Disappearance Of Drug Research Articles

Assessment of subcutaneously administered insulins using in vitro release cartridge: Medium composition and albumin binding

Biotherapeutics is the fastest growing class of drugs administered by subcutaneous injection. In vitro release testing mimicking physiological conditions at the injection site may guide formulation development and improve biopredictive capabilities. Here, anin vitrorelease cartridge (IVR cartridge) comprising a porous agarose matrix emulating subcutaneous tissue was explored. The objective was to assess effects of medium composition and incorporation of human serum albumin into the matrix. Drug disappearance was assessed for solution, suspension and in situ precipitating insulin products (Actrapid, Levemir, Tresiba, Mixtard 30, Insulatard, Lantus) using the flow-based cartridge. UV–Vis imaging and light microscopy visualized dissolution, precipitation and albumin binding phenomena at the injection site. Divalent cations present in the release medium resulted in slower insulin disappearance for suspension-based and in situ precipitating insulins. Albumin-binding acylated insulin analogs exhibited rapid disappearance from the cartridge; however, sustained retention was achieved by coupling albumin to the matrix. An in vitro-in vivorelation was established for the non-albumin-binding insulins.The IVR cartridge is flexible with potential in formulation development as shown by the ability to accommodate solutions, suspensions, and in situ forming formulations while tailoring of the system to probe in vivo relevant medium effects and tissue constituent interactions.

A Reproducible Bioimpedance Transducer for Insulin Noninvasive Measurement

A bioimpedance transducer is proposed for non-invasive monitoring of insulin bioavailability after subcutaneous injection. The insulin bioavailability is assessed indirectly by measuring the local impedance variation due to the drug disappearance from the injection volume. The instrument allows to manage the extreme variability in insulin response by diabetic patients due to skin conditions and/or alterations such as lipodystrophy. In this way, the transducer can also be considered as a key component for new generation of artificial pancreas. The instrument achieves state of art accuracy and uncertainty. Intra-individual reproducibility also resulted improved with respect to previous studies. Moreover, the feasibility of an absorption measurement is proved. After presenting the concept design and the prototype, the metrological characterization during (i) laboratory (on passive electrical components), (ii) in-vitro (on eggplants), and (iii) in-vivo (on an human subject) experiments is reported. In laboratory tests, typical percentage deterministic errors of 1 % on magnitude and phase were obtained. The mean 1-σ repeatability of 0.05 % was obtained for both impedance magnitude and phase. The in-vitro tests were aimed to improve the reproducibility by comparing the electrical behavior of insulin and vehicle in eggplants. During the in-vivo tests, a decrease in percentage 1-σ intra-individual reproducibility was reported with respect to the state of art (from more than 200 % to 36 %), as the impedance magnitude is concerned. In a clinical application framework, an accuracy of 9 μl was obtained by means of a second-order polynomial model. The uncertainty resulted 4.2 μl, well below the typical volume of one insulin unit (10.0 μl).

Replacing carbon cloth by nickel mesh as substrate for air-diffusion cathodes: H2O2 production and carbenicillin degradation by photoelectro-Fenton

The development of air-diffusion electrodes (ADEs) that electrocatalytically produce H2O2 for its decomposition by Fenton’s reaction is gaining relevance. However, attention has been paid to improve the catalytic layer using standard carbonaceous substrates like Ccloth. This work clearly proves the superior endurance of 3 cm2 ADEs fabricated with Nimesh as substrate, achieving stable H2O2 accumulation up to 60 mM at 100 mA for 48 h in an undivided cell. Consequently, the antibiotic carbenicillin could be totally degraded in 13 min by photoelectro-Fenton (PEF) process using the Nimesh|C-PTFE ADE at 20 mA in an acidic model solution. This high performance was confirmed by PEF treatment in urban wastewater, reaching total drug disappearance in 18 min with >80 % TOC abatement. The time course of OH and toxicity was monitored, whereas chromatographic analysis of treated solutions revealed the formation of 32 aromatic and 16 aliphatic byproducts, including 7 linear carboxylic acids.

