Showing papers in "Journal of Pharmacy and Pharmaceutical Sciences in 2008"

Evolution of nonsteroidal anti-inflammatory drugs (NSAIDs): cyclooxygenase (COX) inhibition and beyond

Abstract: Purpose. NSAIDs constitute an important class of drugs with therapeutic applications that have spanned several centuries. Treatment of inflammatory conditions such as rheumatoid arthritis (RA) and osteoarthritis (OA) starting from the classic drug aspirin to the recent rise and fall of selective COX-2 inhibitors has provided an enthralling evolution. Efforts to discover an ultimate magic bullet to treat inflammation continues to be an important drug design challenge. This review traces the origins of NSAIDs, their mechanism of action at the molecular level such as cyclooxygenase (COX) inhibition, development of selective COX-2 inhibitors, their adverse cardiovascular effects, and some recent developments targeted to the design of effective anti-inflammatory agents with reduced side effects. Methods. Literature data is presented describing important discoveries pertaining to the sequential development of classical NSAIDs and then selective COX-2 inhibitors, their mechanism of action, the structural basis for COX inhibition, and recent discoveries. Results. A brief history of the development of NSAIDs and the market withdrawal of selective COX-2 inhibitors is explained, followed by the description of prostaglandin biosynthesis, COX isoforms, structure and function. The structural basis for COX-1 and COX-2 inhibition is described along with methods used to evaluate COX-1/COX-2 inhibition. This is followed by a section that encompasses the major chemical classes of selective COX-2 inhibitors. The final section describes briefly some of the recent advances toward developing effective anti-inflammatory agents such as nitric oxide donor NO-NSAIDs, dual COX/LOX inhibitors and anti-TNF therapy. Conclusions. A great deal of progress has been made toward developing novel anti-inflammatory agents. In spite of the tremendous advances in the last decade, the design and development of a safe, effective and economical therapy for treating inflammatory conditions still presents a major challenge.

Review of the cosolvency models for predicting solubility of drugs in water-cosolvent mixtures

Abstract: The cosolvency models presented from 1960 to 2007 were reviewed and their accuracies for correlating and/or predicting the solubility of drugs in water-cosolvent mixtures were discussed. The cosolvency models could be divided into theoretical, semi-empirical and empirical models, the first group of models provide basic information from the solution, while the last group of models are good suitable for solubility correlation studies. The simplest cosolvency model, i.e. the log-linear model of Yalkowsky, provides an estimate of drug solubility in water-cosolvent mixtures using aqueous solubility of the drug, whereas the Jouyban-Acree model predicts the solubility with an acceptable error with the cost of one more data point (the solubility in neat cosolvent) which is required as input value in the prediction process. A number of error terms used in the literature was also discussed with a brief comments on the acceptable prediction error for pharmaceutical applications.

Antiabsence Effects of Safranal in Acute Experimental Seizure Models: EEG and Autoradiography

Abstract: PURPOSE: We examined the effect of safranal, a constituent of Crocus sativus, in acute experimental animal models of generalized absence seizures. METHODS: We further characterized its effects on the GABAergic system through the regional modification of [3H] flunitrazepam, a benzodiazepine agonist binding site and [3H] CGP54626A, a GABAB receptor antagonist binding site in mouse brain. RESULTS: The systemic administration of safranal resulted in a significant and dose-dependent attenuation in experimental absence seizures elicited by either ?-butyrolactone (GBL), baclofen (BAC) or low doses of GABAA receptor antagonists; pentylenetetrazole (PTZ), picrotoxin (PTX) and bicuculline (BMC). After a single intraperitoneal administration of safranal (291 mg/kg), no changes in baseline electrocorticographic (ECoG) recording were observed, however, a significant decrease in [3H] flunitrazepam binding was seen in the cortex (33.16%, p<0.001), hippocampus (27.36%, p<0.01) and thalamus (29.91%, p<0.01) of mouse brain, while the [3H] CGP54626A binding did not show any modification in the same brain regions. CONCLUSION: These data indicate that there is an antiabsence seizure property in safranal and its effect may be due to modifications on the benzodiazepine binding sites of the GABAA receptor complex.

Validation of a HPLC method for flavonoid biomarkers in skullcap (Scutellaria) and its use to illustrate wide variability in the quality of commercial tinctures.

