Use Of Oral Formulations Research Articles

A Nationwide Cohort Study of Oral and Depot Antipsychotics After First Hospitalization for Schizophrenia

Data on the effectiveness of antipsychotics in the early phase of schizophrenia are limited. The authors examined the risk of rehospitalization and drug discontinuation in a nationwide cohort of 2,588 consecutive patients hospitalized for the first time with a diagnosis of schizophrenia between 2000 and 2007 in Finland. The authors linked national databases of hospitalization, mortality, and antipsychotic prescriptions and computed hazard ratios, adjusting for the effects of sociodemographic and clinical variables, the temporal sequence of the antipsychotics used, and the choice of the initial antipsychotic for each patient. Of 2,588 patients, 1,507 (58.2%) collected a prescription for an antipsychotic during the first 30 days after hospital discharge, and 1,182 (45.7%, 95% confidence interval [CI]=43.7-47.6) continued their initial treatment for 30 days or longer. In a pairwise comparison between depot injections and their equivalent oral formulations, the risk of rehospitalization for patients receiving depot medications was about one-third of that for patients receiving oral medications (adjusted hazard ratio=0.36, 95% CI=0.17-0.75). Compared with oral risperidone, clozapine (adjusted hazard ratio=0.48, 95% CI=0.31-0.76) and olanzapine (adjusted hazard ratio=0.54, 95% CI=0.40-0.73) were each associated with a significantly lower rehospitalization risk. Use of any antipsychotic compared with no antipsychotic was associated with lower mortality (adjusted hazard ratio=0.45, 95% CI=0.31-0.67). In Finland, only a minority of patients adhere to their initial antipsychotic during the first 60 days after discharge from their first hospitalization for schizophrenia. Use of depot antipsychotics was associated with a significantly lower risk of rehospitalization than use of oral formulations of the same compounds. Among oral antipsychotics, clozapine and olanzapine were associated with more favorable outcomes. Use of any antipsychotic was associated with lower mortality.

Efficacy and tolerability of enteral formulations of ibuprofen in the treatment of patent ductus arteriosus in preterm infants

Background: The persistence of a patent ductus arteriosus (PDA) in preterm infants complicates their clinical course and may contribute to increased morbidity. Intravenous preparations of ibuprofen constitute one of the standard therapies for closure of a PDA. However, the unavailability of intravenous ibuprofen in certain regions of the world and the availability of inexpensive oral preparations has led to off-label nasogastric administration of oral ibuprofen in preterm infants with PDA. Objective: This article reviews and comments on the evidence for the enteral use of oral formulations of racemic ibuprofen for PDA closure in preterm infants, with a focus on the risk of necrotizing enterocolitis (NEC). Methods: MEDLINE, Current Contents, and Google Scholar were searched in April 2010 for trials of enteral ibuprofen in the treatment of PDA in preterm or low-birth-weight infants using the terms treatment, pharmacokinetics, ibuprofen, oral, enteral, patent ductus arteriosus, PDA, preterm, premature, low birth weight, infant, and newborn. Relevant congress Web sites were also searched for relevant abstracts. Results: The literature search identified 2 pharmacokinetic studies involving 32 infants and 13 clinical efficacy studies involving 306 infants treated with enteral ibuprofen. The clinical studies reported some benefit for enteral ibuprofen relative to the comparators. However, these studies had methodologic limitations, including small numbers of subjects, lack of blinding, inclusion of preterm infants with a higher gestational age, customized treatment regimens, and second-order statistical error that prevented conduct of a systematic review. When the results of all studies were pooled, NEC was reported in a total of 46 of 281 infants (16%) receiving enteral ibuprofen and 21 of 83 infants (25%) receiving indomethacin. This rate of NEC with enteral ibuprofen was twice that reported for intravenous ibuprofen in a recent meta-analysis (27/356 [8%]). Conclusions: The evidence supporting the off-label use of enteral ibuprofen for PDA in preterm infants is weak. Well-designed, appropriately powered pharmacologic and controlled clinical studies are needed before use of enteral ibuprofen can be recommended. In countries where an intravenous formulation of racemic ibuprofen is approved, off-label use of enteral racemic ibuprofen cannot be supported.