Revisiting the Dissolution of Praziquantel in Biorelevant Media and the Impact of Digestion of Milk on Drug Dissolution.

Praziquantel is a poorly water-soluble drug used to treat parasitic infections. Previous studies have suggested that its rate and extent of dissolution in milk and biorelevant media are slow and limited compared to dissolution in the pharmacopoeial-recommended medium, despite being reported as displaying a positive food effect upon administration. This study aimed to revisit the dissolution of praziquantel in biorelevant media and milk to better understand this apparent dichotomy. The context of digestion was introduced to better understand drug solubilisation under more relevant gastrointestinal conditions. The amount of praziquantel solubilised in the various media during digestion was quantified using high performance liquid chromatography (HPLC) and the kinetics of dissolution were confirmed by tracking the disappearance of solid crystalline drug using in situ small angle X-ray scattering (SAXS). For the dissolution media, where sodium lauryl sulfate (SLS) is typically included as a wetting agent, a prominent effect of SLS on drug dissolution was also apparent where >2.5 fold more drug was solubilised in SLS-containing dissolution medium compared to that without (0.1 M HCl only). In milk, significant dissolution of praziquantel was observed only during digestion and not during dispersion, hence suggesting that (1) milk can be potentially administered with praziquantel to improve oral bioavailability and (2) incorporating a digestion step into existing in vitro dissolution testing can better reflect the potential for a positive food effect when lipids are present.

Development and Evaluation of Amlodipine-Polymer Nanocomposites Using Response Surface Methodology

Introduction. Polymer nanoparticles are a key tool to deliver drugs to specific sites and to increase drug bioavailability. Aim. This research aims to use poly amide-disulfide nanoparticles as drug delivery systems. Method. Amlodipine (Amlop) was used as a model, forming Amlop-polymer nanocomposites. In this work, we investigated the effect of independent variables (polymer, Fe3+, Al3+, and pH) on the dependent variables (loading efficiency (%LE), zeta potential, and particle size). Nanocomposites were prepared by an inotropic method. Nanocomposites were characterized by powder X-ray diffraction (PXRD), field emission scanning electron microscopy (FE-SEM), Fourier transform infrared spectroscopy (FTIR), and a release study. Results. From the XRD data, the Amlop-polymer nanocomposite shows semi crystallinity. In addition, the disappearance of drug peaks indicates that the drug was incorporated between the polymer molecules and was amorphous in behavior. The FTIR for the nanocomposite shows the functional group of the drug, which indicates the incorporation of Amlop into the nanocomposite. From FE-SEM, the results showed that our nanocomposites have an average particle size of approximately 130 nm. The release of amlodipine from the Amlop-polymer nanocomposite was found to be controlled, with approximately 85% within approximately 24 hours. Conclusion. The amide-disulfide polymer nanoparticles are promising carriers for different types of drugs.

Population pharmacokinetic of paracetamol and atorvastatin with co-administration of semaglutide.

Semaglutide is a glucagon‐like‐peptide‐1 (GLP‐1) analogue marketed for once‐weekly subcutaneous administration for type 2 diabetes mellitus. Like other long‐acting GLP‐1 analogues, semaglutide reduces gastric emptying and, potentially, alters the rate of absorption of orally co‐administered drugs. The objective of the current analysis was to evaluate the effects on the gastric emptying rate caused by semaglutide on pharmacokinetic model parameters of paracetamol and atorvastatin in healthy subjects. Non‐linear mixed effect modeling was used to estimate population pharmacokinetic model parameters of paracetamol and atorvastatin after single doses with or without semaglutide. The absorption rate (ka) of paracetamol decreased by 53% when co‐administered with semaglutide. For atorvastatin, ka and transit compartment rate (ktr) decreased by 72% and 91%, respectively. Thus, gastric emptying, measured as T50, i.e., drug disappearance from the absorption compartments, showed an additional 5‐min delay for paracetamol and a 67‐min delay for atorvastatin when co‐administered with semaglutide. Semaglutide affected pharmacokinetic model parameters of paracetamol and atorvastatin, and minor quantitative differences in gastric emptying between placebo vs. semaglutide administration were observed. However, these effects of semaglutide were considered not to be of clinical relevance.

