life incidence of AMB-D-related adverse-drug effects (ADE) and associated costs. Setting Hadassah Hebrew University Medical Center, Jerusalem, Israel, a tertiary 1,100-bed teaching hospital. Methods A 1-year single-center prospective observational study following all patients administered AMB-D. Various parameters related to AMB-D administration were recorded. Main outcome measures Subsequent ADE-related events, discontinuations, switch to alternative antifungals and related resource-utilization were monitored. Results Among 119 patients (60 children, 59 adults) receiving AMB-D, serum creatinine doubling from baseline, hypokalemia and IRE occurred in 14.3 % (15 % in children, 13.6 % in adults), 16.8 % (16.6 % in children, 16.9 % in adults) and 10.9 % (10 % in children, 11.8 % in adults), respectively. AMB-D was discontinued due to an ADE in 12.6 % of patients (6.7 % in children, 18.6 % in adults). The total annual cost associated with AMB-D use was €58,600. Conclusion The clinical as well as economic burden of AMB-D associated ADE, as observed in real-life settings, appears to be manageable. Considering the significant cost implications associated, as suggested by simulated evaluation of an overall theoretic replacement of AMB-D by an equivalent volume of alternative antifungals, total abandonment of AMB-D appears unjustified.

Beta-lactam antimicrobials, commonly used in both veterinary and human medicine, generally present short biologic half-lives, whereas their activity is enhanced as pathogen exposure is prolonged. These properties necessitate multiple-dose regimens of standard dosage forms, thereby hampering pet owner adherence, frequently resulting in therapeutic failure. This study presents a novel controlled-release gastroretentive oral drug delivery system for beta-lactams with which single-dose administration provides an effective antimicrobial course, optimizing pharmacokinetic (PK)-pharmacodynamic (PD) profiles, minimizing adverse effects and emergence of antimicrobial resistance and facilitating adherence. Our prototype sustained-delivery swelling-tablet (SDST), based on a degradable hydrophilic polymeric matrix, was designed to enable continuous input of these drugs to their absorption sites over several days. Several SDST formulations of the beta-lactam amoxicillin were evaluated in in vitro dissolution studies. Two formulations were selected for further in vivo canine studies, for determination of gastric retention and PK-PD profiling. Prolonged gastric retention times maintaining allowed for maintained effective drug concentrations against many clinically relevant pathogens for more than 48 h for one formulation and more than 5 days for the other. Both SDST formulations offer significant advantages over standard immediate-release therapy in achieving PK-PD goals and enhancing adherence. The prototypical formulations represent a novel platform which may be modified to meet various clinical requirements.

Dosage forms of antimicrobials play a critical role in facilitating the attainment of pharmacokinetic-pharmacodynamic (PK-PD) targets as well as adherence in both veterinary and human medicine. The purpose of this study was to develop and evaluate a controlled-release subcutaneous amoxicillin implant for single-dose therapy of large ruminants such as goats, sheep, and deer. The degradable implant, designed to attain PK-PD targets following single administration, was evaluated for amoxicillin release rate and time-concentration profile. In vitro release studies demonstrated constant-rate release of approximately 40% of amoxicillin content within 96 h. In an in vivo study in goats, serving as a model for target animals, a serum concentration of approximately 0.4 mg/L was achieved within 8 h of implant insertion and maintained for >6 days. In comparison, in control goats given a standard single intramuscular amoxicillin dose of 15 mg/kg, amoxicillin peaked at 1.2 mg/L after 1 h, rapidly dropping to below detection level at 8 h. These results suggest that the proposed implant offers a unique modality for animal caregivers to conveniently administer a full antimicrobial course following a single dose of an efficient PK-PD-optimized dosage form. Furthermore, modifications of implant composition may allow for tailoring of its characteristics to various PK, PD, microbiological, and clinical requirements.

Guaifenesin is a very commonly used and prescribed oral expectorant drug. However, its mechanism of action is not completely elucidated and the available information is limited. The purpose was to evaluate whether guaifenesin action on respiratory tract secretion is mediated through a reflex stimulation of the gastric mucosa or by the systemic exposure due to the absorption of the drug to the blood circulation.Guaifenesin was administered to rats by various routes: intravenous bolus, oral gavage, and gastric, jejunal or cecal infusions (through surgically implanted catheters). Phenol red respiratory tract secretion (after intraperitoneal or intravenous injection) was used as a marker for degree of expectorant action. Administration of saline by gavage was used as control.Respiratory secretion following oral bolus was approximately 2-fold higher (p0.05) than that of control. Following IV administration the increase of respiratory secretion did not occur despite the fact that systemic exposure to guaifenesin was 1.5-fold higher than following oral administration. The abdominal surgery was found to eliminate the effect of guaifenesin although it did not change systemic absorption. Guaifenesin was equally absorbed from all parts of the gastrointestinal tract.It was demonstrated that expectorant action of guaifenesin is mediated by stimulation of the gastrointestinal tract and not by the systemic exposure to the drug.

Gastro-retentive dosage form (GRDF) is a controlled-release modality of drug delivery technology that allows continuous administration to the upper part of the gastrointestinal tract. The manuscript summarizes various aspects that should be considered for the successful implementation of these region-specific delivery systems, including underlying physiological principles, technologies, and performance assessment approaches. In particular it focuses on characterization of potential drug candidates for GRDF and the anticipated pharmacokinetic and pharmacodynamic advantages associated with GRDF administration. These considerations are demonstrated using gabapentin as a representative narrow absorption window drug. The pharmacokinetic model that was developed for description of oral absorption of gabapentin in humans included variable intragastric input functions, saturable absorption kinetics and limited absorption window in the proximal gut. The pharmacokinetic profiles obtained via simulation demonstrated the potential benefits that can be accomplished by GRDF for gabapentin, including dose-proportional absorption, extended duration of absorption and thereby reduced dosing frequency and lowered total daily dose. Such pharmacokinetic modeling and simulation are shown to be an important and useful tool that can be used to optimize the selection of the mode of oral drug administration, including GRDF approach.

