High Dosing Frequency Research Articles

Pharmacokinetics and safety of fentanyl sublingual spray and fentanyl citrate intravenous: a multiple ascending dose study in opioid-naïve healthy volunteers

Objective: Fentanyl sublingual spray, with its rapid onset for pain relief, may be efficacious in the management of acute or post-operative pain. Because patients in these settings may be opioid-naïve, the study was conducted to determine the safety, tolerability, and pharmacokinetics of multiple dose administration of fentanyl sublingual spray in an opioid-naïve population.Methods: Fentanyl sublingual spray (100 mcg, 200 mcg, and 400 mcg) and fentanyl citrate intravenous (IV; 50 mcg) were administered every 0.5, 1.0, 2.0, and 4.0 h for up to three doses per cohort in opioid-naïve subjects (ClinicalTrials.gov identifier: NCT02641340). Eight subjects in each cohort were randomly assigned (six subjects received fentanyl sublingual spray; two subjects received fentanyl citrate IV). Pharmacokinetic and safety-related pharmacodynamic assessments were performed through 24 h post-first dose. Safety assessments were collected through Day 7.Results: Ninety-six opioid-naïve subjects, aged 20–55 years, with a body mass index of 18.7–31.5 kg/m2, participated in the study. Multiple doses of fentanyl sublingual spray (100, 200, and 400 mcg) were generally well tolerated. Hypoxia, observed in the 200-mcg and 400-mcg dose groups, increased with increasing doses and higher dosing frequency, but was readily managed by nasal cannula oxygenation. Overall, nausea increased with increasing doses, and ∼52.6% (10 out of 19) cases of nausea that occurred at the highest dose of 400 mcg were treated with concomitant medication. Overall, the reported adverse events were consistent with the known safety profile of fentanyl.Conclusion: Fentanyl sublingual spray (100 mcg, 200 mg, and 400 mcg) administered every 0.5, 1, 2, and 4 h was generally well tolerated in an opioid-naïve population. The results suggest that doses of 200 mcg or lower may be safe for use in an opioid-naïve population.

Chemotherapeutic dosing implicated by pharmacodynamic modeling of in vitro cytotoxic data: a case study of paclitaxel.

Conventional maximum tolerated doses (MTD) in chemotherapy are recently challenged by an alternative dosing method with low doses and high dosing frequency (LDHF). Still, it remains unclear which chemotherapies would potentially benefit from LDHF. The pharmacokinetic (PK) differences between MTD and LDHF are drug exposure magnitude (concentration) and exposure duration (time), two fundamental PK elements that are associated with the pharmacodynamics (PD) of chemotherapies. Here we hypothesized that quantitatively analyzing the contribution of each PK element to the overall cytotoxic effects would provide insights to the selection of the preferred chemotherapeutic dosing. Based on in vitro cytotoxic data, we developed a cellular PD model, which assumed that tumor cells were generally comprised of two subpopulations that were susceptible to either concentration- or time-dependent cytotoxicity. The developed PD model exhibited high flexibility to describe diverse patterns of cell survival curves. Integrated with a PK model, the cellular PD model was further extended to predict and compare the anti-tumor effect of paclitaxel in two dosing regimens: multiple MTD bolus and continuous constant infusion (an extreme LDHF). Our simulations of paclitaxel in treatment of three types of cancers were consistent with clinical observations that LDHF yielded higher patient efficacy than MTD. Our further analysis suggested that the ratio between drug steady-state concentrations and its cytotoxic sensitivity (C ss /KC 50 ) was a critical factor that largely determines favored dosing regimen. LDHF would produce higher efficacy when the ratio C ss /KC 50 is greater than 1. Otherwise MTD was favored. The developed PD model presented an approach simply based on in vitro cytotoxic data to predict the potentially favored chemotherapeutic dosing between MTD and LDHF.

