Obesity is an important causative factor in morbidity, disability and premature death. Increasing levels of obesity will impose enormous health, financial and social burdens on worldwide society unless effective interventions are implemented. For many obese individuals, diet and behavioural modification need to be supplemented by pharmacotherapy. Preclinical research has revealed a greater understanding of the complex nature of the hypothalamic regulation of food intake and has generated a wide range of new molecular targets for the development of drug candidates for obesity treatment. As shown by the clinical results that have been obtained with this next generation of therapies, some approaches, for example, fixed-dose drug combinations, have already demonstrated an ability to deliver levels of efficacy that are not achievable with the current antiobesity drug therapies. The regulatory and marketing landscape for development, registration and commercialisation of novel centrally acting drugs for treatment of obesity and related metabolic disorders has changed substantially in recent years. Now a much greater emphasis is placed on tolerability and safety, as well as efficacy. In this review we briefly describe the therapeutic approaches to tackle obesity that are in late-stage clinical development. We then discuss drugs in late-stage development for the treatment of obesity and also future directions.

Results from in vivo techniques, especially intracerebral microdialysis in freely-moving rats, have provided insights into potential mechanisms responsible for the efficacy and safety of catecholaminergic drugs for ADHD treatment. The drugs reviewed come from distinct pharmacological classes: psychostimulant releasing agents, eg d-amphetamine; psychostimulant reuptake inhibitors, eg dl-threo-methylphenidate (dl-MPH), and non-stimulant reuptake inhibitors, eg atomoxetine. Psychostimulants, which currently deliver the best efficacy in treating ADHD, exhibit the following characteristics on extraneuronal catecholamine concentrations in rodent brain in vivo: 1) They enhance the efflux and function of both noradrenaline and dopamine in the central nervous system. 2) The increase of dopamine efflux that they produce is not limited to cortical regions. 3) They have a rapid onset of action with no ceiling on drug effect. d-Amphetamine has a mechanism independent of neuronal firing rate, displacing intraneuronal stores of catecholamines, delaying their reuptake and inhibiting catabolism by monoamine oxidase. dl-MPH has an enigmatic, extraneuronal action that is neuronal firing rate-dependent and reuptake transporter-mediated, yet paradoxically, almost as powerful as that of d-amphetamine. In safety terms, these powerful catecholaminergic effects also make the psychostimulants liable for abuse. Since efficacy and safety derive from the same pharmacological mechanisms, it has not yet been possible to separate these two components. However, the development of once-daily psychostimulant formulations and a prodrug, lisdexamfetamine, has improved patient compliance and markedly reduced scope for their diversion/abuse. This review will discuss the in vivo pharmacological profiles of approved catecholaminergic drugs for treatment of ADHD and implications for their clinical efficacy and abuse liability.

The increasing global prevalence of obesity unequivocally demonstrates that neither behavioural (diet and exercise) nor pharmacological approaches to this health problem are working. In this area of high unmet clinical need, the 5-HT6 receptor has generated enormous interest amongst academic and pharmaceutical industry scientists as a molecular target for the development of a new generation of safe and more effective anti-obesity drugs. In this review, we have described the major developments that have occurred in the fields of the medicinal chemistry and pharmacology of 5-HT6 ligands, with particular emphasis on their potential application as novel anti-obesity drugs. The last 5 years have witnessed an increasing understanding of the 5-HT6 receptor and its structural requirements that has produced an explosion in the number and diversity of novel, highly selective 5-HT6 receptor agonists, partial agonists and antagonists that have been designed and synthesized. In animal models, 5-HT6 receptor ligands of all functional types have been shown to decrease food intake when given acutely and chronically, to evoke profound and sustained weight-loss in obese animals, and concomitantly to improve a number of cardio-metabolic risk factors. Comparator studies in obese animal models, which are highly predictive of clinical outcomes, indicate that 5-HT6 ligands may have the potential to be more efficacious in the treatment of obesity than the current generation of anti-obesity drugs.