Myasthenia gravis (MG) is an autoimmune disorder of the neuromuscular junction. The complexity of the disease and its treatments make MG patients particularly susceptible to adverse effects of drugs. MG is not a painful condition; however, as pain management armamentarium includes drugs from diverse pharmacological groups and with potential for drug-drug interactions, managing pain in patients with MG can be challenging. The underlying disease and the concomitant medications of each patient must be considered and the analgesic treatment individualized. This review presents an update on the various aspects of pain pharmacotherapy in patients with MG, focusing primarily on medications used to treat chronic pain. Drugs discussed are opioids, nonsteroidal anti-inflammatory drugs, antidepressants, anticonvulsants, muscle relaxants, benzodiazepines, intravenous magnesium, and local anesthetics. Drug interactions with agents used for MG treatment (acethylcholinesterase inhibitors, corticosteroids, immunosuppressants) and plasmapheresis are discussed. The clinical usefulness and limitations of each of the drug classes and agents are described.

Objective Metformin is a polar positively charged compound. The aim of the study was to characterize its permeability across the human placenta using the ex vivo placental perfusion model. Methods Selected cotyledons from term placentas were cannulated and dually perfused. Metformin (10 mg/L, 1000 mg/L) and a permeability reference, antipyrine (50 mg/L), were added to the maternal circulation. Samples from maternal and fetal compartments were analyzed for metformin and antipyrine by high performance liquid chromatography (HPLC). The permeation of metformin was also studied using the parallel artificial membrane permeation assay (PAMPA) that was designed to predict passive transcellular permeability of drugs. Results In this study, 15 complete placental perfusion experimental set-ups were performed. The mean percent transport increased as metformin concentrations were raised and it was 11 ± 1.32 and 16.92 ± 0.98 for 10 mg/L and 1000 mg/L, respectively. The transport rate of metformin across the placenta was asymmetric yet, an active efflux against the gradient concentration could not be observed. Using the PAMPA assay, we confirmed that metformin does not cross by passive diffusion. Conclusion The data suggest that metformin permeability across the placenta is mediated by a carrier that transport cationic compounds bi-directionally, with a higher transfer rate from the fetal to the maternal side. Copyright © 2008 John Wiley & Sons, Ltd.

Objective The aim of the study was to quantify and characterize metformin transfer across the human placenta using an ex vivo placental perfusion model. Study design Placentas were obtained from vaginal deliveries or caesarean sections and selected cotyledons were cannulated and dually perfused. Metformin (1 μg/ml) and a permeability reference marker, antipyrine (50 μg/ml), were added to the maternal circulation. Each perfusion experiment was conducted for 180 min while samples were taken from the maternal and fetal compartments. The integrity and viability of the placenta were determined by measuring the flow rates, fetal artery inflow pressure, and hCG production during the experiments. Results Six complete experimental set-ups were completed. The maternal–fetal transport rates for metformin and antipyrine were 10.61 ± 2.85% and 30.98 ± 5.62%, respectively. The clearance index, calculated as the ratio between the permeabilities of metformin and antipyrine, was 0.34 ± 0.05. Conclusion The results indicate that metformin is able to cross the mature human placenta; thus, fetal exposure must be considered when treating pregnant women with metformin.

The purpose of this study was to evaluate the impact of general anesthesia on the lymphatic transport of orally administered drugs. Vitamin D 3 (0.5 mg/kg), a model lipophilic molecule with significant lymphatic transport, was administered to anesthetized rats in close proximity to the lymphatic cannulation procedure. The lymphatic and non-lymphatic absorption of the vitamin in this experimental model was compared to lymph-duct cannulated freely moving conscious rats. The amounts of vitamin D 3 transported via the lymph in the anesthetized animals throughout the time frame of this experimental model (8 h) were 25% lower as compared to the conscious animals, but showed similar absorption kinetics. However, the duration of the anesthesia is limited and thus failed to produce the complete picture of the absorption process. The cumulative percent of the vitamin dose that was recovered in the lymph as well as the vitamin plasma AUC values were both 25% lower in the anesthetized animals as compared to the conscious animals. Hence, the anesthesia did not influence the proportion of the vitamin fraction absorbed via the different pathways. The lymph flow rate was significantly decreased by the anesthesia (threefold), however, higher lymph vitamin concentrations in these animals led to lower differences in the vitamin lymphatic transport (25%) between the models. In conclusion, the anesthetized rat model is suitable for approximating the lymphatic transport. However, the conscious rat model is still required in order to have a more precise and complete measurement of lymphatic transport.

To assess the effects of the unabsorbed fraction of an orally administered antimicrobial drug which enters the colon on the emergence of resistance among the natural microflora, a phenomenon largely overlooked so far despite its clinical importance, especially when sustained release formulations are used.Effects of an orally administered model beta-lactam antibiotic (amoxicillin) on emergence of resistant bacteria were assessed using a microbiological assay for qualitative and quantitative determination of resistant bacteria in fecal samples of rats following gastric administration of the drug to rats for 4 consecutive days. Time- and site-controlled administration of a beta-lactamase to the rat colon was assessed as a potential strategy for prevention the emergence of resistant bacteria following oral administration of incompletely absorbed antimicrobials.Emergence of resistant bacteria was demonstrated following oral administration of amoxicillin to rats, whereas de-activation of the beta-lactam prior to entering the colon, by infusion of a beta-lactamase into the lower ileum, was shown to prevent the emergence of resistant colonic bacteria.This study illustrates the need to consider the emergence of antimicrobial resistance as a goal equally important to microbiological and clinical cure, when designing oral sustained-release delivery systems of antimicrobial drugs.

Uncertainty in the decision-making process for reimbursement of health technologies could be reduced if additional information were available. Although methods to evaluate the monetary value of the uncertainty have been previously described, an economic evaluation of alternative methods to acquire additional information has not yet been thoroughly explored. Should resources be allocated to a retrospective study design or to a randomised controlled trial (RCT) when additional information is deemed justified? We propose an approach for cost-effectiveness analysis of designs of future studies that are required to evaluate health technologies for reimbursement. Biases inherent in study designs are the main factor that differentiates the ability of the studies to predict the technology's benefit. By quantifying this inherent-bias effect, the incremental effectiveness of future studies can be evaluated. Economic consequences of decisions regarding prioritization of the technologies, along with the expected costs incurred by the study's execution, account for the cost component of the equation. Deducting the result retrieved for the retrospective design from that of the RCT design gives the net information benefit.

