Slow-release Formulation Research Articles

Pharmacokinetics and Safety of Intrathecal Liposomal Cytarabine in Children Aged <3 Years

Liposomal cytarabine (DepoCyte) is a slow-release formulation for intrathecal application, ensuring prolonged drug exposure. Although there is an urgent need for new treatment options for infants with leptomeningeal dissemination of a malignant brain tumour, there are no clinical and pharmacokinetic data available on this drug for children aged <3 years. The objective of this pilot study was to determine the feasibility, safety and pharmacokinetics of cytarabine after intrathecal administration of liposomal cytarabine 25 mg in patients aged <3 years. Six male patients with a mean age of 21 months and CNS primitive neuroectodermal tumours (n = 3) or atypical teratoid/rhabdoid tumours (n = 3) were included. Liposomal cytarabine (25 mg) was administered intraventricularly. One patient also received the drug by lumbar puncture. Dexamethasone was used concomitantly for 3-5 days to prevent arachnoiditis. Cerebrospinal fluid (CSF) and plasma samples were collected before administration of liposomal cytarabine and 1 hour, 12 hours, 24 hours, 1 week and 2 weeks post-dosing. Noncompartmental pharmacokinetic analysis of CSF and plasma was performed. Liposomal cytarabine was generally well tolerated; only grade 2 headache occurred in one patient. After intraventricular administration of cytarabine 25 mg, free and encapsulated drug concentrations above the cytotoxic drug level of 0.1 microg/mL were detectable in the CSF for at least 7 days and up to 14 days post-dosing. The average elimination half-lives were 56.7 hours for encapsulated cytarabine and 59.3 hours for free cytarabine. After intralumbar administration, the elimination half-life of free cytarabine, measured in the ventricular CSF during two courses in one patient, was significantly shorter (32.7 hours). Application of liposomal cytarabine with concomitant dexamethasone appears to be safe and well tolerated in children aged <3 years. Drug exposure in infants aged <3 years after an intraventricular dose of 25 mg is comparable to that after administration of 50 mg in adult patients and 35 mg in older children.

House of Lords Revisits ‘Biogen’ Insufficiency; Novartis' Fluvastatin Patent Obvious; High Court Finds Patent for Slow Release Formulation Valid but not Infringed

House of Lords Revisits ‘Biogen’ Insufficiency; Novartis' Fluvastatin Patent Obvious; High Court Finds Patent for Slow Release Formulation Valid but not Infringed

Fatal and severe codeine intoxication in 3-year-old twins—interpretation of drug and metabolite concentrations

This work presents two cases of codeine intoxication in 3-year-old monozygotic twin brothers while treated with a codeine slow-release formulation. One child had to be admitted to the hospital, whereas the other one died at home after aspiration of gastric content. The concentrations of codeine and major metabolites including morphine and corresponding glucuronide conjugates were measured by liquid chromatography-tandem mass spectrometry in serum, urine, cerebrospinal fluid, and brain tissue, respectively. A genetic polymorphism study was carried out in order to determine the ability of the children to metabolize codeine by O-demethylation. A pharmacokinetic calculation was also performed to estimate the administered dose of codeine in question. High concentrations of all substances were found in samples of both children. The pharmacokinetic estimate suggests an overdose of codeine, and the possible reasons for the high opiate concentrations are discussed. Furthermore, the postmortem distribution--during and after resuscitation--might play a major role in the interpretation of postmortem concentration levels.

Slow release antibiotics for treatment of septic arthritis in large animals

The search for an effective treatment for septic arthritis is ongoing. Current therapies are expensive since they require repeated joint lavage and long term antibiotic treatment. Local application of antimicrobial drugs is advantageous because high concentrations can be attained at the infection site, although repeated injections increase the risk of superinfection of the joint. Thus, slow release formulations, which have the advantage of local treatment yet single application of the drug, are appealing. Antibiotics used in slow release formulations are selected for tissue compatibility, an appropriate antibacterial spectrum, and stability both during the mixing procedure and within the carrier during the release period. Ideally the carriers should be bioresorbable. Promising reports on the clinical use of poly(methyl methacrylate) (PMMA) mixed with several different antibiotics, and of collagen sponges impregnated with gentamicin, should encourage the search for formulations optimally adapted to veterinary medical requirements.