H2O2 production at gas-diffusion cathodes made from agarose-derived carbons with different textural properties for acebutolol degradation in chloride media

The excessive cost, unsustainability or complex production of new highly selective electrocatalysts for H2O2 production, especially noble-metal-based ones, is prohibitive in the water treatment sector. To solve this conundrum, biomass-derived carbons with adequate textural properties were synthesized via agarose double-step pyrolysis followed by steam activation. A longer steam treatment enhanced the graphitization and porosity, even surpassing commercial carbon black. Steam treatment for 20 min yielded the greatest surface area (1248 m2 g-1), enhanced the mesopore/micropore volume distribution and increased the activity (E1/2 = 0.609 V) and yield of H2O2 (40%) as determined by RRDE. The upgraded textural properties had very positive impact on the ability of the corresponding gas-diffusion electrodes (GDEs) to accumulate H2O2, reaching Faradaic current efficiencies of ~95% at 30 min. Acidic solutions of β-blocker acebutolol were treated by photoelectro-Fenton (PEF) process in synthetic media with and without chloride. In urban wastewater, total drug disappearance was reached at 60 min with almost 50% mineralization after 360 min at only 10 mA cm-2. Up to 14 degradation products were identified in the Cl−-containing medium.

“I held on to the police’s leg for mercy”: Experiences of adversity, risk and harm among people who inject drugs during an anti-drug drive in Dhaka, Bangladesh

BackgroundA number of countries across Asia have instituted “drug wars”, aimed at eradicating drug supply and consumption. These wars often employ strategies like arbitrary arrest and detention, increased surveillance, harassment and sometimes extrajudicial killings. However, these measures have not been shown to effectively eliminate drug supply and consumption; rather they often predispose people who use drugs to increased risk and harm. Such a drug war was declared in the form of an anti-drug drive (ADD) in Bangladesh in 2018. This article examined the impact of the ADD on drug injecting activities and harm reduction service uptake among people who inject drugs (PWID). MethodsAn ethnographic study was conducted in Dhaka, Bangladesh. Study participants included PWID, harm reduction service providers and other drug and alcohol experts. Data collection consisted of 2500 hours of observations, 25 in-depth interviews, five focus group discussions and 15 key informant interviews. Data were analysed using thematic analysis. ResultsADD operations and activities subjected PWID to multifaceted forms of violence and harassment including extrajudicial killings, which significantly affected drug procurement and drug using practices and led to increased needle and syringe sharing and a likely increase in HIV transmission. The gradual disappearance of established drug markets, alongside the emergence of new ones at alternate locations, resulted in the dislocation of PWID from outreach services and further increased risky injecting practices such as needle and syringe sharing between new and unfamiliar injecting partners. These harms were compounded by unpredictable drug supply and price increases stemming from the ADD, which in turn also increased needle and syringe sharing. Harm reduction outreach services were not able to adequately adapt to the volatile, dynamic and risky nature of the ADD. ConclusionThe ADD not only precipitated risky injecting practices but also hindered the effective implementation of harm reduction outreach services and thus undermined public health. This warrants concerted efforts to nurture local evidence-based harm reduction approaches as opposed to punitive measures.

Regional Intestinal Drug Permeability and Effects of Permeation Enhancers in Rat.

