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Biomedical subjects

K J Palmer

Publications and source records attributed to K J Palmer.

At least 19 recordsLinked to original sources
PubMed2000

A polymorphic protease-activated receptor 2 (PAR2) displaying reduced sensitivity to trypsin and differential responses to PAR agonists.

Protease-activated receptor 2 (PAR2) is a trypsin-activated member of a family of G-protein-coupled PARs. We have identified a polymorphic form of human PAR2 (PAR(2)F240S) characterized by a phenylalanine to serine mutation at residue 240 within extracellular loop 2, with allelic frequencies of 0.916 (Phe(240)) and 0.084 (Ser(240)) for the wild-type and mutant alleles, respectively. Elevations in intracellular calcium were measured in permanently transfected cell lines expressing the receptors. PAR(2)F240S displayed a significant reduction in sensitivity toward trypsin ( approximately 3.7-fold) and the PAR2-activating peptides, SLIGKV-NH(2) ( approximately 2.5-fold) and SLIGRL-NH(2) ( approximately 2.8-fold), but an increased sensitivity toward the selective PAR2 agonist, trans-cinnamoyl-LIGRLO-NH(2) ( approximately 4-fold). Increased sensitivity was also observed toward the selective PAR-1 agonist, TFLLR-NH(2) ( approximately 7-fold), but not to other PAR-1 agonists tested. Furthermore, we found that TLIGRL-NH(2) and a PAR4-derived peptide, trans-cinnamoyl-YPGKF-NH(2), were selective PAR(2)F240S agonists. By introducing the F240S mutation into rat PAR2, we observed shifts in agonist potencies that mirrored the human PAR(2)F240S, suggesting that Phe(240) is involved in determining agonist specificity of PAR2. Finally, differences in receptor signaling were paralleled in a cell growth assay. We suggest that the distinct pharmacological profile induced by this polymorphism will have important implications for the design of PAR-targeted agonists/antagonists and may contribute to, or be predictive of, an inflammatory disease.

Alleles↗
PubMed2000

Interferon-alpha (IFN-alpha) stimulates anti-melanoma cytotoxic T lymphocyte (CTL) generation in mixed lymphocyte tumour cultures (MLTC).

IFN-alpha administration after primary tumour resection improves the survival of melanoma patients at high risk of relapse. To investigate whether this response might be due to stimulation of anti-tumour immunity, the effect of IFN-alpha on anti-melanoma CTL generation in MLTC was measured. IFN-alpha increased both allogeneic and autologous anti-melanoma CTL generation from peripheral blood lymphocytes stimulated with irradiated primary melanoma cultures. IFN-alpha up-regulated MHC class I expression on primary melanoma cultures, whereas IFN-gamma up-regulated both MHC class I and II expression. However, the effect of IFN-alpha on anti-melanoma CTL generation was often more potent than that of IFN-gamma, equalling the effect of the optimal combination of IL-2 and IL-12. Pre-treatment of primary melanoma cultures with IFN-gamma was sufficient for CTL generation in MLTC, whereas IFN-alpha needed to be present during the MLTC. While direct anti-proliferative effects of IFN-alpha on some tumour cells have been described, IFN-alpha did not inhibit proliferation of primary melanoma cultures. These results suggest that the clinical effects of IFN-alpha in melanoma patients may be immune-mediated.

Antigen Presentation↗
PubMed1997

Cryo-electron microscopy structure of yeast Ty retrotransposon virus-like particles.

The virus-like particles (VLPs) produced by the yeast retrotransposon Ty1 are functionally related to retroviral cores. These particles are unusual in that they have variable radif. A paired mass-radius analysis of VLPs by scanning transmission electron microscopy showed that many of these particles form an icosahedral T-number series. Three-dimensional reconstruction to 38-A resolution from cryo-electron micrographs of T = 3 and T = 4 shells revealed that the single structural protein encoded by the TYA gene assembles into spiky shells from trimeric units.

