High Dosing Frequency Research Articles

Duloxetine HCl Lipid Nanoparticles: Preparation, Characterization, and Dosage Form Design

Solid lipid nanoparticles (SLNs) of duloxetine hydrochloride (DLX) were prepared to circumvent the problems of DLX, which include acid labile nature, high first-pass metabolism, and high-dosing frequency. The DLX-SLNs were prepared by using two different techniques, viz. solvent diffusion method and ultrasound dispersion method, and evaluated for particle size, zeta potential, entrapment efficiency, physical characteristics, and chemical stability. Best results were obtained when SLNs were prepared by ultrasound dispersion method using glyceryl mono stearate as solid lipid and DLX in ratio of 1:20 and mixture of polysorbate 80 and poloxamer 188 as surfactant in concentration of 3%. The mean particle size of formulation and entrapment efficiency was 91.7 nm and 87%, respectively, and had excellent stability in acidic medium. Differential scanning calorimetry and X-ray diffraction data showed complete amorphization of DLX in lipid. In vitro drug release from SLNs was observed for 48 h and was in accordance with Higuchi kinetics. In vivo antidepressant activity was evaluated in mice by forced swim test. DLX-SLNs showed significant enhancement in antidepressant activity at 24 h when administered orally in comparison to drug solution. These results confirm the potential of SLNs in enhancing chemical stability and improving the efficacy of DLX via oral route. The SLN dispersion was converted into solid granules by adsorbing on colloidal silicon dioxide and characterized for particle size after redispersion, morphology, and flow properties. Results indicated that nanoparticles were successfully adsorbed on the carrier and released SLNs when dispersed in water.

Prevalence and Correlates of Self-reported Nonadherence With Eye Drop Treatment

This study aimed to investigate (1) the prevalence of nonadherence with eye drop treatment; (2) selected correlates of nonadherence at the patient and health-care organization level; and (3) the diagnostic value of the ophthalmologists' ratings, using patients' self-reports as standard. This cross-sectional multicenter survey used questionnaires for ophthalmologists and their patients to assess self-reported nonadherence and its correlates. One item, using a 4-point scale [never (ie, adherent) to daily], asked the patients whether they had forgotten to administer eye drops during the past 2 weeks. Ophthalmologists rated their patients as adherent or nonadherent. Nonadherence was also determined by combined methods, whereby either could indicate nonadherence. Given the nested structure of the data, multilevel modeling was used to investigate self-reported nonadherence-correlates. Diagnostic values of ophthalmologists' report were calculated. Of 663 patients (48% female, 44% >69 years), nonadherence was indicated in 39.2% (n=260) through self-reporting, 2.1% (n=14) through ophthalmologists' ratings, and 40% (n=266) through combined measures. The multivariable, multilevel model showed following significant nonadherence-correlates: Male sex (P=0.01), younger age (P=0.027), and higher-dose frequency (P=0.001). No significant correlation with treating ophthalmologist (P=0.21) could be seen. Yet, the patients visiting their ophthalmologists at least every 3 months were less nonadherent than patients with fewer consultations (P=0.01). The ophthalmologists' report showed a sensitivity and specificity of 3% and 98.5%, respectively. The prevalence of self-reported nonadherence was congruent with literature. The patients visiting their ophthalmologists at least every 3 months have a lower risk of nonadherence. Ophthalmologist report is an insensitive method for detecting nonadherence.

Effect of medication-related factors on adherence in people with schizophrenia: A European multi-centre study

To investigate the relation between medication-related factors and adherence in people with schizophrenia in outpatient treatment. The sample comprised 409 outpatients (ICD-10 diagnosis of schizophrenia) with clinician-rated instability in four European cities (Amsterdam, The Netherlands; Verona, Italy; Leipzig, Germany; London, Great Britain). Adherence was assessed using the Medication Adherence Questionnaire (patient perspective), and the Clinician Rating Scale (clinician perspective). Examined medication-related factors were type (atypical vs. typical), application (oral vs. depot), daily dose frequency of antipsychotic medication (Medication History Scale), number of side effects (Liverpool University Neuroleptic Side Effect Rating Scale), and patient attitudes toward medication (Drug Attitude Inventory). Multiple regression analysis was used to identify predictors of adherence by medication-related factors. Adherence, as rated by patient and clinician, was predicted by patient attitude towards medication, but was unrelated to type of drug, formulation or side effects of antipsychotic medication. A high daily dose frequency was associated with better adherence, but only when rated by the patient. In order to improve adherence there is a need to seriously consider and attempt to improve patient attitude toward medication. However, type of antipsychotic and other medication-related factors may not be as closely related to adherence as it has often been suggested.