Attention deficit hyperactivity disorder (ADHD) is a common childhood psychiatric condition that is effectively treated by catecholaminergic drugs with a variety of different mechanisms and the SH rat is frequently used as a model of this disorder. In vivo microdialysis in freely-moving rats has been employed extensively to provide a better understanding of the pharmacodynamics of drugs at their sites of action. In this review, these three topics are brought together to explore the contribution of in vivo microdialysis studies in spontaneously hypertensive (SH) rats to our understanding of the neurochemical deficits in this rat strain and the actions of ADHD drugs on catecholaminergic function in the prefrontocortex (PFC), striatum and nucleus accumbens. What is revealed is that basal efflux of norepinephrine in the PFC is attenuated, whilst striatal and mesolimbic dopaminergic neurotransmission is hyperfunctional; the latter observation fits closely with the hyperactive phenotype of the SH rat. Furthermore, experiments performed with the enantiomers of amphetamine and threo-methylphenidate demonstrate that pharmacodynamic effects of drugs reported from experiments in outbred rat strains, e.g. Sprague–Dawleys, do not necessarily translate to the SH rat. When the findings are compared with the clinical efficacy of drugs used in treating ADHD, they indicate that the most efficacious drugs powerfully increase both norepinephrinergic and dopaminergic neurotransmission.

Radiation-recall reaction, secondary to chemotherapy, is a rare phenomenon most commonly reported to involve the skin [1,2], but other sites have also been documented [3]. Typically, the cutaneous reaction develops after prior exposure to radiotherapy and subsequent treatment with a chemotherapeutic agent. By definition, the inflammatory reaction occurs in the previously irradiated treatment field after exposure to the drug. Onset of the radiation-recall reaction can be within days to weeks of exposure to the precipitating drug [4].

Sediment traps were deployed for 5 days during March 198S, at 20 and 33 m in 42 m of water over the continental shelf off Norfolk, Virginia (SEEP-II study area). During the sediment trap deployment, a time-series study determined the community and age-structure of copepods as well as the standing stocks, production rates and settling velocities of fecal pellets. Fecal pellets comprised less than 1% of the total particulate carbon collected in the sediment traps and ca 0.3% of particulate carbon found in the water column. Mean fecal pellet production by adult copepods feeding in natural seawater ranged from 1 to 2 pellets animal(-1) day(-1), equalling approximately 0.1-0.3 mu g C day(-1). Average fecal pellet volume ranged from 4 x 10(5) mu m(3) for pellets produced by Centropages typicus females to 14 x 10(5) mu m(3), for pellets produced by Calanus finmarchicus females. The pellets produced by C. finmarchicus were important in the downward vertical transport of phytoplankton carbon, while pellets produced by smaller copepods were primarily recycled in the water column. Lateral advective processes altered the species composition of zooplankton at our study site. The onshore and offshore movement of different zooplankton communities with varying size-structure could have a substantial impact on the magnitude of vertical carbon transport on continental shelves.

A high precision x-ray scattering study of the actinide intermetallic, UPd3, was undertaken in a search for structural evidence of the low temperature, first-order phase transition that is known to occur in this system. Earlier neutron scattering measurements indicate the appearance of satellite structures at wavevectors (0.5,0,l) below 6 K. To within the experimental precision of the current measurement these satellites are not observed in x-ray scattering.

In late May 1981, during a 48 h study in the southeast Bering Sea, each Pseudocalanus spp.female produced an average of 5.1 nauplii d-l, resulting in a production of 25,757 nauplii m-2 d-' by the Pseudocalanus spp.population.Similar calculations showed that the only other abundant copepod female at this station, Oithona spp., produced 1,337 nauplii m-2 d-'.From these rates, it is calculated that a standing stock of 721,034 nauplii m-' would result if there were no mortality.However, lower temperatures and lower concentrations of females were found prior to our study and a more realistic estimate of the potential stock is 495,328 nauplii m-'.The average observed stock of nauplii was 463,173 m-2, suggesting a mortality rate between 7 and 36 % of the daily production with values in the lower part of this range being more probable.Pollock larvae, found at an average concentration of 6.3 m-', ingested an average of 115 nauplii m-' d-' and therefore ingested only a small fraction of the daily naupliar production.It is concluded that pollock larvae are insignificant as predators on copepod nauplii, and that overall naupliar mortality is low during the springtime in this area.

High-temperature coal-tar samples were fractionated by a liquid-liquid partition scheme to provide aromatic, aliphatic, basic, acidic and ‘neutral polar’ fractions which were subsequently analysed by an optimum methodology for each compound class. Combined glass-capillary gas chromatography/mass spectrometry was used for the analysis. The results verifty some earlier identifications and also report constituents identified for the first time. Crude-tar samples derived from coals of different geographical origin were found to be similar in their major constituents.

We describe a simple method for collectively determining polyols in the cerebrospinal fluid. The method consists of protein removal, sample derivatization, and gas chromatography of the trimethylsilylated polyols, with use of glass capillary columns. Nine major polyol constituents, the structures of which were verified by combined gas chromatography/mass spectrometry, can be simultaneously assayed. The presence of three polyols in the cerebrospinal fluid is reported here for the first time.