Common cold and influenza symptom management: the use of pharmacokinetic considerations to predict the efficacy of a twice-daily treatment for colds and flu

SUMMARY

Objective: The objective of the two pharmacokinetic studies reported here was to compare the relative bioavailability of an ibuprofen/pseudoephedrine modified-release capsule with each of the active ingredients given alone as standard formulations.

Study design: Evaluation of two open, randomised, cross-over studies, one single dose and one multiple dose, in healthy male volunteers.

Methods: Healthy volunteers were randomised in a cross-over design to single or multiple doses of a combination of ibuprofen (600 mg) plus pseudoephedrine (90 mg) in a slow-release formulation and the individual active products alone as standard formulations; ibuprofen 400mg, pseudoephedrine 60 mg.

Results: The single-dose study demonstrated that the bioavailabilities of ibuprofen and pseudoephedrine achieved with the slow-release formulation were not significantly different from those with standard tablets of each ingredient alone. In addition, mean plasma levels of ibuprofen predictive of clinical efficacy were achieved within 0.5-1 h and lasted for 10-12 h thereafter. The time required to reach clinically effective blood levels of pseudoephedrine was longer, starting at approximately 2 h. However, the plasma levels predicted that the clinical effect would then last for at least a further 12 h. Trough levels from the multiple-dose study showed that clinically relevant analgesic and decongestant plasma levels were maintained for 24 h during twice-daily dosing. The slow-release formulation was well tolerated with only mild adverse events.

Conclusion: Blood levels would predict that the present slow-release fo rmulation of ibuprofen plus pseudoephedrine should offer reliable day and night control of cold and flu and sinus symptoms and be associated with a favourable safety profile.     

Vonoprazan for treatment of gastroesophageal reflux: pharmacodynamic and pharmacokinetic considerations

Introduction: About 30–40% of GERD patients report an inadequate response to proton pump inhibitors (PPIs) due to their suboptimal pharmacological profiles. Recently, a new synthesized P-CABs, vonoprazan, showed higher suppression of gastric acid secretion as compared to lansoprazole.

Areas covered: This review provides an update on the pharmacokinetic properties of vonoprazan and their correlates with pharmacodynamics; preliminary data on the therapeutic efficacy of vonoprazan as compared to lansoprazole in GERD patients

Expert opinion: At variance from all available PPIs, vonoprazan acts directly on H+,K+-ATPase irrespectively of its activity, providing a fast onset of action without requiring acid activation and specific administration timing. Clinical and pharmacological investigations have confirmed a more rapid, potent and prolonged inhibition of acid secretion, including a better nighttime acid control, and a less antisecretory variability, as compared with PPIs. Preliminary data in patients with erosive esophagitis (EE) have shown the non-inferiority of vonoprazan to lansoprazole in terms of symptom relief and healing rate. Since these pharmacokinetic advantages, it is expected that it will have a significant favorable impact on GERD management. However, the clinical use of vonoprazan raises also some issues about its efficacy and safety in the long-term that deserve verification and careful investigation.     

Lopinavir/Ritonavir pharmacokinetic profile: impact of sex and other covariates following a change from twice-daily to once-daily therapy

The aim of this study was to determine the impact of sex on the pharmacokinetics of lopinavir/ritonavir. Interaction between lopinavir/ritonavir and tenofovir was also evaluated. Steady-state plasma samples were obtained from virologically suppressed HIV-infected patients on lopinavir/ritonavir 800/200-mg soft gel capsule taken once daily. Drug assays were performed by high-performance liquid chromatography. Pharmacokinetic parameters estimated by noncompartmental method were reported as 90% confidence intervals (CIs) about the geometric mean ratio (GMR). There were 9 males and 11 females. No sex differences were observed in lopinavir/ritonavir pharmacokinetics profile. The GMR(sex) (women compared with men) for lopinavir area under the concentration-time curve (AUC(24)), maximum concentration (C(max)), and minimum concentration (C(min)) was 0.95 (90% CI, 0.70-1.29), 0.88 (90% CI, 0.67-1.15), and 1.27 (90% CI, 0.60-2.66), respectively. Similarly, the GMR(sex) for ritonavir AUC(24), C(max), and C(min) was 0.84 (90% CI, 0.57-1.24), 0.79 (90% CI, 0.50-1.22), and 1.02 (90% CI, 0.58-1.80), respectively. Tenofovir coadministration led to a reduction in lopinavir/ritonavir plasma exposure, giving a lopinavir GMR(tenofovir) for C(max) of 0.72 (90% CI, 0.57-0.93) and AUC(24) of 0.74 (90% CI, 0.56-0.98), respectively. No difference in lopinavir/ritonavir plasma concentrations between sexes was demonstrated in this study. However, tenofovir coadministration lowered lopinavir/ritonavir plasma exposure.     