Capsid↗
PubMed1996

IL-12 stimulation but not B7 expression increases melanoma killing by patient cytotoxic T lymphocytes (CTL).

Recent studies have demonstrated that rodent tumour cells engineered to secrete a variety of cytokines, or to express foreign antigens, MHC molecules or co-stimulatory molecules, are rejected by syngeneic animals. These observations have led to the initiation of a number of clinical trials using genetically modified tumour cells, to attempt to stimulate a patient anti-tumour immune response. In this study, a protocol has been developed to test in vitro the specific cytotoxic anti-tumour response generated from melanoma patient lymphocytes. The results showed that IL-12 in combination with IL-2 enhanced the autologous anti-melanoma CTL response, whereas B7.1 antigen expression on tumour cells did not increase anti-melanoma CTL generation. This method could be used to design more appropriate genetically modified tumour vaccines.

B7-1 Antigen↗
PubMed1995

Expression and pharmacology of human GABAA receptors containing gamma 3 subunits.

A cDNA encoding the gamma 3 subunit of the human GABAA receptor has been obtained by molecular cloning. Its deduced amino acid sequence shows a high level of sequence identity with the published mouse and rat sequences (96%). The ligand binding pharmacology of the benzodiazepine site formed by stably-expressed human alpha 5 beta 3 gamma 2S and alpha 5 beta 3 gamma 3 GABAA receptor subtypes have been compared for a number of ligands, Benzodiazepine site ligands were found to be either non-selective or gamma 2-selective, with the exception of CL218,872, which was found to be 10-fold selective for the alpha 5 beta 3 gamma 3-containing subtype Two benzodiazepine site ligands. Ro15-4513 and FG8205 were more efficacious at alpha 5 beta 3 gamma 3 receptors than alpha 5 beta 3 gamma 2 receptors expressed in Xenopus oocytes, CL218,872, which is a partial agonist at alpha 1 containing receptors, had no intrinsic activity at either alpha 5 beta 3 gamma 2 or alpha 5 beta 3 gamma 3, alpha 1 beta 2 gamma 2S and alpha 1 beta 2 gamma 3 human GABAA receptors were also expressed in Xenopus oocytes and their benzodiazepine pharmacology investigated. Both the EC50 and efficacy of benzodiazepine site ligands were influenced by the type of gamma subunit coexpressed with alpha 1 and beta 2.

Amino Acid Sequence↗
PubMed1994

Life event stress and myocardial reinfarction: a prospective study.

Earlier studies of life event stress in coronary heart disease (CHD) have been flawed by cross-sectional design and inadequate methods for assessing life-event stress. This 3-year prospective study of acute myocardial infarct (AMI) patients reveals significant independent associations between acute and chronic stressors at first admission, and risk of recurrent AMI and death, occurring in the 3 years of follow-up. Relative risks of reinfarction (or death from reinfarction) in the entire sample, for acute events and chronic difficulties were, 2.5 and 2.3 respectively and were statistically significant. When subjects admitted with first AMI were considered alone, relative risks were 3.1 and 4.1 respectively. The clinical significance of these findings is discussed.

Adult↗
PubMed1993

Propafenone. A reappraisal of its pharmacology, pharmacokinetics and therapeutic use in cardiac arrhythmias.