InforMatrix for attention deficit hyperactivity disorder

The purpose of this review is to facilitate discussion on drug selection for the treatment of ADHD by using only clinically relevant selection criteria and providing an up-to-date overview. The InforMatrix method was used to select drugs to treat attention deficit hyperactivity disorder (ADHD). The following selection criteria were applied: clinical efficacy, safety, tolerability, ease of use, applicability, and cost. The drugs approved for ADHD in the Netherlands were included in the analysis, namely: atomoxetine, immediate-release methylphenidate, and various formulations of slow-release methylphenidate (Concerta, Equasym and Medikinet). Most studies are of limited quality, duration, and size. In one study, Concerta was more effective than atomoxetine. Although no relevant differences were seen in other comparative studies, the clinical experience with atomoxetine is still limited and unexpected toxicity cannot be excluded; few studies have been published with Equasym and Medikinet. No major differences were seen in general tolerability between the drugs. The ease of use of immediate-release methylphenidate is less than for the other drugs. The acquisition cost of immediate-release methylphenidate is considerably lower than that of the slow-release formulations. Atomoxetine is the most expensive drug. The InforMatrix program is available in an interactive format. It enables the user to judge both the importance of the selection criteria and the properties of each therapeutic option per criterion on the basis of his or her own personal expertise and/or the present document.

Adverse event load in bipolar participants receiving either carbamazepine immediate-release or extended-release capsules: a blinded, randomized study

In epilepsy, slow-release formulations of carbamazepine (CBZ) have fewer adverse events (AEs) compared with immediate-release (IR) formulations. As CBZ is used for mania, it is important to determine whether a similar pattern exists for bipolar patients. This was a 3-month, blinded, random-assignment study to an IR formulation or extended-release carbamazepine capsules (ERCC, Equetro) in type I or type II bipolar patients already on CBZ or clinically determined to benefit from it. Dosages were titrated to patients' clinical needs. Mood and AE ratings were performed at baseline and monthly for 3 months. There was no difference in mood ratings or in the total level of AEs in patients receiving IR or ERCC. However, autonomic AEs (5.0+/-1.1 vs. 2.0+/-0.7, P = 0.02) and gastrointestinal AEs (1.6+/-0.4 vs. 0.6+/-0.3, P = 0.05) were significantly less in participants receiving ERCC. CBZ level in patients receiving ERCC were higher (9.2+/-1.7 vs. IR 7.2+/-1.3 microg/ml, P = 0.005). Total AE load was directly related to CBZ level only in participants receiving the IR formulation. In conclusion, ERCC is better tolerated than IR CBZ in bipolar patients.

SCCT guidelines for performance of coronary computed tomographic angiography: A report of the Society of Cardiovascular Computed Tomography Guidelines Committee

The increasing use of coronary computed tomographicangiographic (CTA) requires the establishment of standardsmeant to ensure reliable practice methods and qualityoutcomes. The Society of Cardiovascular ComputedTomography Guidelines Committee was formed to developrecommendations for acquiring, interpreting, and reportingof these studies in a standardized fashion. Indications andcontraindications for specific services or procedures are notincludedinthescopeofthese documents.Theserecommen-dations were produced as an educational tool for practi-tioners to improve the diagnostic care of patients, in theinterest of developing systematic standards of practice forcoronary CTA based on the best available data. Because ofthe highly variable nature of individual medical cases, anapproach to scan performance that differs from these guide-lines may represent an appropriate variation based on alegitimate assessment of an individual patient’s needs.

Solubility Properties of Chlorhexidine Salts

Chlorhexidine (CHX) is effective in treating oral bacterial infections. The solubility was shown to be highly dependent on the salt present in solution. Gluconate enhances the amount of CHX diacetate in solution possibly through mixed micelles formation, because the solubility product is such that the concentration of CHX will exceed the critical micelle concentration. However, only low concentrations of CHX dichloride can be obtained, which is not appreciably solubilized by gluconate ions. The low concentration of CHX that can be achieved in physiological concentrations of chloride in the oral cavity may be problematic for dental, slow release formulations.