Strategy to manage the treatment of severe psoriasis: considerations of efficacy,safety and cost

Psoriasis is a common, unpredictable, chronic immune-mediated disease characterised by skin lesions and frequently associated with arthritis. Although rarely fatal, psoriasis has a tremendous impact on a patients’ quality of life. Traditional therapies for severe psoriasis include phototherapy, methotrexate, oral retinoids and cyclosporin. New biological agents add to the treatment options for psoriasis; however, they raise the already considerable cost of managing the disease. In considering efficacy, safety and cost-effectiveness, ultraviolet Type B (UVB) phototherapy appears to be the best first-line agent for the control of psoriasis. Methotrexate, psoralen plus UVA, alefacept, etanercept and infliximab are appropriate second-line agents, the choice of which requires considerable patient input and physician judgement. Developing rational, effective and acceptable strategies to manage psoriasis treatments would encourage cost-effective psoriasis management.     

Strategy to manage the treatment of severe psoriasis: considerations of efficacy,safety and cost

Psoriasis is a common, unpredictable, chronic immune-mediated disease characterised by skin lesions and frequently associated with arthritis. Although rarely fatal, psoriasis has a tremendous impact on a patients' quality of life. Traditional therapies for severe psoriasis include phototherapy, methotrexate, oral retinoids and cyclosporin. New biological agents add to the treatment options for psoriasis; however, they raise the already considerable cost of managing the disease. In considering efficacy, safety and cost-effectiveness, ultraviolet Type B (UVB) phototherapy appears to be the best first-line agent for the control of psoriasis. Methotrexate, psoralen plus UVA, alefacept, etanercept and infliximab are appropriate second-line agents, the choice of which requires considerable patient input and physician judgement. Developing rational, effective and acceptable strategies to manage psoriasis treatments would encourage cost-effective psoriasis management.     

Drug treatment of patients with insomnia and excessive daytime sleepiness: pharmacokinetic considerations.

Insomnia and excessive daytime sleepiness (EDS) are frequently observed conditions in the general public. A national survey in the USA in 1979 indicated that 35% of American adults experience insomnia in the course of a year. The prevalence of EDS varies depending on the survey (0.3 to 13.3%), but a recent study stated that 2.4% of individuals reported that they continually fell asleep at work. These problems are often long term and negatively affect the individuals' quality of life. People with these sleep problems often have difficulties maintaining high levels of productivity at work or pursuing their daily activities; individuals with insomnia lack the feeling of being rested or refreshed in the morning and EDS is unavoidable in most cases. Behavioural therapy has been shown to be effective for many people affected with insomnia and EDS. However, pharmacological treatments using hypnosedatives and central nervous system (CNS) stimulants are usually necessary, and effective, for those with more severe cases. These compounds have thus been widely prescribed in clinical practice (e.g., 2.6% of all adults surveyed used medically prescribed hypnosedatives and 4.5% used over-the-counter drugs to promote sleep). The onset and duration of action of these hypnosedatives and CNS stimulant drugs are important factors to be considered when prescribing these compounds. These factors primarily depend on physicochemical properties (lipid solubility and protein binding), as well as the pharmacokinetic profile (absorption, distribution, elimination and clearance) of the compounds. Significant differences in profile exist amongst hypnosedatives and CNS stimulants, and these differences may account for the observed variations in clinical action and adverse effects during and after treatment. In this review, we will introduce recently obtained knowledge of the pharmacokinetics of hypnosedatives and CNS stimulants and their applications for patients affected with insomnia and EDS.     

