Pharmacokinetic studies of a Chinese triple herbal drug formula

Yin Chen Hao Tang preparation (YCHTP) is a classic traditional Chinese medicine formula, which is commonly used for clinical treatment of hepatological diseases. In this study, a rapid and validated high-performance liquid chromatography (HPLC) method was developed to simultaneously identify 6,7-dimethylesculetin and geniposide in rat plasma. This assay was performed on a Dikma Diamonsil RP(18) column (200 mmx4.6 mm, 5 mum) with acetonitrile-methanol-water (0.1% formic acid) as the mobile phase, showing acceptable linearity, intra- and inter-day precision and accuracy (R.S.D.=5%), and absolute recovery for two analytes (74%); the limits of quantitation were 0.4 and 1.12 mug/ml, and the limits of detection were 0.06 and 0.09 mug/ml for two analytes. The developed method was successfully applied to study the effect of formula compatibility on the pharmacokinetics of 6,7-dimethylesculetin and geniposide in YCHTP when orally administrating an effective human daily dose of YCHTP to rats. We surmise that formula compatibility can significantly influence the pharmacokinetics of YCHTP, and we have elucidated and validated the compatible administration of YCHTP.

Current status of pharmacogenomics testing for anti-tumor drug therapies : approaches to non-melanoma skin cancer

Skin cancer is one of the most commonly occurring cancer types, with substantial social, physical, and financial burdens on both individuals and societies. Although the role of UV light in initiating skin cancer development has been well characterized, genetic studies continue to show that predisposing factors can influence an individual's susceptibility to skin cancer and response to treatment. In the future, it is hoped that genetic profiles, comprising a number of genetic markers collectively involved in skin cancer susceptibility and response to treatment or prognosis, will aid in more accurately informing practitioners' choices of treatment. Individualized treatment based on these profiles has the potential to increase the efficacy of treatments, saving both time and money for the patient by avoiding the need for extensive or repeated treatment. Increased treatment responses may in turn prevent recurrence of skin cancers, reducing the burden of this disease on society. Currently existing pharmacogenomic tests, such as those that assess variation in the metabolism of the anticancer drug fluorouracil, have the potential to reduce the toxic effects of anti-tumor drugs used in the treatment of non-melanoma skin cancer (NMSC) by determining individualized appropriate dosage. If the savings generated by reducing adverse events negate the costs of developing these tests, pharmacogenomic testing may increasingly inform personalized NMSC treatment.

Impairment of simulated motorcycle riding performance under low dose alcohol

Crash statistics that include the blood alcohol concentration (BAC) of vehicle operators reveal that crash involved motorcyclists are over represented at low BACs (e.g., ≤0.05%). This riding simulator study compared riding performance and hazard response under three low dose alcohol conditions (sober, 0.02% BAC, 0.05% BAC). Forty participants (20 novice, 20 experienced) completed simulated rides in urban and rural scenarios while responding to a safety-critical peripheral detection task (PDT). Results showed a significant increase in the standard deviation of lateral position in the urban scenario and PDT reaction time in the rural scenario under 0.05% BAC compared with zero alcohol. Participants were most likely to collide with an unexpected pedestrian in the urban scenario at 0.02% BAC, with novice participants at a greater relative risk than experienced riders. Novices chose to ride faster than experienced participants in the rural scenario regardless of BAC. Not all results were significant, emphasising the complex situation of the effects of low dose BAC on riding performance, which needs further research. The results of this simulator study provide some support for a legal BAC for motorcyclists below 0.05%.

A phase II study of the modulation of 5-fluorouracil and folinic acid with high-dose infusional hydroxyurea in metastatic colorectal carcinoma