Abstract: Purpose: To compare the flavonoid biomarker content (baicalin, baicalein and wogonin) of eleven commercial tinctures derived from Scutellaria lateriflora aerial parts (n=7) and Scutellaria baicalensis root (n=4). S. lateriflora tinctures are used in by western herbal practitioners to treat anxiety whereas S. baicalensis tinctures are used to treat inflammatory disease. Methods: Baicalin and baicalein were purchased from Aldrich Chemical Co. and Wogonin was purchased from ChromaDex. The internal standard (4-hydroxybenzoic acid) was obtained from Acros Organics. The column used was a Luna C18, 5 ?m (150 x 4.6 mm, Phenomenex) maintained at ambient room temperature. A HP1050 HPLC system was used, comprising a gradient pump with degasser, a variable wavelength UV detector set to 270 nm, and an autosampler. Gradient elution was performed using 0.1% formic acid (eluent A) and methanol (eluent B). The gradient elution initial conditions were 45% B with linear gradient to 60% from 2 to 10 min, followed by linear gradient to 70% B at 30 min, and then linear gradient to 99% B at 31 min, this proportion being maintained for 1 min. The mobile phase was then returned to initial conditions at 33 min and maintained until the end of the run at 35 min. The flow rate was 1 mL/min. The assay was validated for sensitivity, accuracy and reproducibility. Results: The concentration range of biomarkers (baicalin, baicalein and wogonin) in commercial tinctures is reported for S. lateriflora (baicalin: 0-12.66 mg/mL; baicalein: 0-0.63 mg/mL; wogonin: 0-0.16 mg/mL) and for S. baicalensis (baicalin: 0.12-10.61 mg/mL; baicalein: 0.52-5.88 mg/mL; wogonin: 0.08-1.61 mg/mL). Conclusion: The wide variability in biomarker concentrations between commercial tinctures has important implications for the manufacturers of commercial tinctures, for herbal practitioners in the choice of tinctures and not least for pharmacology and clinical researchers.

Efforts towards the development of new antitubercular agents: potential for thiolactomycin based compounds.

Abstract: Development of new chemotherapeutic drugs is the need of the hour to improve tuberculosis control, particularly in the developing world. In the last fourty years no new compound has been brought to the market for the treatment of tuberculosis. However, in recent years there is an enhanced activity in the research and development of new drugs for TB. Some compounds are presently in clinical development, while others are being investigated pre-clinically in an attempt to explore new molecules for the target based treatment of TB. Simultaneously some new targets are being identified and validated for their practical usefulness. Structures based on thiolactomycin could have considerable potential in the development of target based anti-TB agents. The present review provides an overview of the drugs that are being clinically used and the compounds that are in advanced stages of clinical as well as preclinical studies. We have also attempted to highlight the efforts that are being made in the development of new molecules based on thiolactomycin as lead compound, including studies from this laboratory.

Evidence for Non-Linear Pharmacokinetics of Oxytocin in Anesthetizetized Rat

Abstract: Purpose: Because oxytocin (OT) is potentially useful in cardiovascular therapy but has hormonal roles on the cardiovascular and renal systems, we characterized its pharmacokinetic (PK) properties as a function of dose. Methods: A single intravenous bolus of OT was given at doses of 200, 300, 500, 1000, 3000, 5000 and 10000 ng/kg to anesthetized male rats (n >= 4 per dose). Blood samples (6) were taken over 72 min to 150 min, depending on dose. The individual time-courses of plasma OT concentrations were analyzed with a one- or an open two-compartment PK model. Kruskal-Wallis tests (alpha=0.05) were used to compare the PK parameters among groups. Results: At doses up to 500 ng/kg, OT showed a higher median systemic clearance (CLT = 0.0624 L/(min•kg); 0.0622 ± 0.0228 as mean ± SD value), a higher median central compartment volume of distribution (VC = 0.7906 L/kg; 0.6961 ± 0.1754), and a lower median elimination half life (t½(λz) 7.94 min; 9.08 ± 4.3) with respect to the higher doses (CLT = 0.0266 L/(min•kg); 0.0284 ± 0.0098, VC = 0.2213 L/kg; 0.2227 ± 0.1142, and t½(λz) 21.09 min; 28.36 ± 21.8), all differences being significant (p  0.0008). Minimal differences were found for the estimates of these PK parameters among the 4 higher OT doses. Conclusion: The PK properties and persistence of exogenous OT are not proportional to dose, therefore this must be accounted for in dosing regimen design for potential cardiovascular therapy.