Propafenone is an orally active sodium channel blocking agent with beta-adrenoceptor antagonist and weak calcium antagonist activity. The pharmacokinetic profile of propafenone is complex, characterised as typically nonlinear, saturable, stereoselective and dependent on both dose and debrisoquin metaboliser phenotype; individualised dosage titration is required. Both placebo- and drug-controlled studies have confirmed the efficacy of propafenone in the treatment of premature ventricular complexes, ventricular couplets and nonsustained ventricular tachycardia; in a large meta-analysis, propafenone together with amiodarone, flecainide and encainide were significantly more effective in the control of ventricular ectopy than other antiarrhythmic agents. However, the use of propafenone in these indications, like that of other antiarrhythmic agents, is likely to be limited to patients with a favourable risk-to-benefit ratio. Propafenone has also demonstrated efficacy in the treatment of malignant ventricular arrhythmias (ventricular fibrillation and sustained ventricular tachycardia); preliminary mortality data obtained with propafenone have been encouraging in this patient group. In addition, propafenone has a favourable noncardiac tolerability profile and beta-adrenoceptor antagonist activity, which may offer advantages in some specific patient groups. The area of research concerning propafenone which has shown the greatest expansion over the past 5 years is in the treatment of supraventricular arrhythmias. Propafenone has marked efficacy in patients with Wolff-Parkinson-White syndrome and has been recommended as a first-line prophylactic agent in those with rapid anterograde conduction. Propafenone is also effective in the conversion of atrial fibrillation to sinus rhythm, although comparative studies are required to determine advantages over more established agents. Propafenone use has been successfully extended to children with limited data demonstrating consistent efficacy in the control of junctional ectopic tachycardia. As with all antiarrhythmic agents, propafenone has the potential to induce arrhythmias. Comparative studies are required to assess in more detail the cardiac tolerability profile of propafenone against other class Ic agents. In conclusion, propafenone offers a broad spectrum of activity in the treatment of cardiac arrhythmias, although its use in patients with potentially malignant arrhythmias will remain limited for the present. Due to its unique pharmacodynamic profile, propafenone deserves consideration as an individual agent.

Animals↗
PubMed1993

Defibrotide. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in vascular disorders.

Defibrotide is a deoxyribonucleic acid derivative extracted from mammalian organs, which has been developed for the treatment of a number of vascular disorders. It appears to increase fibrinolysis and may possess antithrombotic, antiatherosclerotic and anti-ischaemic actions, probably due to its ability to selectively increase prostaglandin I2 and E2 levels and to increase tissue plasminogen activator and decrease plasminogen activator inhibitor function. Defibrotide is available as an intravenous and intramuscular preparation, and also as an oral formulation for long term use. Trials performed to date have provided initial evidence that defibrotide is effective in the treatment of peripheral obliterative arterial disease and acute thrombophlebitis, while preliminary data suggest possible use in preventing fibrin deposition in the circuitry of renal haemodialysis equipment. Efficacy in preventing deep vein thrombosis after surgery has been demonstrated but defibrotide does not appear to offer any therapeutic advantage over heparin. Further clinical experience is required in other disorders, including acute myocardial infarction, Raynaud's phenomenon, renal thrombotic microangiopathy and renal transplant rejection, before adequate assessment of efficacy in these areas can be made. Defibrotide is well tolerated, as assessed in trials of up to 6 months duration, with a low global incidence of adverse events (< 1 to 9%). Mild allergic reactions and gastrointestinal disturbances have occasionally been described, and a hypotensive effect has also infrequently been observed. Thus, available data suggest that defibrotide is a well tolerated agent with little or no anticoagulant activity, which is conveniently available in both parenteral and oral formulations. Initial data indicate that the drug may be a useful alternative in the treatment of peripheral obliterative arterial disease and thrombophlebitis, while its therapeutic potential in other vascular disorders and efficacy relative to established agents remains to be fully determined.

Animals↗
PubMed1993

Mefloquine. A review of its antimalarial activity, pharmacokinetic properties and therapeutic efficacy.

