Pharmacokinetic study of Sudaxine in dog plasma using novel LC-MS/MS method.

CONTEXT: Sudaxine is a novel respiratory stimulant that increases ventilatory drive via NO+ -thiolate signaling and is under development for reversal of opioid-induced respiratory depression and other critical care indications. OBJECTIVE: This study investigates the pharmacokinetic characteristics after intravenous administration of Sudaxine by using a simple liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. MATERIALS AND METHODS: A sensitive LC-MS/MS method was validated to determine the concentration of Sudaxine in beagle dog plasma after intravenous administration of Sudaxine at (3, 10, 30, and 100 mg/kg). Blood samples (1 mL) were collected at designated time points and SDX concentration was measured for pharmacokinetic study. RESULTS: The calibration curve was linear within the range of 50-5,000 ng/mL with the lower limit of quantification at 50 ng/mL. The CTmax for all doses was reached at 10 minutes (Tmax ). Over the dose range studied, average concentration - time curves and systemic exposure (CTmax and AUC0-t ) increased to Sudaxine dose. The terminal half-life of Sudaxine in dogs ranged from 10 to 30 minutes and about 17.3 ± 1.0% of Sudaxine was protein-bound in dog plasma. DISCUSSION AND CONCLUSIONS: We developed a novel LC-MS/MS method of Sudaxine detection and quantification and determined its pharmacokinetic profiles after intravenous administration in canine subjects. Sudaxine followed first-order kinetics with rapid dose-dependent clearance rates and short half-life making it an ideal candidate for use in a critical care setting with intramuscular or IV administration.

Inhaled Therapy in Respiratory Disease: The Complex Interplay of Pulmonary Kinetic Processes.

The inhalation route is frequently used to administer drugs for the management of respiratory diseases such as asthma or chronic obstructive pulmonary disease. Compared with other routes of administration, inhalation offers a number of advantages in the treatment of these diseases. For example, via inhalation, a drug is directly delivered to the target organ, conferring high pulmonary drug concentrations and low systemic drug concentrations. Therefore, drug inhalation is typically associated with high pulmonary efficacy and minimal systemic side effects. The lung, as a target, represents an organ with a complex structure and multiple pulmonary-specific pharmacokinetic processes, including (1) drug particle/droplet deposition; (2) pulmonary drug dissolution; (3) mucociliary and macrophage clearance; (4) absorption to lung tissue; (5) pulmonary tissue retention and tissue metabolism; and (6) absorptive drug clearance to the systemic perfusion. In this review, we describe these pharmacokinetic processes and explain how they may be influenced by drug-, formulation- and device-, and patient-related factors. Furthermore, we highlight the complex interplay between these processes and describe, using the examples of inhaled albuterol, fluticasone propionate, budesonide, and olodaterol, how various sequential or parallel pulmonary processes should be considered in order to comprehend the pulmonary fate of inhaled drugs.

Co-suspension delivery technology in pressurized metered-dose inhalers for multi-drug dosing in the treatment of respiratory diseases.

Technologies for long-term delivery of aerosol medications in asthma and chronic obstructive pulmonary disease have improved over the past 2 decades with advancements in our understanding of the physical chemistry of aerosol formulations, device engineering, aerosol physics, and pulmonary biology. However, substantial challenges remain when a patient is required to use multiple inhaler types, multiple medications, and/or combinations of medications. Combining multiple drugs into a single inhaler while retaining appropriate dosing of the individual agents in the combination may enhance patient adherence to therapy and reduce device errors that occur when patients are using multiple inhalers. Pressurized metered-dose inhaler (pMDI) devices are widely used by patients for acute symptom relief as well as maintenance treatment, so the pMDI may be a suitable option with which to explore medication combinations. However, optimizing drug formulation remains a key challenge for pMDI delivery systems. This article introduces a new pMDI formulation approach: co-suspension delivery technology, which uses drug crystals with porous, low-density phospholipid particles engineered to deliver combinations of drugs to the airways with accurate and consistent dosing via pMDIs, independent of medication types and combinations. We describe the key characteristics of pMDIs, and discuss the rationale for the co-suspension delivery technology platform based on the limitations associated with traditional formulations. Finally, we discuss the clinical implications of co-suspension delivery technology for developing combination drug therapies administered by pMDIs.