A Novel Fluoride Anion Modified Gelatin Nanogel System

Abstract: Purpose. Controlled drug release, especially tumor-targeted drug release, remains a great challenge. Here, we prepare a novel fluoride anion-modified gelatin nanogel system and investigate its characteristics of ultrasound-triggered drug release. Methods. Adriamycin gelatin nanogel modified with fluoride anion (ADM-GNMF) was prepared by a modified co-precipitation method with fluoride anion and sodium sulfate. The loading and encapsulation efficiency of the anti-neoplastic agent adriamycin (ADM) were measured by high performance liquid chromatography (HPLC). The size and shape of ADM-GNMF were determined by electron microscopy and photo-correlation spectroscopy. The size distribution and drug release efficiency of ADM-GNMF, before and after sonication, were measured by two designed measuring devices that consisted of either a submicron particle size analyzer and an ultrasound generator as well as an ultrasound generator, automatic sampler, and HPLC. Results. The ADM-GNMF was stable in solution with an average diameter of 46±12 nm; the encapsulation and loading efficiency of adriamycin were 87.2% and 6.38%, respectively. The ultrasound-triggered drug release and size change were most efficient at a frequency of 20 kHz, power density of 0.4w/cm2, and a 1~2 min duration. Under this ultrasound-triggered condition, 51.5% of drug in ADM-GNMF was released within 1~2 min, while the size of ADM-GNMF changed from 46 ± 12 nm to 1212 ± 35 nm within 1~2 min of sonication and restored to its previous size in 2~3 min after the ultrasound stopped. In contrast, 8.2% of drug in ADM-GNMF was released within 2~3 min without sonication, and only negligible size changes were found. Conclusions. The ADM-GNMF system efficiently released the encompassed drug in response to ultrasound, offering a novel and promising controlled drug release system for targeted therapy for cancer or other diseases.

Effects of monoglycerides on rhodamine 123 accumulation, estradiol 17 β-D-glucuronide bidirectional transport and MRP2 protein expression within Caco-2 cells

Abstract: Purpose. Oral drug development had been hindered by the bioavailability issue despite vast market popularity. Lipid excipients had shown to enhance bioavailability of a number of reformulated hydrophobic oral drugs, yet the underlying mechanisms of action by lipids are still unclear. One proposed mechanism is that lipid excipients could facilitate drug uptake by altering the activities of apical membrane intestinal efflux transporters. Thus, this study aimed to investigate the effects of 1-monopalmitin, 1-monoolein and 1-monostearin on the efflux activity and protein expression of multidrug resistance-associated protein 2 (MRP2) in vitro. Methods. The 24-hour non-cytotoxic ranges of these monoglycerides were first determined using MTS and LDH assays in Caco-2 cells. Then, both accumulation and bidirectional transport studies were conducted using 10 uM rhodamine 123 (Rh123) and 10 nM estradiol 17 β-D-glucuronide (E217βG), respectively, to assess the functional activities of MRP2. 50 µM MK-571, a specific MRP1 and MRP2 inhibitor, was used as the positive control in both studies. Western blotting was followed to determine the effect of these monoglycerides on MRP2 protein expression. Results. Caco-2 cells were viable when treated with 1-monopalmitin, 1-monostearin and 1-monoolein at concentrations equal or less than 1000 µM, 1000 µM and 500 µM, respectively. Cells treated with 1-monoplamitin, 1-monostearin, 1-monoolein and MK571 resulted in significant increases in Rh123 accumulation and decreases in E217βG efflux ratio compared to the control (medium treated only). MRP2 protein expressions in 1-monopalmitin and 1-monoolein treated cells were decreased by 19% and 35% compared to the control; however, there was no change of MRP2 protein expression in 1-monostearin treated cells. Conclusions. These findings suggested that 1-monoolein, 1-monostearin and 1-monopalmitin could attenuate the activity of MRP2 and possibly other efflux transporters in Caco-2 cells. The reduction of efflux activity of MRP2 by 1-monoolein treatment could be partially accounted by the non-specific down-regulation of MRP2 protein expression.

Drug disease interactions: role of inflammatory mediators in pain and variability in analgesic drug response.