Sufficient colonic absorption is necessary for all systemically acting drugs in dosage forms that release the drug in the large intestine. Preclinically, colonic absorption is often investigated using the rat single-pass intestinal perfusion model. This model can determine intestinal permeability based on luminal drug disappearance, as well as the effect of permeation enhancers on drug permeability. However, it is uncertain how accurate the rat single-pass intestinal perfusion model predicts regional intestinal permeability and absorption in human. There is also a shortage of systematic in vivo investigations of the direct effect of permeation enhancers in the small and large intestine. In this rat single-pass intestinal perfusion study, the jejunal and colonic permeability of two low permeability drugs (atenolol and enalaprilat) and two high-permeability ones (ketoprofen and metoprolol) was determined based on plasma appearance. These values were compared to already available corresponding human data from a study conducted in our lab. The colonic effect of four permeation enhancers—sodium dodecyl sulfate, chitosan, ethylenediaminetetraacetic acid (EDTA), and caprate—on drug permeability and transport of chromium EDTA (an established clinical marker for intestinal barrier integrity) was determined. There was no difference in jejunal and colonic permeability determined from plasma appearance data of any of the four model drugs. This questions the validity of the rat single-pass intestinal perfusion model for predicting human regional intestinal permeability. It was also shown that the effect of permeation enhancers on drug permeability in the colon was similar to previously reported data from the rat jejunum, whereas the transport of chromium EDTA was significantly higher (p < 0.05) in the colon than in jejunum. Therefore, the use of permeation enhancers for increasing colonic drug permeability has greater risks than potential medical rewards, as indicated by the higher permeation of chromium EDTA compared to the drugs.

Evaluation of drug permeability calculation based on luminal disappearance and plasma appearance in the rat single-pass intestinal perfusion model

The rat single-pass intestinal perfusion (SPIP) model is commonly used to investigate gastrointestinal physiology and membrane drug transport. The SPIP model can be used with the intestinal segment inside or outside the abdomen. The rats can also be treated with parecoxib, a selective cycloxygenase-2 inhibitor that has been shown to affect some intestinal functions following abdominal surgery, such as motility, epithelial permeability, fluid flux and ion transport. However, the impact of extra-abdominal placement of the intestinal segment in combination with parecoxib on intestinal drug transport has not been investigated. There is also uncertainty how well intestinal permeability determinations based on luminal drug disappearance and plasma appearance correlate in the rat SPIP model. The main objective of this rat in vivo study was to investigate the effect of intra- vs. extra-abdominal SPIP, with and without, pretreatment with parecoxib. The effect was evaluated by determining the difference in blood-to-lumen 51Cr-EDTA clearance, lumen-to-blood permeability of a cassette-dose of four model compounds (atenolol, enalaprilat, ketoprofen, and metoprolol), and water flux. The second objective was to compare the jejunal permeability values of the model drugs when determined based on luminal disappearance or plasma appearance. The study showed that the placement of the perfused jejunal segment, or the treatment with parecoxib, had minimal effects on membrane permeability and water flux. It was also shown that intestinal permeability of low permeability compounds should be determined on the basis of data from plasma appearance rather than luminal disappearance. If permeability is calculated on the basis of luminal disappearance, it should preferably include negative values to increase the accuracy in the determinations.

Heterogeneous Fenton oxidation of ofloxacin drug by iron alginate support

ABSTRACTA new catalytic wet peroxide oxidation of ofloxacin antibiotic is presented in this work. The removal was achieved using a biodegradable sodium alginate-iron material. Several parameters were studied such as iron content, drying duration of the catalytic support, temperature, solid amount and initial drug concentration. The process showed a strong oxidative ability; at optimum conditions, a nearly complete removal of the drug (around 98%) has been reached after three h of treatment. A relatively low decrease of support activity (around 10%) has been observed after three successive oxidation runs and a low iron leaching has been detected (1.2% of the incorporated quantity). The removal of the substrate has been also examined in the absence of hydrogen peroxide in order to discriminate between the contributions of simple adsorption and oxidation processes in the drug disappearance. We also discussed the influence of the studied experimental parameters on the removal kinetic.