The treatment of staphylococcal infections with special reference to pharmacokinetic, pharmacodynamic and pharmacoeconomic considerations

The choice of antibiotics for the treatment of staphylococcal infections depends to a high degree on the susceptibility patterns in the hospital in question. These may be highly variable and considerable differences between countries and hospitals exist. The insight into the pharmacodynamic aspects of antimicrobial agents has increased considerably in the last 5 years, resulting in new treatments, such as once daily administration of aminoglycosides and continuous infusion of betalactam antibiotics. The antibiotic policy in Dutch hospitals for the treatment of staphylococcal infections is discussed. In most Western countries with a relatively low incidence of MRSA, penicillin–derivatives, such as flucloxacillin (or cloxacillin, methicillin and nafcillin) will be the drug of choice, because of their good in-vitro activity, low toxicity, good clinical efficacy and relatively low cost. If the incidence of MRSA increases, drugs such as the glycopeptides will be of more importance. This will of course have a clear economic impact, as both vancomycin and teicoplanin are considerably more expensive than agents such as flucloxacillin and oral treatment is not possible. Pharmacoeconomic aspects also play a role. As a rule, intravenous antimicrobial agents are considerably more expensive than the oral formulations. Before oral administration can be recommended, a reliable oral absorption, also in seriously ill patients, must have been demonstrated. Other aspects that influence the cost of therapy are hospital stay and the possibility of outpatient treatment.     

Delivery of neurotrophic factors to the central nervous system: pharmacokinetic considerations.

Neurotrophic factors are proteins with considerable potential in the treatment of central nervous system (CNS) diseases and traumatic injuries. However, a significant challenge to their clinical use is the difficulty associated with delivering these proteins to the CNS. Neurotrophic factors are hydrophilic, typically basic, monomeric or dimeric proteins, mostly in the size range of 5 to 30 kDa. Neurotrophic factors potently support the development, growth and survival of neurons, eliciting biological effects at concentrations in the nanomolar to femtomolar range. They are not orally bioavailable and the blood-brain and blood-cerebrospinal fluid barriers severely limit their ability to enter into and act on sites in the CNS following parenteral systemic routes of administration. Most neurotrophic factors have short in vivo half-lives and poor pharmacokinetic profiles. Their access to the CNS is restricted by rapid enzymatic inactivation, multiple clearance processes, potential immunogenicity and sequestration by binding proteins and other components of the blood and peripheral tissues. The development of targeted drug delivery strategies for neurotrophic factors will probably determine their clinical effectiveness for CNS conditions. Achieving significant CNS target site concentrations while limiting systemic exposure and distribution to peripheral sites of action will lessen unwanted pleiotropic effects and toxicity. Local introduction of neurotrophic factors into the CNS intraparenchymally by direct injection/infusion or by implantation of delivery vectors such as polymer matrices or genetically modified cells yields the highest degree of targeting, but is limited by diffusion restrictions and invasiveness. Delivery of neurotrophic factors into the cerebrospinal fluid (CSF) following intracerebroventricular or intrathecal administration is less invasive and allows access to a much wider area of the CNS through CSF circulation pathways. However, diffusional and cellular barriers to penetration into surrounding CNS tissue and significant clearance of CSF into the venous and lymphatic circulation are also limiting. Unconventional delivery strategies such as intranasal administration may offer some degree of CNS targeting with minimal invasiveness. This review presents a summary of the neurotrophic factors and their indications for CNS disorders, their physicochemical characteristics and the different approaches that have been attempted or suggested for their delivery to the CNS. Future directions for further research such as the potential for CNS disease treatment utilising combinations of neurotrophic factors, displacement strategies, small molecule mimetics, chimaeric molecules and gene therapy are also discussed.     

Drug treatment of overactive bladder: efficacy, cost and quality-of-life considerations

Overactive bladder (OAB) syndrome has been recognised by the International Continence Society as an important symptom syndrome that affects millions of people worldwide. Quality of life is affected in most people with OAB; however, the aetiology is unknown. Some researchers suggest that it is because of a damage to central inhibitory pathways or sensitisation of peripheral afferent terminals in the bladder, others suggest that it is a bladder muscle problem; the reality is probably a spectrum encompassing these two main explanations. Therefore, treatment is difficult and is aimed at alleviating symptoms (being those of urgency, with or without urge incontinence, usually with frequency and nocturia) rather than treating the cause. A thorough patient history and physical examination are required to establish a possible diagnosis. Frequency/volume charts form an important aid to the diagnosis. Once a presumptive diagnosis is made, conservative management forms the first line of treatment and includes lifestyle modifications, bladder training and pelvic floor exercises. If this fails, pharmacotherapy, in the form of anticholinergic drugs, is initiated. There are many antimuscarinic drugs, for example oxybutynin, tolterodine and trospium chloride. Each has a different specificity to bladder muscarinic receptors, thus producing different adverse effect profiles (e.g. dry mouth, blurred vision and constipation). Different individuals experience these adverse effects to different extents. New anticholinergic drugs, that have undergone phase III trials and are more specific to the muscarinic M3 human bladder receptor, are being introduced to the market in 2004 (e.g. solifenacin succinate and darifenacin). In addition to adverse effect profile, cost and improvement in quality of life are important factors in choosing treatment. Further research is being conducted on other types of drugs and different administration modalities, for example intravesical botulinum toxin A. Sacral nerve neuromodulation is emerging as a potential treatment, but if all treatments fail then surgery is the last resort.     

