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The genus Xanthocypariswas described in 2002 for a new conifer species X. vietnamensisfrom northern Vietnam, which became well‐known for its rarity. Recently, natural diploid populations were found in a small area of northern Guangxi, China, whereas material from Vietnam plus newly discovered populations from southern Guangxi were determined to be tetraploids. We integrated evidence from multiple data sources to perform a taxonomic evaluation of the two ploidy levels present in Xanthocyparis. Morphometric analyses detected statistically significant differences in cone and leaf characters, whereas microsatellite and transcriptome analyses revealed clear genetic divergence between diploid and tetraploid material. Furthermore, analysis of bioclimatic variables confirmed divergence in ecological niches. Gene trees from homologous sequences indicate that tetraploid material might have arisen via allopolyploidy from the extant diploid material and a third, possibly extinct lineage. Therefore, we recognize and describe a new diploid species from northern Guangxi China: Xanthocyparis guangxiensis.

Greg Towers, Professor of Molecular Virology at University College London, and John Walter, Artist, are interviewed by Professor Richard Milne, Head of Teaching in Infection and Immunity at University College London about their science and art collaboration.

More and more frequently, clinical trials for Alzheimer disease (AD) are targeting cognitively unimpaired individuals who are at increased risk of developing the disease. It is not always clear whether AD biomarker information should be disclosed to research participants: on the one hand, research participants may be interested in learning this information because of its perceived utility, but on the other hand, learning this information may be harmful, as there are very few effective preventive or therapeutic options available for AD. In this article, we bring together three separate sets of ethical guidance literature: on the return of individual research results, on an individual's right to access personal data, and on transparent enrollment into clinical trials. Based on these literatures, we suggest policies for the disclosure of AD biomarker test results in longitudinal observational cohort studies, clinical trials, and hybrid research projects, such as the European Prevention of Alzheimer's Dementia (EPAD) project, in which we served as an ethics team. We also present and critically discuss recommendations for disclosure of AD biomarkers in practice. We underscore that, as long as the clinical validity of AD biomarkers remains limited, there are good reasons to avoid actively disclosing them to cognitively unimpaired research participants.

The aim of this study was to determine how attitudes toward the return of genomic research results vary internationally.

Every July, Sweden provides one of the world's great democratic displays. Politicians of all hues descend on the Baltic island of Gotland for the annual Almedalen festival (1-8 July), meeting [...]

New models of data governance for health data are a focus of growing interest in an era of challenge to the social licence. In this article, we reflect on what the data trust model, which is founded on principles of participatory governance, can learn from experiences of involving and engagement of members of the public and participants in the governance of large-scale biobanks. We distinguish between upstream and ongoing governance models, showing how they require careful design and operation if they are to deliver on aspirations for deliberation and participation. Drawing on this learning, we identify a set of considerations important to future design for data trusts as they seek to ensure just, proportionate and fair governance. These considerations relate to the timing of involvement of participants, patterns of inclusion and exclusion, and responsiveness to stakeholder involvement and engagement. We emphasise that the evolution of governance models for data should be matched by a commitment to evaluation.

Public acceptance is critical for sharing of genomic data at scale. This paper examines how acceptance of data sharing pertains to the perceived similarities and differences between DNA and other forms of personal data. It explores the perceptions of representative publics from the USA, Canada, the UK and Australia (n= 8967) towards the donation of DNA and health data. Fifty-two percent of this public held ‘exceptionalist’ views about genetics (i.e., believed DNA is different or ‘special’ compared to other types of medical information). This group was more likely to be familiar with or have had personal experience with genomics and to perceive DNA information as having personal as well as clinical and scientific value. Those with personal experience with genetics andgenetic exceptionalist views were nearly six times more likely to be willing to donate their anonymous DNA and medical information for research than other respondents. Perceived harms from re-identification did not appear to dissuade publics from being willing to participate in research. The interplay between exceptionalist views about genetics and the personal, scientific and clinical value attributed to data would be a valuable focus for future research.

Feralization is an important evolutionary process, but the mechanisms behind it remain poorly understood. Here, we use the ancient fiber crop ramie (Boehmeria nivea(L.) Gaudich.) as a model to investigate genomic changes associated with both domestication and feralization. We first produced a chromosome-scale de novogenome assembly of feral ramie and investigated structural variations between feral and domesticated ramie genomes. Next, we gathered 915 accessions from 23 countries, comprising cultivars, major landraces, feral populations, and the wild progenitor. Based on whole-genome resequencing of these accessions, we constructed the most comprehensive ramie genomic variation map to date. Phylogenetic, demographic, and admixture signal detection analyses indicated that feral ramie is of exoferal or exo-endo origin, i.e., descended from hybridization between domesticated ramie and the wild progenitor or ancient landraces. Feral ramie has higher genetic diversity than wild or domesticated ramie, and genomic regions affected by natural selection during feralization differ from those under selection during domestication. Ecological analyses showed that feral and domesticated ramie have similar ecological niches that differ substantially from the niche of the wild progenitor, and three environmental variables are associated with habitat-specific adaptation in feral ramie. These findings advance our understanding of feralization, providing a scientific basis for the excavation of new crop germplasm resources and offering novel insights into the evolution of feralization in nature.

The Financial Times ran a video interview last week with SABMiller Chief Graham Mackay on their FT.com site. Mr. Mackay noted that the global economic turmoil is causing slower sales [...]

Many healthy volunteers choose to take part in Alzheimer’s disease (AD) prevention studies because they want to know whether they will develop dementia—and what they can do to reduce their risk—and are therefore interested in learning the results of AD biomarker tests. Proponents of AD biomarker disclosure often refer to the personal utility of AD biomarkers, claiming that research participants will be able to use AD biomarker information for personal purposes, such as planning ahead or making important life decisions. In this paper, the claim that AD biomarkers have personal utility for asymptomatic individuals is critically assessed. It demonstrates that in the absence of clinical validity, AD biomarkers cannot have personal utility and do not serve research participants’ autonomy. Over the next few years, many research groups will be confronted with participants’ preferences to learn the results of AD biomarker tests. When researchers choose to make results available upon explicit request, they should ensure adequate information provision and education, notably on the uncertain clinical significance of AD biomarker information. Routine disclosure of AD biomarkers to cognitively unimpaired individuals in research settings cannot be justified with an appeal to the personal utility of AD biomarker information.

Radiations are especially important for generating species biodiversity in mountainous ecosystems. The contribution of hybridization to such radiations has rarely been examined. Here, we use extensive genomic data to test whether hybridization was involved in evolutionary radiation within Rhododendronsubgenus Hymenanthes, whose members show strong geographic isolation in the mountains of southwest China. We sequenced genomes for 143 species of this subgenus and 93 species of four other subgenera, and found that Hymenantheswas monophyletic and radiated during the late Oligocene to middle Miocene. Widespread hybridization events were inferred within and between the identified clades and subclades. This suggests that hybridization occurred both early and late during diversification of subgenus Hymenanthes, although the extent to which hybridization, speciation through mixing-isolation-mixing or hybrid speciation, accelerated the diversification needs further exploration. Cycles of isolation and contact in such and other montane ecosystems may have together promoted species radiation through hybridization between diverging populations and species. Similar radiation processes may apply to other montane floras in this region and elsewhere.