Production and characterization of a PEGylated derivative of recombinant human deoxyribonuclease I for cystic fibrosis therapy

Recombinant human deoxyribonuclease I (rhDNase) is the mucolytic agent most widely used for the treatment of respiratory disease in cystic fibrosis. However, rhDNase is rapidly cleared from the lungs which implies a high dosing frequency and limited patient adherence. The aim of this study was to produce a long-acting PEGylated derivative of rhDNase presenting a preserved enzymatic activity. Site-specific PEGylation on the N-terminal (N-ter) leucine residue of rhDNase was achieved by reductive alkylation at acidic pH using linear 20kDa, linear 30kDa or two-arm 40kDa polyethylene glycol (PEG) propionaldehydes. Yields of mono-PEGylated products ranged between 45% and 61%. Conjugation to PEG fully preserved the secondary structure and the in vitro enzymatic activity of the native protein. These properties offer interesting perspectives for in vivo inhalation studies of the PEGylated enzyme.

Prescription Factors Associated with Medication Non-adherence in Japan Assessed from Leftover Drugs in the SETSUYAKU-BAG Campaign: Focus on Oral Antidiabetic Drugs.

Background: Medication adherence has an important influence on health outcomes in patients with chronic diseases. However, few studies have been performed in Japan to determine factors related to medication non-adherence.Objective: The aim of this study was to identify prescription factors related to medication non-adherence by investigating patient characteristics, all prescriptions, and prescriptions for oral antidiabetic drugs (OADs).Methods: A retrospective cross-sectional survey of prescription data about implementation of dosing regimen was performed at community pharmacies engaged in appropriate use of leftover drugs. We evaluated the amount of drugs originally prescribed and the reduced amount after use of leftover drugs, and then calculated prescription reduction ratio (PRR). We analyzed prescription factors contributing to non-adherence based on the PRR.Results: Prescription information for 1207 patients was reviewed, revealing that patients were non-adherent to 58% of prescriptions. Lack of a drug copayment, fewer concurrent drugs, and drugs not in single-dose packaging were associated with non-adherence. Among the 1207 patients, 234 prescriptions for diabetes and 452 OAD formulations were included. Forty-seven percent of prescriptions and 29% of the formulations were non-adherent. A higher dosing frequency and preprandial administration were associated with non-adherence. Among the OADs, adherence was lower for α-glucosidase inhibitors and biguanides than for sulfonylureas.Conclusions: Several factors related to patient characteristics, general drug prescriptions, and OAD prescriptions were associated with non-adherence. Further consideration will be needed to improve adherence to medication in Japan. Health care providers should perform more careful monitoring of adherence in patients with the factors identified by this study.

Intensity of language treatment: contribution to children's language outcomes.

Treatment intensity is an important factor in designing and delivering treatments to children with language impairment (LI). However, to date very little is understood about cumulative intervention intensity for children with LI in the US public school system. To examine treatment intensity (dose: time spent on language; frequency: number of sessions; duration: one academic year) as delivered to children with LI within US public schools and to explore its relation to children's language outcomes. A total of 233 children with LI on the caseloads of 73 speech-language pathologists (SLPs) participated. Direct child measures, weekly treatment logs and videotapes were collected to characterize children's language outcomes and treatment experiences. Children on average received 36 min of treatment during 1.3 treatment sessions per week. Children's language severity did not predict children's treatment intensity. Structural equation modelling indicated a significant interaction between frequency and dose of treatment: children receiving high frequency and low dose, or low frequency and high dose treatment had better outcomes than children receiving high frequency, high dose or low frequency, low dose treatment. Findings suggest that more intensive language treatment, measured as time, is not necessarily associated with better treatment outcomes.

Mechanistic investigation of biopharmaceutic and pharmacokinetic characteristics of surface engineering of satranidazole nanocrystals

The designing of surface engineered nanocrystals for improved stability and bioavailability is a multivariate process depending on several critical formulation and process variables. The present investigation deals with formulation of stable nanocrystals of poorly soluble satranidazole (SAT) for improving dissolution rate and pharmacokinetic profiling. SAT has low polar surface area, high dose and dosing frequency. Based on goniometric and stability studies of formulations prepared with various stabilizers, a unique combination of Span 20 and HPMC E-5 was selected for detailed investigation. Lyophilization of SAT nanosuspension was explored with nine different cryoprotectants in varying amounts to obtain easily redispersible nanocrystals (SAT-NC). The mean particle size and zeta potential of SAT-NC were found to be 208.8nm and −41.3mV respectively. DSC and XRPD confirmed the crystalline state of SAT. In vitro release studies of SAT-NC showed almost complete dissolution within 20min in water. Extravascular, one compartment pharmacokinetic modeling of in vivo plasma concentration versus time studies in male Wistar rats revealed twofold increase in Cmax, and AUC0-∞. Method of residuals was employed to calculate rate of absorption Ka and lag time. Nanosizing with appropriate stabilizers and programmed processing conditions successfully produced SAT-NC with improved pharmaceutic and pharmacokinetic characteristics.