Soil properties and lodgepole pine growth on forest landings rehabilitated by tillage and fertilizer application

Soils on forest landings are often degraded and unable to support optimal growth of planted conifers unless rehabilitation practices are applied. This study evaluated the effects of tillage and fertilization on soil properties and growth of lodgepole pine (Pinus contorta Dougl. ex Loud. var. latifolia Engelm.) seedlings on rehabilitated forest landings in the central interior of British Columbia. Six study sites were rehabilitated in 1998 (but without topsoil replacement) and planted with lodgepole pine in 1999. Tillage treatments were: (i) no tillage; (ii) low intensity (one pass of an excavator and six-toothed rake, target clod size 8–10 cm); (iii) medium intensity (two passes, target clod size 4–7 cm); and, (iv) high intensity (three passes, target clod size 1–3 cm). Fertilizers were applied at the time of planting as slow-release formulations; treatments included: (i) no fertilizer; (ii) NPK-fertilizer; and, (iii) NPK + S-fertilizer. After 5 yr, soil mechanical resistance was higher on the untilled control than the tilled treatments. Neither tillage nor fertilization had any effects on soil chemical properties (total C and N, pH, cation exchange capacity, exchangeable cations). Tillage effects after one growing season were variable; however, after four or five growing seasons, the low-intensity tillage resulted in greater seedling height and diameter growth than the untilled control. After one growing season, fertilization increased seedling height and diameter growth relative to the untreated control, but after four or five growing seasons, fertilization had no effect on lodgepole pine growth. Our findings indicate that a single pass with the excavator and rake was the most suitable rehabilitation practice on these sites. Key words: Forest soil rehabilitation, landing and road rehabilitation, soil conservation, soil degradation, soil compaction, soil productivity

Effect of a slow release preparation of levodopa on Parkinson's disease in combination with a peripheral decarboxylase inhibitor

Plasma concentrations of levodopa were determined after therapeutic oral levodopa-carbidopa doses. The wide fluctuations observed in plasma levodopa levels could be considerably reduced by the addition of a slow release levodopa preparation. This kind of combination medication was given to 15 parkinsonian patients, whose earlier therapy had proved inadequate. With the combination medication, levodopa-carbidopa, on an average 420 mg/42 mg combined with 950 mg of levodopa in slow release form, a statistically significant improvement in parkinsonian signs could be achieved without any worsening of the side effects. The results suggest that parkinsonian patients may tolerate much higher daily levodopa doses if the fluctuations in plasma levels of the drug can be diminished.

Pharmacokinetic comparison of two carbamazepine slow-release formulations

In a single-blind pharmacokinetic study patients being treated with conventional carbamazepine (CBZ) in a t.i.d. regimen were randomly allocated to identical doses of two CBZ slow-release formulations (Trimonil Retard and Tegretol Retard) administered once daily. Statistical analysis involved the following parameters: AUC, Cmin, Cmax and Fluctuation Index (FI). With regard to Cmin and FI statistically significant differences in favour of Tegretol Retard were observed.

A novel Diclofenac-carrier for local treatment of osteoarthritis applying live-animal MRI

The prevailing chronic treatment for osteoarthritis — oral administration of NSAIDs — is accompanied by severe adverse effects and risks of gastrointestinal (GI) toxicity. The working hypothesis of this study was that increased NSAID-efficacy and alleviation of adverse effects can be achieved by local administration of a new slow-release NSAID-carrier formulation. Diclofenac was the test NSAID and collagomers — novel vesicular-shaped microparticles based on collagen–lipid conjugates — were the carriers. Collagomers were stable in simulated synovial fluid and showed: high-efficiency drug encapsulation (85%); slow drug release ( τ ½ = 11 days); high affinity to target cells (Kd = 2.6 nM collagen). In vitro activity of Diclofenac released from the carriers was similar to fresh drug solutions. Diclofenac-collagomer therapeutic effects were studied in osteoarthritis-induced rats, using live-animal MRI. A single intra-articular injection of the Diclofenac-collagomer formulation reduced inflammation over 3 weeks significantly vs. untreated animals ( p < 0.001), and vs. the conventional treatment which is free drug PerOs ( p < 0.03). Bypassing the GI, the novel treatment circumvents adverse effects of the conventional approach. In conclusion, the collagomers performed as functional Diclofenac-depots for local treatment of osteoarthritis, avoiding GI adverse effects. The in vivo results merit further investigations of this novel NSAID formulation as a valid option to the conventional treatment.