Background: Hydroxyurea (HU), an inhibitor of ribonucleotide reductase, may potentiate the activity of 5-fluorouracil (5-FU) and folinic acid (FA) by reducing the deoxyribonucleotide pool available for DNA synthesis and repair. However as HU may inhibit the formation of 5-fluoro-2-deoxyuridine-5- monophosphate (FdUMP), one of the principal active metabolites of 5-FU, the scheduling of HU may be critical. In vitro experiments suggest that administration of HU following 5-FU, maintaining the concentration in the region of I mM for six or more hours, significantly enhances the efficacy of 5-FU. Patients and methods: 5-FU/FA was given as follows: days 1 and 2 - FA 250 mg/m 2 (max. 350 mg) over two hours followed by 5-FU 400 mg/m 2 by intravenous bolus (ivb) over 15 minutes and subsequently 5-FU 400 mg/m 2 infusion (ivi) over 22 hours. HU was administered on day 3 immediately after the 5-FU with 3 g ivb over 15 minutes followed by 12 g ivi over 12 hours. Results: Thirty patients were entered into the study. Median survival was nine months (range 1-51 + months). There were eight partial responses (28%, 95% CI: 13%-47%). The median duration of response was 6.5 (range 4-9 months). Grade 3-4 toxicities included neutropenia (grade 3 in eight patients and grade 4 in five), anaemia (grade 3 in one patient) and diarrhoea (grade 3 in two patients). Neutropenia was associated with pyrexia in two patients. Phlebitis at the infusion site occurred in five patients. The treatment was complicated by pulmonary embolism in one patient and deep venous thrombosis in another. Conclusion: HU administered in this schedule is well tolerated. Based on these results and those of other phase II studies, a randomised phase III study of 5-FU, FA and HU versus 5-FU and FA using the standard de Gramont schedule is recommended.

A phase I dose-escalating study of DaunoXome, liposomal daunorubicin, in metastatic breast cancer

The aims of this phase I study were to establish the maximum tolerated dose, safety profile and activity of liposomal daunorubicin, DaunoXome (NeXstar Pharmaceuticals), in the treatment of metastatic breast cancer. DaunoXome was administered intravenously over 2 h in 21 day cycles and doses were increased from 80 to 100, 120 and 150 mg m 2. Sixteen patients were enrolled. A total of 70 cycles of DaunoXome were administered. The maximum tolerated dose was 120 mg m 2, the dose-limiting toxicity being prolonged grade 4 neutropenia or neutropenic pyrexia necessitating dose reductions at 120 and 150 mg m 2. Asymptomatic cardiotoxicity was observed in three patients: grade 1 in one treated with a cumulative dose of 800 mg m 2 and grade 2 in two, one who received a cumulative dose of 960 mg m 2 and the other a cumulative dose of 600 mg m 2 with a previous neoadjuvant doxorubicin chemotherapy of 300 mg m 2. Tumour response was evaluable in 15 patients, of whom two had objective responses, six had stable disease and seven had progressive disease. In conclusion, DaunoXome is associated with mild, manageable toxicities and has anti-tumour activity in metastatic breast cancer. The findings support further phase II evaluation of DaunoXome alone and in combination with other standard non-anthracycline cytotoxic or novel targeted agents. Although the dose-limiting toxicity for DaunoXome was febrile neutropenia at 120 mg m 2, we would recommend this dose for further evaluation, as the febrile neutropenia occurred after four or more cycles in three of the four episodes seen, was short lived and uncomplicated. © 2002 Cancer Research UK.

A qualitative investigation of drug use among Pakistani road users

Background Statistics on drug use by Pakistani drivers are not available, yet considerable numbers of drivers are believed to be drug addicted. The National Drug Abuse Assessment 2006/07, conducted by the United Nation Office on Drugs and Crime and the Ministry of Narcotics Control Pakistan reported that opiate users numbered 628,000, of which 77%were chronic heroin abusers. Injecting drug users have reportedly doubled in the decade to 2006 and drug use has been linked with many major crashes involving professional drivers. Aims This study explored a broad range of risk taking behaviours of road users, including drug use. It also investigated associations between risky road use and fatalism and other cultural beliefs. Methods This paper reports findings relating to drug driving in the cities of Lahore, Rawalpindi and Islamabad. Thirty semi-structured interviews were conducted with bus, truck, and taxi drivers, policy makers and field police officers. Results Interviews suggested widespread use of illicit drugs, particularly among bus, truck and taxi drivers. Reasons for drug use included recreational purposes, stimulants during long driving episodes, and substance addiction. Furthermore, the use of drugs and any association with road crashes was generally viewed as linked to fatalism rather than to any fault of an individual. In other words, people did not believe there was an association between drug use and road crashes, even if they had personally experienced such. Police knowledge of drug use among drivers was evident, although there is no formal drug driving testing regime in Pakistan. Discussion and conclusions The substantial increase in drug use among the population in recent years highlights a significant public health challenge in Pakistan. This qualitative research, although recognized as not representative of the broader population, suggests that there is significant cause for concern about drug driving, especially among professional drivers, and a need for further investigation and intervention.