Vincristine sulfate loaded dextran microspheres amalgamated with thermosensitive gel offered sustained release and enhanced cytotoxicity in THP-1, human leukemia cells: In vitro and in vivo study

Vincristine sulfate (VCS) is a drug of choice for the treatment of childhood and adult acute lymphocytic leukemia, Hodgkin's, non-Hodgkin's lymphoma as well as solid tumors including sarcomas. However, poor biopharmaceutical and pharmacokinetic traits of VCS like short serum half-life (12min), high dosing frequency (1.4mg/m2 per week for 4weeks) and extensive protein binding (75%) limit the clinical potential of VCS in cancer therapy. In present investigation, injectable vincristine sulfate loaded dextran microspheres (VCS-Dextran-MSs) were prepared and amalgamated with chitosan-β-glycerophosphate gel (VCS-Dextran-MSs-Gel) to surmount the biopharmaceutical and pharmacokinetic limitations of VCS that consequently induced synergistic sustained release pattern of the drug. Particle size and zeta-potential of VCS-Dextran-MSs were measured to be 6.8±2.4μm and −18.3±0.11mV along with the encapsulation efficiency of about 60.4±4.5%. Furthermore, VCS-Dextran-MSs and VCS-Dextran-MSs-Gel exhibited slow release pattern and 94.7% and 95.8% of the drug was released in 72h and 720h, respectively. Results from cell viability assay and pharmacokinetic as well as histopathological analysis in mice indicated that VCS-Dextran-MSs-Gel offers superior therapeutic potential and higher AUClast than VCS-Dextran-MSs and drug solution. In conclusion, VCS-Dextran-MSs-Gel warrants further preclinical tumor growth study to scale up the technology.

Update on denosumab in the management of postmenopausal osteoporosis: patient preference and adherence.

Patient adherence to many osteoporosis treatments, primarily bisphosphonates, is generally poor, thus leading to a significant reduction in antifracture efficacy. Patient perceptions about the necessity of the prescribed medication to treat osteoporosis and the concerns about the potential adverse effects are important and potentially modifiable determinants of adherence, in addition to other factors, such as difficult dosing regimens and high dosing frequency. Denosumab (Dmab) is a fully human monoclonal antibody against the receptor activator of nuclear factor-κB ligand (RANKL), which, through the prevention of the RANKL/RANK interaction, inhibits osteoclast-mediated bone resorption and significantly reduces the risk of vertebral, nonvertebral, and hip fractures. It is administered subcutaneously every 6 months for the treatment of postmenopausal osteoporosis. Preference and adherence to Dmab treatment were assessed in various clinical trials. Although with some limitations, available data suggest that Dmab is preferred to bisphosphonates, produces greater satisfaction than bisphosphonates, and would be preferentially chosen for long-term treatment. Moreover, patient perceptions about the necessity of Dmab treatment clearly outweigh the concerns about the injections, and positive beliefs about treatment positively influence medication-taking behavior. According to these data, Dmab may represent a reasonable alternative to bisphosphonates, particularly for osteoporotic women in whom a suboptimal or even poor adherence to oral treatments is expected.

Public knowledge and factors associated with inappropriate analgesic use: a survey in Thailand.