Abstract: Pain has both physical and emotional components. Physical noxious stimuli activate peripheral sensory neurons that, in turn, relay signals to the spinal and supraspinal nuclei. Subsequently, these signals activate areas within the brain associated with pain. Despite considerable knowledge in this area, analgesics may provide pain complete relief in only one out of five patients. Failure to manage pain may be due to a lack of understanding of the neurobiological processing of pain. Factors such as anticipation, anxiety and pain history play roles in the perception of pain. Non-neuronal cells such as those of the immune system influence perception and modulation of pain by the nervous system. In post-dental surgery patients, the severity of the pain and the relief following administration of anti-inflammatory analgesics has been linked to the time course of inflammatory mediators. Similarly, the relief of post-operative pain after abdominal surgery is also associated with a reduction in expression of pro-inflammatory mediators. Administration of anti-cytokines to sciatica patients and subsequent pain relief further emphasizes the role of pro-inflammatory mediators in modulation of pain. Increased expression of inflammatory mediators may also alter response to analgesia. For example, rheumatoid patients with temporal mandibular joint disease with increased expression of interleukins prior to treatment demonstrate inadequate pain relief after administration of anti-TNF-?. In addition, pain or its trauma impairs absorption of oral analgesics causing therapeutic failure. Improved analgesic pharmacotherapy may require a better understanding of the involvement of the inflammatory pathways.

The Impact of Electronic Prescribing on the Professionalization of Community Pharmacists: A Qualitative Study of Pharmacists' Perception

Abstract: Purpose. To understand how the technology of electronic prescription (e Rx) can transform the community pharmacist’s role through its effects on professionalization. We define professionalization as a pharmaceutical practice centred on clinical activities and made possible by the establishment of professional pharmaceutical services. Methods. We asked 12 community pharmacists who had participated in an e Rx pilot project in the Canadian province of Quebec to fill out a qualitative survey on their experience. We then analyzed the pharmacists’ perceptions of this new technology using a conceptual framework based on the Davenport typology that presents an exhaustive list of mechanisms, specific to Information Technologies, and thus e-Rx, that can potentially modify information management process and then the role of pharmacists. Results. The pharmacists identified five main mechanisms by which e Rx could affect the professionalization of community pharmacists: analytical capabilities of the pharmacist and physician, dissemination of knowledge, integration of process tasks, process automation and elimination of intermediaries. These mechanisms can assist pharmacists in exercising their professional judgement by improving the quality of available information and facilitate the execution of prescriptions by improving the quality of orders. E Rx technology can also strengthen pharmacists’ credibility as medication specialists in the eyes of both patients and physicians. Thus, e Rx can become a collaborative technology to the extent that it improves collaboration between community pharmacists and prescribing physicians. However, the potential benefits of this technology would appear to depend on its characteristics and how prescribing physicians use it. Conclusions. E-Rx proposes ways of working and communicating that were previously unimaginable. These new possibilities pave the way for transformations that can significantly increase the professionalization of community pharmacists. The results of this study indicate that community pharmacists have a favourable opinion of e Rx, believing it can be an ally in their professionalization.

Bicarbonate supplementation as a preventive way in statins-induced muscle damage

Abstract: – Purpose. The aim of this study was to evaluate the bicarbonate-induced improvement of statins, cerivastatin, simvastatin acid and lovastatin acid -induced apoptosis using rat myoblast cell line (L6) as a model of in vitro skeletal muscle and of cerivastatin-induced muscle damage in vivo study. Methods. Statin-induced reduction of cell viability and apoptosis was measured by 3-(4,5-dimethylthiazol-2-yl)2,5-diphenyl tetrazolium bromide (MTT) assay and caspase assay. In vivo, we evaluated plasma creatine phosphokinase (CPK) level in cerivastatin-treated rat. Results. Bicarbonate prevented cerivastatin-, simvastatin- acid and lovastatin acid -induced reduction of cell viability, morphological change and caspase activation in L6 cells. Moreover, in the in vivo study, bicarbonate prevented cerivastatin-induced increase in CPK concentrations. Conclusions. These results from in vitro and in vivo studies support that bicarbonate supplementation prevented statin-induced muscle damage.

Functional food and nutraceutical registration processes in Japan and China: a diffusion of innovation perspective.