The Loxocarpinae, also known as the “Boeagroup”, are the subtribe of Gesneriaceae which includes Boeaand a number of segregated genera and close relatives. This group currently comprises over 200 species in 15 genera. Here we present the most up-to-date phylogeny, covering all the genera known to belong to the group, based on Bayesian inference and parsimony of the nuclear ITS and the plastid regions trnL-trnF(intron and spacer) and ndhF-trnLUAG(spacers). The results show discrepancies between the current generic delimitation in the subtribe and the clades delineated by the phylogeny. As a result Boea, Damrongia, Paraboeaand Streptocarpusare recircumscribed in an attempt to establish a more natural classification and new combinations are made. The new genus Middletoniais described.

For companies using the capital markets, 2010 was a banner year. Week by week, new records were set. First Microsoft and then Walmart issued three-year bonds at less than 1 [...]

Berberisis the largest genus in the Berberidaceae, comprising more than 500 species. It is now recognised to include all of the compound‐leaved species formally ascribed to Mahonia, as well as simple‐leaved species comprising Berberiss.str. Berberiss.l. has a mainly Northern Hemisphere distribution, with a centre of diversity in the Sino‐Himalaya region, while Berberiss.str. extends into South America where it has a secondary centre of diversity. We analyzed nuclear ITS and chloroplast ndhFsequence data from 68 accessions of Berberiss.l. The results support the monophyly of Berberiss.l., but compound‐leaved Berberisare shown to be paraphyletic. The analysis supports Berberis higginsae, a member of North American B. sect. Horridae, as sister to all other Berberis species. Our results, interpreted in the light of fossil evidence, suggest a North American origin of Berberiss.l., but the area of origin of the simple‐leaved group remains uncertain.

EDITOR--The paper by Nanchahal et al indicates that substantially fewer men and women without overt cardiovascular disease would be eligible for drug treatment if the standard 1991 Framingham risk equation [...]

The taxonomy of Nyssa(Nyssaceae) in China is confused and uncertain due to differing views about how many species should be recognized, and a scarcity of good morphological differential characters. In the present study, we examined 52 morphological characters from up to fifty accessions each of six of the seven species recognized in the Flora of China: N. yunnanensis, N. javanica, N. sinensis, N. shangszeensis, N. shweliensisand N. wenshanensis.Based on both principal coordinate analysis and UPGMA cluster analysis, N. yunnanensisand N. javanicawere both morphologically distinct. However, accessions of N. sinensis, N. shangszeensis, N. shweliensisand N. wenshanensiswere intermixed in both analyses and could not be discriminated from each other. Sequence data from nuclear ITS and the chloroplast regions trnH-psbA, rps16r-f, trnL-rps32F, trnS-Gand trnL-Fwere used to further analyze the Nyssaspecies listed above, together with N. aquaticaand N. sylvaticafrom North America. All analyses of the DNA data using maximum parsimony, maximum likelihood and Bayesian methods strongly supported the monophyly of Nyssa.Within Nyssa, N. yunnanensisand N. javanicawere resolved as sister species, which were genetically distinct. The other four Chinese taxa were barely differentiated by molecular data, with only N. shangszeensisand N. wenshanensisweakly supported as monophyletic. Hence, based on morphological and molecular data, we recommend that N. shangszeensis, N. shweliensisand N. wenshanensisbe reduced to synonyms of N. sinensis,and only N. sinensis, N. yunnanensisand N. javanicabe recognized for Flora of China.The American N. aquaticaand N. sylvaticawere sister species in the cpDNA but not in the ITS analyses, indicating possible reticulate evolution.

Cytomegalovirus end-organ disease can be prevented by giving ganciclovir when viraemia is detected in allograft recipients. Values of viral load correlate with development of end-organ disease and are moderated by pre-existing natural immunity. Our aim was to determine whether vaccine-induced immunity could do likewise.

Abstract The levels and partitioning of genetic diversity and inbreeding depression were investigated in Tupistra pingbianensis, a narrow endemic of southeast Yunnan, China, characterized by a naturally fragmented distribution due to extreme specialization on a rare habitat type. Here genetic diversity and patterns of genetic variation within and among 11 populations were analyzed using amplified fragment length polymorphism markers with 97 individuals across its whole geographical range. High levels of genetic variation were revealed both at the species level (P99= 96.012%; Ht= 0.302) and at the population level (P99= 51.41%; Hs= 0.224). Strong genetic differentiation among populations was also detected (FST= 0.2961; ?II= 0.281), which corresponded to results reported for typical animal-pollinated, mixed selfing, and outcrossing plant species. This result was consistent with mating patterns detected by our pollination experiments. The indirect estimate of gene flow based on ?IIwas low (Nm= 0.64). Special habitat and its life history traits might play an important role in shaping the genetic diversity and the genetic structure of this species. A pollination experiment also failed to detect significant inbreeding depression upon F1fruit set, seed weight, and germinate rate fitness-traits. As a naturally rare species, T. pingbianensisis not seriously genetically impoverished and likely to have adapted to tolerating a high level of inbreeding early in its history, we propose this species need only periodic monitoring to ensure their continued persistence, but not intervention to remain viable.

Abstract A universal method of molecular dating that can be applied to all families and genera regardless of their fossil records, or lack thereof, is highly desirable. A possible method for eudicots is to use a large phylogeny calibrated using deep fossils including tricolpate pollen as a fixed (124 mya) calibration point. This method was used to calculate node ages within three species-poor disjunct basal eudicot genera, Caulophyllum, Podophyllumand Pachysandra, and sensitivity of these ages to effects such as taxon sampling were then quantified. By deleting from one to three accessions related to each genus in 112 different combinations, a confidence range describing variation due only to taxon sampling was generated. Ranges for Caulophyllum, Podophyllumand Pachysandrawere 8.4–10.6, 7.6–20.0, and 17.6–25.0 mya, respectively. However, the confidence ranges calculated using bootstrapping were much wider, at 3–19, 0–32 and 11–32 mya, respectively. Furthermore, deleting 10 adjacent taxa had a large effect in Pachysandraonly, indicating that undersampling effects are significant among Buxales. Changes to sampling density in neighboring clades, or to the position of the fixed fossil calibration point had small to negligible effects. Non-parametric rate smoothing was more sensitive to taxon sampling effects than was penalized likelihood. The wide range for Podophyllum, compared to the other two genera, was probably due to a high degree of rate heterogeneity within this genus. Confidence ranges calculated by this method could be narrowed by sampling more individuals within the genus of interest, and by sequencing multiple DNA regions from all species in the phylogeny.