Results of the Queensland 2007-2012 roadside drug testing program : the prevalence of three illicit drugs

The purpose of this investigation is to present an overview of roadside drug driving enforcement and detections in Queensland, Australia since the introduction of oral fluid screening. Drug driving is a problematic issue for road safety and investigations of the prevalence and impact of drug driving suggest that, in particular, the use of illicit drugs may increase a driver’s involvement in a road crash when compared to a driver who is drug free. In response to the potential increased crash involvement of drug impaired drivers, Australian police agencies have adopted the use of oral fluid analysis to detect the presence of illicit drugs in drivers. This paper describes the results of roadside drug testing for over 80,000 drivers in Queensland, Australia, from December 2007 to June 2012. It provides unique data on the prevalence of methamphetamine, cannabis and ecstasy in the screened population for the period. When prevalence rates are examined over time, drug driving detection rates have almost doubled from around 2.0% at the introduction of roadside testing operations to just under 4.0% in the latter years. The most common drug type detected was methamphetamine (40.8%) followed by cannabis (29.8%) and methamphetamine/cannabis combination (22.5%). By comparison, the rate of ecstasy detection was very low (1.7%). The data revealed a number of regional, age and gender patterns and variations of drug driving across the state. Younger drivers were more likely to test positive for cannabis whilst older drivers were more likely to test positive for methamphetamine. The overall characteristics of drivers who tested positive to the presence of at least one of the target illicit drugs are they are likely to be male, aged 30-39 years, be driving a car on Friday, Saturday or Sunday between 6:00PM and 6:00AM and to test positive for methamphetamine.

Management of endocrine resistant breast cancer

Metastatic breast cancer (MBC) may present de novo but more commonly develops in women initially presenting with early breast cancer despite the widespread use of adjuvant hormonal and cytotoxic chemotherapy. MBC is incurable. Hormone sensitive MBC eventually becomes resistant to endocrine therapy in most women. Anthracyclines are the agents of choice in the treatment of endocrine resistant MBC. With the widespread use of anthracyclines in the adjuvant setting, taxanes have become the agents of choice for many patients. Recently capecitabine has become established as a standard of care for patients pretreated with anthracyclines and taxanes. However, a range of agents have activity as third line treatment. These include gemcitabine, vinorelbine and platinum analogues. The sequential use of non-cross resistant single agents rather than combination therapy is preferable in most women with MBC. Even though combination therapy can improve response rates and increase progression free interval, there is no robust evidence to indicate an advantage in terms of overall survival. Moreover, combination therapy is associated with a higher toxicity rate and poor quality of life. There is no role for dose-intense therapy, high dose therapy or maintenance chemotherapy outside the context of a clinical trial. The introduction of trastuzumab, monoclonal antibody targeting growth factor receptors, has improved the therapeutic options for women with tumours overexpressing HER2/neu. DNA micro-array profiles of tumours can potentially help to individualise therapy in future. Molecular targeted therapy has the potential to revolutionise the management of MBC.

Gemcitabine and paclitaxel associated pneumonitis in non-small cell lung cancer : report of a phase I/II dose-escalating study

The aim of this phase I/II dose escalating study was to establish the maximum tolerated dose (MTD) of gemcitabine and paclitaxel given in combination in non-small cell lung cancer (NSCLC). 12 patients with stage IIIB and IV NSCLC received paclitaxel administered intravenously over 1 h followed by gemcitabine given over 30 min on days 1, 8 and 15 every 28 days. Pneumonitis was the principal side-effect observed with 4 patients affected. Of these, 1 experienced grade 3 toxicity after one cycle of treatment and the others had grade 2 toxicity. All 4 cases responded to prednisolone. No other significant toxicities were observed. Of the 8 evaluable patients, 3 had a partial response and 2 had minor responses. The study was discontinued due to this dose-limiting toxicity. The combination of paclitaxel and gemcitabine shows promising antitumour activity in NSCLC, however, this treatment schedule may predispose to pneumonitis. (C) 2000 Elsevier Science Ltd.

Dry powder inhaler formulations-effect of polymer carrier size on the drug dispersion

Background The size of the carrier influences the aerosolization of drug from a dry powder inhaler (DPI) formulation. Currently, lactose monohydrate particles in a variety of sizes are preferably used in carrier based DPI formulations of various drugs; however, contradictory reports exist regarding the effect of the size of the carrier on the dispersion of drug. In this study we examined the influence of the intrinsic particle size of the polymeric carrier on the aerosolization of a model drug salbutamol sulphate (SS). Methods Four different sizes (20–150 lm) of polymer carriers were fabricated using solvent evaporation technique and the dispersion of SS particles from these carriers was measured by a Twin Stage Impinger (TSI). The size and morphological properties of polymer carriers were by laser diffraction and SEM, respectively. Results The FPF from these carriers was found to be increasing from 5.6% to 21.3% with increasing the carrier size. The FPF was found to be greater (21%) with the highest particle size of the carrier (150 lm). Conclusions The aerosolization of drug was dependent on the size of polymer carriers. The smaller size of the carrier resulted in lower FPF which was increased with increasing the carrier size. For a fixed mass of drug particles in a formulation, the mass of drug particles per unit area of carriers is higher in formulations containing the larger carriers, which leads to an increase in the dispersion of drug due to the increased mechanical forces occurred between the carriers and the device walls.