Abstract: Purpose - This paper looks into the functional food and nutraceutical registration processes in Japan and China. The Japanese have developed the Foods for Specified Health Use (FOSHU) registration process whereas the Chinese have put into place the Health Food (HF) registration process. The aim of this paper is to compare the regulation processes between the two countries in search for answers to three core empirical questions: (1) how have the registration processes developed and changed? (2) What are the similarities and differences between the processes of registration in the two countries investigated? (3) Why are the registration processes similar/different? Method – The study was conducted using secondary sources. The literature surveyed covered academic journals, trade journals, magazine and newspaper articles, market reports, proceedings, books and web pages of relevant regulatory authorities and regulatory consultants. Information from the more recently published sources was used preferentially over older sources. As well as using the most recent sources, information was selected on the basis of which source it was from. Official regulations and SFDA and MHLW websites would contain accurate and up to date information and information from here would be taken as true over other sources of information. Results - The two diagrams of the registration processes respectively in Japan and China clearly show that there are similarities and differences. There are six categories under which these can be found: (1) the scientific evidence required; (2) the application process; (3) the evaluation process; (4) the law and the categories of products; (5) the labels and the types of claims; and finally (6) the cost and the time involved. Conclusions -The data analysis suggests that the process of diffusion of innovation played a role in the development of the regulations. Further it was found that while Japan was at the outset a pioneer innovator in nutraceutical registration processes, there are indications that in more recent years it too imitated other countries. NOVELTY STATEMENT: The assortment of regulatory regimes creates much uncertainty for the firms and the lack of familiarity and poor knowledge of the regulatory situation increases the risk of failure. The research presented in this paper provides highly valuable information to any biotech/pharmaceutical/nutraceutical companies developing their market entry strategy in Japan and China. There are few national and international studies of drug registration application processes but even fewer comparative studies of functional food and neutraceutical registration application processes such as this one and none using a diffusion of innovation perspective.

Discovery of chlorogenic acid-based peptidomimetics as a novel class of antifungals. A success story in rational drug design.

Abstract: Life-threatening fungal infections have increased dramatically in recent decades in immunocompromised patients. An estimated 40% of all deaths from hospital-acquired infections are due to infections caused by opportunistic fungi. The current treatment options are either causing serious toxicity, or becoming inactive against the drug-resistant fungal strains. Thus, the discovery and development of new antifungal agents that are economically feasible, have excellent therapeutic value, and address the problems of toxicity and species resistance is very important. We have recently designed and synthesized a series of chlorogenic acid-based peptidimimetics using structure-based methodology starting with cyclic peptides of the candin class of antifungals. These novel and totally synthetic compounds exhibit promising antifungal activity against pathogenic fungi with very low toxicity against brine shrimps. The possible novelty in their mechanism of action and economically feasible synthetic approach are the attractive features of this class of compounds that make them different from the already utilized antifungal agents.

Emergence of power laws in the pharmacokinetics of paclitaxel due to competing saturable processes.

Abstract: Purpose: This study presents the results of power law analysis applied to the pharmacokinetics of paclitaxel. Emphasis is placed on the role that the power exponent can play in the investigation and quantification of nonlinear pharmacokinetics and the elucidation of the underlying physiological processes. Methods: Forty-one sets of concentration-time data were inferred from 20 published clinical trial studies, and 8 sets of area under the curve (AUC) and maximum concentration (Cmax) values as a function of dose were collected. Both types of data were tested for a power law relationship using least squares regression analysis. Results: Thirty-nine of the concentration-time curves were found to exhibit power law tails, and two dominant fractal exponents emerged. Short infusion times led to tails with a single power exponent of -1.57 ± 0.14, while long infusion times resulted in steeper tails characterized by roughly twice the exponent. The curves following intermediate infusion times were characterized by two consecutive power laws; an initial short slope with the larger alpha value was followed by a crossover to a long-time tail characterized by the smaller exponent. The AUC and Cmax parameters exhibited a power law dependence on the dose, with fractional power exponents that agreed with each other and with the exponent characterizing the shallow decline. Computer simulations revealed that a two- or three-compartment model with both saturable distribution and saturable elimination can produce the observed behaviour. Furthermore, there is preliminary evidence that the nonlinear dose-dependence is correlated with the power law tails. Conclusion: Assessment of data from published clinical trials suggests that power laws accurately describe the concentration-time curves and non-linear dose-dependence of paclitaxel, and the power exponents provide insight into the underlying drug mechanisms. The interplay between two saturable processes can produce a wide range of behaviour, including concentration-time curves with exponential, power law, and dual power law tails.