Nonsteroidal anti-inflammatory drugs, including indomethacin, have been found in both epidemiological and clinical studies to reduce the prevalence and severity of Alzheimer's disease. However, long-term use of indomethacin is limited by significant gastrointestinal and renal toxicities. An indomethacin prodrug that delivers low and continuous blood levels of the drug showed a superior safety profile and similar efficacy in comparison to an equivalent dose of free indomethacin because of limited systemic exposure and preferred brain uptake. The purpose of the present investigation was to evaluate whether sustained systemic input causes an increased brain influx in comparison to rapid input of the drug. Oral indomethacin, indomethacin prodrug, or intravenous indomethacin infusion was administered to rats. The infusion was designed to mimic the plasma indomethacin levels resulting from the prodrug. The resultant blood levels and brain indomethacin uptake were evaluated. The brain indomethacin concentrations 8 h following indomethacin administration were 0.45, 0.3, and 0.31 microg/g after the oral indomethacin, oral prodrug, and intravenous infusion, respectively. The corresponding plasma concentrations were 14.1, 4.1, and 4 microg/ml. Therefore, brain versus plasma indomethacin level ratios were 2.5-fold higher after slow systemic input of indomethacin in comparison to rapid drug input. In conclusion, indomethacin brain uptake was found to be mode of administration-dependent, and a sustained input function increases the drug brain uptake. Thus, these unique results indicate that an appropriate indomethacin controlled release delivery system may induce the desirable brain-related pharmacodynamic effects, while avoiding the concentration-dependent adverse effects. These findings may contribute to improved therapy in Alzheimer's disease.

Indomethacin has been suggested for the treatment of Alzheimer's disease (AD), but its use is limited by gastrointestinal and renal toxicity. To overcome this limitation, D-Pharm Ltd. (Rehovot, Israel) developed DP-155 (mixture of 1-steroyl and 1-palmitoyl-2-{6-[1-(p-chlorobenzoyl)-5-methoxy-2-methyl-3-indolyl acetamido] hexanoyl}-Sn-glycero-3-phosophatidyl [corrected] choline), a lecithin derivative of indomethacin. Safety was tested by daily oral administration of DP-155 or indomethacin to rats in a dose range of 0.007 to 0.28 mmol/kg. The prevalence of gastrointestinal ulceration was significantly lower (10-fold) for DP-155 than for indomethacin, and the ulcerations were delayed. Signs of renal toxicity, namely reduced urine output and increased urine N-acetyl glycosaminidase to creatinine ratio, were 5-fold lower for DP-155. Indomethacin, but not an equimolar dose of DP-155, reduced urine bicyclo-prostaglandin E(2). An equimolar oral dose of DP-155 or indomethacin, administered every 4 h for 3 days, was equally efficacious in reducing the levels of Abeta42 in the brains of Tg2576 mice. Indomethacin was the principal metabolite of DP-155 in the serum. After DP-155 oral administration, indomethacin's half-life in the serum and the brain was 22 and 93 h, respectively, compared with 10 and 24 h following indomethacin oral administration. The brain to serum ratio was 3.5 times higher for DP-155 than indomethacin. This finding explains the efficacy of DP-155 in reducing Abeta42 brain levels, despite the low systemic blood concentrations of indomethacin derived from DP-155. In conclusion, compared with indomethacin, DP-155 has significantly lower toxicity in the gut and kidney while maintaining similar efficacy to indomethacin in lowering Abeta42 in the brains of Tg2576 mice. This superior safety profile highlights DP-155's potential as an improved indomethacin-based therapy for AD.

In Israel, ‘Madjhool’ has become the major date variety, thanks to its large size and pleasant appearance, which attract buyers who pay a price that is double or more than that of other varieties. However, this variety has a short shelf life and a tendency to develop “skin blisters.” Because of these limitations the growers plan to increase the proportion of fruit marketed as “Fresh Madjhool” – dates that are partially dried before delivery. The main physical property that has to be measured and controlled is fruit water content, and a novel instrument has been developed for this, based on the dielectric effect. Four round flat electrodes are manually positioned so that they touch the date and gently press on it. The electrodes and date constitute a unique capacitor. An RF signal is transmitted through the fruit, and its characteristics are correlated to water-content data. Calibration measurements with this instrument indicated an accuracy of ±2% wet basis (wb). This accuracy enables a representative accumulative distribution chart to be drawn, based on measurements on a sample of 50 fruits. On the basis of such charts several managerial quality decisions can be implemented. The device is controlled by a microprocessor that performs data collection and calculates the average water content of the measured sample. Four prototypes were built and have been tested in several warehouses, where they have yielded useful results.

Expandable gastroretentive dosage forms (GRDFs) have been designed for the past 3 decades. They were originally created for possible veterinary use, but later the design was modified for enhanced drug therapy in humans. These GRDFs are easily swallowed and reach a significantly larger size in the stomach due to swelling or unfolding processes that prolong their gastric retention time (GRT). After drug release, their dimensions are minimized with subsequent evacuation from the stomach. Gastroretentivity is enhanced by the combination of substantial dimensions with high rigidity of the dosage form to withstand the peristalsis and mechanical contractility of the stomach. Positive results were obtained in preclinical and clinical studies evaluating GRT of expandable GRDFs. Narrow absorption window drugs compounded in such systems have improved in vivo absorption properties. These findings are an important step towards the implementation of expandable GRDFs in the clinical setting. The current review deals with expandable GRDFs reported in articles and patents, and describes the physiological basis of their design. Using the dog as a preclinical screening model prior to human studies, relevant imaging techniques and pharmacokinetic-pharmacodynamic aspects of such delivery systems are also discussed.

Metformin, a commonly used antidiabetic drug, exerts its glucose-lowering effect due to metabolic activities at several sites of action (biophases), including liver, intestine, muscle cells, and adipocytes. The relative contribution of the individual biophases to the overall glucose-lowering effect is not known. Thus, the aims of this investigation were to study the influence of mode of drug administration on the kinetics of glucose-lowering action of metformin in diabetic rats and identify the contribution of different sites of action to the overall response. Streptozotocin diabetic rats received metformin in crossover fashion via intraduodenal, intravenous, and intraportal routes as bolus dose or infusion regimens designed to yield similar pharmacokinetic profiles. Metformin plasma concentrations and blood glucose levels were measured following each mode of administration. Despite the similarity in the concentration-time profiles obtained for different routes of metformin administration, intraduodenal administration produced larger response than intraportal metformin infusion, and lowest response was observed following intravenous administration. This finding indicates that a significant "first-pass" pharmacodynamic effect, which occurs in the presystemic sites of action (liver and the gastrointestinal wall), contributes to the overall glucose-lowering response of metformin. We applied a combined pharmacokinetic-pharmacodynamic modeling approach to study the nature of the first-pass pharmacodynamic effect. The observed data were successfully described by a novel integrated indirect response pharmacokinetic-pharmacodynamic model that revealed a correlation between the temporal metformin concentrations that transit the portal vein and through the gut wall rather than with drug concentrations that accumulated in the liver and the intestinal wall.

