Combining etanercept with traditional agents in the treatment of psoriasis: a review of the clinical evidence.

Psoriasis is a chronic, systemic inflammatory disorder manifesting primarily in skin and potentially in joints, frequently necessitating treatment with conventional systemic therapies, phototherapy or biological agents. Patients with moderate to severe disease suffer a diminished quality of life, experience significant comorbidities and have a higher mortality. Although traditional treatments are effective in the short-term, their use is often limited by concerns over long-term toxicity, including end-organ damage and risk of malignancy. Combination therapy is a commonly used approach and is often more effective than any single agent. Lower doses of two treatments in combination can also minimize potential side effects from a single agent at higher doses. Etanercept is a recombinant human tumour necrosis factor (TNF)α receptor (p75) protein fused with the Fc portion of IgG1 that binds to TNFα. This article reviews the evidence on the efficacy and safety of etanercept in combination with methotrexate, acitretin, narrowband UVB and cyclosporin. The largest body of evidence assesses the combination with methotrexate, although evidence is available for the other combinations. Data suggest that although highly effective as monotherapy, etanercept in combination with a conventional systemic agent can enhance efficacy and allow drug sparing. Potentially, the combination may also result in faster treatment responses and permit safe transitioning from one systemic agent to another. Evidence to date suggests that these benefits can be achieved without significant additional toxicity, although long-term data on the efficacy and safety of the combination in psoriatic populations is limited and further evaluation is warranted.

Tetanus toxin induces long-term changes in excitation and inhibition in the rat hippocampal CA1 area.

Intrahippocampal tetanus toxin induces a period of chronic recurrent limbic seizures in adult rats, associated with a failure of inhibition in the hippocampus. The rats normally gain remission from their seizures after 6-8 weeks, but show persistent cognitive impairment. In this study we assessed which changes in cellular and network properties could account for the enduring changes in this model, using intracellular and extracellular field recordings in hippocampal slices from rats injected with tetanus toxin or vehicle, 5 months previously. In CA1 pyramidal neurones from toxin-injected rats, the slope of the action potential upstroke was reduced by 32%, the fast afterhyperpolarisation by 32% and the slow afterhyperpolarisation by 54%, suggesting changes in voltage-dependent conductances. The excitatory postsynaptic potential slope was reduced by 60% and the population synaptic potential slope was reduced at all stimulus intensities, suggesting a reduced afferent input in CA1. Paired-pulse stimulation showed an increase of the excitability ratio and an increase of cellular excitability only for the second pulse, suggesting a reduced inhibition. The polysynaptic inhibitory postsynaptic potential was reduced by 34%, whereas neither the inhibitory postsynaptic potential at subthreshold stimulus intensities,nor the pharmacologically isolated monosynaptic inhibitory postsynaptic potential were different in toxin-injected rats, suggesting a reduced synaptic excitation of interneurones. Stratum radiatum stimuli in toxin-injected rats, and not in controls, evoked antidromic activation of CA1 neurones, demonstrating axonal sprouting into areas normally devoid of CA1 pyramidal cell axons.We conclude that this combination of enduring changes in cellular and network properties, both pro-epileptic (increased recurrent excitatory connectivity, reduced recurrent inhibition and reduced afterhyperpolarisations) and anti-epileptic (impaired firing and reduced excitation), reaches a balance that allows remission of seizures, perhaps at the price of persistent cognitive impairment.

Dynamic modulation of excitation and inhibition during stimulation at gamma and beta frequencies in the CA1 hippocampal region.

Fast oscillations at gamma and beta frequency are relevant to cognition. During this activity, excitatory and inhibitory postsynaptic potentials (EPSPs and IPSPs) are generated rhythmically and synchronously and are thought to play an essential role in pacing the oscillations. The dynamic changes occurring to excitatory and inhibitory synaptic events during repetitive activation of synapses are therefore relevant to fast oscillations. To cast light on this issue in the CA1 region of the hippocampal slice, we used a train of stimuli, to the pyramidal layer, comprising 1 s at 40 Hz followed by 2--3 s at 10 Hz, to mimic the frequency pattern observed during fast oscillations. Whole cell current-clamp recordings from CA1 pyramidal neurons revealed that individual stimuli at 40 Hz produced EPSPs riding on a slow biphasic hyperpolarizing-depolarizing waveform. EPSP amplitude initially increased; it then decreased concomitantly with the slow depolarization and with a large reduction in membrane resistance. During the subsequent 10-Hz train: the cells repolarized, EPSP amplitude and duration increased to above control, and no IPSPs were detected. In the presence of GABA(A) receptor antagonists, the slow depolarization was blocked, and EPSPs of constant amplitude were generated by 10-Hz stimuli. Altering pyramidal cell membrane potential affected the time course of the slow depolarization, with the peak being reached earlier at more negative potentials. Glial recordings revealed that the trains were associated with extracellular potassium accumulation, but the time course of this event was slower than the neuronal depolarization. Numerical simulations showed that intracellular chloride accumulation (due to massive GABAergic activation) can account for these observations. We conclude that synchronous activation of inhibitory synapses at gamma frequency causes a rapid chloride accumulation in pyramidal neurons, decreasing the efficacy of inhibitory potentials. The resulting transient disinhibition of the local network leads to a short-lasting facilitation of polysynaptic EPSPs. These results set constraints on the role that synchronous, rhythmic IPSPs may play in pacing oscillations at gamma frequency in the CA1 hippocampal region.

On the synchronizing mechanisms of tetanically induced hippocampal oscillations.

gamma (30-100 Hz) and beta (10-30 Hz) oscillations follow tetanic stimulation in the CA1 region of the rat hippocampal slice. Pyramidal neurons undergo a slow depolarization after the tetanus and generate synchronous action potentials. The slow depolarization was previously attributed to metabotropic glutamate receptor (mGluR) activation. However, we found that this event was mediated by GABA(A) receptors, being blocked by bicuculline (50 microM) and accompanied by a dramatic drop in input resistance. Experiments with NMDA and non-NMDA glutamate receptor antagonists revealed that fast synaptic excitation was not necessary for oscillations. IPSPs were strongly depressed during the oscillations. Instead, synchronization was caused by field effects, as shown by: (1) Action potentials of pyramidal neurons proximal (<200 micrometer) to the stimulation site were often preceded by negative deflections of the intracellular potential that masked a net transmembrane depolarization caused by the population spike. (2) Pyramidal neurons located on the surface of the slice, where field effects are weak, fired repetitively but were not synchronized to the network activity. (3) A moderate decrease (50 mOsm) in artificial CSF (ACSF) osmolality did not affect the slow depolarization but increased oscillation amplitude and duration and recruited previously silent neurons into oscillations. (4) 50 mOsm increase in ACSF osmolality dramatically reduced, or abolished, post-tetanic oscillations. Phasic IPSPs, not detectable in proximal neurons, were present, late in the oscillation, in cells located 200-400 micrometer from the stimulation site and possibly contributed to slowing the rhythm during the gamma to beta transition.