Commentary on "A Framework for Quantifying the Influence of Adherence and Dose Individualization".

Drugs that provide long durations of action after a last-taken dose are said to be "forgiving," as they allow the patient a degree of latitude in the timing of sequential doses. New research, by Assawasuwannakit et al.,(1) based on exemplary methods, enriches the pharmacometric analysis of forgiveness, which for several decades had been a simply descriptive reminder that the beneficial actions of some drugs can continue for hours or days after the disappearance of detectable drug.

O1: Contribution of in-utero drug exposure when interpreting hair results in young children

Aim Hair specimen is necessary to complement blood and/or urine analyses as it permits differentiation of a single exposure from chronic use of a drug by segmentation of the hair for a stated growth period. Moreover, due to a frequent long delay between event and police declaration, hair can be the only solution for lack of corroborative evidence of a committed crime. Excepting the lower amount of biological material in children versus adults, there is no specific analytical problem when processing samples from children. The issue is the interpretation of the findings, with respect to the different pharmacological parameters. In some very young children, the interpretation can be complicated by potential in-utero exposure. Method Two examples from daily practice are used to document these difficulties. Case 1: a 9 months old boy was found dead in his bed (sudden child death). Both parents were cannabis regular smokers. The investigators wanted know if the child had been exposed to drugs. A strand of hair that was 4,5 cm in length and brown in colour was collected. Case 2: a mother under treatment was suspected of administering methadone to an 11 months old child. A strand of hair that was 6 cm in length and blonde in colour was collected. Drugs were tested by GC/MS (THC, cannabinol, cannabidiol) and LC/MS/MS (methadone, EDDP) after decontamination by dichloromethane (2 × 5 ml), segmentation, and liquid-liquid specific extraction. Results & discussion In both cases, the mother admitted having used drugs during pregnancy. THC tested positive in the hair of the child in case 1 at 0.42, 0.51 and 0.86 ng/mg in the 0–1.5, 1.5–3 and 3–4,5 cm segment, respectively. Cannabinol and cannabidiol were always identified. Methadone tested positive in the hair of the child in case 2 at 0.42, 0.46, 0.59 and 1.58 ng/mg in the 0–1.5, 1.5–3, 3–4.5 and 4.5–6 cm segment, respectively. EDDP only tested positive in the 2 last segments. Obviously, the concentrations measured in the hair are much lower than those observed in subjects using these drugs. In that sense, the frequency of exposures appears as un-frequent (low level of exposure), with marked decrease in the more recent period. However, the parents denied any administration in both cases. A least, four possible interpretations of the measured drug concentrations can be addressed: 1. decrease in administration in the more recent period; 2. increase of body weight due to growing, so the same dosage will result in lower concentrations in hair; 3. sweat contamination from the parents/mother at the time the child is with them in bed, the older hair being longer in contact with the bedding; and 4. contribution (from 1 to 100%) of in-utero exposure during pregnancy. Very few papers have been published about the disappearance of drug after discontinuation of use or exposure (in case of in-utero exposure). In adults, it can take 6 to 9 months to have a negative hair result after ethanol, heroin or cocaine abstinence. The time course after delivery of disappearance of a drug incorporated during pregnancy has never been reported. Conclusion In these cases, it was impossible to conclude that both children were deliberately administered drug. The results of the analysis of hair could indicate that they were in an environment where drug was being used and where the drug was not being handled and stored with appropriate care. Contribution of in-utero exposure should be reviewed when the case involves a child under 1 year. In view of these results we concluded that a single determination should not be used firmly to discriminate long-term exposure to a drug.

Delayed and Prolonged Histone Hyperacetylation with a Selective HDAC1/HDAC2 Inhibitor.