Doxapram-mediated Increase in Cardiac Output Reduces Opioid Plasma Concentrations: A Pharmacokinetic/Pharmacodynamic-Pharmacokinetic/Pharmacodynamic Modeling Study in Healthy Volunteers.

Doxapram is an analeptic that induces ventilatory stimulation and increases blood pressure and cardiac output (CO). Its mechanism of action is the blockade of background K+ -channels expressed on type 1 carotid body cells. In the randomized controlled trial, the authors explored the role of the increase in CO by doxapram (plasma concentration (Cp) 1,000-3,500 ng/mL) on the pharmacokinetics (PKs) and pharmacodynamics (PDs) of the potent opioid alfentanil (Cp 100-200 ng/mL). Population PK-PD analyses were performed on the doxapram PK-CO data and the alfentanil PK-antinociception data. The analyses showed that the doxapram-induced increase in CO explained the increase in alfentanil distribution and elimination clearances causing a significant reduction in plasma alfentanil Cp and antinociception. This novel approach in which one PK-PD model effectively drives another PK-PD model highlights the importance of physiological influences on PK and PD of a potent opioid with rapid onset of effect and low clinical margin of safety.

Ethanol Reversal of Tolerance to the Respiratory Depressant Effects of Morphine.

Opioids are the most common drugs associated with unintentional drug overdose. Death results from respiratory depression. Prolonged use of opioids results in the development of tolerance but the degree of tolerance is thought to vary between different effects of the drugs. Many opioid addicts regularly consume alcohol (ethanol), and post-mortem analyses of opioid overdose deaths have revealed an inverse correlation between blood morphine and ethanol levels. In the present study, we determined whether ethanol reduced tolerance to the respiratory depressant effects of opioids. Mice were treated with opioids (morphine, methadone, or buprenorphine) for up to 6 days. Respiration was measured in freely moving animals breathing 5% CO2 in air in plethysmograph chambers. Antinociception (analgesia) was measured as the latency to remove the tail from a thermal stimulus. Opioid tolerance was assessed by measuring the response to a challenge dose of morphine (10 mg/kg i.p.). Tolerance developed to the respiratory depressant effect of morphine but at a slower rate than tolerance to its antinociceptive effect. A low dose of ethanol (0.3 mg/kg) alone did not depress respiration but in prolonged morphine-treated animals respiratory depression was observed when ethanol was co-administered with the morphine challenge. Ethanol did not alter the brain levels of morphine. In contrast, in methadone- or buprenorphine-treated animals no respiratory depression was observed when ethanol was co-administered along with the morphine challenge. As heroin is converted to morphine in man, selective reversal of morphine tolerance by ethanol may be a contributory factor in heroin overdose deaths.

Lumacaftor and ivacaftor in the management of patients with cystic fibrosis: current evidence and future prospects.

Cystic fibrosis (CF) is a genetic disorder that causes multiorgan morbidity and premature death, most commonly from pulmonary dysfunction. Mutations in the CF transmembrane conductance regulator (CFTR) gene, of which almost 2000 have been described, result in a dysfunctional CFTR protein. This protein is an adenosine triphosphate binding anion channel, present primarily at the surface of epithelial cells. Loss of function mutations in this anion channel result in decreased or absent chloride/bicarbonate transport. The subsequent abnormal salt and water transport at epithelial cell surfaces leads to thickened secretions, and infection or inflammation in affected organs. In the last 20 years, therapeutics have been developed to treat the signs and symptoms of CF. However, in 2012, the small molecule drug, ivacaftor, became the first approved therapy that addresses the basic defect in CF. Ivacaftor is a potentiator of CFTR channels defective in their chloride/bicarbonate gating/conductance, but present at the epithelial cell surface. It is only approved for 10 mutations carried by approximately 7% of the population of patients with CF. F508del is the most common CFTR mutation, present in homozygosity in approximately 50% of patients with CF. The F508del mutation results in multiple CFTR channel defects that require both correction (stabilization of misfolded CFTR and trafficking to the epithelial cell membrane) and potentiation. This article reviews the in vitro and clinical trial data for the potential use of the potentiator, ivacaftor, and the corrector, lumacaftor, in patients with CF.

A kinetic study of the main guaco metabolites using syrup formulation and the identification of an alternative route of coumarin metabolism in humans.

