Is it time to regulate over‐the‐counter weight‐loss formulations?

Many products claiming to promote weight loss are freely available to purchase over the counter and are used by a substantial proportion of the population in many countries, who are often seeking rapid weight loss without long-term lifestyle changes. While there are multiple outlets for these products, surveys in England and Australia have found that at least 70% of community pharmacies stock these products and they are also available through internet pharmacies. Since the products are formulated as tablets and capsules, consumers may regard them as medicines, particularly when sold from a pharmacy. Manufacturers often make extravagant claims for their products, suggesting they suppress appetite, increase metabolism, block absorption of fat or carbohydrates and/or bring about diuresis, but there is little robust evidence of efficacy. Most products contain a variety of herbal ingredients and are not without adverse effects. Since very few of the hundreds of products sold in pharmacies are licensed medicines, they are not subject to the controls required for over-the-counter medicines, in terms of efficacy, safety, quality or provision of a standardised patient information leaflet. Pharmacists themselves perceive these products to be unsafe, but have little knowledge about them, other than that supplied by manufacturers. The role of community pharmacy in supporting effective weight management is increasingly important, given the rise in obesity. We question the widespread supply through pharmacies of ineffective products with extravagant claims and suggest that tighter regulation of their promotion and supply may be required.     

Similar renoprotection after renin‐angiotensin‐dependent and ‐independent antihypertensive therapy in 5/6‐nephrectomized Ren‐2 transgenic rats: are there blood pressure‐independent effects?

1. Hypertension plays a critical role in the progression of chronic kidney disease (CKD) to end-stage renal disease (ESRD), but it has also been postulated that antihypertensive drugs that block the renin-angiotensin system (RAS) show class-specific renoprotective actions beyond their blood pressure (BP)-lowering effects. 2. Because this notion has recently been questioned, in the present study we compared the effects of a RAS-dependent antihypertensive therapy (a combination of trandolapril, an angiotensin-converting enzyme inhibitor (ACEI) and losartan, an angiotensin-II (AngII) receptor subtype 1A receptor antagonist) with a 'RAS-independent' antihypertensive therapy (a combination of labetalol, an alfa- and beta-adrenoreceptor antagonist with the diuretics, hydrochlorothiazide and furosemide) on the progression of CKD after 5/6 renal ablation (5/6 NX) in Ren-2 renin transgenic rats (TGR), a model of AngII-dependent hypertension. Normotensive transgene-negative Hannover Sprague-Dawley (HanSD) rats after 5/6 NX served as controls. 3. RAS-dependent and -independent antihypertensive therapies normalized BP and survival rate, and prevented the development of cardiac hypertrophy and glomerulosclerosis to the same degree in 5/6 NX HanSD rats and in 5/6 NX TGR. The present findings show that renoprotection, at least in rats after 5/6 NX, is predominantly BP-dependent. When equal lowering of BP was achieved, leading to normotension, cardio- and renoprotective effects were equivalent irrespective of the type of antihypertensive therapy. 4. These findings should be taken into consideration in attempts to develop new therapeutic approaches and strategies aimed to prevent the progression of CKD and to lower the incidence of ESRD.     

A double‐blind placebo‐controlled study of buspirone‐stimulated prolactin release in non‐ulcer dyspepsia—are central serotoninergic responses enhanced?

BACKGROUND: Dyspepsia is a common symptom for which an organic cause is found in only 40% of patients. When no cause is apparent and the dyspepsia is considered to be idiopathic, a diagnosis of non-ulcer dyspepsia is made. The pathophysiology of non-ulcer dyspepsia is poorly understood and numerous theories have been put forward, including a theory of enhanced central serotoninergic receptor sensitivity. AIM: To determine the sensitivity of serotonin receptors in non-ulcer dyspepsia. METHODS: Using a randomized, double-blind, placebo-controlled design, we compared buspirone (a serotonin type 1a partial agonist)-stimulated prolactin release in 50 patients and 59 healthy comparison subjects. Buspirone, 30 mg, or matching placebo was administered on two separate occasions and prolactin release over 180 min was monitored. Patients and healthy subjects received both treatments in random order, 1 week apart. RESULTS: Overall, patients with non-ulcer dyspepsia had greater prolactin release in response to the buspirone challenge than the healthy comparison subjects, with differences most significant at 90 min following the challenge. Enhancement occurred in patients both with and without Helicobacter pylori infection. Female subjects, both patients and healthy volunteers, showed a greater response to buspirone than male subjects, and the augmentation of response observed in male and female patients was greater in females. CONCLUSIONS: Patients with non-ulcer dyspepsia have enhanced central serotoninergic responses and such responses are independent of H. pylori infection. Blockade of such receptors might be an appropriate therapeutic strategy.     

Long‐term follow‐up of coeliac disease – what do coeliac patients want?