The identification and in vitro and in vivo characterization of a potent SHI-1:2 are described. Kinetic analysis indicated that biaryl inhibitors exhibit slow binding kinetics in isolated HDAC1 and HDAC2 preparations. Delayed histone hyperacetylation and gene expression changes were also observed in cell culture, and histone acetylation was observed in vivo beyond disappearance of drug from plasma. In vivo studies further demonstrated that continuous target inhibition was well tolerated and efficacious in tumor-bearing mice, leading to tumor growth inhibition with either once-daily or intermittent administration.

A method to study the kinetics of oral mucosal drug absorption from solutions.

A method has been developed which allows the kinetics of oral mucosal drug absorption from solutions to be studied in a single 15-20 min test. This is an improvement over the traditional buccal absorption test which requires a separate experiment for each time point, thus taking days for each kinetic profile. It should also allow for disappearance of drug from the mouth and appearance in the plasma to be monitored simultaneously. The drug solution includes 8 micrograms mL-1 phenol red as a marker for salivary secretion. Samples are withdrawn at suitable times with a positive displacement pipettor and analysed for drug and phenol red. Salivary volume time data are described by least squares polynominals. Kinetic parameters are estimated by non-linear least squares regression. The method, which requires that phenol red is not lost during a test, provides an internal test for this. It also requires that phenol red and the drug do not interfere with each other's assay, that saliva does not affect the assays of these materials, and that phenol red does not interfere with the absorption of the drug.

Réunion : institut d’épidémiologie neurologique et de neurologie tropicale (IENT)

Two trials were carried out in order to compare the prophylactic effect of a subcutaneously implanted sustained release device (SRD) containing a mixture of a biodegradable copolymer, poly(caprolactone-co-l-lactide), and isometamidium (ISMM) with that obtained after intramuscular injection of the drug. In a first experiment under controlled conditions, two groups of cattle were treated with 0.5 mg/kg isometamidium either as a SRD or intramuscularly (i.m.), and exposed at monthly intervals to Glossina morsitans morsitans infected with Trypanosoma congolense. The average protection period was at least 24 months in the SRD treated against 5.7 months in the i.m. treated group. Using an ISMM enzyme-linked immunosorbent assay, the drug could be detected until 140 days post-treatment in the latter group, whereas in the former group, traces of the drug were detectable until 330 days after treatment. Furthermore, a field trial was carried out at the Madina Diassa ranch in Mali involving three groups of N’Dama cattle, each containing 23 or 24 animals. Two groups were treated with 1 mg/kg ISMM either as a SRD or i.m. and a third group served as untreated control. Twelve months after treatment, the cumulative infection rates were 56.5, 87.8 and 91.6% in the SRD implanted, the i.m. treated and the control groups, respectively. The ISMM concentrations were slightly lower than in the laboratory trial, but the overall pattern of drug disappearance from the sera of the SRD treated cattle was very similar in both trials. Statistical analysis showed that the incidence of trypanosomiasis was significantly lower in the SRD treated than in the i.m. treated group.

Abstract 353: Pharmacokinetic studies on a novel recombinant human granulocyte colony stimulating factor in rats