Isotretinoin: state of the art treatment for acne vulgaris

Summary Isotretinoin (13-cis retinoic acid) is the most potent known inhibitor of sebum production. The multiple modes of action for isotretinoin, including suppression of sebaceous gland activity, normalization of the pattern of keratinization within the sebaceous gland follicle, inhibition of inflammation, reduction of growth of Propionibacterium acnes in a secondary manner and, as currently shown, normalization of the expression of matrix tissue metalloproteinases and their inhibitors make this compound the single most effective in the treatment of severe recalcitrant nodulocystic acne, and in the prevention of acne scarring. Several generic formulations for oral use have recently been introduced, in addition to the brand formulations Roaccutane and Accutane (Roche). This development, considering the high risk of teratogenicity associated with oral isotretinoin use, has led the European Commission and the European Medicines Agency (EMEA) to release a directive towards the harmonization of the Summary of Product Characteristics (SPC). This has similarities to US FDA regulations, a matter that caused the reaction of the Forum for the Improvement of Clinical Trials in Acne. Physician's experience, coupled with proper patient selection, dose adjustment or discontinuation of treatment, and routine monitoring for potential toxicity, has allowed the successful prevention and management of most adverse effects associated with isotretinoin.

Isotretinoin: state of the art treatment for acne vulgaris

Isotretinoin (13-cis retinoic acid) is the most potent known inhibitor of sebum production. The multiple modes of action for isotretinoin, including suppression of sebaceous gland activity, normalization of the pattern of keratinization within the sebaceous gland follicle, inhibition of inflammation, reduction of growth of Propionibacterium acnes in a secondary manner and, as currently shown, normalization of the expression of matrix tissue metalloproteinases and their inhibitors make this compound the single most effective in the treatment of severe recalcitrant nodulocystic acne, and in the prevention of acne scarring. Several generic formulations for oral use have recently been introduced, in addition to the brand formulations Roaccutane® and Accutane™ (Roche). This development, considering the high risk of teratogenicity associated with oral isotretinoin use, has led the European Commission and the European Medicines Agency (EMEA) to release a directive towards the harmonization of the Summary of Prod...

Sex Hormones and Thrombosis

There is compelling evidence that use of oral formulations of female hormone replacement and of the combined oral contraceptive induces a prothrombotic state. This translates to an increased thrombotic risk. Within the individual, the absolute risk is determined by the interaction between that induced by hormone use and heritable and acquired risk factors for thrombosis. Knowledge of the accumulating epidemiologic and clinical trial-derived data on this topic is essential for the delivery of evidence-based counseling in the clinical environment and is the subject of this review.

The Importance of the Cosolvent Propylene Glycol on the Antimicrobial Preservative Efficacy of a Pharmaceutical Formulation by DOE-Ruggedness Testing

The aim of this study was to statistically evaluate the influence of the concentration of the co-solvent propylene glycol on the preservative efficacy of a complex pharmaceutical suspension-emulsion formulation containing methyl- and propylparaben.Preservative Efficacy Tests (PETs) were performed using the validated pharmacopoeial methodology with five test organisms over 1 month on lab-scale test formulations. These were independently prepared according to a Box-Behnken experimental design with a triplicate central point at 0.22% m/m methylparaben, 0.22% m/m propylparaben, and 2.75% m/m propylene glycol, and with an additional corner point of the Box-Behnken cube. We evaluated the preservative efficacies against the criteria of the United States Pharmacopeia (USP) and European Pharmacopoeias (PhEur) for formulations for oral use, as well as by the statistical comparison of the slopes obtained by linear regression of log (CFU/g) vs. time.With an initial bacterial challenge of 106 CFU/g for each of the three bacterial strains, no survivals were detected after 7 days. For the two fungal strains, box plots and analysis of variance showed significant, concentration-dependent, main effects: the three variables significantly influenced the kill-rate of C. albicans, while A. niger was predominantly influenced by the cosolvent propylene glycol, and only to a minor extent by methylparaben and not at all by propylparaben. These findings were confirmed by taking the pharmacopoeial criteria as the evaluation basis, where the dominant influence of propylene glycol concentration is apparent.It was concluded that the cosolvent propylene glycol is at least of equal preservative importance than both parabens.