Development of dissolution tests for the quality control of complementary/alternate and traditional medicines: Application to African potato products

Abstract: - Purpose: Unlike orthodox medicines, specific guidelines for dissolution testing of complementary/alternate (CAMs) and traditional medicines (TMs) have not been developed nor is dissolution testing a requirement for the quality control of such products. In this report, the dissolution of African Potato (AP) products, an African traditional medicine (ATM) which has been ingested by man for a diversity of ailments, has been investigated. A norlignan glycoside namely hypoxoside and a sterol, ?-sitosterol (BSS) are purported to be the most important phytochemicals in marketed products of AP. Dissolution testing of AP products containing labelled content of sterols and those containing only hypoxoside is proposed whereby BSS and hypoxoside are monitored as markers for the release of the contents of the abovementioned products, respectively. Methods: The FDA dissolution guidance for industry was used to study the best dissolution condition for several formulations of AP. Buffers in the range of pH 1.2 to 7.5 were used to investigate the dissolution of AP products containing hypoxoside as a marker compound. Similarly, biorelevant dissolution media such as fasted state simulation fluid (FaSSIF) and fed state simulation fluid (FeSSIF) at different pH were used to investigate the release of BSS in AP formulations labelled to contain sterols which exhibited poor water solubility. Results: Dissolution testing of AP products containing hypoxoside, conducted at pH 1.2 using USP Apparatus 1 indicated that more than 75% of hypoxoside was released within 1 hr. Dissolution testing of products containing sterols, conducted in FeSSIF at a pH of 5.0 resulted in a release of at least 75% of BSS after 1 hr for all but one of the products tested. Conclusions: Dissolution testing conditions have been developed for AP products containing two different marker compounds where one of the components, hypoxoside, is water soluble, whereas another component, BSS is poorly water soluble. This necessitated the use of different dissolution media and pHs in order to monitor the respective release of hypoxoside and BSS from AP products. The results of this study indicate the necessity and possibility of developing appropriate dissolution testing procedures for use in the quality control of CAMs/TMs.

Bioequivalence assessment of topical clobetasol propionate products using visual and chromametric assessment of skin blanching

Abstract: - PURPOSE: The assessment of the degree of skin blanching following the application of a formulation containing a topical corticosteroid has been established as a surrogate method for the determination of bioequivalence of such topical preparations. Whereas initially the procedure involved visual assessment of the blanching response, an instrumental procedure using a chromameter was subsequently recommended as the method of choice in such evaluations. In this study, both visual and chromametric assessments have been carried out on two topical creams containing clobetasol propionate (0.05%) and the results from both methods are compared and discussed. METHODS: Human subjects (volunteers) were subjected to screening using a cream containing 0.05% clobetasol propionate, in order to identify appropriate subjects for inclusion in the study. Subsequently the study was implemented according to the FDA guidance using both visual and chromameter assessment techniques. Blanching responses were assessed visually by three trained, independent observers and instrumentally using a Chromameter. An ED50 of 36 min was used as the dose duration based upon data previously obtained from a pilot study using the same topical corticosteroid reference product. A visual rating scale of 0-4 and the a-scale readings from the chromameter were used. RESULTS: The visual and chromameter blanching profiles showed similar blanching responses and corresponded well with each other. The 90% confidence interval for the visual and chromameter data were calculated using Lock's method and when only the data obtained from 23 subjects who were identified as "detectors" (according to the FDA guidance) were used, the products fell within the bioequivalence acceptance range of 80-125% using the visual assessment method (99.3-111.6%) whereas the data using a chromameter (86.5-129.3%) were just outside the acceptance limits. However, when all subjects (n=34) were included in the calculations, both the visual (97.9-109.2) and chromameter (90.2-120.7) data fell within the acceptance range for the declaration of bioequivalence.CONCLUSIONS: Whereas visual data indicated bioequivalence using either data from "detectors" or data from all subjects, the chromameter data from "detectors" only indicated bioinequivalence but inclusion of all subject data fell within the acceptance range to be declared bioequivalent.

Effect of malnutrition on the pharmacokinetics of cefuroxime axetil in young rats.