This study aims to evaluate knowledge of analgesics and factors associated with inappropriate analgesic use among the public. The cross-sectional study was carried out in one large city in the south of Thailand. The survey was conducted using interview of people of age 16 or older. The questionnaire elicited information regarding knowledge, attitudes and behaviours on analgesic use including prevalence of taking paracetamol >4 g/day (overdosage) and not taking non-steroidal anti-inflammatory drugs (NSAIDs) with meals (inappropriate taking). Of 1982 participants, paracetamol overdose (n = 595) and inappropriate NSAID users (n = 751) were less likely to give correct answers about analgesics compared with appropriate users. The overdose use was inversely associated with knowledge on paracetamol (odds ratio (OR) 0.90; 95% confidence interval (CI), 0.83, 0.98) but directly associated with positive attitudes towards high dose taking (OR 2.15; 95% CI, 1.49, 3.11), and high frequency of analgesic use (OR 1.78; 95% CI, 1.24, 2.54). Inappropriate NSAID ingestion was inversely associated with knowledge on NSAIDs and directly associated with more commonly obtaining analgesics from community pharmacies (OR 0.87; 95% CI, 0.82, 0.92 and OR 1.27; 95% CI, 1.01, 1.61, respectively). Poor knowledge, positive attitudes towards high dose or high frequency of analgesic consumption and the patterns of using drugs were associated with inappropriate analgesic use especially that of paracetamol.

APPROACHES TO OVERCOME NSAID INDUCED ULCERATION IN ARTHRITIC PAIN MANAGEMENT: PERSPECTIVES AND PROSPECTS

Rheumatoid arthritis is an auto-immune joint disorder involving pain and inflammation. Various approaches are used for pain management and relief from arthritis with single and multiple dose therapy. In single dose therapy, use of non-steroidal anti-inflammatory drugs like diclofenac aceclofenac, celicoxib etc. reported many side effects mainly leading to decrease in production of prostaglandin and holding the ulcer. High dosing frequency of these drugs is also a major factor of risk. Recently developed novel formulations are especially suitable for achieving controlled and delayed release profile with low risk of dose dumping. These systems have received great attention of pharmaceutical industry as they deliver accurate amount of drug at the right time and location thus increasing patient compliance and economic feasibility and avoiding drug associated side effects. Present review mainly deals with the problem of ulceration in pain management, various approaches to overcome this and specifically explore the possibilities to apply novel drug delivery systems for this purpose. Keywords: Arthritis, Drug delivery systems, Gastroretentive, NSAIDs, Pain, Rheumatoid arthritis, Rheumatic pain management.

Pharmacokinetics of neamine in rats and anti-cervical cancer activity in vitro and in vivo.

To study the pharmacokinetics of neamine in rats and to evaluate its anti-cervical cancer activity. The plasma level of neamine was determined by HPLC-ELSD. Pharmacokinetic parameters were calculated using DAS 2.0 software. Tissue microarray analysis was conducted to examine angiogenin (ANG) expression in normal and cancerous cervical tissues and to determine its correlation with clinical and pathologic presentations of cervical cancers. The anti-cervical cancer activity of neamine was assessed both in vitro and in vivo. After intravenous (i.v.) administration of 15, 30, and 60mgkg(-1) neamine, the pharmacokinetic parameters were as follows: AUC(0-t), 9,398.0±653.4, 19,235.2±2,939.0, and 35,437.7±3,772.2mgL(-1)min; C max, 170.8±13.1, 353.3±15.8, and 464.0±33.1mgL(-1); T 1/2, 34.9±4.1, 46.8±5.1, and 58.0±12.5min, respectively. The bioavailability of neamine administered through intramuscular, subcutaneous, intraperitoneal and intragastric route was 14.0±3.0, 8.4±0.6, 6.5±3.3, and 3.1±0.2%, respectively. Up-regulated ANG expression and increased nuclear translocation were observed in cervical cancers as compared to normal cervical tissues. Moreover, upregulation of ANG was positively correlated with primary tumor invasion. Neamine inhibited ANG-induced HUVEC and HeLa cell proliferation as well as nuclear translocation of ANG. Consistently, neamine inhibited both the establishment and progression of xenograft human cervical cancers in athymic mice. The bioavailability of neamine administered through extravascular routes was low. The half-life of neamine through i.v. administration was short. This suggests that a higher dosing frequency in order to maintain a therapeutic effect. Neamine holds potential against cervical cancer. The mechanisms of neamine inhibition are through blocking nuclear translocation of ANG thereby inhibiting both angiogenesis and cancer cell proliferation.

Recent Research on Matrix Tablets for Controlled Release-A Review

Oral drug delivery is the leading and the oldest segment of the total drug delivery system in the market. It is the greatest growing and most favored route for drug administration so oral controlled release of drugs becomes a very promising approach for drugs that having the shorter half-life and high dose frequency. Matrix tablets are an interesting option and new break through when developing an oral controlled release drugs delivery system. The use of various classes of release rate retardants like hydrophilic, hydrophobic, polymers and their degradation products are focused also. Release of drugs from matrices formulated with hydrophobic polymers is slower than from matrices formulated with hydrophilic Polymers.