Objective To determine what triggers the use of digoxin therapeutic drug monitoring (TDM) that adheres to established indications and the change in digoxin dosage after the result of monitoring is obtained. Methods This prospective study included 86 patients admitted to 6 medicine wards and 2 intensive cardiac care unit wards in a tertiary-care center. Data on patients' demographics, drug therapy, serum chemistry values, indications for digoxin therapy, indications for ordering the drug assay, timing of the blood sample relative to administration of the last dose, and physicians' decisions after attaining serum digoxin concentrations were collected. Results Eighty-six digoxin assays were evaluated. Indications for the use of a digoxin assay were mostly routine without a clear indication (66%); in only 22% of the assays were orders considered clinically justified. Eleven patients had concentrations >2 ng/mL, but only 8 patients had digoxin intoxication. In only 31% of patients did the medical staff respond to the results. In only 21% of patients with subtherapeutic drug concentrations was there a change in digoxin dose. Conclusions Although there are clear indications for the use of digoxin TDM, physicians seem to routinely order these blood tests. The clinicians did not adequately use the digoxin concentration data to optimize therapy. The assistance of a clinical pharmacist or pharmacologist is warranted for use of the assays, to optimize digoxin therapy.

We studied the differences in pharmacokinetics and pharmacodynamics of the same dose of alendronate administered subcutaneously as intermittent bolus injection or continuous infusion in rats. Two rat models of bone disease were applied. Bone cancer was produced by intratibial inoculation of Walker carcinosarcoma cells, and a model of augmented bone resorption was produced by vitamin D(3) treatment of rats that had undergone thyroidparathyroidectomy. Higher amounts of alendronate were found in bones and in internal organs after bolus drug administration as compared with continuous infusion. Drug effects on plasma calcium levels and on urine calcium excretion were similar in both modes of alendronate administration. Results of the study indicate that the pharmacokinetics (disposition) of alendronate is administration-dependent. The total amount found in bone does not directly represent the amount of alendronate that is pharmacologically active at the site of action in the bone and that affects bone remodeling. The findings suggest that there is no pharmacodynamic advantage for continuous infusion of alendronate. It is concluded that the preferred mode of administration should be selected according to secondary clinical criteria (like incidence of adverse effects and convenience of administration).

We examined the pharmacokinetic (PK) and pharmacodynamic (PD) rationales to develop controlled release (CR) formulations of metformin. Unrestrained diabetic rats received the drug as intravenous bolus (i.v.), oral solution (p.o.), intra-duodenal bolus, 4-h infusion, or intra-colonic bolus. In addition, we developed two CR-gastroretentive dosage forms (CR-GRDF) that released the drug over 3 or 6 h (in vitro), and retained in the rats’ stomach for 8–10 h. Metformin exhibited flip-flop PK. The colonic absorption was low but sustained and was associated with highly variable glucose-lowering effects, thus providing a PK rationale to develop CR-GRDF. In addition, the glucose-lowering effect was greater following p.o. vs. i.v. administration, despite equivalent AUC, indicating a first pass PD effect, thus, adding a PD rationale to develop metformin CR-GRDF. When administered to the diabetic rats, CR-GRDFs produced bioavailability and extent of glucose-lowering effects that were similar to those of the duodenal infusion and p.o. metformin administration. These findings are attributed to the adsorption of metformin to the intestine that yields slow and prolonged absorption even following p.o. administration of drug solution. The data indicates that unless the CR formulation could significantly extend the absorption period, it is not likely to improve glucose-lowering efficacy.

The goal of this investigation was to optimize antilipid therapy by utilizing the combined activity of two lipid-lowering agents, niacin and bezafibrate, and improve their efficacy by targeting them to their presumed presystemic site(s) of action. Thus, continuous duodenal (IGI) administration of the drug combination should augment their efficacy in comparison with intermittent oral treatment. Three hyperlipidemic rat models were studied: Models A and B were based on cholesterol-enriched diets and Model C was based on on acute hyperlipidemia induced by triton injection. Continuous IGI administration of the drug combination [bezafibrate, 30mg/kg/day, and niacin, 40 mg/kg/day for 3 days (Models A and B) or for 18 h (Model C)] produced significantly greater lowering of total cholesterol and triglycerides and elevation of high-density lipoprotein (HDL) cholesterol in comparison with intermittent oral administration of the same doses either given individually or in combination (Models A and B). Similar results were found in Model C for the IGI administration of the drug combination in contrast to oral and also to intravenous infusions. The results indicate that the combination of bezafibrate and niacin produces a significant hypolipidemic response, with major site(s) of action located presystemically. Because a slow-release matrix tablet of the drug combination resulted in a similar magnitude of effect as the IGI administration, the present study provides a pharmacodynamic rationale for the use of a slow-release low-dose niacin-bezafibrate combination.

Purpose. To evaluate the role of different routes and modes of administration of bezafibrate (BZF) on its hypolipidemic activity. We hypothesize that the major sites of BZF action are located presystemically as in other 'gastrointestinal (GI) drugs.' Thus, continuous administration of the drug to the GI tract is expected to augment its efficacy and provides a rationale for an oral sustained release preparation of the drug.

The effect of different routes and modes of administration of niacin (nicotinic acid) on its hypolipidaemic activity has been evaluated. Our working hypothesis was that the major sites of niacin action are located presystemically (i.e. in the gut wall or the liver, or both) which would make niacin a gastrointestinal drug. For such drugs continuous administration to the gastrointestinal tract is expected to augment their efficacy compared with bolus oral administration or parenteral administration. The hypothesis was examined in two rat models of experimentally induced hyperlipidaemia—Model A, based on a cholesterol-enriched diet, and Model B, in which acute hyperlipidaemia is induced by intraperitoneal administration of triton (225 mg kg−1). Continuous administration of niacin into the duodenum at 1.66 mg h−1 (total dose 40 mg kg−1 day−1) for up to 7 days (Model A) or at 2.22 mg h−1 over 18 h (Model B) had significantly greater lipid-reducing effects both on total cholesterol and on triglyceride levels (15–25%) and elevation of high-density lipoprotein (HDL) cholesterol levels than did bolus oral administration of the same dose. Continuous duodenal infusion of niacin also had an even greater lipid-reducing effect than continuous intravenous infusion of the drug at the same rate and dose. The results indicate that the site(s) of action are located presystemically and that continuous duodenal administration of a low dose of niacin (40 mg kg−1) has a greater lipid-lowering effect than a higher dose (200 mg kg−1) administered by peroral bolus administration. These conclusions were validated by administration of a specially designed niacin sustained-release matrix tablet formulation that was non-invasively administered to hyperlipidaemic rats. The hypolipidaemic activity of the sustained-release tablet was of similar magnitude to that resulting from continuous duodenal administration, thus providing a pharmacodynamic rationale for this mode of administration.

