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Biomedical subjects

M J Parnham

Publications and source records attributed to M J Parnham.

At least 19 recordsLinked to original sources
PubMed2006

Accelerated healing of excisional skin wounds by PL 14736 in alloxan-hyperglycemic rats.

PL 14736 is a synthetic peptide, originally isolated from human gastric juice, that has anti-inflammatory and tissue-protective actions in experimental models of gastrointestinal inflammation. To investigate its possible benefit in poorly healing skin wounds, the effects of the topical application of PL 14736 in a gel formulation have been studied on full-thickness excisional wounds in rats, either healthy or made hyperglycemic by alloxan (175 mg/kg s.c.) 5 days previously. The effects of becaplermin gel (platelet-derived growth factor, PDGF-BB, Regranex, a standard therapy for diabetic foot ulcers, were investigated for comparison. Healing was evaluated for up to 7 days after wounding, using digital planimetry analysis, macroscopic scoring and histology. While healing was too rapid in healthy rats to observe enhancement by either treatment, in the hyperglycemic rats which exhibited delayed healing, PL 14736 (10-1,000 microg/wound) produced a dose-dependent acceleration of wound healing (determined by macroscopic scoring) equivalent at the highest doses to that observed with becaplermin. The beneficial effect on healing was associated with increased deposition of organized granulation tissue by day 7 for both PL 14736 and becaplermin, as determined histologically. PL 14736 tended to have a greater effect than becaplermin on the formation of granulation tissue containing mature collagen. Wound contraction, as measured by planimetry, was not significantly affected. In conclusion, topical PL 14736 produces a dose-dependent acceleration of deficient skin wound healing in hyperglycemic rats by facilitating granulation tissue formation, similar to the response seen with topical becaplermin, the standard therapy for diabetic skin wounds. PL 14736 may represent an alternative therapy for delayed wound healing, such as that seen with diabetic foot ulcers, without the proliferative concerns or immunogenicity associated with growth factors.

Alloxan↗
PubMed2005

The novel antifungal agent PLD-118 is neither metabolized by liver microsomes nor inhibits cytochrome P450 in vitro.

PLD-118 is a novel, oral antifungal drug, under development for the treatment of Candida infections. Possible metabolism of PLD-118 by rat, dog and human S9 liver homogenates and inhibition of human cytochrome P450 (CYP) enzymes were investigated. PLD-118 (10 and 100 microM) incubated for 0-60 min with S9 fractions and NADPH was determined by HPLC, using the Waters AccQ.Tag method after derivatization of amino acids to stable, fluorescent derivatives. CYP assays were performed using pooled human liver microsomes with substrates, selective towards human CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP3A, incubated at concentrations around the Km. Incubation mixtures were preincubated with PLD-118 (0.1-100 microM) or control inhibitor for 5 min. No metabolism of PLD-118 was detected with rat and dog S9 fractions. A small (8%) decrease in PLD-118 at 100 microM (not detected at 10 microM) with human microsomes was considered to be biologically irrelevant. PLD-118 did not inhibit any of the tested CYPs. PLD-118, at concentrations up to 100 microM, is not metabolized by rat, dog or human liver S9 homogenates and does not inhibit human CYPs in vitro, suggesting little likelihood for interaction of PLD-118 with drugs metabolized by these enzymes.

Administration, Oral↗
PubMed2001

Anti-inflammatory effects of macrolide antibiotics.

Macrolides are widely used as antibacterial drugs. Clinical and experimental data, however, indicate that they also modulate inflammatory responses, both contributing to the treatment of infective diseases and opening new opportunities for the therapy of other inflammatory conditions. Considerable evidence, mainly from in vitro studies, suggests that leukocytes and neutrophils in particular, are important targets for modulatory effects of macrolides on host defense responses. This underlies the use of the 14-membered macrolide erythromycin for the therapy of diffuse panbronchiolitis. A variety of other inflammatory mediators and processes are also modulated by macrolides, suggesting that the therapeutic indications for these drugs may be extended significantly in future.