A Review on Oral Extended Release Technology

In recent decades pharmaceutical industries are focusing on development of extended release formulations due to its various advantages. The drugs which are having the shorter half-life and high dosing frequency are suitable for extended release formulations. Extended release drug delivery system which reduce the dosing frequency of certain drugs by releasing the drug at slow rate and extended period of time. This formulation helps to avoid the side effects associated with low and high concentrations. The ideal order release rate and maintain the constant plasma concentrations. The extended release formulations may maintain therapeutic concentrations over prolonged periods. The use of extended release formulations avoids the high blood concentration. Extended release formulations have the potential to improve the patient compliance, reduce the toxicity by slowing drug absorption, minimize drug accumulation with chronic dosing, usage of less total drug and reduce the dose frequency, improvement the bioavailability of some drugs. Developing oral extended release tablets for drug at constant release rate has always been a challenge to the pharmaceutical technologist. There are various physicochemical and biological properties which affect the extended release dosage form. This article discusses the recent literature regarding development and design and fabrication of extended release system and in-vitro performance of extended release formulation.

Towards Successful Implementation of Pharmacokinetic-Guided Prophylactic Dosing of Clotting Factor Concentrate in Hemophilia; The Do’s and Don’ts after Discrete Choice Experiment Analysis

Towards Successful Implementation of Pharmacokinetic-Guided Prophylactic Dosing of Clotting Factor Concentrate in Hemophilia; The Do’s and Don’ts after Discrete Choice Experiment Analysis

Development of a biocompatible nanodelivery system for tuberculosis drugs based on isoniazid-Mg/Al layered double hydroxide.

The primary challenge in finding a treatment for tuberculosis (TB) is patient non-compliance to treatment due to long treatment duration, high dosing frequency, and adverse effects of anti-TB drugs. This study reports on the development of a nanodelivery system that intercalates the anti-TB drug isoniazid into Mg/Al layered double hydroxides (LDHs). Isoniazid was found to be released in a sustained manner from the novel nanodelivery system in humans in simulated phosphate buffer solutions at pH 4.8 and pH 7.4. The nanodelivery formulation was highly biocompatible compared to free isoniazid against human normal lung and 3T3 mouse fibroblast cells. The formulation was active against Mycobacterium tuberculosis and gram-positive bacteria and gram-negative bacteria. Thus results show significant promise for the further study of these nanocomposites for the treatment of TB.

Rapid Syllable Transitions (ReST) treatment for Childhood Apraxia of Speech: The effect of lower dose-Frequency

This study investigated the effectiveness of twice-weekly Rapid Syllable Transitions (ReST) treatment for Childhood Apraxia of Speech (CAS). ReST is an effective treatment at a frequency of four sessions a week for three consecutive weeks. In this study we used a multiple-baselines across participants design to examine treatment efficacy for four children with CAS, aged four to eight years, who received ReST treatment twice a week for six weeks. The children's ability to acquire new skills, generalize these skills to untreated items and maintain the skills after treatment was examined. All four children improved their production of the target items. Two of the four children generalized the treatment effects to similar untreated pseudo words and all children generalized to untreated real words. During the maintenance phase, all four participants maintained their skills to four months post-treatment, with a stable rather than rising profile. This study shows that ReST treatment delivered twice-weekly results in significant retention of treatment effects to four months post-treatment and generalization to untrained but related speech behaviors. Compared to ReST therapy four times per week, the twice-weekly frequency produces similar treatment gains but no ongoing improvement after the cessation of treatment. This implies that there may be a small but significant benefit of four times weekly therapy compared with twice-weekly ReST therapy.Learning outcomes: Readers will be able to define dose–frequency, and describe how this relates to overall intervention intensity. Readers will be able to explain the acquisition, generalization and maintenance effects in the study and describe how these compare to higher dose frequency treatments. Readers will recognize that the current findings give preliminary support for high dose–frequency CAS treatment.