Mefloquine is an orally administered blood schizontocide. Initial dose-finding and comparative studies performed between 1977 and 1989 demonstrated efficacy of mefloquine as prophylaxis in nonimmune individuals and in the suppression and treatment of malaria in adults and children caused by multidrug-resistant Plasmodium falciparum. It was also effective against P. vivax infection, while data concerning the treatment of P. ovale and P. malariae infections were limited. In an attempt to delay the emergence of resistance to this promising antimalarial agent, mefloquine was combined with sulfadoxine and pyrimethamine. Although initial clinical trials indicated that this regimen was effective in preventing and treating falciparum malaria, recent treatment failures, the potential for severe dermatological reactions and lack of therapeutic advantage over mefloquine alone has prompted the World Health Organization to recommended that the combination be no longer used for treatment or prophylaxis of malaria. Mefloquine is generally well tolerated in both adults and children, with nausea, vomiting, diarrhoea, headache, dizziness, rash, pruritus and abdominal pain being the most common adverse effects, although it is difficult to distinguish between disease- and treatment-related events. The incidence of these adverse effects is similar to or lower than those observed with other antimalarial agents. Cardiovascular changes, such as bradycardia, occasionally occur. The most notable adverse effects associated with mefloquine are neuropsychiatric disturbances; precipitation of such events should be closely monitored and requires termination of prophylaxis or therapy. The eventual emergence of resistance to mefloquine, as with many other antimalarial agents, was inevitable. Mefloquine resistance is established in certain areas of Thailand and may be becoming a growing problem in other regions of the world. In order to preserve the efficacy of mefloquine in non-resistant areas, this useful agent should be used with care and only prescribed for prophylaxis in travellers and treatment in areas of multidrug-resistant plasmodia. Future options to combat mefloquine resistance may include the combination of mefloquine with other antimalarial agents such as qinghaosu derivatives. Thus, with cautious use and possible combination with other agents, mefloquine is likely to remain an important treatment option for falciparum malaria, a widespread parasitic disease for which an increasing number of drugs have proved inadequate.

Animals↗
PubMed1993

Gliclazide. An update of its pharmacological properties and therapeutic efficacy in non-insulin-dependent diabetes mellitus.

Gliclazide is a second generation sulphonylurea oral hypoglycaemic agent used in the treatment of non-insulin-dependent diabetes mellitus (NIDDM). It improves defective insulin secretion and may reverse insulin resistance observed in patients with NIDDM. These actions are reflected in a reduction in blood glucose levels which is maintained during both short and long term administration, and is comparable with that achieved by other sulphonylurea agents. Gradually accumulating evidence suggests that gliclazide may be useful in patients with diabetic retinopathy, due to its haemobiological actions, and that addition of gliclazide to insulin therapy enables insulin dosage to be reduced. Thus, gliclazide is an effective agent for the treatment of the metabolic defects associated with NIDDM and may have the added advantage of potentially slowing the progression of diabetic retinopathy. These actions, together with its good general tolerability and low incidence of hypoglycaemia have allowed gliclazide to be well placed within the array of oral hypoglycaemic agents available for the control of NIDDM.

Animals↗
PubMed1993

Zidovudine: a review of pharmacoeconomic and quality-of-life considerations for its use in patients with human immunodeficiency virus.

In patients with human immunodeficiency virus (HIV) infections or the acquired immunodeficiency syndrome (AIDS), zidovudine is a first-line therapy that reduces morbidity and may reduce mortality. By delaying progression to AIDS, the drug reduces the duration and incidence of hospitalisations in a given time period, resulting in overall decreases in the cost of medical treatment per unit of survival time. In current therapeutic dosages zidovudine is generally well tolerated. Most pharmacoeconomic and quality-of-life studies of this agent were conducted using data relating to higher dosages and higher drug acquisition costs than those currently applicable, but nevertheless generally support the cost-effectiveness of zidovudine in patients with HIV disease. Studies examining the use of the drug in higher dosages demonstrate neither clear positive nor negative effects of the drug on quality of life. The cost effectiveness of the drug as prophylaxis against seroconversion after occupational exposure to HIV is dependent primarily on the establishment of clinical effectiveness in this condition. Further pharmacoeconomic studies should examine changes to dosage and cost factors, along with direct nonmedical treatment costs, indirect medical treatment costs and the effects of the drug on quality of life. An evaluation of existing studies suggests that if these factors were accounted for, zidovudine might be shown to be more clearly cost effective, and indeed its use in the treatment of patients with HIV disease might be found to result in cost savings.

Acquired Immunodeficiency Syndrome↗
PubMed1993

Role of the beta subunit in determining the pharmacology of human gamma-aminobutyric acid type A receptors.

