Clinical and experimental pharmacology & physiology
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Clin. Exp. Pharmacol. Physiol. · Nov 2001
ReviewAdenoviral vector-mediated delivery of glial cell line-derived neurotrophic factor provides neuroprotection in the aged parkinsonian rat.
1. The long-term delivery of neurotrophic factors to specific regions of the central nervous system via gene therapy offers a new strategy for the treatment of neurodegenerative disorders. 2. The neurotrophic factor glial cell line-derived neurotrophic factor (GDNF) is a potent dopaminergic (DA) trophic factor that ameliorates the behavioural and histological consequences of lesioning DA neurons in rodent and primate models of Parkinson's disease. 3. ⋯ Injection of GDNF vector into either the striatum or the SN provided significant cell protection against 6-OHDA. However, only striatal injection of Ad GDNF protected against the development of behavioural and neurochemical changes that occur in the DA-depleted brain. 7. The results of this study are reviewed here and the behavioural and cellular effects of GDNF gene delivery into striatal versus mesencephalic sites are discussed.
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Clin. Exp. Pharmacol. Physiol. · Mar 2001
ReviewRole of human airway smooth muscle in altered extracellular matrix production in asthma.
1. The underlying abnormality in asthma is not fully understood; however, inflammation, airway remodelling and bronchial hyperresponsiveness are key factors. The plasma exudate from the microvascular leakage plays a significant role in remodelling, which includes extracellular matrix (ECM) protein deposition/breakdown and airway smooth muscle (ASM) hyperplasia/hypertrophy. 2. ⋯ The role of current asthma treatments in the prevention or reversal of airway ECM changes is an area that has only recently become of interest, with the majority of the in vivo work focusing on the effects of corticosteroids. 7. The evidence presented in this review indicates that the ASM may influence its own environment/proliferation through the production of ECM proteins, MMP and TIMP. Further studies are needed to fully understand the role of the ASM in the production of ECM proteins, MMP and TIMP andtheir potential influence in the mechanisms underlying asthma.
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Clin. Exp. Pharmacol. Physiol. · Jul 2000
ReviewNeuroexcitatory effects of morphine and hydromorphone: evidence implicating the 3-glucuronide metabolites.
1. Morphine is recommended by the World Health Organization as the drug of choice for the management of moderate to severe cancer pain. 2. Education of health professionals in the past decade has resulted in a large increase in the prescribing of opioids, such as morphine, and in the magnitude of the doses administered, resulting in an improvement in the quality of pain relief available for many cancer patients. 3. ⋯ Several studies have shown that, following chronic oral or subcutaneous morphine administration to patients with cancer pain, the cerebrospinal fluid (CSF) concentrations of M3G exceed those of morphine and morphine-6-glucuronide (analgesically active morphine metabolite) by approximately two- and five-fold, respectively. 9. These findings suggest that when the M3G concentration (or H3G by analogy) in the CSF exceeds the neuroexcitatory threshold, excitatory behaviours will be evoked in patients. 10. Thus, rotation of the opioid from morphine/HMOR to a structurally dissimilar opioid, such as methadone or fentanyl, will allow clearance of M3G/H3G from the patient central nervous system over hours to days, thereby producing a time-dependent resolution of the neuroexcitatory behaviours while maintaining analgesia with methadone or fentanyl.
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Clin. Exp. Pharmacol. Physiol. · Nov 1998
ReviewCerebrovascular pressure transmission analysis as a guide to the pathophysiology of raised intracranial pressure.
1. Raised intracranial pressure (ICP) is a major factor associated with morbidity and mortality in patients with severe head injury. Identifying the mechanisms responsible for raised ICP may be difficult and, as a result, treatment prescribed may be non-specific and often ineffective. 2. ⋯ Laboratory models have identified specific CVPT patterns associated with various causes of raised ICP. These studies have been extended to clinical practice and have been used to define patterns of CVPT in head-injured patients, which may be used to identify mechanisms responsible for raised ICP, thus assisting in directing treatment strategy. Clinical usefulness of this technique in patient management is currently under investigation.
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1. Sepsis is the leading reversible cause of death in patients requiring modern intensive care services. 2. ⋯ As septic shock is the most common early manifestation of severe sepsis, an understanding of mechanisms of myocardial dysfunction is of clinical relevance. In the present review, we will discuss mechanisms of remote organ failure in sepsis, focusing in particular on the pathogenesis of myocardial dysfunction.