For decades guaco species have been empirically used for the treatment of respiratory diseases. However, studies have shown that the toxic and therapeutic effects of the main guaco metabolites are dose-dependent, and none clinical study was done to evaluate the behavior of these substances in humans. In this work, a pilot study measuring the kinetic profile of the main guaco metabolites was performed leading to the knowledge of an alternative route of coumarin metabolism in humans. Initial screenings demonstrated that the administration of 60 mL of guaco syrup (single dose) did not provide sufficient levels of coumarin (COU), 7-hydroxycoumarin (7-HCOU), o-coumaric acid (OCA) and kaurenoic acid (KAU). The pharmacokinetic parameters were calculated by orally administering 60 mL of guaco syrup spiked with 1500 mg of COU. The kinetic study demonstrated that the plasmatic levels of 7-HCOU (considered the main metabolite of COU) were 10 times lower than the levels of COU, and the kinetic profile of 7-HCOU suggests sequential metabolism in the liver with low access of 7-HCOU to the systemic circulation. The study also demonstrated that OCA is one of the main bioavailable metabolites of COU. Therefore, the hydrolysis of the lactone ring forming a carboxylated compound is one of the possible routes of COU metabolism in humans. The half-lives of COU, 7-HCOU and OCA were approximately 4.0, 1.0 and 3.0 h, respectively and there was evidence that the recommended dosage of guaco syrup did not provide sufficient levels of COU, 7-HCOU or OCA to obtain a bronchodilation effect. Clinical studies are necessary to prove the efficacy and safety of products based on guaco.

The pharmacokinetics of conventional and bioenhanced tablet formulations of danirixin (GSK1325756) following oral administration in healthy, elderly, human volunteers.

Danirixin (GSK1325756) is a small, high-affinity, selective and reversible CXCR2 antagonist in development for treatment of chronic obstructive pulmonary disease. The objective of the study was to evaluate the relative bioavailability, including the inter-subject variability, of a conventional immediate-release (IR) formulation and two prototype bioenhanced formulations of danirixin during gastric acid suppression in a healthy, elderly population. A single-centre, crossover study in healthy male and female volunteers aged 65-80 years was conducted. Subjects were randomised to receive danirixin 50 mg IR in the fed and fasted states and danirixin 50 mg Bioenhanced Formulation 1 and 2 in the fasted state. All subjects also received omeprazole 20 mg each morning beginning 4 days prior to the first treatment period and continuing through danirixin dosing in the final treatment period. Twenty subjects were randomised and completed the study. Bioenhanced Formulation 2 in the fasted state demonstrated the highest adjusted geometric means for AUC(0-t), AUC(0-inf), AUC(0-24) and C max. Danirixin IR demonstrated adjusted means that were higher in the fed state compared with the fasted state. For all formulations tested, there was substantial inter-subject variability (CVb >100 % for all formulations). The overall incidences of adverse events (AEs) were 10 % for danirixin IR (both in the fed and fasted states) and 15-20 % for the bioenhanced formulations. The majority of AEs were mild in intensity. There were no serious AEs. Concomitant use of omeprazole resulted in large inter-subject variability in the exposure to danirixin. Bioenhanced formulation strategies could not overcome the effect of omeprazole on exposure and variability between subjects.

Consenso SEPAR-ALAT sobre terapia inhalada SEPAR-ALAT / Consensus for Inhaled Therapies

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Methods for reduction of cohesive forces between carrier and drug in DPI formulation.

Dry powder inhaler (DPI) has become a well accepted drug delivery for pulmonary system to treat many related diseases including symptomatic and life threatening diseases. Successful delivery of dry powder to the lung requires careful consideration of powder production process, formulation and inhaler device. The formulation of DPI mostly comprises of lactose as a carrier for drug delivery. In DPI formulation, particulate interactions within the formulation govern both the drug dissociation from carrier particles and the disaggregation of drug into primary particles with a capacity to penetrate deep into lung. Two contradictory requirements must be fulfilled for this type of dry powder formulation. On one hand, adhesion between carrier and drug must be sufficient for the blend drug/carrier to be stable. On the other hand, adhesion drug/carrier has to be weak enough to enable the release of drug from carrier during patient inhalation. Thus the carrier use restricted due to detachment problem. Different methods are proposed to reduce the cohesive forces between drug and carrier to desired level. Various studies conducted for understanding the mechanism of deposition into lungs and making formulation with optimum carrier drug cohesive force. This review provides information on various processes involved in reducing the cohesive forces between drug and carrier, to a required level.

Deposition of inhaled particles in the lungs.