BACKGROUND: Coeliac disease affects up to 1% of the population and the British Society of Gastroenterology recommends long-term follow-up of these patients, although the absolute risk of complications is small. AIM: To determine what proportion of patients with coeliac disease remain under specialist follow-up and to examine patients' perspectives on the long-term management of coeliac disease. METHODS: A questionnaire was sent to 183 patients who had a duodenal biopsy between July 1994 and July 2004 which was consistent with coeliac disease. RESULTS: A total of 126 (69%) patients returned their questionnaire. Patients had on average been diagnosed with coeliac disease 5.4 years earlier. Eighty-eight percentage were trying to follow a strict gluten-free diet. Sixty-two percentage of patients were under regular follow-up although this varied between hospital clinic (doctor/dietitian, 92%) and General Practitioner (8%). Most patients found at least one aspect of the hospital out-patient clinic very useful. The preferred method of coeliac disease follow-up was to see a dietitian with a doctor being available (P < 0.05 vs. all other options). CONCLUSIONS: Respondents to this study showed great variation in follow-up of their coeliac disease -38% were under no active follow-up. Patients would prefer to see a dietitian for long-term follow-up.     

Is nose‐to‐brain transport of drugs in man a reality?

The blood-brain barrier that segregates the brain interstitial fluid from the circulating blood provides an efficient barrier for the diffusion of most, especially polar, drugs from the blood to receptors in the central nervous system (CNS). Hence limitations are evident in the treatment of CNS diseases, such as Parkinson's and Alzheimer's diseases, especially exploiting neuropeptides and similar polar and large molecular weight drugs. In recent years interest has been expressed in the use of the nasal route for delivery of drugs to the brain, exploiting the olfactory pathway. A wealth of studies has reported proof of nose-to-brain delivery of a range of different drugs in animal models, such as the rat. Studies in man have mostly compared the pharmacological effects (e.g. brain functions) of nasally applied drugs with parenterally applied drugs and have shown a distinct indication of direct nose-to-brain transport. Recent studies in volunteers involving cerebrospinal fluid sampling, blood sampling and pharmacokinetic analysis after nasal, and in some instances parenteral administration of different drugs, have in my opinion confirmed the likely existence of a direct pathway from nose to brain.     

Systematic review: coxibs,non‐steroidal anti‐inflammatory drugs or no cyclooxygenase inhibitors in gastroenterological high‐risk patients?

Selective cyclooxygenase-2 inhibitors have been marketed as alternatives of conventional, non-steroidal anti-inflammatory drugs with the purpose of reducing/eliminating the risk of ulcer complications. Unexpectedly, randomized-controlled trials revealed that long-term use of coxibs, such as rofecoxib, significantly increased the risk of myocardial infarction and stroke, while the use of valdecoxib was associated with potentially life-threatening skin reactions. Subsequently, rofecoxib and valdecoxib were withdrawn from the market. Although more strict precautions for other coxibs, such as celecoxib, etoricoxib, lumiracoxib and parecoxib, may be accepted/recommended by regulatory agencies, a critical review of published data suggests that their use may not be justified - even in high-risk patients - taking benefits, costs and risks into consideration. Clinicians should, therefore, never prescribe coxibs to patients with cardiovascular risk factors, and should only reluctantly prescribe coxibs to patients with a history of ulcer disease or dyspepsia to overcome persistent pain due to, e.g. rheumatoid arthritis or osteoarthritis. Instead, they should consider using conventional non-steroidal anti-inflammatory drugs in combination with a proton pump inhibitor or a prostaglandin analogue, especially for patients with increased cardiovascular risks, i.e. established ischaemic heart disease, cerebrovascular disease and/or peripheral arterial disease, or alternatively acetaminophen. An evidence-based algorithm for treatment of a chronic arthritis patient with one or more gastrointestinal risk factors is presented.     

Over‐the‐counter ibuprofen: how and why is it used?

Objectives — To pilot an over‐the‐counter (OTC) medicine pharmacovigilance project, using ibuprofen as a model. Method — All users of any tablet or capsule form of ibuprofen (excluding compound products) purchased from 61 participating community pharmacies, aged ≥18 years and able to give informed consent, were eligible to join the study. A postal questionnaire one week after the index purchase monitored the follow‐up rate, drug usage, past medical history, concurrent medication, symptoms and health service utilisation. Setting — Primary care: community pharmacies in Grampian, Scotland. Key findings — A total of 443/544 (81 per cent) questionnaires were completed. The recommended daily dose of OTC ibuprofen (1,200mg) was exceeded by 35 customers (8 per cent) on at least one day and the recommended maximum daily dose that can be prescribed by a physician (2,400mg) was exceeded on five occasions. During the seven days after the index purchase, ibuprofen was used by 15 customers (4 per cent) with an active or past history of peptic ulcer, and 30 (7 per cent) with an active or past history of asthma. Thirty‐eight per cent had purchased ibuprofen for a chronic condition and 32 per cent were still taking it at the end of the initial seven‐day period. Twenty‐eight of 412 customers (7 per cent) sought advice during the seven‐day period about at least one symptom: 13 consulted their general practitioner, 12 consulted a pharmacist, two consulted both their GP and a pharmacist, and one consulted a hospital doctor. Some of these consultations (23/28, 82 per cent) might have related to an adverse reaction to ibuprofen: 11 customers (3 per cent) consulted about lower abdominal symptoms, nine about gastric symptoms and three about wheeziness. Conclusions — This pilot study identifies instances of contraindicated and excessive use of OTC ibuprofen, indicating a need for pharmacovigilance studies of OTC medicines; it also demonstrates the feasibility of a major study.     