Clinical Pharmacology of Tramadol

Tramadol, a centrally acting analgesic structurally related to codeine and morphine, consists of two enantiomers, both of which contribute to analgesic activity via different mechanisms. (+)-Tramadol and the metabolite (+)-O-desmethyl-tramadol (M1) are agonists of the mu opioid receptor. (+)-Tramadol inhibits serotonin reuptake and (-)-tramadol inhibits norepinephrine reuptake, enhancing inhibitory effects on pain transmission in the spinal cord. The complementary and synergistic actions of the two enantiomers improve the analgesic efficacy and tolerability profile of the racemate. Tramadol is available as drops, capsules and sustained-release formulations for oral use, suppositories for rectal use and solution for intramuscular, intravenous and subcutaneous injection. After oral administration, tramadol is rapidly and almost completely absorbed. Sustained-release tablets release the active ingredient over a period of 12 hours, reach peak concentrations after 4.9 hours and have a bioavailability of 87-95% compared with capsules. Tramadol is rapidly distributed in the body; plasma protein binding is about 20%. Tramadol is mainly metabolised by O- and N-demethylation and by conjugation reactions forming glucuronides and sulfates. Tramadol and its metabolites are mainly excreted via the kidneys. The mean elimination half-life is about 6 hours. The O-demethylation of tramadol to M1, the main analgesic effective metabolite, is catalysed by cytochrome P450 (CYP) 2D6, whereas N-demethylation to M2 is catalysed by CYP2B6 and CYP3A4. The wide variability in the pharmacokinetic properties of tramadol can partly be ascribed to CYP polymorphism. O- and N-demethylation of tramadol as well as renal elimination are stereoselective. Pharmacokinetic-pharmacodynamic characterisation of tramadol is difficult because of differences between tramadol concentrations in plasma and at the site of action, and because of pharmacodynamic interactions between the two enantiomers of tramadol and its active metabolites. The analgesic potency of tramadol is about 10% of that of morphine following parenteral administration. Tramadol provides postoperative pain relief comparable with that of pethidine, and the analgesic efficacy of tramadol can further be improved by combination with a non-opioid analgesic. Tramadol may prove particularly useful in patients with a risk of poor cardiopulmonary function, after surgery of the thorax or upper abdomen and when non-opioid analgesics are contraindicated. Tramadol is an effective and well tolerated agent to reduce pain resulting from trauma, renal or biliary colic and labour, and also for the management of chronic pain of malignant or nonmalignant origin, particularly neuropathic pain. Tramadol appears to produce less constipation and dependence than equianalgesic doses of strong opioids.

Clinical trials of ayurvedic formulations in the treatment of acne vulgaris

Oral and externally used dermatological preparation for acne vulgaris employing herbal extracts have been developed and standardized, the herbal extracts used here were of the plants described in ayurvedic treatise like Bhavprakasha Nighantu and Charak Samhita. The efficacy of the treatment using the oral formulation with or without external preparation has been assessed through conduct of Phase II clinical trials in 53 patients for 4 weeks in a randomized, double-blind, placebo-controlled fashion and following Good Clinical Practices guidelines. The results were statistically analyzed and indicated that combination of use of internal and external preparation showed better efficacy as compared to the use of oral formulation alone.