Abstract: Purpose: To determine the pharmacokinetics of cefuroxime axetil in malnourished rats using a diet with a restriction in energy and nutrients (group M), a diet with a low quality protein (group K) and a good quality diet (group C) as a control. Methods. The rats were fed with the corresponding diet during 21 days. After this period a single oral dose of cefuroxime axetil (equivalent to a 2.2 mg dose of cefuroxime) was administered, and plasma samples were taken at 0, 5, 10, 30, 45, 60, 90, 120, 180, 240, 300 and 360 minutes; samples were assayed using an HPLC assay. Biochemical parameters were also measured an a microscopy study of the small intestine was done. After a 21 day period of recovery of the malnourished groups a second pharmacokinetic study was performed using the same sample times as in the first study. Results: In malnourished animals of group K the levels of plasma proteins were low, and showed higher concentrations of fat in the liver. The relative bioavailability of cefuroxime was 78.2% for group M and 64.4% for group K. Groups M and K presented lower values of area under the curve, which means that the amount of antibiotic absorbed was lower than group C. In the second pharmacokinetic study although the animals received a good quality diet, it was observed that the area under the curve of group K was lower, and the relative bioavailability was 54.3%, while group M had similar pharmacokinetic values than control group. Conclusions: The pharmacokinetics of cefuroxime was affected by malnutrition, suggesting that the absorption process via the transporter was modified in the malnourished groups, specially in the group fed with a low quality protein.

A study of intestinal absorption of bicyclol in rats: active efflux transport and metabolism as causes of its poor bioavailability.

Abstract: Purpose.To determine the possible mechanism of poor bioavailability of bicyclol, and clarify the respective contribution of P- glycoprotein (P-gp) and Cytochrome 3A (CYP3A). Methods. Rat in situ single-pass intestinal perfusion and Caco-2 cell monolayer model with selective inhibitors of CYP3A and P-gp were employed. Results. In rat intestinal perfusion, bicyclol (50µM) appearance in mesenteric blood (Pblood) was increased 3, 12, 16-fold by addition of inhibitors of P-gp (LSN335984), CYP3A ( troleandomycin, TAO) or P-gp and CYP3A (Cyclosporin A, CsA), respectively, whereas permeability of midazolam (CYP3A substrate only) was unchanged by LSN335984 and increased 5 and 1-fold by TAO and CsA. In addition, the metabolized fraction of bicyclol was decreased by 9%, 33%, 36% with inhibitor of P-gp, CYP3A, or P-gp and CYP3A. Moreover, the cumulative amount of bicyclol in mesenteric blood was increased at concentration range 10-100µM of bicyclol in perfusate. The ER (Pappba/Pappab) value of bicyclol in Caco-2 monolayer was significantly deceased by LSN335984 and CsA. Conclusion. The poor bioavailability of bicyclol was mostly due to the P-gp mediated efflux and metabolism by CYP3A in intestine, while CYP3A was believed to make more contribution than P-gp.

Effect of Radical Scavenger N-Tert-Butyl-α-Phenylnitrone on Stroke in a Rat Model Using a Telemetric System

Abstract: We used malignant stroke-prone spontaneously hypertensive rats (M-SHRSP) as a stroke model to explore the effects of the radical scavenger N-tert-butyl-alpha-phenylnitrone (PBN) on stroke. PBN was administrated in drinking water to M-SHRSP. Circadian rhythms in heart rate, blood pressure, and locomotive activity in M-SHRSP were monitored with a telemetric system, in addition to measurement of water intake and body weight. Stroke-onset was assessed by changes in neurological symptoms, water intake, and body weight. Circadian rhythms were basically the same between PBN-treated and control rats several days after stroke onset. Significant differences were seen in blood pressure, relative weight of brain and water intake, heart rate, and locomotive activity between two groups. As a result, no significant difference in age of stroke onset was seen between PBN-treated and control rats, but PBN-treated rats displayed prolonged mean life spans. PBN might be effective in prolonging life span.