Antibiotic Dose Impact on Resistance Selection in the Community: a Mathematical Model of β-Lactams and Streptococcus pneumoniae Dynamics

Streptococcus pneumoniae is a major pathogen in the community and presents high rates of resistance to the available antibiotics. To prevent antibiotic treatment failure caused by highly resistant bacteria, increasing the prescribed antibiotic dose has recently been suggested. The aim of the present study was to assess the influence of beta-lactam prescribed doses on the emergence of resistance and selection in the community. A mathematical model was constructed by combining S. pneumoniae pharmacodynamic and population-dynamic approaches. The received-dose heterogeneity in the population was specifically modeled. Simulations over a 50-year period were run to test the effects of dose distribution and antibiotic exposure frequency changes on community resistance patterns, as well as the accuracy of the defined daily dose as a predictor of resistance. When the frequency of antibiotic exposure per year was kept constant, dose levels had a strong impact on the levels of resistance after a 50-year simulation. The lowest doses resulted in a high prevalence of nonsusceptible strains (> or =70%) with MICs that were still low (1 mg/liter), whereas high doses resulted in a lower prevalence of nonsusceptible strains (<40%) and higher MICs (2 mg/liter). Furthermore, by keeping the volume of antibiotics constant in the population, different patterns of use (low antibiotic dose and high antibiotic exposure frequency versus high dose and low frequency) could lead to markedly different rates of resistance distribution and prevalence (from 10 to 100%). Our results suggest that pneumococcal resistance patterns in the community are strongly related to the individual beta-lactam doses received: limiting beta-lactam use while increasing the doses could help reduce the prevalence of resistance, although it should select for higher levels of resistance. Surveillance networks are therefore encouraged to collect both daily antibiotic exposure frequencies and individual prescribed doses.

Potential of treating tuberculosis with a polymeric nano-drug delivery system

Abstract summary An effective therapeutic regimen is available for the treatment of tuberculosis (TB), however in developing countries; patient non-compliance due to high dose frequency and the lengthy duration of treatment, presents a major challenge, thus resulting in treatment failure. To address this challenge, the project seeks to develop a nano-drug delivery system whereby anti-TB drugs can be administered in a single dose that maintains an active level of the drug for at least one week.

Adherence to and Gastrointestinal Tolerability of Monthly Oral or Quarterly Intravenous Ibandronate Therapy in Women with Previous Intolerance to Oral Bisphosphonates: A 12-Month, Open-Label, Prospective Evaluation

Background: Gastrointestinal (GI) symptoms and high dosing frequency have been cited as reasons for inadequate adherence to daily or weekly oral bisphosphonate therapy. Inadequate adherence may lead to poor therapeutic outcomes. Objective: The PRIOR study evaluated adherence to and GI tolerability of monthly therapy with oral and quarterly intravenous ibandronate in postmenopausal women with osteoporosis or osteopenia. Methods: This 12-month, multicenter, prospective, nonrandomized, open-label, noninferiority study included postmenopausal women with osteoporosis or osteopenia who had discontinued previous daily or weekly oral bisphosphonate therapy because of GI intolerance. Participants chose to receive either monthly oral ibandronate 150 mg or quarterly intravenous ibandronate 3 mg and were permitted to switch formulations once during the study. For oral treatment, adherence was assessed based on doses taken, as recorded on the case-report form; for intravenous treatment, adherence was assessed based on doses administered, as recorded by study site personnel. Participants who took ≥75% of protocol-specified doses were considered adherent. The rate of adherence to oral ibandronate was protocol defined as noninferior to that of intravenous ibandronate if the upper limit of the 2-sided 90% CI for the adjusted difference in adherence rates was >20%. At screening, participants assessed the tolerability of their previous bisphosphonate therapy using the GI Experience Survey; using the same instrument, they assessed the tolerability of ibandronate 1 month from baseline and at months 4, 7, and 10. Results: Of 543 participants in the intent-to-treat population, 147 (27.1%) chose to receive oral treatment and 396 (72.9%) chose to receive intravenous treatment. The mean age of participants was <66 years in both groups, and >90% of participants were white. A significantly greater proportion of participants who selected intravenous versus oral treatment had a primary diagnosis of osteoporosis (72.2% vs 57.1%, respectively; P < 0.001) and a history of fracture as an adult (35.6% vs 22.4%; P ≥ 0.004); significantly fewer recipients of intravenous versus oral ibandronate were currently working (29.0% vs 39.5%; P ≥ 0.021). Overall, 82.9% of participants had previously received alendronate and 44.9% had previously received risedronate. Eleven participants switched from oral to intravenous therapy and 16 switched from intravenous to oral therapy during the study. In the perprotocol population, 69.7% of participants in the oral group (101/145) and 82.9% of participants in the intravenous group (325/392) were adherent to their originally selected therapy. Adherence to oral therapy fell within the prespecified boundary for noninferiority to intravenous therapy (adjusted difference: 12.4%; 90% CI, 5.1–19.7). Mean GI tolerance scores were significantly improved from screening at all subsequent assessment times in both treatment groups ( P < 0.001); >75% of participants had a ≥10% increase in GI tolerability scores from screening. Both dosing regimens were generally well tolerated. Conclusion: Self-selected monthly oral or quarterly intravenous ibandronate therapy was associated with high adherence rates among these postmenopausal women with osteoporosis or osteopenia who had previously discontinued oral bisphosphonate treatment because of GI intolerance.