Assessment of the physical stability of lyophilized MK-0591 by differential scanning calorimetry

Abstract MK-0591, a potent indirect leukotriene biosynthesis inhibitor, is poorly absorbed when administered orally as a crystalline sodium salt, primarily because of its low aqueous solubility (5 μg/mL). However, the lyophilized X-ray amorphous form with much higher aqueous solubility is very well absorbed and physically stable for long time periods. To better understand the physical stability of the amorphous state, conditions at which the compound will crystallize from the amorphous state were investigated in the context of its glass transition temperature. The physical stability of X-ray amorphous MK-0591 was evaluated by DSC with enhanced sensitivity using the crystallization exotherm at ca. 185°C (10°C/min) to detect crystallization in the solid matrix. No crystal formation was observed at 30°C for 6 months, 60°C for 6 months or 30°C at 75% RH for 6 months. This prolonged physical stability was attributable to two factors: its high glass transition temperature (ca. 125°C) and liquid crystal formation in aqueous solutions at concentrations greater than 60 mg/mL. Crystallization could not be induced after isothermally holding the X-ray amorphous MK-0591 at 120°C for 17 h. Seeding with crystalline MK-0591 (10%) also failed to induce crystallization at 50°C for 6 months or at 30°C at 75% RH for 6 months. Water plasticizes lyophilized MK-0591, lowering the Tg and inducing the onset of crystallization to 100°C. Crystallization at room temperature does not occur with equilibration at high relative humidites probably because of the additional stability imparted to the system by the formation of a lyotropic liquid crystalline phase. The behaviour of amorphous MK-0591, with its high Tg in the solid state and its liquid crystalline properties in concentrated aqueous solution, provided sufficient physical stability to permit its use in oral formulations.

硫酸化シクロデキストリンの難水溶性アルミニウム塩による塩基性線維芽細胞増殖因子の安定化および放出制御

Basic fibroblast growth factor(bFGF)is a prototype of heparin-binding growth factor family and could play a crucial role in wound healing processes. Water-insoluble aluminum salts of cyclodextrin sulfates (Al·CyD-Suls) were prepared, and their potential use in oral formulations of bFGF intended for treatment of gastrointestinal ulcers was investigated. Adsorbates of bFGF with Al·CyrD-Suls were prepared by incubating the growth factor with a suspension of Al·CyD-Suls in water. The mitogenic activity of bFGF released from the adsorbate was almost comparable to that of the intact bFGF. Al·CyD-Suls significantly protected bFGF against proteolytic degradation by pepsin, compared with their sodium salts and other sulfated oligosaccharides tested. The in vitro release of bFGF from the Al·β-CyD-Sul adsorbate into isotonic phosphate buffer (pH 7.4) was sustained in proportion to a rise in the ratio of Al·βCyD-Sul to the growth factor. The oral administration of the adsorbate of bFGF with Al·β-CyD-Sul had the most prominent healing effects on acetic acid-induced gastric ulcers. These results suggest that Al·CyD-Suls may potentiate the healing effect of bFGF by both stabilizing and anchoring the growth factor at the site where its action is desired.

A possible pH-controlled drug delivery system based on a derivative of the polysaccharide scleroglucan.

Four carboxylated derivatives of scleroglucan have been obtained by oxidation, to different extents, of the glucopyranose side chains of the natural polysaccharide. The diffusion of model molecules through aqueous solutions of these new products was measured at various pH values. The reversible pH induced sol-gel transition of some of the polyelectrolyte solutions tested effects a remarkable variation in the diffusion rate of the permeating species; in this sense the most interesting polysaccharide appears to be the product with 70% oxidized glucopyranose moieties. The behaviour of scleroglucan and its derivatives has been compared with that of carboxymethylcellulose and the mechanism involved in drug permeation and release discussed. The possible application of one of the new products in controlled release formulations for oral use is also reported.