Is epinephrine administration by sublingual tablet feasible for the first‐aid treatment of anaphylaxis? A proof‐of‐concept study

PURPOSE: In order to explore the feasibility of sublingual administration of epinephrine tablets as a non-invasive first-aid treatment for anaphylaxis, we studied epinephrine absorption from this dosage form in an animal model. METHODS: In a prospective, randomized, four-way crossover study, six rabbits received epinephrine 2.5 or 10 mg as a sublingual tablet, epinephrine 0.03 mg (0.3 ml) by intramuscular (IM) injection (positive control), and 0.9% NaCl (0.3 ml) IM (negative control). Pre- and post-dose blood samples were obtained for measurement of plasma epinephrine concentrations by HPLC-EC. RESULTS: After administration of epinephrine 2.5 mg as a sublingual tablet, the mean (+/-SEM) C(max) was 2369+/-392 pg/ml, and the t(max) was 20.8+/-5.7 min. After administration of epinephrine 10 mg sublingually, the C(max) was 10836+/-2234 pg/ml, and the t(max) was 21.7+/-5.4 min. After IM epinephrine, the C(max) was 6445+/-4233 pg/ml, and the t(max) was 15.8+/-4.7 min. After IM 0.9% NaCl, the C(max) (endogenous epinephrine) was 518+/-142 pg/ml. The t(max) after both of the sublingual epinephrine tablet doses did not differ significantly from the t(max) after IM epinephrine, and the C(max) after the 10 mg sublingual epinephrine tablet dose did not differ significantly from the C(max) after IM epinephrine. CONCLUSIONS: In this proof-of-concept study, administration of epinephrine as a sublingual tablet formulation resulted in rapid achievement of peak plasma epinephrine concentrations. Absorption studies in humans are needed. DEFINITIONS: HPLC-high performance liquid chromatography; EC - electrochemical detection; C(max) - maximum plasma epinephrine concentration after dosing; t(max) - time of maximum plasma epinephrine concentration.     

Does the well‐stirred model assess the intestinal first‐pass effect well?

The pre-systemic intestinal extraction ratio (E(g)) has been estimated by an equation based on the well-stirred model, which does not have a term of membrane transport. In this report, we have identified the application limitations of the well-stirred model equation to assess the pre-systemic intestinal extraction ratio. The E(g) of metoprolol (CYP2D6 substrate) was assessed by three methods. Intrinsic clearances for metoprolol metabolism in hepatic and gastrointestinal microsomes were from a published report. Method 1 (model-independent method): the E(g) of 0.228 was obtained according to the equation, F = F(f) x (1 - E(g)) x F(h), where F, F(f) and F(h) were the bioavailability, the fraction entering the intestinal tissue and the hepatic availability, respectively. Method 2: the E(g) of 0.0071 was calculated according to the well-stirred model equation, and was much lower than the value of 0.228. Method 3: the E(g) of 0.213 was obtained by the transport-metabolism-flow (TMF) model equation, and was much closer to the value of 0.228 obtained by the model-independent method than the E(g) of 0.0071 calculated by the well-stirred model equation. Therefore, we propose that the factor of membrane transport process be incorporated into the pharmacokinetic model for the assessment of the pre-systemic intestinal extraction ratio.     

Should we eradicate Helicobacter pylori in non‐steroidal anti‐inflammatory drug users?

The interaction between Helicobacter pylori and non-steroidal anti-inflammatory drugs (NSAIDs) in ulcerogenesis has been visited by many studies. Apparently these studies yielded conflicting results. This is a result of a wide diversity of methodology, selection of patient groups and definitions of outcome used by different investigators. This review attempts to analyse separately studies dealing with new or chronic NSAID users, primary or secondary prophylaxis, complicated or uncomplicated ulcers in NSAID or aspirin users. Evidence suggests that eradication of Helicobacter pylori infection may reduce the risk of ulcer and ulcer complications in patients requiring NSAIDs and aspirin. Whether or not one should test-and-treat H. pylori before prescribing NSAIDs is a complicated issue. Factors such as the ulcer risk of patients, previous history of NSAID usage and the use of aspirin or NSAIDs would guide the strategy.