Indications for 5-aminosalicylate in inflammatory bowel disease: is the body of evidence complete?

Mesalazine is a safe drug, although adverse events may be seen in a minority of patients. This applies also to pregnant women and children. The role of mesalazine in combination therapy to improve efficacy and concomitant drug pharmacokinetics, or in chemoprevention against inflammatory bowel disease (IBD)-related colonic carcinoma has not yet been completely elucidated. Therapeutic success of mesalazine may be optimized by a combination of high dose and low frequency of dosage to improve compliance. Therefore, due to its superior safety profile and pharmacokinetic characteristics, mesalazine is preferable to sulphasalazine. This paper reviews the literature concerning mechanisms of action, indications and off-label use, pharmacokinetic properties and formulations, therapeutic efficacy, compliance, paediatric indications, chemoprevention, and safety issues and adverse event profile of mesalazine treatment versus sulphasalazine. It also highlights these controversies in order to clarify the potential benefits of mesalazines in IBD therapy and evidence for its use.

An evaluation of pulsed shortwave on knee osteoarthritis using radioleucoscintigraphy: a randomised, double blind, controlled trial

Objective. – To evaluate the effects of pulsed shortwave on osteoarthritis of the knee. Methods. – A double blinded, randomised, controlled trial. Thirteen female and 14 male patients with radiographic evidence of knee osteoarthritis were randomly allocated to either low dose (10 W), or high dose (20 W) or placebo high frequency pulsed shortwave. Knee radioleucoscintigraphy was performed pre and post treatment as well as objective functional and subjective evaluations. Results. – There were no significant differences between the groups in the pre and post treatment percentage change for radioleucoscintigraphy ( P > 0.05). Functional and subjective measures also revealed no pre and post treatment differences between the groups ( P > 0.05), except for improved knee range of motion in the placebo group ( P < 0.05). Conclusion. – Joint inflammation in knee osteoarthritis, measured using radioleucoscintigraphy, was not altered significantly by pulsed shortwave, therefore this therapeutic modality has little or no anti-inflammatory effect on conditions such as osteoarthritis of the knee.

Évaluation par la scintigraphie aux leucocytes marqués de l'efficacité des ondes courtes pulsées dans le traitement de l'arthrose du genou : étude randomisée, en double insu

Objective. – To evaluate the effects of pulsed shortwave on osteoarthritis of the knee. Methods. – A double blinded, randomised, controlled trial. Thirteen female and 14 male patients with radiographic evidence of knee osteoarthritis were randomly allocated to either low dose (10W), or high dose (20W) or placebo high frequency pulsed shortwave. Knee radioleucoscintigraphy was performed pre and post treatment as well as objective functional and subjective evaluations. Results. – There were no significant differences between the groups in the pre and post treatment percentage change for radioleucoscintigraphy ( P > 0.05). Functional and subjective measures also revealed no pre and post treatment differences between the groups ( P > 0.05), except for improved knee range of motion in the placebo group ( P < 0.05). Conclusion. – Joint inflammation in knee osteoarthritis, measured using radioleucoscintigraphy, was not altered significantly by pulsed shortwave, therefore this therapeutic modality has little or no anti inflammatory effect on conditions such as osteoarthritis of the knee.

The argument against the use of cyclophosphamide and mitoxantrone in the treatment of multiple sclerosis

Mitoxantrone (MITX) and cyclophosphamide (CPM) are potent immunosuppressive agents with efficacy in the treatment of multiple sclerosis (MS). Both agents appear effective in those patients with active inflammatory disease but are probably less effective in patients with a secondary progressive (SP) course dominated by a degenerative component. Given these agents are effective patients with active inflammation the question arises as to whether they are more effective than high dose interferon therapy. Interferon beta administered at high dose and high frequency suppresses enhancing lesions by as much as 90% and brings about a 35% decrease in relapse rates in addition to decreasing the progression of disability. Interferons have an excellent safety profile even after years of administration. What then is the advantage of immunosuppressive agents such as cyclophosphamide and mitoxantrone over safer and still effective treatments? The answer lies in the magnitude of effect in those with the most active and aggressive disease states. While interferons are safe and effective in those with mild or moderate inflammatory disease states, they are probably not sufficient to bring about control in disease that is highly active and resilient. Both mitoxantrone and cyclophosphamide have the ability to suppress inflammation that may be resistant to therapy with more conservative agents. Given the safety profile of these agents their use should be restricted to those patients with aggressive disease resistant to treatment with more conservative agents.