Animals↗
PubMed2000

Oxaceprol is a well-tolerated therapy for osteoarthritis with efficacy equivalent to diclofenac.

The therapeutic equivalence and safety of treatment for 21 days with 400 mg t.i.d. oxaceprol (n = 132) and 50 mg t.i.d. diclofenac (n = 131) were assessed in a multicentre, randomised, double-blind study of a mixed population of patients with osteoarthritis of the knee and/or hip. In a per-protocol analysis of efficacy, the mean Lequesne index decreased by 2.5 points in the oxaceprol group (n = 109) and by 2.8 points in the diclofenac group (n = 109). The 95% confidence interval for the end-point difference revealed therapeutic equivalence. This was confirmed by assessments (visual analogue scale) of pain at rest, weight-bearing pain, pain on standing and pain on movement, all of which decreased to a similar extent under both treatments. The pain-free walking time increased in both groups from 10 min to 25 min by the end of the treatment period. Mobility was also increased to a similar extent by both drugs. The physicians assessed treatment as good or very good in 45-46% of patients in both groups. In all patients who received treatment, 28 and 37 adverse events were reported by 25 out of 132 (18.9%) and 33 out of 131 (25.2%) patients treated with oxaceprol and diclofenac, respectively. In 15 patients (11.4%) with 15 adverse events in the oxaceprol group and 25 patients (19.1%) with 27 adverse events in the diclofenac group, a relation to the medication was considered probable. The difference between the groups was statistically significant (p = 0.04106) for the number of these adverse events. Oxaceprol is therapeutically equivalent to diclofenac, but better tolerated than diclofenac in the treatment of osteoarthritis.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1999

Antirheumatic agents and leukocyte recruitment. New light on the mechanism of action of oxaceprol.

Most anti-inflammatory agents used in the treatment of joint diseases exert inhibitory effects on leukocyte infiltration. Methotrexate, a disease-modifying drug, and corticosteroids also inhibit leukocyte accumulation during inflammation. However, the mechanisms of action of these different compounds on leukocytes vary and in the case of non-steroidal anti-inflammatory drugs (NSAIDs) the mechanism(s) may be indirect. No current drug for inflammatory or degenerative joint disease has been proposed to act specifically by an inhibitory action on neutrophilic leukocytes. Oxaceprol is an amino acid derivative that has been used for several years for the treatment of osteoarthritis and rheumatoid arthritis, ameliorating pain and stiffness and showing good gastrointestinal safety, particularly in comparison with NSAIDs. Recent experimental studies have shown that oxaceprol does not inhibit the synthesis of prostaglandins in vitro, but markedly inhibits neutrophil infiltration into the joints of rats with adjuvant arthritis. These results support earlier screening data showing inhibition by oxaceprol of leukocyte infiltration into sites of acute inflammation. In studies on surgical ischemia reperfusion in hamsters in vivo, oxaceprol was an effective inhibitor of leukocyte adhesion and extravasation. It is proposed that oxaceprol represents a therapeutic agent for degenerative and inflammatory joint diseases, which acts predominantly by inhibiting leukocyte adhesion and migration.

Anti-Inflammatory Agents↗
PubMed1998

Inflammation: from molecular biology to clinic.

The 3rd World Congress on Inflammation reflected an emphasis on cytokines and cell signaling, but also provided an overview of some of the current hot topics in inflammation research. The chemokines are an exponential growth area for researchers in several fields, and chemokine antagonists are under study for potential use in inflammatory disease. The use of soluble receptors, antibodies and gene deletion has already validated a number of new approaches, notably those targeted at TNF-alpha, IL-8 and, as revealed at this meeting, IL-6, NFkappaB and AP-1. The pharmacological regulation of apoptosis for disease therapy is also becoming a possibility. It is probable that within the next 12 months a number of small-molecule synthetic compounds will be reported as likely candidates for future antiinflammatory agents. The marketing of specific COX-2 inhibitors is likely to provide a significant step forward in therapeutic tolerability. Gene therapy for inflammation still lies several years in the future, but initial clinical studies are under way.