Inhaled medication is the first-line treatment of diseases such as asthma or chronic obstructive pulmonary disease. Its effectiveness is related to the amount of drug deposited beyond the oropharyngeal region, the place where the deposit occurs and its distribution (uniform or not). It is also important to consider the size of the inhaled particles, the breathing conditions, the geometry of the airways and the mucociliary clearance mechanisms. Currently, mathematical models are being applied to describe the deposition of inhaled drugs based on the size of the particles, the inspiratory flow and the anatomical distribution of the bronchial tree. The deposition of particles in the small airways gets maximum attention from pharmaceutical companies and is of great interest as it is related with a better control in patients receiving these drugs.

Pirfenidone: antifibrotic agent for idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a devastating disease with rare incidence but high mortality, and the pathogenesis of which is still poorly understood. Available treatment options have been empirically applied but evidence-based benefits have not yet been confirmed. Pirfenidone is an antifibrotic agent that is potentially effective for IPF treatment. Preclinical studies have been reported using experimental animal models, which revealed inhibitory effects pn profibrotic and proinflammatory cytokines. Several clinical studies provided promising and reproducible effects for inhibition of IPF disease progression in different nations. The efficacy is demonstrated in patients with mild-to-moderate impairment of pulmonary functions, but not confirmed for patients with severe impairment. Major adverse events are photosensitivity and anorexia, but the treatment was generally safe and well tolerated. In this article, the usefulness and limitations of pirfenidone in IPF treatment are discussed to determine its potential for the management of IPF progression.

Thiopurine S- methyltransferase [corrected] testing in idiopathic pulmonary fibrosis: a pharmacogenetic cost-effectiveness analysis.

Azathioprine in combination with N-acetylcysteine (NAC) and steroids is a standard therapy for idiopathic pulmonary fibrosis (IPF). Its use, however, is limited by its side effects, principally leukopenia. A genotypic assay, thiopurine S-methyltransferase (TPMT), has been developed that can potentially identify those at risk for developing leukopenia with azathioprine, and thereby limit its toxicity. In those with abnormal TPMT activity, azathioprine can be started at lower dose or an alternate regimen selected. Determine the cost-effectiveness of a treatment strategy using TPMT testing before initiation of azathioprine, NAC, and steroids in IPF by performing a computer-based simulation. We developed a decision analytic model comparing three strategies: azathioprine, NAC and steroids with and without prior TPMT testing, and conservative therapy, consisting of only supportive measures. Prevalence of abnormal TPMT alleles and complication rates of therapy were taken from the literature. We assumed a 12.5% incidence of abnormal TPMT alleles, 4% overall incidence of leukopenia while taking azathioprine, and that azathioprine, NAC, and steroids in combination reduced IPF disease progression by 14% during 12 months. TPMT testing before azathioprine, NAC, and steroids was the most effective and most costly strategy. The marginal cost-effectiveness of the TPMT testing strategy was $49,156 per quality adjusted life year (QALY) gained versus conservative treatment. Compared with azathioprine, NAC and steroids without prior testing, the TPMT testing strategy cost only $29,662 per QALY gained. In sensitivity analyses, when the prevalence of abnormal TPMT alleles was higher than our base case, TPMT was "cost-effective." At prevalence rates lower than our base case, it was not. TPMT testing before initiating therapy with azathioprine, NAC, and steroids is a cost-effective treatment strategy for IPF.

The pharmacokinetics of orally administered fudosteine in healthy Chinese volunteers.

The pharmacokinetics of fudosteine in healthy Chinese volunteers was investigated for the first time after single- and multiple-dose administration. Five male and five female volunteers were enrolled in this study. Each subject received 400 mg fudosteine capsules (the therapeutic dose) on day 1 after overnight fasting for the single-dose study and three times daily oral administration (400 mg) for 5 consecutive days until the sixth morning for the multiple-dose study. Serial blood samples were collected at specified time intervals up to 16 hours following the first and last doses of fudosteine. Plasma harvested from the blood was separated and analyzed for fudosteine levels by a validated high-performance liquid chromatography-electrospray ionization mass spectrometry (HPLC/ESI/MS) method employing percolumn derivatization with 9-fluorenylmethyl chloroformate (FMOC-Cl). Noncompartmental analysis was used for the calculation of the total area under the plasma concentration-time curve (AUC) from time zero to time infinity and the terminal half-life (t1/2) of fudosteine. The pharmacokinetic parameters for single- and multiple-dose administration were estimated as follows: Cmax amounted to 10.13+/-4.39 microg/mL and 11.75+/-6.51 microg/mL, tmax to 0.69+/-0.36 h and 0.53+/-0.12 h and t1/2 to 2.33+/-0.63 h and 2.40+/-0.37 h, respectively. No significant differences were found between single- and multiple-dose oral administration, although gender differences were observed.