In this review, we outline the rationale for targeting blood pressure and blood cholesterol lowering drug treatments to patients at high absolute cardiovascular risk, irrespective of their blood pressure or blood cholesterol levels. Because the specific levels of blood pressure and cholesterol are of little clinical relevance when considered in isolation from other risk factors, terms such as hypertension or hypercholesterolaemia have limited value. Separate management guidelines for raised blood pressure and blood cholesterol need to be replaced by integrated cardiovascular risk management guidelines, and absolute cardiovascular risk prediction scores should be used routinely. Since cardiovascular risk factors interact with each other, moderate reductions in several risk factors can be more effective than major reductions in one. An affordable daily pill combining low doses of various drugs could be useful for the many individuals with slightly abnormal cardiovascular risk factors.

Many regional floras contain a high proportion of recently introduced plant species. Occasionally, hybridization between an introduced species and another species (introduced or native) can result in interspecific gene flow. This may occur even in instances where the F1hybrid shows very high sterility, but occasionally produces a few viable gametes. We provide examples of gene flow occurring between some rhododendrons recently introduced to the British flora, and between an introduced and native Seneciospecies. Neutral molecular markers have normally been employed to obtain evidence of interspecific gene flow, but the challenge now is to isolate and characterize functional introgressed genes and to determine how they affect the fitness of introgressants and whether they improve adaptation to novel habitats allowing introgressants to expand the range of a species. We outline a candidate gene approach for isolating and characterizing an allele of the RAYgene in Senecio vulgaris, which is believed to have introgressed from S. squalidus, and which causes the production of ray florets in flower heads. We discuss the effects of this introgressed allele on individual fitness, including those that originate directly from the production of ray florets plus those that may arise from pleiotropy and/or linkage.

Human herpesvirus entry mediator C (HveC) is an alphaherpesvirus receptor which binds to virion glycoprotein D (gD). We identified porcine HveC and studied its interaction with pseudorabies virus (PrV) and herpes simplex virus type 1 (HSV-1) gD. Porcine and human HveC have 96% amino acid identity and HveC from African green monkey, mouse, hamster, and cow are similarly conserved. Porcine HveC mediates entry of HSV-1, HSV-2, PrV, and bovine herpesvirus type 1. Truncated soluble forms of HSV-1 and PrV gD bind competitively to porcine HveC. Biosensor analysis shows that PrV gD binds with a 10-fold higher affinity than HSV-1 gD. Monoclonal antibodies against human HveC recognize the porcine homologue and can block gD binding and entry of HSV-1 and PrV. Porcine HveC is functionally indistinguishable from human HveC. Our results are consistent with the suggestion that HveC is a pan-alphaherpesvirus receptor that interacts with a conserved structural domain of gD.

Ondansetron (GR 38032F) is a highly selective 5- HT3receptor antagonist, one of a new class of compounds which may have several therapeutic applications. Animal and clinical studies show that ondansetron reduces the 24- hour incidence and severity of nausea and vomiting induced by cytotoxic drugs, including cisplatin, and by single exposure, high dose radiation. Ondansetron is more effective than high dose metoclopramide in the 24 hours following chemotherapy, and preliminary clinical evidence suggests that it is equally effective in the following 4 days. It is also more effective than the ‘moderate’ doses of metoclopramide used to suppress emesis following radiotherapy. The antiemetic efficacy of ondansetron is enhanced by dexamethasone in cisplatintreated patients. Importantly, extrapyramidal effects have not been reported with ondansetron. Further comparisons are required with standard combination antiemetic therapy to complement the data presently available. Thus, ondansetron is a promising new agent for prophylaxis against nausea and vomiting in chemotherapy and radiotherapy. It may be particularly useful in young and elderly patients who are more susceptible to extrapyramidal symptoms induced by high dose metoclopramide. With its improved tolerability and clinical response profiles, ondansetron represents an important advance in a difficult area of therapeutics. Ondansetron is a new carbazole which blocks serotoninergic neurotransmission at serotonin3(5-HT3) receptors. It is a potent, highly selective and competitive antagonist of the depolarising effects of serotonin in the rat and rabbit isolated vagus nerve and the rat superior cervical ganglion. Ondansetron blocks the depolarising effect of the 5-HT3-selective agonist 2-methyl-5-HT in longitudinal smooth muscle of guinea-pig ileum, and the Bezold-Jarisch reflex response to 2-methyl-5-HT in anaesthetised rats and cats, but has little effect on 5-HT1and 5-HT2mediated responses or on α1, β1muscarinic, nicotinic, histamine1, histamine2or GABAareceptors. In vitro, it is at least 70 times more potent than metoclopramide at peripheral 5-HT3receptors, but has no effect on stereotyped movements induced by dopamine agonists. In animal models parenterally administered ondansetron reduces the incidence of emetic episodes induced by radiation, cyclophosphamide and cisplatin-based chemotherapies. Since both radiation and cisplatin may release serotonin from chromaffin cells in the intestinal mucosa, and since serotonin activates vagal and possibly splanchnic afferent nerves which in turn reflexly induce nausea and vomiting, it has been proposed that ondansetron acts by blocking serotonininduced depolarisation of vagal afferent nerves. It may also block serotoninergic action in the chemoreceptor trigger zone in the area postrema and the nucleus tractus solitarius of the brainstem, which contain 5-HT3binding sites probably located on vagal afferent nerve terminals. Ondansetron may slow colonie transit times but this effect is unrelated to its antiemetic action. It has no effect on motion sickness or on emesis induced by dopamine receptor agonists. Ondansetron can be administered either intravenously or orally. Following oral administration of ondansetron 8mg, peak plasma concentrations of about 30 µg/L are reached in 1 to 1.5 hours. Orally administered ondansetron is about 60% bioavailable in healthy subjects and about 75% bound to plasma proteins. The apparent volume of distribution is large (160L) and the mean elimination half-life is 3 hours. The clearance of ondansetron may be lower in the elderly. In healthy subjects 60% of a single intravenous radiolabelled dose is eliminated by the kidneys and 25% in faeces, mostly as metabolites. Clinically relevant metabolites have not been reported. Most clinical trials have studied the control of vomiting over the first 24 hours following chemotherapy. Ondansetron has been given either intravenously (IV) or orally, as a loading dose within the first 30 minutes IV or 1 to 2 hours orally prior to chemotherapy, followed by continuous infusion or by 2 or 3 oral or intravenous doses at intervals of 2 to 8 hours. In a moderate size noncomparative study ondansetron (0.18 mg/kg intravenously 6- or 8-hourly) completely controlled acute vomiting induced by cisplatin-based chemotherapy in 55% of patients, and reduced the number of emetic episodes to fewer than 3 in a further 20% of patients. Ondansetron delayed the onset of emesis from a median of 2.8 hours with placebo to a median of 11.6 hours after administration of cisplatin, and reduced the incidence of emetic episodes 4-fold and the incidence of retching 3-fold during the 24 hours after administration. No cisplatin-treated patients receiving ondansetron required rescue antiemetic therapy compared with 12 of 14 receiving placebo. Compared with metoclopramide in several studies, including 4 double-blind crossover trials, ondansetron was more effective in ameliorating nausea and vomiting on the day of chemotherapy. In the largest trial complete or major control of emesis (fewer than 3 emetic episodes in 24 hours) was achieved in 75% of patients with ondansetron compared with 42% with metoclopramide. Preliminary evidence suggests that ondansetron is as efficacious as metoclopramide in the 4 days following cisplatin chemotherapy. In all patients included in one study, ondansetron 8mg orally three times daily provided complete or major protection against vomiting induced by single high dose upper abdominal radiotherapy, and was more effective than metoclopramide 10mg orally three times daily. Overall, ondansetron is well tolerated by patients receiving radiotherapy or chemotherapy. The most frequently reported adverse event associated with ondansetron is headache, which responds to standard analgesics. However, it is noteworthy that in healthy subjects headache occurred as frequently in placebo recipients as in those receiving ondansetron. Mild constipation or diarrhoea occurs in a small minority of patients. Importantly, extrapyramidal effects such as those produced by metoclopramide would not be expected from the pharmacodynamic profile of ondansetron and have not been reported in clinical trials or in studies with healthy volunteers. When used to prevent nausea and vomiting induced by highly emetogenic chemotherapeutic regimens a loading dose of ondansetron 8mg infused 30 minutes before cancer therapy, with 2 additional 8mg doses administered at least 4 hours apart, or infusion of 1 mg/h for 24 hours, is recommended. For less emetogenic chemotherapeutic regimens, and for radiotherapy, ondansetron administered orally should be started as a loading dose (8mg) 1 to 2 hours prior to chemotherapy or radiotherapy and continued with 2 additional 8mg doses at 8-hour intervals. All regimens should be followed by 8mg orally for up to 5 days.