Novel sequential methods in dose-finding designs : extensions of the continual reassessment method

Dose-finding trials are a form of clinical data collection process in which the primary objective is to estimate an optimum dose of an investigational new drug when given to a patient. This thesis develops and explores three novel dose-finding design methodologies. All design methodologies presented in this thesis are pragmatic. They use statistical models, incorporate clinicians' prior knowledge efficiently, and prematurely stop a trial for safety or futility reasons. Designing actual dose-finding trials using these methodologies will minimize practical difficulties, improve efficiency of dose estimation, be flexible to stop early and reduce possible patient discomfort or harm.

Incorporating adverse event relatedness into dose-finding clinical trial designs

Dose-finding designs estimate the dose level of a drug based on observed adverse events. Relatedness of the adverse event to the drug has been generally ignored in all proposed design methodologies. These designs assume that the adverse events observed during a trial are definitely related to the drug, which can lead to flawed dose-level estimation. We incorporate adverse event relatedness into the so-called continual reassessment method. Adverse events that have ‘doubtful’ or ‘possible’ relationships to the drug are modelled using a two-parameter logistic model with an additive probability mass. Adverse events ‘probably’ or ‘definitely’ related to the drug are modelled using a cumulative logistic model. To search for the maximum tolerated dose, we use the maximum estimated toxicity probability of these two adverse event relatedness categories. We conduct a simulation study that illustrates the characteristics of the design under various scenarios. This article demonstrates that adverse event relatedness is important for improved dose estimation. It opens up further research pathways into continual reassessment design methodologies.

Tailored interventions based on exhaled nitric oxide versus clinical symptoms for asthma in children and adults

Background The measurement of severity and control of asthma in both children and adults can be based on subjective or objective measures. It has been advocated that fractional exhaled nitric oxide (FeNO) can be used to monitor airway inflammation as it correlates with some markers of asthma. Interventions for asthma therapies have been traditionally based on symptoms and/or spirometry. Objectives To evaluate the efficacy of tailoring asthma interventions based on exhaled nitric oxide in comparison to clinical symptoms (with or without spirometry/peak flow) for asthma related outcomes in children and adults. Search methods We searched the Cochrane Airways Group Specialised Register of Trials, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE and reference lists of articles. The last search was completed in February 2009. Selection criteria All randomised controlled comparisons of adjustment of asthma therapy based on exhaled nitric oxide compared to traditional methods (primarily clinical symptoms and spirometry/peak flow). Data collection and analysis Results of searches were reviewed against pre-determined criteria for inclusion. Relevant studies were independently selected in duplicate. Two authors independently assessed trial quality and extracted data. Authors were contacted for further information with response from one. Main results Two studies have been added for this update, which now includes six (2 adults and 4 children/adolescent) studies; these studies differed in a variety of ways including definition of asthma exacerbations, FeNO cut off levels, the way in which FeNO was used to adjust therapy and duration of study. Of 1053 participants randomised, 1010 completed the trials. In the meta-analysis, there was no significant difference between groups for the primary outcome of asthma exacerbations or for other outcomes (clinical symptoms, FeNO level and spirometry). In post-hoc analysis, a significant reduction in mean final daily dose inhaled corticosteroid per adult was found in the group where treatment was based on FeNO in comparison to clinical symptoms, (mean difference -450 mcg; 95% CI -677 to -223 mcg budesonide equivalent/day). However, the total amount of inhaled corticosteroid used in one of the adult studies was 11% greater in the FeNO arm. In contrast, in the paediatric studies, there was a significant increase in inhaled corticosteroid dose in the FeNO strategy arm (mean difference of 140 mcg; 95% CI 29 to 251, mcg budesonide equivalent/day). Authors' conclusions Tailoring the dose of inhaled corticosteroids based on exhaled nitric oxide in comparison to clinical symptoms was carried out in different ways in the six studies and found only modest benefit at best and potentially higher doses of inhaled corticosteroids in children. The role of utilising exhaled nitric oxide to tailor the dose of inhaled corticosteroids cannot be routinely recommended for clinical practice at this stage and remains uncertain.