Abstract Background: Recombinant human granulocyte colony stimulating factor (G-CSF) has been used as a therapeutic drug for leukopenia of cancer patients who receive myelo-suppressive radio- or chemotherapy. Due to its intrinsic instability, G-CSF has to be administered to patients frequently to maintain high plasma concentrations for therapeutic effects. We report here that a recombinant G-CSF derivative (rhG-CSFa), which was previously found to exhibit a greater biological activity than wild-type G-CSF does, displays enhanced stability in vitro, and superior bioavailability in vivo. Methods: The pharmacokinetics of rhG-CSFa and G-CSF was investigated in rats; various groups of the rats received either intravenous (i.v.) or subcutaneous (s.c.) injection of rhG-CSFa, at one of three different doses (20, 50 or 100 µg/kg). The serum samples were collected at multiple time points after the drug administration (from 0.08 to 12 h). The concentrations of rhG-CSFa and wild-type G-CSF in various serum samples were determined by a sandwich ELISA. Pharmacokinetic parameters were analyzed by fitting the serum drug concentration-time data to a one- or two-compartment model, with use of the Winnonlin 5.2 software. For proteolytic studies in vitro, the concentrations of rhG-CSFa or G-CSF were determined at 3-min intervals after addition of the respective drug to rat serum or plasma. Results: Pharmacokinetic analysis of serum rhG-CSFa or G-CSF levels indicated that, at each dose tested, for either routes of drug administration, the area under concentration-time curve (AUC) values were higher for rhG-CSFa than for G-CSF. For example, at the dose of 20 µg/kg, s.c., the AUC value was 850 ± 80 ng*hr/ml for rhG-CSFa and 430 ± 50 for ng*hr/ml for G-CSF (n=5). At the dose of 20 µg/kg, i.v., the AUC value was 1150 ± 480 ng*hr/ml for rhG-CSFa and 810 ± 150 for ng*hr/ml for G-CSF (n=5). Differences in other pharmacokinetics parameters, including serum half-life (t1/2) and maximum serum concentration (Cmax), were also observed, further indicating greater serum bioavailability of the rhG-CSFa, as compared to G-CSF. Results from subsequent in vitro serum and plasma stability studies showed that the rates of drug disappearance were slower for rhG-CSFa than for G-CSF, when the respective drug was added to either serum (by 1.5 fold) or plasma (by 1.8 fold). This finding suggested that the rates of proteolysis of the rhG-CSFa were much slower, as compared to the rates of proteolysis of the wild-type G-CSF, either in serum or in plasma. Conclusions: The novel rhG-CSFa has a much better serum and plasma stability in vitro and a much higher bioavailability in vivo, as compared to the conventional G-CSF. The increased stability and bioavailability of the rhG-CSF may explain, at least partly, the greater therapeutic efficacy of rhG-CSFa than that of G-CSF in rats, and suggests that rhG-CSFa will also have enhanced therapeutic efficacy in human patients. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 353.

Pharmacokinetics of drugs in rats with diabetes mellitus induced by alloxan or streptozocin: comparison with those in patients with type I diabetes mellitus

In rats with diabetes mellitus induced by alloxan (DMIA) or streptozocin (DMIS), changes in the cytochrome P450 (CYP) isozymes in the liver, lung, kidney, intestine, brain, and testis have been reported based on Western blot analysis, Northern blot analysis, and various enzyme activities. Changes in phase II enzyme activities have been reported also. Hence, in this review, changes in the pharmacokinetics of drugs that were mainly conjugated and metabolized via CYPs or phase II isozymes in rats with DMIA or DMIS, as reported in various literature, have been explained. The changes in the pharmacokinetics of drugs that were mainly conjugated and mainly metabolized in the kidney, and that were excreted mainly via the kidney or bile in DMIA or DMIS rats were reviewed also. For drugs mainly metabolized via hepatic CYP isozymes, the changes in the total area under the plasma concentration-time curve from time zero to time infinity (AUC) of metabolites, AUC(metabolite)/AUC(parent drug) ratios, or the time-averaged nonrenal and total body clearances (CL(NR) and CL, respectively) of parent drugs as reported in the literature have been compared. After intravenous administration of drugs that were mainly metabolized via hepatic CYP isozymes, their hepatic clearances were found to be dependent on the in-vitro hepatic intrinsic clearance (CL(int)) for the disappearance of the parent drug (or in the formation of the metabolite), the free fractions of the drugs in the plasma, or the hepatic blood flow rate depending on their hepatic extraction ratios. The changes in the pharmacokinetics of drugs that were mainly conjugated and mainly metabolized via the kidney in DMIA or DMIS rats were dependent on the drugs. However, the biliary or renal CL values of drugs that were mainly excreted via the kidney or bile in DMIA or DMIS rats were faster. Pharmacokinetic studies of drugs in patients with type I diabetes mellitus were scarce. Moreover, similar and different results for drug pharmacokinetics were obtained between diabetic rats and patients with type I diabetes mellitus. Thus, present experimental rat data should be extrapolated carefully in humans.