Celiprolol is a hydrophilic, β1-selective adrenoceptor antagonist with mild selective β2-agonist as well as weak vasodilator properties. Celiprolol 200 to 400mg once daily by mouth is similar in antihypertensive efficacy to usual doses of propranolol, atenolol, metoprolol and pindolol in patients with mild to moderate systemic hypertension. Similar doses of celiprolol are as efficacious as propranolol and atenolol in improving exercise tolerance and reducing the frequency of anginal attacks in patients with angina pectpris. Further clinical experience suggests that celiprolol does not produce bronchoconstriction and may have mild bronchodilating activity in asthmatic patients; it may also enhance the effects of bronchodilator drugs. Celiprolol has a slightly beneficial effect on serum lipid profiles, and does not appear to exert adverse effects on carbohydrate metabolism. If the apparent pharmacodynamic advantages of celiprolol translate into clinical benefits and are confirmed in well designed long term clinical trials, then celiprolol should represent a definite advance in β-blocker therapy. In vitrostudies and results obtained in humans show that celiprolol is a moderately potent, relatively β1-selective adrenoceptor antagonist. It is about as β1-selective as, but 3 to 4 times more potent than, acebutolol or atenolol, and 29 times more selective but 5.5 times less potent than propranolol. Celiprolol also exerts mild positive inotropic and chronotropic effects. Studies in isolated atrial tissue, in anaesthetised dogs and in patients with ischaemic heart disease suggest that these effects are mediated by cardiac β2-adrenoceptors and possibly also by a non-β-mediated action. The haemodynamic profile of celiprolol is characterised by reductions in total peripheral resistance and blood pressure with relatively minor effects on resting heart rate and contractility. Celiprolol has a weak vasodilator action as evidenced by enhanced femoral arterial blood flow and reduced total peripheral resistance in dogs; slightly reduced diastolic blood pressure in the presence of an increase in resting heart rate and contractility in human volunteers; enhanced forearm blood flow, as well as diminished total peripheral resistance and mean arterial pressure without concomitant reductions in resting cardiac output or contractility in hypertensive patients. Celiprolol has a mild vasodilator action but is. a very weak antagonist at α2-adrenoceptors. Thus vasodilatation is likely to be mediated by β2-agonism, possibly supplemented by weak postsynaptic α2-antagonism or other unknown mechanisms. Celiprolol has no local anaesthetic activity. In patients with mild to moderate hypertension, celiprolol reduces both diastolic and systolic blood pressure. Since heart rate and cardiac output are only slightly changed, the acute anti-hypertensive effect is largely due to reduced total peripheral resistance. In addition celiprolol, like other β-blockers and unlike enalapril, attenuates the cardiostimulatory effects of exercise. Celiprolol lowers daytime peaks in systolic and diastolic blood pressure, and improves left ventricular ejection fraction and pulmonary blood flow. Thus celiprolol preserves resting cardiac output but moderates the effects of exercise on heart rate. Long term monotherapy with celiprolol improves left ventricular ejection fraction and reduces left ventricular hypertrophy. Celiprolol has neutral or slightly positive effects on respiratory function, presumably because of its mild selective β2-agonist action. In rats and cats it reverses the bronchoconstricting effects of several agents and in healthy volunteers it has minimal effect on forced vital capacity, forced expiratory volume in 1 second or expiratory flow rate at 50% lung volume. In asthmatic hypertensive patients celiprolol has minimal deleterious effect and a possible mild beneficial effect on respiratory function, and does not block the action of bronchodilators. Evidence from a few patients with atrial fibrillation suggests that celiprolol attenuates exercise-induced elevations of heart rate and reduces ventricular tachycardia but also reduces exercise tolerance. In contrast to propranolol, atenolol and metoprolol, celiprolol has neutral or slightly beneficial effects on lipid profiles. Evidence from clinical trials indicates that 6 months or more administration of celiprolol reduces total cholesterol, triglycerides, low density lipoprotein cholesterol (LDL-C) levels, total cholesterol to high density lipoprotein cholesterol (HDL-C) ratios and apolipoprotein B levels, especially in patients with high baseline LDL-C levels. In contrast to earlier β-blockers, celiprolol has little adverse effect upon glucose metabolism in patients with type II diabetes. The bioavailability of orally administered celiprolol increases with dose, probably because of dose-dependent absorption, and is 30% at 100mg and 70% over the range 300 to 400mg. The extent of absorption may be reduced by food (an effect which appears not to be clinically relevant in long term therapy), and by concomitant administration of chlorthalidone, hydrochlorothiazide, theophylline, or digoxin. In vitro, the steady state rate of diffusion of celiprolol across human placenta is 3 to 4 times lower than that of propranolol, timolol and labetalol. Oral doses of 100 to 600mg produce mean peak plasma concentrations in the range 300 to 3000 μg/L. Celiprolol is minimally metabolised and there are no known clinically relevant metabolites. The elimination half-life is 4 to 5 hours, with 10 to 15% of an orally absorbed dose excreted in the urine and the balance in faeces. Values for area under the dose-effect curve for bolus doses appear to be higher in patients with renal impairment than in volunteers, after single doses and at steady state. A short term postmarketing survey in large numbers of patients with mild to moderate hypertension showed that monotherapy with celiprolol 200 to 300mg once daily reduced diastolic blood pressure to the target of 95mm Hg in 74% of patients. More recently it has been shown that 6 months’ monotherapy with celiprolol 200mg once daily normalised diastolic blood pressure in 80% of patients with mild to moderate hypertension. Small but well designed comparative studies have shown that celiprolol 200 to 600mg once daily is at least equivalent in efficacy to propranolol 30 to 12.0mg, atenolol 50 to 100mg, metoprolol 100 to 200mg, acebutolol 400mg, or enalapril 20mg. Celiprolol reduced diastolic blood pressure by 5 to 10mm Hg and systolic blood pressure by 5 to 12mm Hg compared to placebo. Small comparative trials suggest that celiprolol 200 to 600mg is more efficacious than placebo and at least equivalent in efficacy to atenolol 50 to 100mg and propranolol 80 to 320mg daily in reducing the frequency of anginal attacks and improving exercise capacity in patients with ischaemic heart disease. Importantly, it produces less bradycardia than atenolol. Celiprolol is equivalent in efficacy to atenolol in reducing nitroglycerin intake and in increasing time to onset of angina, and depression of the ST segment of the electrocardiogram, during exercise. Double-blind controlled studies and postmarketing surveys indicate little difference between placebo and celiprolol in the incidence of adverse events. 0.7% of 4000 patients treated with 200mg celiprolol once daily for 6 months discontinued therapy because of adverse events. Dizziness and fatigue or tiredness are less likely to be found in association with celiprolol than with propranolol or atenolol usage. Short term studies indicate no significant change in renal or respiratory function. Celiprolol has been used safely in small numbers of patients with asthma or chronic obstructive airways disease, although longer term studies are required to confirm safety. Small noncomparative studies suggest that carbohydrate metabolism is unimpaired in patients with type II diabetes. Celiprolol slightly improves lipid ratios, especially in patients with high initial LDL-C levels. The recommended initial dose of celiprolol used to treat mild to moderate hypertension or angina pectoris is 200mg orally once daily, increasing in a single step to 400mg if control is inadequate.

