Treatment of glioblastoma with re-purposed renin-angiotensin system modulators: Results of a phase I clinical trial.

Glioblastoma is the most common and most aggressive primary brain cancer in adults. Standard treatment of glioblastoma consisting of maximal safe resection, adjuvant radiotherapy and chemotherapy with temozolomide, results in an overall median survival of 14.6 months. The aggressive nature of glioblastoma has been attributed to the presence of glioblastoma stem cells which express components of the renin-angiotensin system (RAS). This phase I clinical trial investigated the tolerability and efficacy of a treatment targeting the RAS and its converging pathways in patients with glioblastoma. Patients who had relapsed following standard treatment of glioblastoma who met the trial criteria were commenced on dose-escalated oral RAS modulators (propranolol, aliskiren, cilazapril, celecoxib, curcumin with piperine, aspirin, and metformin). Of the 17 patients who were enrolled, ten completed full dose-escalation of the treatment. The overall median survival was 19.9 (95% CI:14.1-25.7) months. Serial FET-PET/CTs showed a reduction in both tumor volume and uptake in one patient, an increase in tumor uptake in nine patients with decreased (n = 1), unchanged (n = 1) and increased (n = 7) tumor volume, in the ten patients who had completed full dose-escalation of the treatment. Two patients experienced mild side effects and all patients had preservation of quality of life and performance status during the treatment. There is a trend towards increased survival by 5.3 months although it was not statistically significant. These encouraging results warrant further clinical trials on this potential novel, well-tolerated and cost-effective therapeutic option for patients with glioblastoma.

Randomized crossover trial of the acceptability of snus, nicotine gum, and Zonnic therapy for smoking reduction in heavy smokers.

INTRODUCTION: Novel approaches to nicotine replacement therapy (NRT) are needed to improve the modest long-term quit rate of 10%. Snus (Swedish tobacco) and Zonnic (oral nicotine sachet) rapidly deliver nicotine via buccal absorption and have potential as NRTs. As a prelude to formal evaluation of either product as a smoking cessation therapy, it is necessary to determine their acceptability and the willingness of smokers to use them in populations with no history of access to oral tobacco products. METHODS: An open-label crossover study of ad libitum snus, Zonnic, and nicotine gum among 63 smokers for 2 weeks each, and smoking reduction if the subjects did not feel the desire to smoke. Diary cards recorded use of products and cigarettes; formal and ad hoc scales measured urges to smoke, withdrawal symptoms, and the sensory quality of the products. RESULTS: Subjects preferred snus and Zonnic over gum. Snus and Zonnic were superior to gum in reducing urges to smoke and caused fewer side effects. All three products suppressed withdrawal symptoms. Subjects reduced their smoking by Ms of 33%, 37%, and 42% during the gum, snus, and Zonnic fortnights, respectively. DISCUSSION: Most subjects reported a strong desire to use Zonnic or snus to quit smoking. Subjects preferred snus and Zonnic, which both had significantly fewer gastrointestinal side effects than gum and resulted in greater reductions in smoking. Snus and Zonnic are effective in suppressing desires to smoke and reducing smoking, and further studies are warranted to investigate their effect on long-term quit rates.

High blood pressure advice given by natural health food stores.

AIM: Complimentary and alternative medicines are widely used but are not registered medicines. The aim of the study was to compare advice given by health food stores and pharmacists for hypertension. METHODS: Twenty-six health food stores and 26 pharmacies were visited by an individual for advise on a hypothetical problem of hypertension. RESULTS: Staff in 25 out of 26 health food stores did not refer the researcher to a medical practitioner; instead they recommended and sold a wide variety of compounds of unproven efficacy. CONCLUSIONS: We recommend the implementation of a formal training programme for health food stores staff and that complimentary and alternative medicines-use in New Zealand is regulated.

A pilot study of nicotine delivery to smokers from a metered-dose inhaler.

INTRODUCTION: The present study generated preliminary data on the acceptability and pharmacokinetics of nicotine administered by a simple metered-dose inhaler (MDI). METHODS: We conducted a nonrandomized, open-label cross-over trial of 10 current smokers. On Day 1, a single cigarette was smoked ad libitum. On Day 2, participants took 10 puffs (20 inhalations) of 50 microg nicotine/puff through the inhaler, and on Day 3, they took 10 puffs (20 inhalations) of 100 microg nicotine/puff, each over 5 min. Nicotine pharmacokinetics, changes in heart rate and blood pressure, and the acceptability of the inhalers were measured and recorded. RESULTS: Nicotine administered by an MDI produced a median maximum plasma concentration that was about 50% of that obtained by smoking a cigarette (12.5 vs. 25.9 ng/ml) and took twice the time to reach that concentration, 6 versus 3 min. Self-rated satisfaction and reduced urge to smoke were similar for the MDIs and a cigarette. DISCUSSION: The results suggest that nicotine can be delivered effectively by the pulmonary route using a standard MDI. The inhaler appears to provide a satisfaction level and reduction in the urge to smoke relatively similar to that provided by smoking a cigarette. These conclusions require verification in a larger controlled study.

Recurrent back pain and fevers.

An elderly woman presented with her third episode of back pain, fever and neurological deficits. She subsequently developed pseudogout of the knee, and a diagnosis was made of systemic calcium pyrophosphate deposition disease (CPPD) involving the spine and causing intermittent cauda equina syndrome. This case illustrates the difficulty of differentiating infection from CPPD.