A cDNA encoding the human gamma-aminobutyric acid (GABA)A receptor beta 2 subunit has been cloned and sequenced. The deduced amino acid sequence of this cDNA shows only a single amino acid change from the rat sequence (Asn-347 in rat, serine in human). Using polymerase chain reaction amplification of human-specific products from human x rodent somatic cell hybrid DNAs, the gene has been assigned to human chromosome 6. By expressing recombinant human GABAA receptors containing different beta subunits (beta 1, beta 2 or beta 3) in both transfected cells and Xenopus oocytes, we have been able to determine the influence of the beta subunit on the pharmacology of the receptor. For a number of benzodiazepine binding site compounds, a barbiturate, and several neurosteroids, neither the affinity nor the efficacy of the compounds is influenced by the type of beta subunit present in the receptor molecule. These data suggest that the beta subunit does not significantly influence the benzodiazepine, barbiturate, or steriod site pharmacologies of human GABAA receptor subtypes.

Amino Acid Sequence↗
PubMed1993

Cloning of cDNA sequences encoding human alpha 2 and alpha 3 gamma-aminobutyric acidA receptor subunits and characterization of the benzodiazepine pharmacology of recombinant alpha 1-, alpha 2-, alpha 3-, and alpha 5-containing human gamma-aminobutyric acidA receptors.

cDNAs encoding human alpha 2 and alpha 3 gamma-aminobutyric acidA receptor subunits have been cloned. Their deduced amino acid sequences show much sequence identity with the published bovine sequences (98.2% and 97.0% for alpha 2 and alpha 3, respectively). Human alpha 1 beta 1 gamma 2, alpha 2 beta 1 gamma 2, alpha 3 beta 1 gamma 2, and alpha 5 beta 1 gamma 2 subunit combinations were expressed in transiently transfected cells and their pharmacologies were characterized using a series of benzodiazepine (BZ) binding site ligands. Human alpha 1-containing receptors exhibited a BZ1-type pharmacology, and alpha 2-, alpha 3-, and alpha 5-containing receptors exhibited a broadly BZ2-type pharmacology. The partial inverse agonist Ro15-4513 showed an approximately 10-15-fold higher affinity for alpha 5-containing than for alpha 1-, alpha 2-, or alpha 3-containing receptors and is thus the first compound shown to have a significantly higher affinity for another receptor subtype than for alpha 1 beta 1 gamma 2.

Amino Acid Sequence↗
PubMed1992

Transdermal Nicotine. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy as an aid to smoking cessation.

Transdermal nicotine delivery systems are a cigarette smoking cessation aid designed to deliver nicotine into the systemic circulation via the skin. The partial replacement of plasma nicotine, which would have otherwise been obtained from cigarettes, reduces the severity of nicotine withdrawal symptoms, and so allows the smoker to abstain from smoking more easily. The systems are available in 16- and 24-hour application regimens, and are recommended for daily use for up to 20 weeks, including a series of 'weaning-off' courses. Clinical trials have shown that abstinence rates of 30 to 41% can be achieved during the first 6 weeks of application of transdermal nicotine systems, compared with 4 to 21% with placebo systems. The use of concomitant behavioural therapy may increase the success of treatment, with initial abstinence rates of up to 86% reported. However, long term abstinence rates (greater than 6 months) are considerably lower with or without behavioural therapy, often falling to less than half of the initial rates. Transdermal nicotine systems have been well tolerated in clinical trials, with local irritation at the site of application being the most common adverse event. Mild gastric, central nervous system (CNS) and sleep disturbances have also been reported. The ease of use and unobtrusive nature of the systems have resulted in a high degree of patient compliance. Thus, transdermal nicotine systems offer a convenient form of nicotine replacement therapy which are well tolerated and, due to their pharmacokinetic profile, probably have a low dependency potential. The short term abstinence rates achieved with this therapy are encouraging; however, the maintenance of abstinence in the long term is harder to achieve. Transdermal nicotine replacement therapy, therefore, represents an important advance in the difficult area of smoking cessation management.

Administration, Cutaneous↗