Synopsis: Recombinant granulocyte colony-stimulating factor (rG-CSF) therapy is associated with a dose-proportional reduction in the frequency, duration and severity of neutropenia associated with cytotoxic chemotherapy. This is associated with a decrease in the incidence of infection, with subsequent reductions in the number of hospitalisations, days of hospitalisation and antibiotic requirements. These effects produce marked reductions in costs, and could contribute substantially towards offsetting the costs of rG-CSF, although the magnitude of the savings will vary between institutions and with the chemotherapy regimen used. Other benefits include a reduction in the frequency and severity of mucositis, and an improved patient quality of life. However, further research is required to evaluate other potentially important considerations including the targeting of specific patient populations (e.g. those receiving regimens with a curative intent), and additional improvements in patient quality of life and, perhaps, mortality. Disease Considerations: Myelosuppression, predominantly neutropenia, is a frequent finding in patients receiving cytotoxic chemotherapy for cancer and is often dose limiting. Severe neutropenia (agranulocytosis) is present when the peripheral blood neutrophil count is less than 0.5 × 109/L (WHO grade IV). Infection is the most common cause of death in oncology patients receiving cytotoxic chemotherapy and the incidence of infection is increased in neutropenic patients. Febrile patients with severe neutropenia have an 80% incidence of infection, usually involving endogenous and nosocomial organisms. The mortality rate is about 10% in neutropenic cancer patients with documented infection, and higher in patients receiving high dose chemotherapy followed by autologous bone marrow transplantation. Pharmacoeconomic Benefits: rG-CSF is clinically effective in preventing or ameliorating chemotherapy-induced neutropenia, producing a significant reduction in both severity and duration. This was associated with a 50% reduction in the incidence of infection, and days of hospitalisation and antibiotic therapy, in a large, placebo-controlled phase III study. These benefits are also observed in patients receiving high dose chemotherapy followed by autologous bone marrow rescue and/or peripheral blood progenitor cell infusions who receive rG-CSF. Other benefits include a reduction in the frequency and severity of mucositis, and improved adherence to planned chemotherapy treatment schedules. Thus, rG-CSF produced significant reductions in hospitalisation costs and in the costs associated with antibiotic therapy. Pharmacoeconomic Costs: Product price and administration costs are the major costs associated with rG-CSF therapy. Both will vary according to the dose and route of administration used, as subcutaneous administration will almost certainly prove more cost-effective than intravenous therapy. Pharmacoeconomic Analysis: Formal pharmacoeconomic analyses of rG-CSF are limited as yet. Analysis of direct cost savings associated with rG-CSF therapy in a large, placebo-controlled, phase III study, indicates the use of rG-CSF at least partially offsets drug purchase costs and can result in substantial cost savings. Relevant evaluations would include cost-benefit comparisons of rG-CSF with chemotherapy vschemotherapy alone or chemotherapy plus prophylactic antibiotic therapy, comparison of rG-CSF derived from eukaryotic and prokaryotic systems, and possibly a comparison with recombinant granulocyte-macrophage colony-stimulating factor (rGM-CSF) if this is shown to be effective in similar indications. However, it seems likely that the cost savings from the reduced need for hospitalisation and antibiotic therapy will substantially offset the cost of rG-CSF therapy, with the potential for further cost-benefit justification as a result of improved quality of life.