Extended release promethazine HCl using acrylic polymers by freeze-drying and spray-drying techniques: formulation considerations

The present study investigated a novel extended release system of promethazine hydrochloride (PHC) with acrylic polymers Eudragit RL100 and Eudragit S100 in different weight ratios (1:1 and 1: 5), and in combination (0.5+1.5), using freeze-drying and spray-drying techniques. Solid dispersions were characterized by Fourier-transformed infrared spectroscopy (FT-IR), differential scanning calorimetry (DSC), Powder X-ray diffractometry (PXRD), Nuclear magnetic resonance (NMR), Scanning electron microscopy (SEM), as well as solubility and in vitro dissolution studies in 0.1 N HCl (pH 1.2), double-distilled water and phosphate buffer (pH 7.4). Adsorption tests from drug solution to solid polymers were also performed. A selected solid dispersion system was developed into capsule dosage form and evaluated for in vitro dissolution studies. The progressive disappearance of drug peaks in thermotropic profiles of spray-dried dispersions were related to increasing amount of polymers, while SEM studies suggested homogenous dispersion of drug in polymer. Eudragit RL100 had a greater adsorptive capacity than Eudragit S100, and thus its combination in (0.5+1.5) for S100 and RL 100 exhibited a higher dissolution rate with 97.14% drug release for twelve hours. Among different formulations, capsules prepared by combination of acrylic polymers using spray-drying (1:0.5 + 1.5) displayed extended release of drug for twelve hours with 96.87% release followed by zero order kinetics (r²= 0.9986).

Pharmacokinetics of disappearance of cocaine from hair after discontinuation of drug use

Methods that employ detection of drugs of abuse in hair are important for monitoring compliance with drug abstinence. Understanding the mechanisms and timeline of drug disappearance from hair is critical for clinical and forensic application of hair testing. We aimed to evaluate the kinetics of disappearance of cocaine and its metabolite, benzoylecgonine (BE), from hair after discontinuation of drug use. Methods The Motherisk laboratory at the Hospital for Sick Children in Toronto routinely receives hair samples for toxicology analysis. Cocaine and BE hair results were obtained from the Motherisk Database for calculation of half-life of these compounds in hair. Subjects were included in the study if they had gradually decreasing concentrations of cocaine and/or BE in sequential hair samples, with higher levels in the 1–3 cm distal segments (i.e. earlier in time) and low or non-measurable levels in the segment closest to the scalp (i.e. closer to the date of sampling). Elimination half-life of cocaine and BE in hair was calculated using standard kinetics calculations. The study was anonymous, and received ethics approval by the Ethics Review Board of our institution. Results 137 subjects met the inclusion criteria for the study. The median half-life of cocaine in hair was 1.5 months (95% CI 1.2–1.8) in females and 1.5 months (95% CI 1.1–1.8) in males. The median half-life of BE was 1.5 months (95% CI 1.1–2) in females and 1.5 months (95% CI 0.8–1.8) in males. Half lives of cocaine or BE were not statistically different between males and females (Mann–Whitney U-test; P = 0.93 for cocaine, P = 0.99 for BE). Half lives of cocaine and BE were strongly correlated (Spearman rank rho = 0.73; P < 0.001). Conclusion Cocaine and BE could be detected in hair of former drug users for several months after abstinence. The calculated half-life of over 1 month for cocaine implies that, assuming first order elimination, approximately 3–4 months have to pass for hair testing to become negative in the segment proximal to the scalp. This finding should be incorporated in interpreting compliance with abstinence of former drug users, and suggests that caution has to be exerted when evaluating potential breaches of abstinence.