The use of antithrombotics in patients presenting with stroke and atrial fibrillation.

Antithrombotics have been shown to decrease the risk of stroke in patients with atrial fibrillation (AF). However they are associated with an increased risk of bleeding. We assessed the frequency and appropriateness of antithrombotic therapy in patients admitted to our service with stroke and AF. A retrospective case study of 219 patients (mean age 77.2 years) admitted between January 1999 and 31 December 2001 with a diagnosis of stroke and AF was done. Patient characteristics, presence of comorbid conditions, knowledge of preadmission AF, medication history and appropriateness of antithrombotic treatment were recorded. One hundred and fifty patients were known to have had AF prior to admission. Forty-one presented with an intracranial hemorrhage (19 on warfarin, 10 on aspirin). Of those patients with known AF only 43 were on treatment consistent with the guidelines. Warfarin was recommended in 144 of the whole cohort, but only 39 were taking it. Fifty-three patients were receiving aspirin although warfarin was the recommended treatment. Fifty-four with known AF were not on any antithrombotic treatment. Factors significantly associated with the use of antithrombotic treatment were history of AF (p = 0.0004), valvular heart disease (p = 0.02), venous thromboembolism (p = 0.04), risk of thromboembolism (p = 0.003) and presentation with a nonischemic infarct (p = 0.008). Antithrombotic therapy use in our patients differs significantly from guideline recommendations.

The pulmonary and extra-pulmonary effects of high-dose formoterol in COPD: a comparison with salbutamol.

OBJECTIVES: Formoterol, a beta(2) agonist with a rapid onset of effect and long duration of action, can be used as maintenance and reliever medication for asthma and COPD. We compared the pulmonary and extra-pulmonary effects of cumulative doses of formoterol and salbutamol in patients with COPD to assess efficacy and safety. METHODOLOGY: In a randomized, double-blind, cross-over study, 12 patients with moderate to severe COPD inhaled, via Turbuhaler, 10 doses of formoterol (total metered dose, 120 microg, equivalent to a 90- microg delivered dose), salbutamol (total metered dose 2000 microg) or placebo at 2-min intervals on separate days. The effects on lung function (FEV(1) and PEF), heart rate, blood pressure, oxygen saturation, corrected QT interval (QTc), T-wave height and plasma potassium were assessed before each dose, 15 min after each dose, and at half-hourly intervals for 3 h following the final dose. RESULTS: Inhalation of formoterol or salbutamol resulted in significant improvement in lung function (measured 30 min after the last dose) when compared with placebo. There were no clinically important or statistically significant changes in heart rate, QTc, T-wave height, plasma potassium, oxygen saturation, or systolic and diastolic blood pressures with formoterol or salbutamol. One patient developed ventricular trigeminy after both formoterol and salbutamol. She had had ventricular ectopics on her screening electrocardiogram. CONCLUSION: Formoterol and salbutamol both produced significant improvement in lung function and were similarly well tolerated in high doses, as might be taken by a patient for relief of COPD symptoms.

Use of isotonic nebulised magnesium sulphate as an adjuvant to salbutamol in treatment of severe asthma in adults: randomised placebo-controlled trial.

BACKGROUND: Intravenous magnesium can cause bronchodilation in treatment of severe asthma, however its effect by the nebulised route is uncertain. We aimed to assess the effectiveness of isotonic magnesium sulphate as an adjuvant to nebulised salbutamol in severe attacks of asthma. METHODS: We enrolled 52 patients with severe exacerbations of asthma presenting to the emergency departments at two hospitals in New Zealand. A severe exacerbation was defined as a forced expiratory volume at 1 s (FEV(1)) of less than 50% predicted 30 min after initial administration of 2.5 mg salbutamol via nebulisation. In this randomised double-blind placebo-controlled trial patients received 2.5 mg nebulised salbutamol mixed with either 2.5 mL isotonic magnesium sulphate or isotonic saline on three occasions at 30 min intervals. The primary outcome measure was FEV(1) at 90 min. Analysis was per protocol. FINDINGS: At 90 min the mean FEV1 in the magnesium group was 1.96 L (95% CI 1.68-2.24) and in the saline group 1.55 L (1.24-1.87). The difference in the mean FEV(1) between the magnesium and saline groups was 0.37 L (0.13-0.61, p=0.003). INTERPRETATION: Use of isotonic magnesium as an adjuvant to nebulised salbutamol results in an enhanced bronchodilator response in treatment of severe asthma.

Do natural health food stores require regulation?

AIM: To compare advice provided by health food stores (HFS) and pharmacies in relation to medical conditions and assess the need for regulation of HFS. METHODS: We assessed the advice provided by 26 health food stores (HFS) and 26 pharmacies to an individual presenting with symptoms suggestive of moderate to severe asthma who had not seen a general practitioner. RESULTS: The advice provided by the two stores differed markedly. 22/26 pharmacy staff diagnosed asthma/probable asthma, whereas only 15/26 HFS staff reached the same conclusion. 92.3% of pharmacy staff compared to 34.6% of HFS staff referred the investigator to a doctor; 5 HFS advised the investigator against seeing a doctor. A wide variety of remedies were recommended by the HFS, none of which are known to be beneficial in the treatment of asthma. CONCLUSION: HFS promoting herbal products for medical conditions should be regulated in a similar fashion to shops that dispense pharmaceutical products.