Epidemiological and intervention study results support reduction of coronary heart disease (CHD) risk, and hence direct and indirect costs, by lowering plasma lipids. Cost-effectiveness of a lipid-lowering strategy thus depends significantly on the extent of plasma lipid decrease achieved. The 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor simvastatin is a well tolerated and highly effective antihyperlipidaemic agent. Despite a current lack of direct evidence that simvastatin reduces CHD incidence, the cost-effectiveness of the drug [in terms of years of life saved (YOLS)] has been studied, based on findings of epidemiological trials. Simvastatin 20 mg/day is more cost-effective than cholestyramine 4g 3 times daily, particularly in men and in those with a higher pretreatment cholesterol level (> 8 mmol/L) and other risk factors. Cost-effectiveness is also enhanced if treatment is started at a younger age (35 to 45 years) and maintained for a defined period rather than lifelong. Thus, while additional direct comparative studies are needed to confirm this finding, present evidence suggests simvastatin is a cost-effective intervention in appropriately selected patients. Epidemiological studies support the relationship between increased risk of coronary heart disease (CHD) and elevated plasma cholesterol, particularly low density lipoprotein (LDL)-cholesterol. The Multiple Risk Factor Intervention Trial (MRFIT) revealed a 4-fold greater risk of CHD mortality in middle-aged men with a serum cholesterol level > 4.68 mmol/L, and the Framingham Heart Study demonstrated a 2.5-fold increased CHD risk in men and 1.5-fold increased risk in women with levels > 6.89 mmol/L compared with those with a level of < 5.7 mmol/L. Primary prevention studies (i.e. reducing serum cholesterol in individuals without evidence of CHD) support the causal relationship. The Lipid Research Clinics Coronary Primary Prevention Trial reported a 19% reduction in CHD death and/or nonfatal myocardial infarction following cholestyramine-induced decreases of 8.5 and 12.6%, respectively, in total and LDL-cholesterol after 7 years’ follow-up. Similarly, a 34% lower frequency of cardiac events occurred in gemfibrozil recipients compared with those receiving placebo in the Helsinki Heart Study. In patients already with clinical evidence of CHD, secondary prevention trials yield a 1.5 and 2% decrease in CHD incidence, respectively, for each diet- and drug-induced reduction of 1% in serum cholesterol level. The benefit of simvastatin, an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, resides in its ability to lower elevated cholesterol levels. Simvastatin reduces total and low density lipoprotein (LDL)-cholesterol by 30 to 45% in patients with heterozygous familial and nonfamilial hypercholesterolaemia, a magnitude of effect greater than that of probucol, the bile acid sequestrants cholestyramine and colestipol, and the fibrates gemfibrozil, bezafibrate, fenofibrate and clofibrate. Simvastatin is at least comparable to other HMG-CoA reductase inhibitors at conventional doses, and more potent on a weight for weight basis. The drug is very well tolerated, so that costs incurred treating adverse effects or providing additional therapy to account for poor efficacy related to noncompliance are likely to be negligible, although regular liver function tests are necessary. The cost-effectiveness of simvastatin, and indeed other antihyperlipidaemic drugs, depends to a substantial degree on its ability to decrease plasma lipid levels and hence reduce costs associated with CHD. This latter factor must be extrapolated from the estimated effect on CHD incidence, based on findings of epidemiological and primary prevention studies, since direct evidence of reduced CHD mortality and morbidity during simvastatin therapy is not yet available. Cost-effectiveness analysis of the drug is generally expressed in terms of YOLS, based on epidemiological data. Cost of the drug itself (the most critical input factor), costs of medical care and costs of side effects, minus the cost savings associated with CHD reduction, are all accounted for and may vary greatly between studies and countries. In a cohort of 35- to 74-year old candidates for antihyperlipidaemic therapy from the Netherlands, without evidence of CHD, simvastatin 20 mg/day was more cost-effective than cholestyramine 4g 3 times daily [in men, cost per YOLS F1 (Netherlands guilders) 50 000 to 110 000 vsFl 220 000 to 510 000]. The cost-effectiveness of both agents was greater in men, in those with higher pretreatment total serum cholesterol level, in those with other CHD risk factors (e.g. hypertension, diabetes), and if initiated at a younger age. However, simvastatin maintained its cost-effectiveness advantage in all high and lower risk groups. An Australian study reported a higher monthly cost of simvastatin compared with standard (unspecified) therapy in high risk patients ($A68.03 vs$A8.11), but considerably better efficacy and tolerability. A congener of simvastatin, lovastatin, has been shown more cost-effective than probucol, colestipol, cholestyramine and gemfibrozil. Thus, simvastatin appears to be more cost-effective than other lipid-lowering agents (particularly in certain targeted subgroups), although more direct comparisons are required to confirm this.

This study compares the antihypertensive and lipid modifying effects of treatment of mild to moderate hypertension with celiprolol or atenolol. It also models the 5-year cardiovascular risk reduction and the cost effectiveness of monotherapy from a partial societal perspective. The effects of celiprolol and atenolol on systolic blood pressure (SBP), total serum cholesterol (TC) and high density lipoprotein cholesterol (HDL-C) were obtained from a pooled analysis of published studies. Although celiprolol and atenolol had similar effects on SBP, celiprolol reduced the ratio of TC to HDL-C by 10.2% [95% confidence intervals (95% CI) −16.4%, −4.0%] but atenolol increased the ratio by 7.7% (95% CI of 3.4%, 12.0%). The 5-year absolute risks of an initial coronary or cerebrovascular event or cardiovascular death were computed for cohorts of patients treated with either agent or remaining untreated, using an accelerated failure time (AFT) model, based on Framingham Heart Study data. Inputs to the model were age, gender, smoking status, SBP, TC and HDL-C. The change in absolute risk was estimated using the changes in SBP and TC: HDL-C obtained from the pooled analysis. Average life-months gained by therapy were computed as differences between the Kaplan-Meier survival curves estimated from the model plus differences in 5-year cardiovascular death rates multiplied by average life expectancy obtained from life tables. Direct medical costs included drug treatment, and the costs of acute care for initial coronary and cerebrovascular events deferred by therapy over the 5-year treatment period. The model shows that in the lowest-risk base case (60-year-old men who are nondiabetic and nonsmokers with SBP of 160mm Hg and a 5-year absolute cardiovascular risk of 12%), celiprolol (271 mg/day) is 2-fold more effective than atenolol (77.4 mg/day) in reducing coronary event risk, and equally effective in reducing cerebrovascular event risk. The number of individuals that would have to be treated for 5 years to avoid 1 coronary event is about 30 for celiprolol versus 70 for atenolol. Therapy with celiprolol yields more life-months and at current prices, the cost per life-year gained by therapy is significantly lower. Both drugs are cost effective by international standards in the treatment of patients with 5-year absolute cardiovascular risk greater than 10%, and are more cost effective in those patients at higher levels of absolute cardiovascular risk. The direct medical costs of treatment for 5 years with celiprolol are the same or slightly less than treatment with atenolol at the dosages used in the clinical trials, despite a 19% higher tablet price. Both drugs are more cost effective in patients at higher levels of absolute cardiovascular risk. These findings are sensitive to the drug dosages, tablet prices and the discount rate. Based on epidemiological and clinical data, replacing atenolol with celiprolol in patients with mild to moderate hypertension, but without overt cardiovascular disease, is predicted to have similar effects on stroke risk, but to be substantially more effective in reducing the risk of coronary events at no additional direct medical cost over a 5-year treatment period.