Carrier-based strategies for targeting protein and peptide drugs to the lungs.

With greater interest in delivery of protein and peptide-based drugs to the lungs for topical and systemic activity, a range of new devices and formulations are being investigated. While a great deal of recent research has focused on the development of novel devices, attention must now be paid to the formulation of these macromolecular drugs. The emphasis in this review will be on targeting of protein/peptide drugs by inhalation using carriers and ligands.

Dosing of medications in morbidly obese patients in the intensive care unit setting.

OBJECTIVE: To derive recommendations for the dosing of commonly used medications in the morbidly obese patient in the ICU. DATA SOURCES: Articles were obtained through computerized searches involving MEDLINE. The bibliographies of retrieved publications and textbooks were reviewed for additional references. STUDY SELECTION: All studies involving the pharmacokinetics or pharmacodynamics of medications in obese subjects or patients. DATA EXTRACTION: The emphasis was on studies involving morbidly obese patients but, in the absence of such data, investigations involving lesser forms of obesity were extracted. DATA SYNTHESIS: There is a paucity of data upon which to make recommendations for dosing commonly used medications in the morbidly obese patient in the ICU, although recommendations were provided based on the available information. CONCLUSIONS: There is clearly a need for more investigations involving dosing regimens of medications in the morbidly obese population. Until such studies are available, the clinician must try to derive the best dosing regimens for medications based on the limited pharmacokinetic data available for some agents and clinical judgement.

Treatment of apnea of prematurity.

In the last decade, knowledge regarding the neurodevelopment and functional aspects of the respiratory centers during postnatal maturation has increased substantially. However, an increase in such knowledge has not provided a basis for change in practice. The diagnosis of apnea of prematurity (AOP) is one of exclusion. All causes of secondary apnea must be ruled out before initiating treatment for AOP. Treatment will depend on the etiology as well as effectiveness and tolerability of the treatment by the patient. The primary goal of any treatment of AOP is to prevent the frequency of apnea lasting >20 seconds, and/or those that are shorter, but associated with cyanosis and bradycardia. The clinical management of AOP is not much different today than it was two decades ago, with pharmacologic and nonpharmacologic treatment options remaining the mainstay of therapy. Methylxanthines are still the most widely used pharmacologic agents. Due to the wider therapeutic index of caffeine and ease of once daily administration, it should be the preferred agent. Doxapram, or nonpharmacologic treatment measures such as nasal continuous positive airway pressure, may be considered in infants who are unresponsive to methylxanthine treatment alone. Treatment should be continued until there is complete resolution of apnea, and for some time thereafter. The choice of method for weaning treatment remains one of individual physician preference. Discharge from hospital after apnea requires close monitoring and some infants will require home apnea monitors. The decision to provide a home apnea monitor should be individualized for each patient, depending on the effectiveness of treatment and clinical response.

A quantitative analysis of the intranasal delivery of topical nasal drugs to the middle meatus: spray versus drop administration.

The delivery of nasal drugs specifically to the middle meatus is of critical importance in the medical treatment of rhinosinusitis. In this respect, topical nasal drug administration by drops has generally been perceived to be superior to nasal sprays, although there is a lack of evidence to support this notion. This study aims to compare the intranasal delivery of nasal sprays and drops to the middle meatus in vivo, using a novel quantitative method. A surgical patty was placed in the middle meatus. Radio-labelled topical nasal drops and aqueous sprays were administered in a standardized fashion in normal volunteers (10 nasal cavities). The subsequent absorption of administered radio-labelled saline on the patty was measured using a gamma counter. A randomized prospective crossover design was used for the study. The mean percentage (range) of absorbed administered saline on the swab was 8.7 (0.3-39.5) and 9.7 (0.03-20.4) for the spray and drop administration techniques respectively (p = 0.8). Thus, there is wide variation in the delivery of topical nasal drugs and the perceived superiority of nasal drop administration, in terms of delivery to the middle meatus, may be incorrect.