pharmacokinetic properties of methadone given by i.v. or epidural routeswerecomparedina rat model of thermal nociception. † Although pharmacokinetically similar, epidural methadone was a more effective analgesic than i.v. methadone. Background.Thepropertiesofmethadonesuggestapotentialadvantageforepiduraloveri.v. administration for pain relief, but little supportive evidence exists. Methods. To investigate the pharmacokinetic and the pharmacodynamic properties of epidural and i.v. methadone, four doses of methadone (0.1, 0.25, 0.5, and 0.75 mg kg 21 ) were investigated by each route in a rat model. The tail-flick and hot water tail immersion test were used for thermal nociception. The magnitude of antinociceptive efficacy was expressed as per cent maximal possible effect (%MPE) of tail withdrawal latency, and the area under the %MPE vs time curve indicated the cumulative antinociceptive effect. A pharmacokinetic model describing the disposition and elimination of methadone was established. Results. The pharmacokinetic profiles of methadone were not significantly different after epidural and i.v. administration. A two-compartment model with saturable elimination provided a good fit of the experimental data. At equivalent doses, epidural methadone produced higher cumulative antinociceptive effect in both thermal models. Supraspinal opioid effect, assessed by pinna reflex presence, was significantly lower with epidural methadone at equivalent doses. The duration of antinociceptive effect was longer with epidural administration of 0.5 and 0.75 mg kg 21 doses. Conclusions. Epidural administration of methadone in rats resulted in systemic exposure similar to that after i.v. administration, but improved thermal antinociceptive efficacy, and reduced supraspinal undesired effects. The findings suggest the presence of local effect at the spinal cord level, in addition to the systemic effect produced by epidural methadone.

High molecular weight drugs in general, and peptides/proteins in particular, are usually delivered by parenteral routes because they are poorly absorbed or degraded in the gastrointestinal tract. Long-term, repeated injections are often required because of the drug's short half-life, and the chronic nature of many diseases. To optimize therapy, it is essential to search for a non-parenteral route of drug administration. We describe here the absorption and the systemic biological effect of model drugs, after instillation into the uterus of the rat. In addition, we describe here results of calcitonin and insulin absorption from controlled-release devices inserted in the rat uterus. The amount and duration of the hypoglycemic and the hypocalcemic effects induced by intrauterine delivery of insulin and calcitonin, respectively, were equivalent to those obtained after subcutaneous injections. The therapy of a number of clinically important diseases could benefit from this discovery.

We have recently discovered that peptides are absorbed biologically intact from the rat uterus. The purpose of this investigation was to assess whether EPO, a large polypeptide hormone (34.5 kDa), can be absorbed from the uterus into the systemic blood circulation in a biologically active form, and to compare the biological effects of continuous transendometrial (TE) administration of EPO with those of the pulsatile mode. Sprague-Dawley rats with gentamicin-induced anemia were treated with recombinant human erythropoietin (r-HuEPO) 200 U/kg per day for 5 days as follows: (1) the daily dose was instilled as a bolus through an indwelling cannula in the uterus; (2) the daily dose was continuously delivered into the uterus at a constant rate of 2 U /h by mini-osmotic pump connected to a similar cannula; (3) the third group received the daily r-HuEPO dose through the jugular vein; and (4) a control group treated with normal saline solution instilled in the uterus (as in group 1). The hematological parameters were measured for 53 days following initiation of r-HuEPO treatment. It was found that the biological effects following bolus daily transendometrial (TE) administration of EPO, expressed by red blood cell count and hematocrit levels, were equipotent to i.v. injection. On the other hand, the biological response following continuous TE EPO administration was significantly better than that observed following pulsatile administration. It is concluded that r-HuEPO is absorbed from the uterus in its bioactive form, with no deleterious effects on the uterine tissue. Slow release of EPO from a TE device may induce a beneficial biological response in comparison to pulsatile delivery.

The purpose of the present investigation was to evaluate whether antiinflammatory drugs affect the pharmacodynamics of theophylline-induced seizures. Adult male Lewis rats were treated with either dexamethasone (DEX), hydrocortisone (HYD), ibuprofen (IBU), or mefenamic acid (MFA), for 4 consecutive days. On the fourth day they received a constant infusion of theophylline (2 mg/min IV) until the onset of maximal seizures. Then, blood and cerebrospinal fluid (CSF) were obtained for theophylline concentration determinations by HPLC. It was found that pretreatment with the corticosteroids DEX and HYD elevated the CSF theophylline concentration required to induce maximal seizures in comparison to the untreated rats (242 +/- 6, 232 +/- 6, and 203 +/- 10 mg/l, respectively, n = 10, p0.05). MFA also increased the CSF theophylline concentration at that end-point in comparison to the controls (p0.01), whereas pretreatment with IBU had no effect (280 +/- 10 MFA, 225 +/- 9 IBU vs. 220 +/- 8 controls, n = 12). The data suggests that concomitant treatment with antiinflammatory drugs, together with theophylline, do not increase the risk for theophylline-induced seizures. Moreover, in certain cases they may elevate the seizure threshold and protect against these hazardous episodes.

The purpose of this investigation was to determine whether paraplegia induced by neoplastic cord compression affects the pharmacodynamics of phenobarbital general anesthesia or of pentylenetet-razol (PTZ)-induced convulsions. Paraplegic rats harboring a thora-columbar epidural tumor, or an identical hindlimb tumor mass, received an i.v. infusion of phenobarbital until the onset of anesthesia. At that point, the phenobarbital concentrations in the CSF and serum were measured. Similarly, PTZ was infused until the onset of maximal seizures. It was found that changes related to systemic tumor growth and newly developed paraplegia due to neoplastic spinal cord compression did not attenuate the pharmacodynamics of phenobarbital. However, sustained paraplegia of 4 days’ duration reduced CNS sensitivity to the hypnotic action of the barbiturate as evidenced by the higher cerebrospinal fluid phenobarbital concentration required to induce anesthesia (170 ± 31 vs 125 ± 20 mg/L; P < 0.05). On the other hand, sustained paraplegia did not affect brain threshold concentration for PTZ-induced seizures.