Comparison of the bioavailability and pharmacokinetic profile of a theophylline pellet formulation designed for once-daily dosage with a pellet preparation designed for twice-daily dosage

In a double blind randomized cross-over design including 18 healthy male volunteers a pellet formulation designed for twice-daily dosage (reference-formulation) and of common use in the Federal Republic of Germany was compared to Euphylong-pellets (formulation E) with respect to bioavailability and pharmacokinetic profile. Volunteers received 500 mg theophylline each as pellets enclosed in a capsule on day one at 8 p.m. Serum levels of theophylline were monitored in 2 to 4 h intervals until 48 h after ingestion of the drug. After a five day wash-out period the medication was changed according to the protocol. There was no difference in extent of absorption, maximum serum concentration and absolute residual concentration after 24 h. The increase in serum concentration was slower with formulation E than for the reference formulation which led to a difference in tmax (10 vs. 7 h), the percentage of residual concentration after 24 h (47 vs. 32%) and a plateau time that was 25% longer for formulation E. Absorption profiles of the reference formulation showed in 6 of 18 subjects dose-dumping phenomena which were not be observed for formulation E. The low interindividual variability in the pharmacokinetic profiles with formulation E is attributed to the independence of the drug release with respect to different possible gastrointestinal influences.     

Pharmacological considerations in the use of stiripentol for the treatment of epilepsy

Introduction: Despite the fact that more than 20 antiepileptic drugs (AEDs) are currently available, about one-third of patients still present drug resistance. Further efforts are required to develop novel and more efficacious therapeutic strategies, especially for refractory epileptic syndromes showing few and anecdotic therapeutic options.

Areas covered: Stiripentol (STP) is a second generation AED that shows GABAergic activity, with immature brain selectivity, and an indirect metabolic action on co-administered AEDs. Two pivotal studies demonstrated STP efficacy in patients with Dravet syndrome with refractory partial seizures, and marketing authorization in Europe, Canada and Japan was granted thereafter. Post-marketing surveys reported a good efficacy and tolerability profile. In addition, interesting data is currently emerging regarding off-label experimentation of STP in other forms of epilepsy.

Expert opinion: STP is an important addition to the limited treatment options available for patients resistant to common AEDs. The possibility to inhibit seizures through the metabolic pathway of lactate dehydrogenase and the inhibitory effects on the entry of Na⁺ and Ca²⁺ are the most recent findings to emerge about STP and could be proof of its neuroprotective action. Moreover, its positive effects on cognitive function, its good safety and tolerability profile and the increasing data about STP efficacy on other refractory epileptic syndromes may prove to be fertile grounds for further investigation.     

Safety and efficacy of over- the-counter cough and cold medicines for use in children

Importance of the field: Over-the-counter (OTC) cough and cold medications have been used widely for years and continue to be a preferred choice for temporary relief of symptoms of upper respiratory tract infections in children. These medications are being placed under extraordinary scrutiny in the pediatric population due to the lack of conclusive evidence about their therapeutic efficacy and increased reports of associations with serious adverse events and even mortality.

Areas covered in this review: A PubMed search was conducted to identify articles published up to August 2009 describing the efficacy and safety of OTC cough and cold medications in children. The objective was to provide an overview of the relevant literature and regulatory history and to comment on the available data on this important topic.

What the reader will gain: The paper provides a detailed up-to-date review of the key efficacy and safety studies published on the subject. In addition, the reader is presented with an overview of the regulatory history and recent developments surrounding the use of OTC cough and cold medications in children in the US.

Take home message: This review confirms the lack of efficacy of OTC cough and cold products in children and reaffirms that although the overall incidence of related serious adverse events is low, such events continue to occur. The conclusions in this paper support a recommendation that OTC cough and cold medications should not be given to infants and very young children. Furthermore, additional research is needed to evaluate the safety and efficacy of these medicines in the broader pediatric population.     