A systematic review and meta-analysis : tailoring asthma treatment on eosinophilic markers (exhaled nitric oxide or sputum eosinophils)

Asthma severity and control can be measured both subjectively and objectively. Traditionally asthma treatments have been individualised using symptoms and spirometry/peak flow. Increasingly treatment tailored in accordance with inflammatory markers (sputum eosinophil counts or fractional exhaled nitric oxide (FeNO) data) is advocated as an alternative strategy. The objective of this review was to evaluate the efficacy of tailoring asthma interventions based on inflammatory markers (sputum analysis and FeNO) in comparison with clinical symptoms (with or without spirometry/peak flow) for asthma-related outcomes in children and adults. Cochrane Airways Group Specialised Register of Trials, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE and reference lists of articles were searched. The last searches were in February 2009. All randomised controlled comparisons of adjustment of asthma treatment based on sputum analysis or FeNO compared with traditional methods (primarily clinical symptoms and spirometry/peak flow) were selected. Results of searches were reviewed against predetermined criteria for inclusion. Relevant studies were selected, assessed and data extracted independently by at least two people. The trial authors were contacted for further information. Data were analysed as 'intervention received' and sensitivity analyses performed. Six (2 adults and 4 children/adolescent) studies utilising FeNO and three adult studies utilising sputum eosinophils were included. These studies had a degree of clinical heterogeneity including definition of asthma exacerbations, duration of study and variations in cut-off levels for percentage of sputum eosinophils and FeNO to alter management in each study. Adults who had treatment adjusted according to sputum eosinophils had a reduced number of exacerbations compared with the control group (52 vs. 77 patients with >=1 exacerbation in the study period; p=0.0006). There was no significant difference in exacerbations between groups for FeNO compared with controls. The daily dose of inhaled corticosteroids at the end of the study was decreased in adults whose treatment was based on FeNO in comparison with the control group (mean difference -450.03 mug, 95% CI -676.73 to -223.34; p<0.0001). However, children who had treatment adjusted according to FeNO had an increase in their mean daily dose of inhaled corticosteroids (mean difference 140.18 mug, 95% CI 28.94 to 251.42; p=0.014). It was concluded that tailoring of asthma treatment based on sputum eosinophils is effective in decreasing asthma exacerbations. However, tailoring of asthma treatment based on FeNO levels has not been shown to be effective in improving asthma outcomes in children and adults. At present, there is insufficient justification to advocate the routine use of either sputum analysis (due to technical expertise required) or FeNO in everyday clinical practice.

Crushed tablets : does the administration of food vehicles and thickened fluids to aid medication swallowing alter drug release?

Purpose. To evaluate the influence of co-administered vehicles on in vitro dissolution in simulated gastric fluid of crushed immediate release tablets as an indicator for potential drug bioavailability compromise. Methods. Release and dissolution of crushed amlodipine, atenolol, carbamazepine and warfarin tablets were tested with six foods and drinks that are frequently used in the clinical setting as mixers for crushed medications (water, orange juice, honey, yoghurt, strawberry jam and water thickened with Easythick powder) in comparison to whole tablets. Five commercial thickening agents (Easythick Advanced, Janbak F, Karicare, Nutilis, Viscaid) at three thickness levels were tested for their effect on the dissolution of crushed atenolol tablets. Results. Atenolol dissolution was unaffected by mixing crushed tablets with thin fluids or food mixers in comparison to whole tablets or crushed tablets in water, but amlodipine was delayed by mixing with jam. Mixing crushed warfarin and carbamazepine tablets with honey, jam or yoghurt caused them to resemble the slow dissolution of whole tablets rather than the faster dissolution of crushed tablets in water or orange juice. Crushing and mixing any of the four medications with thickened water caused a significant delay in dissolution. When tested with atenolol, all types of thickening agents at the greatest thickness significantly restricted dissolution, and products that are primarily based on xanthan gum also delayed dissolution at the intermediate thickness level. Conclusions. Dissolution testing, while simplistic, is a widely used and accepted method for comparing drug release from different formulations as an indicator for in vivo bioavailability. Thickened fluids have the potential to retard drug dissolution when used at the thickest levels. These findings highlight potential clinical implications of the addition of these agents to medications for the purpose of dose delivery and indicate that further investigation of thickened fluids and their potential to influence therapeutic outcomes is warranted.