Effects of Dose Frequency of Early Communication Intervention in Young Children With and Without Down Syndrome

Children with intellectual disability were randomly assigned to receive Milieu Communication Teaching (MCT) at one 1-hr session per week (low dose frequency, LDF) or five 1-hr sessions per week (high dose frequency, HDF) over 9 months ( Fey, Yoder, Warren, & Bredin-Oja, 2013 . Non-Down syndrome (NDS) and Down syndrome (DS) subgroups were matched on intelligence, mental age, and chronological age. The NDS group had significantly more growth in spoken vocabulary than the DS group. In the DS subgroup, the HDF group had more spoken vocabulary growth than the LDF group when IQ was controlled. In both etiological subgroups, the HDF group yielded greater vocabulary production outcomes than the LDF group for children who played functionally with a range of objects.

Evaluation of mitochondrial divisions in mouse with type‐2 diabetes and effect of glucose‐oxidase on mouse islet cells RIN‐m5F

To elucidate the relationship between dynamic variations of insular β cell mitochondria and type-2 diabetes by using a mouse model, the dynamic variation (fusion or fission) of insular β cell mitochondria present in two groups of Wistar mice with type-2 diabetes (high fat feeding and streptozotocin (STZ) adding with low dose and high frequency, high fat feeding and STZ adding with high dose and low frequency), and normal Wistar mouse were systematically compared. By analysing the insulin secretion level and other related indexes, the molecular mechanism of the fusion or fission phenomenon of insular β cell mitochondria in two different models (high fat feeding and STZ adding with low dose and high frequency, high fat feeding and STZ adding with high dose and low frequency) of mice with type-2 diabetes were initially elucidated. The phenomenon of mitochondrial fusion and fission was clearly seen. In initially determining the relationship between the change of insular β cell mitochondrial structure and its cell apoptosis generated by some factors such as treatment by glucose-oxidase (GO), the effect of GO on the mouse islet cells RIN-m5F including the effects on cell growth, reactive oxygen species (ROS), cell cycle, cell apoptosis of RIN-m5F were systematically examined. GO showed some influence on the mouse islet cells RIN-m5F cell activity, ROS and apoptosis, but its effect on the cell cycle was not significant.

PATENTED PHARMACEUTICAL ORAL CONTROLLED RELEASE MATRIX SYSTEM

Abstrac t Oral controlled release drug delivery system becomes a very promising approach for those drugs that are given orally but having the high dosing frequency and shorter half - life. Matrix tablets serves as an important tool for oral controlled release dosage forms. Problems like patient compliance, drug targeting, local side effects, frequent administration and fluctuations in blood concentration levels, associated with their counterparts, the conventional dosage forms were rectified. Many of the pharmaceutic al dosage form are formulated as sustained release dosage form to retard the release of a therapeutic agent such that its appearance in the systemic circulation is prolonged and its plasma profile is sustained in duration. Tablets offer the lowest cost app roach to controlled and sustained release dosage forms. Matrix tablet as controlled release has given a new breakthrough for novel drug delivery system in the field of pharmaceutical technology. This review focuses on the various types of matrix systems ba sed on polymer used and porosity of matrix system i.e. hydrophilic, hydrophobic, fat wax, porous, non - porous, pH sensitive. An effort has been made to consolidate different types of patents granted across the globe for last thirty years in the field of mat rix system viz. tablet, pellets etc.

Oral multiunit pellet extended release dosage form: A review

Oral drug delivery is the most preferred route for the various drug molecules among all other routes of drug delivery, because ease of administration which lead to better patient compliance. So, oral extended release drug delivery system becomes a very promising approach for those drugs that are given orally but having the shorter half-life and high dosing frequency. Recent trends indicate that multiparticulate drug delivery systems are especially suitable for achieving extended release oral formulations with low risk of dose dumping, flexibility of blending to attain different release patterns as well as reproducible and short gastric residence time. The release of drug from pellets depends on a variety of factors including the carrier used to form pellets and the amount of drug contained in them. Consequently, pellets provide tremendous opportunities for designing new controlled and extended release oral formulations, thus extending the frontier of future pharmaceutical development.DOI: http://dx.doi.org/10.3329/icpj.v2i10.16413 International Current Pharmaceutical Journal, September 2013, 2(10): 177-184