Evolutionary Artificial Neural Networks as Tools for Predicting the Internal Structure of Microemulsions

Abstract: PURPOSE. The purpose of this study was to predict microemulsion structures by creating two artificial evolutionary neural networks (ANN) combined with a genetic algorithm. The first ANN would be able to determine the type of microemulsion from the desired composition, and the second to determine the type of microemulsion directly from a differential scanning calorimetry (DSC) curve. METHODS. The algorithms and the structures for each ANN were constructed and programmed in C++ computer language. The ANNs had a feed forward structure with one hidden level and were trained using a genetic algorithm. DSC was used to determine the microemulsion type. RESULTS. The ANNs showed very encouraging accuracy in predicting the microemulsion type from its composition and also directly from the DSC curve. The percentage success, calculated over the tested data, was over 90%. This enabled us, with satisfactory accuracy, to construct several pseudoternary diagrams that could facilitate the selection of the microemulsion composition to obtain the optimal desired drug carrier. CONCLUSIONS. The ANN constructed here, enhanced with a genetic algorithm, is an effective tool for predicting the type of microemulsion. These findings provide the basis for reducing research time and development cost for characterizing microemulsion properties. Its application would stimulate the further development of such colloidal drug delivery systems, exploit their advantages and, to a certain extent, avoid their disadvantages.

Preparation and Preliminary Evaluation of Novel β-Cyclodextrin/IUDR Prodrug Formulations

Abstract: PURPOSE. Iododeoxyuridine (IUdR) has a very short in vivo half-life and consequently achieves low target-tissue concentrations with concomitant lower efficacy than would be predicted from in vitro studies. This work reports the preparation of IUdR:?-cyclodextrin (?-CyD) inclusion complexes designed to reduce in vivo inactivation of IUdR. METHODS. IUdR was derivatized with either 1-adamantanecarbonyl chloride or 4-(1-adamantyl-carbamoyl)butanoic acid, to prepare 5’-O-(1-adamantoyl)-5-iodo-2’-deoxyuridine 1 and 5’-O-(4-(1-adamantylcarbamoyl)butoyl)-5-iodo-2’-deoxy-uridine 4, respectively. ?-CyD complexes 5 and 6 were formed by vigorous stirring of 1:1 solutions of ?-CyD and 1 or 4, respectively, in D2O under argon. Complexation was inferred from DSC, powder x-ray diffractometry and NMR spectrometry. The dissociation of 5 in water and under cholesterol challenge, and the effect of complexation on the stability of 1 was determined by incubation in plasma. RESULTS. IUdR coupling with adamantanecarbonyl chloride proceeded smoothly to afford 1 (69 %) and the di-substituted derivative, 3’,5’-di-O-(1-adamantoyl)-5-iodo-2’-deoxyuridine 2 (8 %); 4 was obtained in 42 % yield. The formation of 1:1 complexes 5 and 6 was inferred from NMR chemical shift data. In serum, 1 was 90 % hydrolyzed to IUdR in 30 min, compared to 10 % hydrolysis of 1 to IUdR when from complex 5. CONCLUSIONS. Inclusion complexes were formed between ?-CyD and adamantamine-IUdR conjugates at 1:1 molar ratios. The complex 5 was resistant to dissociation by cholesterol challenge, and 5 was more slowly converted to IUdR than non-complexed 1. In vivo studies are required to further exploit the ?-CyD inclusion complex approach for improved delivery of nucleoside derivatives.

Pharmacodynamics of rocuronium in cholestatic patients with or without hepatocellular injury: normal onset time of initial dose and prolonged duration time after repeated doses.

Abstract: Purpose. A prospective controlled study was designed to observe the pharmacodynamics of rocuronium in cholestatic patients with or without hepatocellular injury. Methods. Sixty patients undergoing abdominal surgery were allocated into three groups: group I had 20 cholestatic patients with hepatocellular injury; group II had 20 cholestatic patients without hepatocellular injury, and group III (control group) had 20 patients without hepatic disease. Anesthetized with propofol and fentanyl, all patients received rocuronium 0.6 mg/kg for initial dose followed by intermittent repeated administration of rocuronium 0.15 mg/kg. The twitch high of adductor pollicis muscle was monitored by acceleromyography. The onset time of the initial dose, the duration time of the initial and the repeated doses, and the recovery index were observed. Results. The onset and the duration time of the initial dose had no significant difference among the three groups (P>0.05). After administration of the 5th dose, the duration time of the repeated doses was significantly prolonged than that of the 2nd dose in group I (31±8 versus 22±4 min) and group II (28±5 versus 21±4 min) (P 0.05). The recovery index of rocuronium was longer in group I (48±13 min) and group II (46±9 min) than that in group III (24±5 min) (P<0.05). Conclusion. Cholestatic patients experience prolonged duration time and longer recovery index after repeated use of rocuronium, despite normal onset time after the initial dose.