A prospective study of predictors of adherence to combination antiretroviral medication.

Adherence to complex antiretroviral therapy (ART) is critical for HIV treatment but difficult to achieve. The development of interventions to improve adherence requires detailed information regarding barriers to adherence. However, short follow-up and inadequate adherence measures have hampered such determinations. We sought to assess predictors of long-term (up to 1 year) adherence to newly initiated combination ART using an accurate, objective adherence measure. A prospective cohort study of 140 HIV-infected patients at a county hospital HIV clinic during the year following initiation of a new highly active ART regimen. We measured adherence every 4 weeks, computing a composite score from electronic medication bottle caps, pill count and self-report. We evaluated patient demographic, biomedical, and psychosocial characteristics, features of the regimen, and relationship with one's HIV provider as predictors of adherence over 48 weeks. On average, subjects took 71% of prescribed doses with over 95% of patients achieving suboptimal (<95%) adherence. In multivariate analyses, African-American ethnicity, lower income and education, alcohol use, higher dose frequency, and fewer adherence aids (e.g., pillboxes, timers) were independently associated with worse adherence. After adjusting for demographic and clinical factors, those actively using drugs took 59% of doses versus 72% for nonusers, and those drinking alcohol took 66% of doses versus 74% for nondrinkers. Patients with more antiretroviral doses per day adhered less well. Participants using no adherence aids took 68% of doses versus 76% for those in the upper quartile of number of adherence aids used. Nearly all patients' adherence levels were suboptimal, demonstrating the critical need for programs to assist patients with medication taking. Interventions that assess and treat substance abuse and incorporate adherence aids may be particularly helpful and warrant further study.

Dithranol

Psoriasis is chronic autoimmune disorder mediated via T cell activation affecting 3% of population globally and is characterized by various features including erythema, scaling, hyperkeratosis, hyperplasia, plaques etc. Inspite of on going extensive researches in this disease area there is not a single therapy which claims complete cure and their primary focus is based on ameliorating the major symptoms underlying this pathophysiology and improving the medical condition. Out of the various currently assessable therapies, topical drug delivery approaches are mostly preferred because of their several advantages including direct targeting to desired site eliminating exposure to remaining body organs and hence minimizing the adverse side effects. The conventional drug delivery approaches (gels, creams and ointments) available as over the counter (OTC) products are associated with several disadvanatges due to local toxicity (irritation, burning, atropy etc), systemic toxicity (associated with drug leaching), reduced treatment efficacy (due to lower penetration of active in the viable epidermal region and poor retentive capability) and high dosing frequency with poor patient compliance because of reduced benefit to risk ratio. To address the above challenges and improve the benefit to risk ratio, nanoformulation based strategies are adopted due to several advantages including slow and sustained drug release (eliminating local toxicity due to sudden exposure of drug), deeper skin penetration, higher cellular uptake with localized retention with negligible systemic leaching. This review emphasizes on various types of nano-carriers (liposomes, niosomes, nano-emulsions, solid lipid nanoparticles, polymeric nanoparticles, etc) loaded with different anti-psoriatic small molecules in psoriasis treatment.

Retinoids

Psoriasis is chronic autoimmune disorder mediated via T cell activation affecting 3% of population globally and is characterized by various features including erythema, scaling, hyperkeratosis, hyperplasia, plaques etc. Inspite of on going extensive researches in this disease area there is not a single therapy which claims complete cure and their primary focus is based on ameliorating the major symptoms underlying this pathophysiology and improving the medical condition. Out of the various currently assessable therapies, topical drug delivery approaches are mostly preferred because of their several advantages including direct targeting to desired site eliminating exposure to remaining body organs and hence minimizing the adverse side effects. The conventional drug delivery approaches (gels, creams and ointments) available as over the counter (OTC) products are associated with several disadvanatges due to local toxicity (irritation, burning, atropy etc), systemic toxicity (associated with drug leaching), reduced treatment efficacy (due to lower penetration of active in the viable epidermal region and poor retentive capability) and high dosing frequency with poor patient compliance because of reduced benefit to risk ratio. To address the above challenges and improve the benefit to risk ratio, nanoformulation based strategies are adopted due to several advantages including slow and sustained drug release (eliminating local toxicity due to sudden exposure of drug), deeper skin penetration, higher cellular uptake with localized retention with negligible systemic leaching. This review emphasizes on various types of nano-carriers (liposomes, niosomes, nano-emulsions, solid lipid nanoparticles, polymeric nanoparticles, etc) loaded with different anti-psoriatic small molecules in psoriasis treatment.