Journal Article↗
PubMed1997

COX-2 inhibitors at the 8th International Conference of the Inflammation Research Association.

An intensive search is underway for novel selective inhibitors of cyclo-oxygenase (COX)-2. These compounds promise to be potent anti-inflammatory agents with little gastrointestinal intolerance. Meloxicam, with some selectivity for COX-2, is already marketed, and at least two companies are carrying out clinical studies with selective inhibitors. A variety of potential successor compounds were presented at the 8th International Conference of the Inflammation Research Association (IRA) in Hershey, PA on 27-31 October 1996.

Journal Article↗
PubMed1996

Oxaceprol, an atypical inhibitor of inflammation and joint damage.

Oxaceprol, an established therapeutic agent for osteoarthritis, had no effect on macrophage prostaglandin E2 release in vitro and inhibited carrageenan paw oedema at high doses (18-150 mg/kg p.o.). In the same dose range, oxaceprol was comparable to indomethacin (3 mg/kg p.o.) as an inhibitor of yeast hyperalgaesia and at 6-50 mg/kg/day p.o. had a mild, variable inhibitory effect on cotton pellet granuloma formation. In adjuvant arthritic rats, oxaceprol (6-54 mg/kg/day p.o.) given therapeutically had no effect on the primary paw oedema response, but inhibited secondary lesions in the ears and tail. Histologically, oxaceprol markedly inhibited inflammatory cell infiltration and bone damage in the adjuvant-injected paw. In contrast to indomethacin, oxaceprol was more effective at inhibiting periarticular soft tissue inflammation but did not affect cartilage breakdown in this model. Oxaceprol has a clearly different spectrum of action to NSAIDs such as indomethacin and may act by inhibiting leucocyte infiltration and late connective tissue changes during inflammatory joint disease.

Animals↗
PubMed1996

Aceclofenac in rheumatoid arthritis: a useful and novel anti-inflammatory.

The efficacy and safety of 100 mg aceclofenac twice daily was investigated in 73 patients with active rheumatoid arthritis in a multi-centre, double blind, randomised, parallel group, placebo controlled study over a period of 4 weeks. Treatment with aceclofenac was effective in improving the Ritchie articular index (predetermined primary end point), duration of morning stiffness, joint swelling, ARA functional class, patient's and physician's global assessments, and pain. All these improved to a significantly (P < 0.05) greater extent than in placebo-treated patients. Grip strength showed a significant improvement from baseline in the aceclofenac-treated group and this was greater than the improvement measured in placebo treated patients. No significant difference was detected between the treatment groups for the number of subjects reporting an adverse event. Aceclofenac administered orally at 100 mg twice daily for four weeks thus produced significant improvements in patients with active rheumatoid arthritis. This treatment was well tolerated with an adverse event profile similar to that of placebo.

Administration, Oral↗
PubMed1996

Clinical pharmacokinetics of molsidomine.

Molsidomine is a prodrug for the formation of nitric oxide (NO). Its pharmacokinetics are characterised by rapid absorption and hydrolysis, taking a short time to achieve maximal systemic concentrations of both the parent compound and its active metabolite, SIN-1. The time to peak plasma drug concentration (tmax) is 1 to 2 hours. The bioavailability of the parent compound after oral administration in tablet form is 44 to 59%, but further metabolism to release NO and form polar metabolites is rapid; the half-life (t-1/2) of SIN-1 is 1 to 2 hours. Urinary excretion accounts for more than 90% of the part of the administered dose of molsidomine which is not excreted unchanged. Protein binding of the parent compound is very low (3 to 11%) and its volume of distribution (Vd) corresponds to the range of bodyweight. Single-dose studies (1, 2 and 4 mg) have revealed linear pharmacokinetics, and multiple dose studies in healthy individuals (2 mg 3 times daily for 7 days) and coronary artery disease (CAD) patients (4 mg 4 times daily for 4 weeks) do not show any accumulation of the drug. A study in young and elderly individuals indicated that the first-pass effect is decreased and t-1/2 prolonged with age, resulting in an increased area under the concentration-time curve (AUC) of molsidomine and SIN-1. In patients with liver disease and congestive heart failure similar changes were observed, but much less so in patients with CAD. Clearance was also impaired in patients with liver disease, but the pharmacokinetics of molsidomine were not markedly altered by impaired renal function. In general, due to a large therapeutic dose range, dosage adjustments are not required on the basis of clinical experience. In certain patients a lower starting dose may be recommended, such as in those with impaired liver or kidney function, in congestive heart failure or in the presence of concomitant treatment with other vasoactive compounds. A linear dose-effect relationship is observed with counterclockwise hysteresis, i.e. a greater effect associated with the decrease of plasma concentrations than during their increase, which may be at least partly due to the metabolic delay in the formation of NO from SIN-1. Accordingly, the duration of action of molsidomine is longer than would be expected on the basis of the elimination half-life. The pharmacokinetics of molsidomine support the recommended dosages for use in angina pectoris.