Concentration dependent aggregation properties of chlorhexidine salts

Purpose Chlorhexidine (CHX), a chemical antiseptic, is known to bind to dentin and has been shown to be effective in treating bacterial infections caused by microbes. The solubility and aggregation properties of CHX salts were determined to guide the development of a sustained release formulation for long-term disinfection. Methods The amount of CHX in solution was determined as a function of counterion concentration (chloride, acetate (Ac) or gluconate (G)) by UV spectrophotometry at 255 nm. The weight average molecular weight was determined from the angular dependence of the scattered light. Proton NMR spectroscopy was used to investigate the dependence of the peak intensity and chemical shift on solution concentration and diffusion measurements were performed by Fourier-transform pulsed-field gradient spin-echo (PFG-SE) 1H NMR. Results The observed CHX concentration was highly dependent on the type and concentration of salt present in solution with the greatest CHX concentration achieved with gluconate, moderate to low with diacetate, and very low with dichloride solutions. Addition of sodium gluconate enhanced the amount of CHX-Ac 2 in solution; however, only low concentrations of chlorhexidine can be achieved in the presence of chloride ions. For solutions of CHX-G 2, the aggregate number appeared to range from a dimer at 40 mM to perhaps a pentamer at 150 mM. In contrast, no aggregation of CHX-Cl 2 or CHX-Ac 2 was detected, which was corroborated by diffusion NMR results. The change in chemical shift of protons is consistent with association of the phenyl group of one CHX with the hexamethylene chain of a second CHX. Based on the analysis of NMR peak intensities of CHX, gluconate, and acetate in saturated solutions, it appears that solubilization of the diacetate species occurs within digluconate aggregates, since the solubility product of chlorhexidine diacetate is such that the concentration of CHX will exceed the critical micelle concentration (CMC). However, no solubilization of CHX-Cl 2 occurs because the solubility product falls below the CMC. Conclusions The low concentration of CHX that can be achieved in physiological concentrations of chloride in the oral cavity may be problematic for dental and slow release formulations. Achieving a high concentration of CHX appears to require that the monomer be present at a concentration greater than that required to produce self-association.

Effectiveness of Pyriproxyfen and Diflubenzuron Formulations as Larvicides Against Aedes aegypti

The efficacy of technical pyriproxyfen and diflubenzuron was evaluated at the laboratory level against Aedes aegypti, where we achieved adult emergence inhibition (EI50) values of 0.048 and 1.59 ppb (microg/liter), respectively. We compared these data with values obtained for temephos. We prepared emulsifiable concentrate formulations of pyriproxyfen and diflubenzuron in the laboratory and obtained EI50 values of 0.01 and 0.02 ppb, respectively. We also obtained 100% adult emergence inhibition with 0.1% slow-release sand formulations of pyriproxyfen and diflubenzuron. In a simulated field study, the granular sand formulations of pyriproxyfen, diflubenzuron, and temephos remained active for over 4 mo. In a field study, a 0.2% granular formulation of diflubenzuron and 1% temephos showed a similar performance.

Treatment of lymphomatous and leukemic meningitis with liposomal encapsulated cytarabine.

Liposomal encapsulated cytarabine (DepoCyte, Mundipharma GmbH, Limburg/Lahn, Germany) is a slow-release formulation of conventional cytarabine. It is licensed for intrathecal use in patients with lymphomatous and leukemic meningitis. DepoCyte obtained superior response rates, improved patient quality of life and improved the time to neurological progression in a randomized albeit small clinical trial. In this review we briefly summarize the clinical data and discuss them in light of clinical problems and possible treatment scenarios.

Esterification of insoluble fibres using high-pressure homogenisation and their potential vitamin carrying and releasing abilities

The esterification of carambola (starfruit) insoluble fibre (IF) and cellulose using high-pressure homogenisation without chemical catalyst was carried out as well as the evaluation of vitamin carrying and releasing abilities of the esterified fibres. Fourier transform infrared spectroscopic analyses showed that these fibres underwent structural changes and were esterified with lactic acid via a simple and fast process of high-pressure homogenisation. In vitro studies showed that the esterified fibres were capable of carrying vitamin E (∼11.2 mg g −1 composite) and releasing nutrient slowly. In vivo studies further demonstrated that feeding the esterified carambola IF-vitamin composite could help maintain plasma vitamin E at relatively higher concentrations (∼1.7- to 3.8-fold of the initial value) for better utilisation for at least 5 h. The results suggested that the esterified insoluble fibres, especially the esterified carambola IF, could be exploited as potential nutrient carriers in functional food applications and slow-release formulations.