Pharmacokinetic and toxicity considerations for the use of anthracyclines in ovarian cancer treatment

INTRODUCTION: Safe and effective treatments are needed for ovarian cancer. While there are many drugs currently available, there has recently been a renewed novel interest in the use of anthracyclines. AREAS COVERED: This review summarizes the available evidence on pharmacokinetic (PK) and toxicology implications of anthracyclines and pegylated liposomal doxorubicin (PLD) in the clinical management of women with epithelial ovarian cancer. This article consists of material obtained via Medline, PubMed and EMBASE literature searches, up to September 2010. EXPERT OPINION: PLD is a liposomal formulation of doxorubicin (DXR), with a distinct pharmacokinetic profile, characterized by extended circulation time and a reduced clearance and volume of distribution with respect to the free drug. PLD is effective and well tolerated in relapsed ovarian cancer. The toxicity profile of PLD is characterized by dose-limiting mucosal and cutaneous toxicities, mild myelosuppression and decreased cardiotoxicity compared to free DXR. The good response rate, toxicity profile and pharmacokinetic profile of PLD suggest that PLD could be an option in first-line and second-line treatment in ovarian cancer; especially in those who had experienced taxane-induced toxicity or had a poor performance status.     

吸入性扎那米韦治疗流感及流感样患者的疗效及安全性研究

目的观察吸入性扎那米韦治疗我国流感患者及流感样患者的疗效和安全性。方法选择2010年9月至2011年4月在我院感染科就诊的具有流感样症状的疑似流感患者40例,男24例,女16例,年龄15～78岁,应用吸入性扎那米韦10 mg,2次/d,治疗5 d,第1次随访（第1天）：观察患者症状和体征,记录血常规、血生化（谷丙转氨酶ALT、谷草转氨酶AST、尿素氮BUN、肌酐CR）、心电图,咽拭子取样,RT-PCR方法进行流感病毒阳性确诊;第2次随访（第3天）：观察患者症状和体征,药物不良反应,同时咽拭子取样进行病毒耐药检测;第3次随访（第6～8天）：观察患者症状和体征,进行血常规、血生化、心电图和咽拭子取样的病毒耐药检测。结果确诊流感患者16例（包括H1N1和H3N2）,男10例,女6例,平均年龄46.75岁（15～73岁）;流感样患者24例,男14例,女10例,平均年龄46岁（19～78岁）。流感样患者与流感患者入组前临床表现与实验室检查项目比较,差异无统计学意义。流感患者使用扎那米韦前流感症状评分12.000±3.359,使用3 d后流感症状评分4.133±2.669,使用5 d后流感症状评分2.000±2.420,与使用药物前比较,差异均有统计学意义（P〈0.05,P〈0.01）。流感患者使用扎那米韦前、后,患者红细胞、血红蛋白、白细胞和血小板水平差异无统计学意义;ALT、AST、CR、BUN差异无统计学意义;但中性粒细胞比例及淋巴细胞比例差异有统计学意义（P=0.001,P=0.000）;流感患者使用扎那米韦疗程结束时,咽拭子病毒检测7例患者阳性。24例流感样患者,1例出现皮疹,其他患者未见不良反应。结论吸入性扎那米韦治疗我国流感患者安全、有效,流感样患者吸入后,未见明显的不良反应。     

Lifetime substance use and HIV sexual risk behaviors predict treatment response to contingency management among homeless, substance-dependent MSM

Homeless, substance-dependent men who have sex with men (MSM) continue to suffer health disparities, including high rates of HIV. One-hundred and thirty one homeless, substance-dependent MSM were randomized into a contingency management (CM) intervention to increase substance abstinence and health-promoting behaviors. Participants were recruited from a community-based, health education/risk reduction HIV prevention program and the research activities were also conducted at the community site. Secondary analyses were conducted to identify and characterize treatment responders (defined as participants in a contingency management intervention who scored at or above the median on three primary outcomes). Treatment responders were more likely to be Caucasian/White (p < .05), report fewer years of lifetime methamphetamine, cocaine, and polysubstance use (p < or = .05), and report more recent sexual partners and high-risk sexual behaviors than nonresponders (p < .05). The application of evidence-based interventions continues to be a public health priority, especially in the effort to implement effective interventions for use in community settings. The identification of both treatment responders and nonresponders is important for intervention development tailored to specific populations, both in service programs and research studies, to optimize outcomes among highly impacted populations.