The aim of this investigation was to assess whether immunosuppression induced by total-body irradiation (TBI) affects the pharmacodynamics of centrally acting drugs. Female Sabra rats were exposed to a single dose of gamma irradiation (5.3 Gy). Four days later, when both the cellular and the humoral immune responses were impaired, they received an i.v. infusion of either phenobarbital (0.8 mg/min), ethanol (16.3 mg/min), pentylenetetrazol (PTZ; 0.618 mg/min), or theophylline (as aminophylline; 2 mg/min). The infusion was stopped at the onset of the pharmacologic end point—loss of righting reflex for the depressant agents or maximal seizures for the stimulant drugs—and the concentrations of the neuroactive drugs at that point were determined. In the ethanol experiment, blood samples were also taken upon awakening. The radiation-induced immunosuppression significantly decreased the CNS sensitivity to the depressant action of both phenobarbital and ethanol as indicated by the higher CSF phenobarbital concentrations required to induce sleep in the irradiated rats versus controls (156±4 vs 133 ±5 mg/L, respectively; P < 0.05), and the higher serum ethanol concentrations at the onset and offset of sleep in the immunosuppressed group versus control values (4.6±0.2 and 1.68±0.01 vs 3.79±0.17 and 1.32±0.9 mg/mL, respectively; P < 0.04). Exposure to TBI did not alter the pharmacodynamics of the two convulsant drugs (theophylline andPTZ).

Seizures, often with fatal outcome, are a manifestation of pronounced theophylline toxicity. Prodromal symptoms are not always apparent, and the seizures are reported to be, in certain cases, refractory to treatment with anticonvulsant drugs. The purpose of this investigation was to examine, by an established animal model, which of the commonly used anticonvulsants can reduce the central nervous system sensitivity to theophylline neurotoxicity and what should be the preferred treatment in cases in which theophylline toxicity is anticipated. The anticonvulsant agents in doses that are found to be effective in other types of experimentally induced seizures in rats, clonazepam 5 mg/ kg, diazepam 5 mg/kg, phenytoin 8 mg/kg, phenobarbital 100 mg/kg, valproic acid 150 mg/kg, and magnesium sulphate 300 mg/kg, or the vehicle (controls) were administered intravenously to Lewis female rats. Thirty minutes later, theophylline was infused at a constant rate of 1.3 mg/min until onset of maximal seizures. Theophylline concentrations in the cerebrospinal fluid, brain, and serum were assayed by a high-performance liquid chromatography method. It was found that pretreatment with either clonazepam, diazepam, phenobarbital, or valproic acid increased the central nervous system thresholds to the theophylline-induced seizures, whereas phenytoin and magnesium sulphate did not attenuate the sensitivity of the brain to the stimulatory action of this widely used bronchodilator. Therefore, whenever theophylline toxicity is suspected, treatment with either diazepam, clonazepam, phenobarbital, or valproic acid can reduce the hazard associated with theophylline-induced seizures.

High molecular weight drugs in general, and peptides in particular, are usually delivered by parenteral route because they are poorly absorbed or degraded in the gastrointestinal tract. To optimize therapy, it is desirable to search for nonparenteral routes of administration and to deliver the drug in a controlled-release fashion. We report here on the absorption and the systemic biological effect of two peptides, insulin and calcitonin, after instillation into the uterus of the rat. Intrauterine delivery was compared to subcutaneous injections in intact and ovariectomized rats. In addition, we describe results of a preliminary study on calcitonin absorption from controlled-release matrices inserted in the rat uterus. The amount and duration of the hypoglycemic and the hypocalcemic effects induced by intrauterine delivery of insulin and calcitonin, respectively, were equivalent to those obtained after subcutaneous injections. The results were similar in intact and ovariectomized rats. It is concluded that the intrauterine administration of both insulin and calcitonin is bioequivalent to subcutaneous injection. The therapy of a number of clinically important diseases could benefit from this discovery.

Chemotherapy with high-dose methotrexate (HD-MTX) is often associated with acute neurotoxicity. We determined whether the altered neuronal function after HD-MTX [such as the reduced regional cerebral metabolic glucose rate (rCMRGlc) and slow electroencephalographic pattern] affects the sensitivity of the CNS to centrally acting drugs: the depressant phenobarbital, which reduces rCMRGlc, and the analeptic agent pentylenetetrazol (PTZ), which elevates rCMRGlc. Adult male Sabra rats received an i.v. infusion of MTX, 0.51 mg/min, to induce neurotoxicity or saline solution for 24 hr. Subsequently, MTX-treated and control groups were infused in one experiment with phenobarbital until loss of the righting reflex and in the second experiment with PTZ until the onset of maximal seizures. HD-MTX did not affect the infused hypnotic dose or serum, brain, and cerebrospinal fluid concentrations of phenobarbital at the onset of anesthesia. The convulsive dose and PTZ concentrations in the serum and brain at the onset of maximal seizures were significantly higher in the HD-MTX-treated animals. These outcomes indicate that HD-MTX and the reduced rCMRGlc that follows this treatment do not contribute to the hypnotic action of phenobarbital. On the other hand, treatment with HD-MTX exhibited anticonvulsant properties as evidenced by the reduced CNS sensitivity to PTZ-induced seizures.

Although abdominal surgery is a routine procedure in clinical practice and in preclinical investigation, little is known regarding its effect on the intestinal absorption of drugs. The aim of this study was to investigate the effect of abdominal surgery on the intestinal absorption of highly lipophilic compounds with different absorption mechanisms following oral administration. The 2 compounds that were tested were biopharmaceutical classification system (BCS) class 2 model lipophilic cannabinoid derivatives, dexanabinol and PRS-211,220. Although dexanabinol is mostly absorbed via passive diffusion to the portal blood, PRS-211,220 is absorbed mostly via lymphatic transport. In this work, we compared the absorption of these compounds after abdominal surgery in rat with the absorption data obtained from naive animals. The outcomes of this investigation showed that the abdominal surgery mostly affected the absorption process on the preenterocyte level, as indicated by the 2-fold increase in the extent of intestinal absorption of dexanabinol, which is a compound with a low degree of intestinal lymphatic transport. However, the lymphatic transport was not affected by the surgical procedure as evident by the absence of change in the extent of absorption of PRS-211,220, which is transported to the systemic circulation mainly by intestinal lymphatics. In conclusion, abdominal surgery can significantly affect the intestinal absorption of lipophilic drugs; however, intestinal lymphatic transport seems to be less affected by the abdominal surgery.