Absorption↗
PubMed1996

Stimulation of cytokine production via a special standardized mistletoe preparation in an in vitro human skin bioassay.

The mistletoe preparation Lektinol is standardized with respect to bioactive mistletoe lectin, the active component of mistletoe. This standardized mistletoe preparation and its active components (mistletoe lectins) were compared in the skin2 bioassay in vitro for their capacity to stimulate interleukin 1 alpha and interleukin 6 release from skin analogue tissue, composed of human cells in their naturally secreted matrix. The standardized mistletoe preparation, its basic ingredient, aqueous mistletoe extract, and pure mistletoe lectins all stimulated IL-1 alpha and IL-6 release from skin2 tissues during 24 h incubation. The amounts of cytokines released from various skin2 tissue lots by mistletoe lectin I (ML I) (0.75-8.0 ng/ml) and by the standardized mistletoe preparation remained relatively constant across a series of different batches. Concentration-response curves to the standardized mistletoe preparation and ML I were similar for IL-1 alpha and IL-6 release. The importance of the concentration of mistletoe lectins for the cytokine-releasing action of the standardized mistletoe preparation was confirmed using a neutralizing anti-mistletoe lectin antiserum. CONCLUSIONS. Using the skin2 method it was shown that reproducible stimulation of cytokine release by a standardized mistletoe preparation from batch to batch is one of the notable features of its pharmaceutical quality. This standardized mistletoe preparation therefore represents a preparation with constant immunobiological effects. Mistletoe lectins of the standardized mistletoe preparation are the active substances in the skin2 bioassay. The skin2 method is a reliable quantitative bioassay for determination of immunopharmacological effects.

Biological Assay↗
PubMed1995

A multi-centre, double-blind comparative study of the efficacy and safety of aceclofenac and diclofenac in the treatment of rheumatoid arthritis.

A long term multi-centre, double-blind, parallel group study was undertaken to investigate the efficacy and safety of aceclofenac (170 patients, 100 mg b.i.d. and placebo once daily) in comparison to diclofenac (173 patients, 50 mg t.i.d.) given for 6 months to patients of both sexes with active rheumatoid arthritis. Efficacy was evaluated in 131 aceclofenac and 130 diclofenac patients at 15 days, 1, 2, 4 and 6 months. Although both treatment groups showed significant improvement in all evaluations of pain and inflammation (assessed by a Visual Analogue Scale and the Ritchie Index) and a progressive reduction in morning stiffness, there were no significant differences between the groups. There was, however, a trend towards greater improvement in hand grip strength with aceclofenac (22% improvement) than diclofenac (17% improvement). Adverse events in both groups were minor, predominantly gastro-intestinal, and fewer patients tended to experience gastro-intestinal events on aceclofenac (13%) than on diclofenac (17%). The overall assessment of tolerance, however, did not differ significantly between groups. In summary, this study supports a therapeutic role for aceclofenac in the treatment of rheumatoid arthritis, and suggests it is an effective and safe NSAID for the treatment of this disease.

Adult↗