Continuous versus pulsatile administration of rotigotine in 6-OHDA-lesioned rats: contralateral rotations and abnormal involuntary movements

Sustained drug delivery providing continuous dopaminergic stimulation is thought to prevent or delay the induction of motor complications (dyskinesia) in Parkinson's disease, whereas pulsatile administration is supposed to promote them. This study investigated the inducibility of sensitization and abnormal involuntary movements (AIMs), comparing continuous and pulsatile administration of rotigotine with pulsatile administration of 3,4-dihydroxy-L-phenylalanine (L-DOPA) for reference. Rats were unilaterally lesioned with 6 hydroxydopamine (6-OHDA). For pulsatile administration, L-DOPA-methylester (10 mg/kg L-DOPA i.p.) or rotigotine (1 mg/kg i.p.) were administered once or twice daily. For continuous administration, a slow release formulation of rotigotine was injected s.c. at a dose of 1 mg/kg every 48 h (experiment I) or every 24 h (experiment II). Pulsatile administration of rotigotine and L-DOPA caused contraversive rotations increasing progressively upon each successive treatment. AIMs started to occur after the second administration of L-DOPA but hardly after pulsatile rotigotine. Continuous rotigotine increased rotations, which reached a plateau after the second administration. No AIMs were observed under continuous administration. The continuous administration of rotigotine did not induce sensitization or AIMs, suggesting that continuous stimulation of dopaminergic receptors by rotigotine has no propensity to induce dyskinesia in this experimental model.

Diurnal lamotrigine plasma level fluctuations: clinical significance and indication of shorter half-life with chronic administration

For therapeutic monitoring of antiepileptic drugs (AEDs), morning trough levels (MTLs) are generally used. For specific questions like verification of breakthrough seizures or reported toxicity, however, other measures such as minimal and maximal concentrations (C(min), C(max)) can be important and may require daily profiles. For clinical reasons, 20 daily profiles of lamotrigine (LTG) plasma levels were determined in nine patients. The results revealed fluctuations exceeding those expected from its elimination half-life (t(1/2)) of 22h as reported in the literature. Patients on twice-daily regimens without pharmacokinetic interactions exhibited C(min)/C(max) ratios between 0.62 and 0.69. Fluctuations were smaller in those co-medicated with valproate, and reached a ratio of 0.55 in those co-medicated with phenobarbital. The C(max) was as much as 58% above the MTL. Therefore, verification of complaints indicating toxicity requires determination of drug levels when the symptoms are present. Our findings indicate that the t(1/2) of LTG with chronic treatment is shorter than generally assumed, and suggest that a slow-release formulation could be helpful in achieving full seizure control in patients with a narrow individual therapeutic index for LTG.

The Potential of Soluble Epoxide Hydrolase Inhibition in the Treatment of Cardiac Hypertrophy

The Potential of Soluble Epoxide Hydrolase Inhibition in the Treatment of Cardiac Hypertrophy

Environmentally Friendly Slow Release Formulations of Alachlor Based on Clay-Phosphatidylcholine

A new clay-liposome complex was developed for reducing leaching of herbicides and contamination of groundwater. The liposomes were composed of the neutral and Environmental Protection Agency approved phospholipid phosphatidylcholine (PC). Adsorption of PC liposomes on the clay mineral montmorillonite could exceed the cation exchange capacity of the clay, and was well simulated by the Langmuir equation. X-ray diffraction results for 6 mM PC and 1.6 g/L clay (3 day incubation) yielded a basal spacing of 7.49 nm, which was interpreted as the formation of a supported planar bilayer on montmorillonite platelets. Fluorescence methods demonstrated structural changes which reflected adsorption of PC followed by loss of vesicle integrity as measured by the penetration of dithionite into the internal monolayer of fluorescently labeled liposomes, resulting in a decrease in fluorescence intensity to 18% of initial after 4 h. Energy transfer was demonstrated after 1 h from labeled liposomes to montmorillonite labeled by an acceptor. The neutral herbicide alachlor adsorbed on the liposome-clay complex, yielding a formulation of up to 40% active ingredient, and 1.6-fold reduction in herbicide release in comparison to the commercial formulation. Hence, the PC-montmorillonite complex can form a basis for environmentally friendly formulations of herbicides, which would yield reduced leaching.