Increased life expectancy is associated with an increased prevalence of chronic diseases and drug consumption. Changes often occur in the medication regimen after hospitalization. The extent and nature of these changes and the adherence of elderly patients have not yet been fully investigated.To investigate the extent and reasons for modifications to the medication regimens of elderly patients and their adherence to treatment during the first month following hospital discharge.This was a prospective cohort study of 198 patients agedor=65 years in the Acute Geriatric Ward, Beilinson Hospital, Rabin Medical Center, Israel. Clinical, demographic and medication regimen data were recorded for all patients at an interview conducted prior to discharge. After 1 month, the patient, caregiver or general practitioner (GP) were interviewed regarding the extent and reasons for modifications to the medication regimen and adherence to treatment.At 1-month post-discharge, on average, 36.7% of patient medications had been modified compared with the discharge prescription. No modification was found in 16% of patients. During the observation month, 62% of prescribed long-term medications were taken without modification as recommended at discharge and during follow-up, 50% of all changes were characterized by the addition of a drug or an increase in dosage, and 26%, 16% and 8% consisted of cancelling, omission or switching within the same medication type, respectively. Seventy percent of medication regimen changes were based on specialists' recommendations or secondary to a change in the patients' medical state, and 13%, 8%, 3% and 6% were as a result of poor adherence, adverse effects, administrative restrictions and other reasons, respectively. There was no correlation between medication regimen change and age, gender, physical function, cognitive function and length of hospital stay. Patients discharged home experienced less regimen modification than those discharged elsewhere (p=0.02). Patients who visited their GP only once experienced less regimen modification (p=0.03). Regression analysis showed that the only factors affecting medication regimen changes were GP visits and chronic diseases (p0.01, R2=0.09). The overall mean adherence among 145 home-dwelling patients was 96.7%. Twenty-seven percent and 6% were under- and over-adherent, respectively, to at least one drug; under-adherence was more widespread than over-adherence. No correlation was found between the overall mean adherence and other clinical parameters or regimen change. However, non-adherence to at least one drug was associated with more medication regimen changes (p=0.001), was more common in patients discharged with prescriptions for seven or more drug types per day (p=0.01) and was associated with failing to visit the patient's GP 1 month after discharge (p=0.02).The majority of elderly patients experienced modifications in their medication regimen during the first month following hospital discharge. Thirty percent of patients were non-adherent to at least one drug. To improve adherence to a hospital medication regimen, patients should be encouraged to visit their GP and the number of long-term drugs should be reduced.

The design of a proper region-specific oral drug delivery system has to take into consideration the differences in anatomy, physiology and absorption characteristics that exist between segments within the gastrointestinal (GI) tract, as well as transit kinetics of the dosage form and the site of drug release within the GI tract.The aim of this review is to examine the various biopharmaceutical aspects of region-specific drug delivery in the GI tract.This review is mainly focused on pharmacokinetic and pharmacodynamic aspects of region-selective drug delivery with special emphasis on drug absorption pathways (para- and transcellular, absorption and efflux transporters, lymphatic uptake etc.). It includes a discussion of gastroretentive systems, colonic delivery, and lipid-based formulations. The review also addresses targeted therapy of local diseases within the GI tract.The advances in pharmaceutical technology allow for the development of a variety of region-specific drug delivery systems for oral administration to optimize local and systemic therapy.

The central nervous system (CNS) sensitivity to the hypnotic (general anesthetic) action of pheno-barbital and to the neurotoxic (convulsive) action of theophylline is greater in rats with acute renal failure than in normal animals, consistent with clinical observations. In the case of phenobarbital, this increased sensitivity can be produced in normal rats by infusion of a solution of the lyophilized dialysate of serum from rats with renal failure. It was hypothesized that the relevant constituent(s) of this dialysate may circulate between the blood and the intestinal lumen and that it (they) can be adsorbed by orally administered activated charcoal and thereby removed from the body. If so, treatment of renal failure rats with activated charcoal should partly reverse the increased CNS sensitivity to phenobarbital and to other drugs similarly affected. Accordingly, rats with renal failure produced by bilateral ligation of ureters were given an aqueous suspension of activated charcoal, about 1 g per kg body weight, orally every 8 hr for six doses. Uremic controls received equal volumes of water. About 2 hr after the last dose, the animals were infused i.v. with phenobarbital to onset of loss of righting reflex or with theophylline to onset of maximal seizures. In the phenobarbital study, charcoal treatment partly reversed the hypothermia associated with renal failure and caused a reduction of creatinine and total bilirubin concentrations in serum. The cerebrospinal fluid (CSF) concentration of phenobarbital at onset of loss of the righting reflex was significantly higher in charcoal treated rats than in their controls. In the theophylline experiment, charcoal treatment had no significant effect on the measured biochemical variables but caused a large increase in the dose and concentrations of theophylline required to produce maximal seizures. In both experiments, administration of activated charcoal caused a reversal of the hyperalgesia associated with renal failure, as determined before drug administration by tail flick latency. These results are consistent with the hypothesis that oral administration of activated charcoal can cause a reduction in the concentration of the circulating endogenous substance(s) that alters the pharmacodynamics of certain drugs in renal failure.