Ondansetron is more effective than high-dose metoclopramide in the prevention of acute nausea and vomiting due to highly emetogenic chemotherapy, and, unlike metoclopramide, is rarely associated with extrapyramidal effects. Pharmacoeconomic analyses have demonstrated that, in specified clinical settings, ondansetron (8mg 4-hourly for 3 doses or 8mg followed by 1 mg/h for 24 hours) is equally cost-effective as high-dose metoclopramide (3 mg/kg followed by 0.5 mg/kg/h for 8 hours) in the prophylaxis of emesis in patients receiving highly emetogenic chemotherapy, at an acquisition cost 4- or 5-fold higher than that of the metoclopramide regimen. Furthermore, the combination of dexamethasone plus ondansetron has been shown to be more effective than ondansetron monotherapy in controlling emesis. In patients receiving high-dose (> 50 mg/m2) cisplatin-based chemotherapy, antiemetic therapy with ondansetron (8mg intravenously as a single dose) plus dexamethasone (16mg total intravenous dose) was shown to be more cost-effective than the combination of high-dose metoclopramide (11 mg/kg total intravenous dose), dexamethasone (8mg intravenously as a single dose) plus lorazepam (1 to 1.5mg intravenously as a single dose). In a limited number of studies, quality-of-life scores, as assessed using the Rotterdam Symptom Checklist or the Functional Living Index — Emesis instrument, were significantly higher with ondansetron than with other antiemetic agents, including metoclopramide. Together, these results suggest that ondansetron, as an alternative to antiemetic regimens including high-dose metoclopramide, is appropriate cost-effective therapy for the prevention of acute nausea and vomiting in patients receiving highly emetogenic chemotherapy. Ondansetron is effective in controlling acute emesis associated with moderately emetogenic chemotherapy, and its use in this clinical setting may best be reserved for patients who have not responded well to previous antiemetic therapy with more traditional agents. However, poorly controlled emesis can lead to anticipatory nausea and vomiting in subsequent courses of chemotherapy, thus; consideration should also be given to the use of ondansetron in patients receiving moderately emetogenic chemotherapy, although further pharmacoeconomic investigations are required to clarify its use in this clinical setting. It is estimated that in the US, 600 000 cancer patients are candidates for chemotherapy each year. Nausea and vomiting can be the most distressing treatment-related effects of cancer chemotherapy. Cisplatin is particularly emetogenic, and virtually all patients who receive high doses without or with inadequate antiemetic therapy will vomit during the 24 hours following its administration. These effects can result in anticipatory nausea and vomiting with future chemotherapy regimens, and may ultimately lead to a patient’s refusal to continue receiving potentially beneficial cancer treatment. A large body of evidence supports the theory that cancer chemotherapy induces nausea and vomiting, at least in part, by inflicting cellular damage which releases serotonin from intestinal mucosa, thereby depolarising vagal afferent neurones and triggering the vomiting reflex. Thus, serotonin appears to play a major role in cytotoxic drug-induced emesis through its effect on abdominal visceral afferents, and serotonin3(5-HT3) receptor binding sites in the nucleus tractus solitarius which are mainly located on vagal afferent fibres originating from the gut. Ondansetron probably ameliorates vomiting by blocking these 5-HT3receptor sites. Ondansetron is a potent and selective 5-HT3receptor antagonist which achieves complete or major control of acute emesis (0 to 2 emetic episodes in the first 24 hours) in 70 to 80% of patients treated with high-dose (> 50 mg/m2) cisplatin-or cyclophosphamide-based chemotherapy regimens. In comparative clinical trials, ondansetron was more effective than high-dose metoclopramide in controlling emesis during the 24 hours after administration of highly emetogenic chemotherapy. Compared with ondansetron monotherapy, the addition of dexamethasone to ondansetron regimens produced statistically and clinically significant improvements in the control of emesis following high-dose cisplatin-based chemotherapy. Extrapyramidal effects, which occur in up to 5% of patients treated with high-dose metoclopramide, have been reported in only a few isolated cases with ondansetron. Thus, the results of several clinical trials demonstrate that ondansetron is superior to high-dose metoclopramide in controlling emesis due to highly emetogenic cancer chemotherapy and is better tolerated. Two detailed UK-based cost-effectiveness analyses compared ondansetron and metoclopramide antiemetic regimens in patients receiving highly emetogenic chemotherapy. When direct costs of antiemetic therapy and costs per effective treatment were considered, ondansetron appeared to be equally cost-effective as proprietary metoclopramide at an acquisition cost approximately 4 or 5 times the £10 acquisition cost of the metoclopramide regimen. A separate analysis evaluated the cost-effectiveness of antiemetic therapy with ondansetron plus dexamethasone versus a combination of high-dose metoclopramide, lorazepam plus dexamethasone in patients receiving high-dose cisplatin. The ondansetron regimen was deemed to be more cost-effective on the basis of cost per effective treatment calculated from acquisition drug costs and antiemetic response rates. In clinical practice, high-dose metoclopramide is typically used in combination with 1 or more other antiemetics, such as dexamethasone and lorazepam, to prevent nausea and vomiting with high-dose cisplatin. Results of formal quality-of-life assessments comparing ondansetron with other antiemetics, including metoclopramide, have also favoured ondansetron. Using the Rotterdam Symptom Checklist, statistically significant improvements from baseline in psychological subscale scores were observed among ondansetron recipients compared with metoclopramide recipients. Similarly, when ondansetron replaced previously ineffective antiemetic therapy, mean quality-of-life scores assessed using the Functional Living Index — Emesis instrument were significantly improved in patients receiving equally emetogenic cancer chemotherapy.

Selegiline (deprenyl) is a selective, irreversible cerebral monoamine oxidase type B inhibitor (MAO-B) that is used in the treatment of Parkinson’s disease. It has a relatively mild adverse effect profile without risk of the tyramine (‘cheese’ reaction at normal therapeutic doses. In about half to two-thirds of patients with mild levodopa response fluctuations, selegiline improves overall disability and ‘end-of-dose’ fluctuations, with a levodopa-sparing effect. Selegiline thus may improve patient quality of life, although formal cost-utility analyses are required to establish the costs of these benefits. Cost-effectiveness studies may help characterise the relative pharmacoeconomic benefits of selegiline and the dopamine agonists, agents which can also be administered as adjuvant therapy at this stage of the disease. There is also evidence to suggest that selegiline may delay the need for levodopa therapy by up to 11 months in patients with early Parkinson’s disease, although the relative contribution of neuroprotective and symptomatic effects of selegiline in these patients has yet to be clarified. From a societal perspective, a theoretical analysis indicates that the economic benefits of selegiline therapy are likely to be substantial. An agent which slowed progression of disability by around 10% would realise savings, through reduction in both direct and indirect costs, in the order of $US330 million per annum in the United States. Available data suggest that selegiline slows progression of symptoms well in excess of 10%. Further, if a simple and inexpensive method is developed to identify preclinical Parkinson’s disease before nigrostriatal damage is advanced, selegiline may be useful in a broader patient population with possible financial benefits to society through reduction of the considerable indirect costs of Parkinson’s disease. Idiopathic Parkinson’s disease is a progressive and incurable disease characterised by tremor, bradykinesia, rigidity and postural instability. Secondary symptoms can include depression, dementia, fear of falling, sexual dysfunction, pain and bowel problems. Dependence and feelings of isolation in the patient can be exacerbated by speech difficulties. The disease thus significantly impairs the quality of life of sufferers. Falls that can occur as a result of disease-associated disability are a major costly health problem. Idiopathic Parkinson’s disease results from the progressive loss of dopaminergic cells in the substantia nigra. It is thought that disease symptoms occur only after 70 to 80% of nerve terminals in the striatum have been destroyed. Two pathophysiological hypotheses concerning the neurodegenerative process in Parkinson’s disease assign a central role to the enzyme, monoamine oxidase. The first suggests that oxygen free radicals, produced via normal MAO-B-mediated dopamine metabolism in the nigrostriatal pathway, cause oxidative damage to lipid and protein cellular components. The second hypothesis proposes that conversion of the selective protoxin, 1-methyl-4-phenyl-l,2,3,6-tetrahydropyridine (MPTP) to the l-methyl-4-phenylpyridinium ion (MPP+) is again mediated by MAO-B; in humans, MPTP produces neuropathological changes and clinical symptoms similar to those seen in idiopathic Parkinson’s disease. It has thus been suggested that environmental analogues of MPTP may act as neurotoxins. Inhibition of MAO, with an agent such as selegiline, may therefore have a role in the prevention of the neurodegenerative process. MAO-B is also responsible for dopamine metabolism in the brain; inhibition of MAO-B increases nigrostriatal dopamine levels thus increasing levels of disease-depleted dopamine. Selegiline, at the dosage recommended for use in Parkinson’s disease, is a selective and irreversible MAO-B inhibitor. It is generally well tolerated, and is not associated with the tyramine (‘cheese’) reaction. In patients with Parkinson’s disease, selegiline has been investigated for use in 2 distinct areas. First, selegiline improves overall disability and ‘end-of-dose’ fluctuations in some patients receiving long term levodopa therapy, which has important implications for patient quality of life. Selegiline often has a levodopa-sparing effect in this patient group, which may produce some cost savings. Dopamine agonists can also be administered as adjuvant therapy at this stage of the disease; one trial demonstrated that low dose bromocriptine and selegiline had comparable efficacy in this indication. Second, when administered as monotherapy in patients with early Parkinson’s disease, selegiline may slow symptom progression and therefore delay the need for symptomatic treatment and reduce direct costs. Selegiline may be unique in this respect; all other currently available agents have unequivocal symptomatic effects when administered alone. However, there is still an ongoing debate over whether the observed effects of selegiline are neuroprotective, symptomatic or both. No formal pharmacoeconomic studies directly involving selegiline have been performed to date but current data make some analysis possible. In patients with levodopa response fluctuations, cost-effectiveness analyses may help clinicians choose between selegiline and the dopamine agonists as adjuvant therapy. Improvements in patient disability have been observed with selegiline in this patient group; thus, better quality of life would be expected after adjunct treatment with selegiline, although formal studies are required to quantify this. In pharmacoeconomics terms, it is anticipated that selegiline will have greatest impact as an agent which delays the onset of disability. One source estimated that annual cost savings of $US327 million (including both direct and indirect costs in 1988 $US) would be achieved in the United States with a hypothetical agent which slowed disease progression by 10%; available data indicate that selegiline may slow progression of symptoms well in excess of this level. If data from current trials are substantiated, selegiline may have a place in the treatment of all patients with early Parkinson’s disease. Given the long preclinical phase of Parkinson’s disease (i.e. lack of symptom onset until nigrostriatal loss is 70 to 80%), selegiline may also have a role in presymptomatic patients, although currently there is no means of widely identifying preclinical disease.