DP-155 is a lipid prodrug of indomethacin that comprises the latter conjugated to lecithin at position sn-2 via a 5-carbon length linker. It is cleaved by phospholipase A2 (PLA)(2) to a greater extent than similar compounds with linkers of 2, 3, and 4 carbons. Indomethacin is the principal metabolite of DP-155 in rat serum and, after DP-155 oral administration, the half-life of the metabolite was 22 and 93 h in serum and brain, respectively, compared to 10 and 24 h following indomethacin administration. The brain to serum ratio was 3.5 times higher for DP-155 than for indomethacin. In vitro studies demonstrated that DP-155 is a selective cyclooxygenase (COX)-2 inhibitor. After it is cleaved, its indomethacin derivative nonselectively inhibits both COX-1 and -2. DP-155 showed a better toxicity profile probably due to the sustained, low serum levels and reduced maximal concentration of its indomethacin metabolite. DP-155 did not produce gastric toxicity at the highest acute dose tested (0.28 mmol/kg), while indomethacin caused gastric ulcers at a dose 33-fold lower. Furthermore, after repeated oral dosing, gastrointestinal and renal toxicity was lower (10- and 5-fold, respectively) and delayed with DP-155 compared to indomethacin. In addition to reduced toxicity, DP-155 had similar ameliorative effects to indomethacin in antipyretic and analgesia models. Moreover, DP-155 and indomethacin were equally efficacious in reducing levels of amyloid ss (Ass)42 in transgenic Alzheimer's disease mouse (Tg2576) brains as well as reducing Ass42 intracellular uptake, neurodegeneration, and inflammation in an in vitro AD model. The relatively high brain levels of indomethacin after DP-155 administration explain the equal efficacy of DP-155 despite its low systemic blood concentrations. Compared to indomethacin, the favored safety profile and equal efficacy of DP-155 establish the compound as a potential candidate for chronic use to treat AD-related pathology and for analgesia.

The purpose of this study was to assess the contribution of lymphatics to the systemic bioavailability of macromolecules following SC administration in a rat model. The rat model included continuous lymph collection from the thoracic lymph duct and concurrent serial blood sampling from freely moving animals. A thoracic lymph duct-jugular vein shunt produced by an implanted connective cannula, and maintained during the recovery period, enabled superior rat survival and prevented lymphatic cannula occlusion. The SC absorption of three macromolecules (bovine insulin, bovine serum albumin, and recombinant human erythropoietin alpha) was assessed in comparison to the non-lymph cannulated control group. For all tested molecules, only minimal amounts (less than 3%) of the SC administered dose were detected in the collected lymph. In the rat model, following SC administration, the macromolecules were absorbed mainly through the blood capillaries with minimal contribution of the lymphatic system to systemic bioavailability. The relatively small elevation in the lymphatic concentration, which occurred in all molecules, may be attributed to the redistribution of the molecules from the blood to the interstitial fluid compartment. These findings are important since rodents are commonly used in preclinical evaluation of macromolecular drugs.

‘Bone-seeking agents’ are drugs characterised by high affinity for bone, and are disposed in bone for prolonged periods of time while maintaining remarkably low systemic concentrations. As a consequence, the bone becomes a reservoir for bone-seeking agents, and a site of both desirable and adverse effects, depending on the pharmacological activities of the specific agent. For some agents, significant systemic effects may also be produced following their prolonged release from bone, a process that is governed mostly by the rate of bone remodelling. This review covers the pharmacokinetic and pharmacodynamic features of bone-seeking agents with different pharmacological properties, including drugs (bisphosphonates, drug-bisphosphonate conjugates, radiopharmaceuticals and fluoride), bone markers (tetracycline, bone imaging agents) and toxins (lead, chromium, aluminium). In addition, drugs that do not possess bone-seeking properties but are used for therapy of bone diseases (such as antibacterials for treatment of osteomyelitis) are discussed, along with targeting of these drugs to the bone by conjugation to bone-seeking agents, local delivery systems, and other approaches. The pharmacokinetic and pharmacodynamic behaviour of bone-seeking agents is extremely complex due to heterogeneity in bone morphology and physiology. This complexity, accompanied by difficulties in human bone research caused by ethical and other limitations, gave rise to modelling approaches to study bone drug disposition. This review describes the pharmacokinetic models that have been proposed to describe the pharmacokinetic behaviour of bone-seeking agents and predict bone concentrations of these agents for different doses and patient populations. Models of different types (compartmental and physiologically based) and of different complexity have been applied, but their relevance to drug effects in the bone tissue is limited since they describe the behaviour of the ‘average’ drug molecule. Understanding of the cellular and molecular processes responsible for the heterogeneity of bone tissue will provide better comprehension of the influence of microenvironment on drug bone disposition and the resulting pharmacological response.

The objective of this study was to evaluate the pharmacokinetic and pharmacodynamic properties of furosemide following gastroretentive dosage from (GRDF) administration. A furosemide (60 mg) GRDF, releasing the drug during 6 hours in vitro, or an immediate-release tablet was administered to healthy male volunteers (N = 14) in a crossover design. Food and liquid intake were standardized; urine was collected, weighed, and assayed for furosemide and sodium concentrations. Pharmacokinetics of furosemide following the GRDF administration, as compared to the tablet, showed lower Cmax and indicated a prolonged absorption phase leading to longer mean residence time in the stomach. The sustained input of the drug significantly improved diuretic and natriuretic efficiencies during the first 5 hours and thereby increased the total effects measured over 24 hours. The unfolding controlled-release GRDF of furosemide improved the pharmacodynamic actions due to the sustained absorption in the stomach and jejunum, which delayed the body's counteractivity to the drug effect.

Controlled release gastroretentive dosage forms (CR-GRDF) enable prolonged and continuous input of the drug to the upper parts of the gastrointestinal (GI) tract and improve the bioavailability of medications that are characterized by a narrow absorption window. CR-GRDF provide a means to utilize all the pharmacokinetic (PK) and pharmacodynamic (PD) advantages of controlled release dosage forms for such drugs. Thus, CR-GRDF may improve therapy with clinically used medications, as well as enable oral administration of drugs, or drug candidates, that hitherto had to be infused parenterally. This manuscript discusses the complexity of the PK and PD factors that influence the treatment benefits of CR-GRDF and summarizes the results of our recent in vivo investigations in animal models (rats and dogs) and in human subjects. We found that a CR-GRDF formulation was superior to the other modes of administration for levodopa and riboflavin, but not for metformin. The PK and PD rationales of GRDFs for the studied drugs are presented and discussed. We conclude that due to the complexity of the PK and PD factors for a certain drug, the rationale for continuous administration obtained by CR-GRDF should be assessed and established in vivo.

The present study aimed to investigate whether the pharmacodynamics of a lipophilic barbiturate, heptabarbital, is altered by liver dysfunction. Heptabarbital was slowly infused i.v., to rats with liver necrosis induced by carbon-tetrachloride, until the rats lost their righting reflex. The concentrations of the drug in serum, brain and CSF were determined in both the diseased animals and solvent-treated controls. Although the concentrations of heptabarbital in the CSF, serum and brain were not significantly different between controls and diseased rats, the total heptabarbital dose required to induce sleep was markedly lower in the diseased animals. Accordingly, the pharmacodynamics of heptabarbital is unaffected in experimental liver dysfunction in rats.