This paper provides an overview of issues related to the emerging discipline of pharmacoeconomics and its relationship to the outcomes movement. The focus is upon the evolving Management Care Organisation (MCO) and the demands placed upon the pharmaceutical industry as it attempts to provide new innovative anti-infective treatments. Similarly, the challenge is to meet the ever increasing requirements for approval and reimbursement of new anti-infective pharmaceutical products. Outcomes research is playing an increasingly important role in such decisions throughout the world, including the United States. Unfortunately, most decisions and analysis at the national level and within MCOs regarding the adoption and utilisation of pharmaceuticals are rather unsophisticated in terms of the proper utilisation of pharmacoeconomic data. There is a prevalent need to better utilise this information to develop cost-effective disease and therapy intervention models and guidelines. Also, information on the application of pharmacoeconomics for the evaluation of pharmaceutical care services that enhance the cost effectiveness of drug therapy needs to be seriously considered. Specifically, this should include a consideration of the economic consequences of drug-related problems and the potential impact of pharmaceutical care on drug-related morbidity/mortality associated with the treatment of infectious disease.

A letter to the editor is presented in response to the article "We Will Fight For You" by Jad Adams in the September 2014 issue.

ObjectiveTo evaluate whether provision of fixed dose combination treatment improves adherence and risk factor control compared with usual care of patients at high risk of cardiovascular disease in primary care.DesignOpen label randomised control trial: IMPACT (IMProving Adherence using Combination Therapy).Setting54 general practices in the Auckland and Waikato regions of New Zealand, July 2010 to August 2013.Participants513 adults (including 257 indigenous Māori) at high risk of cardiovascular disease (established cardiovascular disease or five year risk ≥15%) who were recommended for treatment with antiplatelet, statin, and two or more blood pressure lowering drugs. 497 (97%) completed 12 months’ follow-up.InterventionsParticipants were randomised to continued usual care or to fixed dose combination treatment (with two versions available: aspirin 75 mg, simvastatin 40 mg, and lisinopril 10 mg with either atenolol 50 mg or hydrochlorothiazide 12.5 mg). All drugs in both treatment arms were prescribed by their usual general practitioners and dispensed by local community pharmacists.Main outcome measuresPrimary outcomes were self reported adherence to recommended drugs (antiplatelet, statin, and two or more blood pressure lowering agents) and mean change in blood pressure and low density lipoprotein cholesterol at 12 months.ResultsAdherence to all four recommended drugs was greater among fixed dose combination than usual care participants at 12 months (81% v46%; relative risk 1.75, 95% confidence interval 1.52 to 2.03, P<0.001; number needed to treat 2.9, 95% confidence interval 2.3 to 3.7). Adherence for each drug type at 12 months was high in both groups but especially in the fixed dose combination group: for antiplatelet treatment it was 93% fixed dose combination v83% usual care (P<0.001), for statin 94% v89% (P=0.06), for combination blood pressure lowering 89% v59% (P<0.001), and for any blood pressure lowering 96% v91% (P=0.02). Self reported adherence was highly concordant with dispensing data (dispensing of all four recommended drugs 79% fixed dose combination v47% usual care, relative risk 1.67, 95% confidence interval 1.44 to 1.93, P<0.001). There was no statistically significant improvement in risk factor control between the fixed dose combination and usual care groups over 12 months: the difference in systolic blood pressure was −2.2 mm Hg (−4.5 v−2.3, 95% confidence interval −5.6 to 1.2, P=0.21), in diastolic blood pressure −1.2 mm Hg (−2.1 v−0.9, −3.2 to 0.8, P=0.22) and in low density lipoprotein cholesterol −0.05 mmol/L (−0.20 v−0.15, −0.17 to 0.08, P=0.46). The number of participants with cardiovascular events or serious adverse events was similar in both treatment groups (fixed dose combination 16 vusual care 18 (P=0.73), 99 v93 (P=0.56), respectively). Fixed dose combination treatment was discontinued in 94 participants (37%). The most commonly reported reason for discontinuation was a side effect (54/75, 72%). Overall, 89% (227/256) of fixed dose combination participants’ general practitioners completed a post-trial survey, and the fixed dose combination strategy was rated as satisfactory or very satisfactory for starting treatment (206/227, 91%), blood pressure control (180/220, 82%), cholesterol control (170/218, 78%), tolerability (181/223, 81%), and prescribing according to local guidelines (185/219, 84%). When participants were asked at 12 months how easy they found taking their prescribed drugs, most responded very easy or easy (224/246, 91% fixed dose combination v212/246, 86% usual care, P=0.09). At 12 months the change in other lipid fractions, difference in EuroQol-5D, and difference in barriers to adherence did not differ significantly between the treatment groups.ConclusionsAmong this well treated primary care population, fixed dose combination treatment improved adherence to the combination of all recommended drugs but improvements in clinical risk factors were small and did not reach statistical significance. Acceptability was high for both general practitioners and patients, although the discontinuation rate was high.Trial registrationAustralian New Zealand Clinical Trial Registry ACTRN12606000067572.