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Biomedical subjects

P McIntyre

Publications and source records attributed to P McIntyre.

At least 19 recordsLinked to original sources
PubMed2003

Review article: Oral, modified-release mesalazine formulations--proprietary versus generic.

Products containing mesalazine have been used in the treatment of inflammatory bowel disease for many years. Many of the oral, modified-release products are reaching the point of patent expiration, and it is expected that several new 'generic' versions will be developed. As mesalazine acts topically, the drug needs to be available at the site of inflammation to be effective. For this reason, the currently available products have been developed with individual formulations so that physicians have a choice when matching the different release profiles to the site and extent of disease. As such, the current guidelines state that oral, delayed-release mesalazine formulations are not interchangeable and should be prescribed by their proprietary (brand) name. The standard regulatory assessment process for generic or 'copy' products, using systemic bioequivalence data, does not appear to be sufficient when evaluating topically acting, oral, modified-release products. We therefore recommend that the regulatory bodies should require that new, oral mesalazine products should be assessed by a combination of dissolution, bioequivalence and (a minimum of one) adequately powered, comparative trial to determine therapeutic equivalence. Of most importance here is that the assessment of new modified-release products is sufficiently rigorous to allow patients and physicians to be confident in their use.

Administration, Oral↗
PubMed2003

Corticosteroids in acute bacterial meningitis.

BACKGROUND: Acute bacterial meningitis remains a disease with high mortality rate, ranging from 10 to 30 percent, despite advances in critical care. It has been estimated that between 5 to 40 percent of all patients can suffer hearing loss. The use of corticosteroids as adjuvant therapy in the treatment of acute bacterial meningitis is controversial despite several controlled clinical trials and three meta-analyses. In particular there are few data on the use of corticosteroids in adult meningitis. OBJECTIVES: We conducted a systematic review examining the efficacy and safety of adjuvant corticosteroid therapy in children and adults with acute bacterial meningitis. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library issue 1, 2003)); MEDLINE (1966 to April 2002); EMBASE (1974 to April 2002); and HEALTHLINE (1988 to April 2002) and Current Contents for trials published before the April 1st 2002, and reference lists of articles. We also contacted manufacturers and researchers in the field. SELECTION CRITERIA: Eligible studies were published or non-published randomised controlled trials on corticosteroids as adjuvant therapy in acute bacterial meningitis. Patients of any age and in any clinical condition, treated with antibacterial agents and randomised to corticosteroid therapy (or placebo) of any type, could be included. At least case fatality rate or hearing loss had to be recorded for inclusion. DATA COLLECTION AND ANALYSIS: Two reviewers independently assessed trial quality and extracted data. Study authors were contacted for additional information. Adverse effects information was collected from the trials. MAIN RESULTS: Eighteen studies involving 1853 people were included. Overall, adjuvant corticosteroids were associated with lower case fatality (relative risk (RR) 0.76, 95% confidence intervals (CI) 0.59 to 0.98) and lower rates of both severe hearing loss (RR 0.36, 95% CI 0.22 to 0.60) and long-term neurological sequelae (RR 0.66, 95% CI 0.44 to 0.99). In children, corticosteroids reduced severe hearing loss in bacterial meningitis caused by Haemophilus influenzae (RR 0.31, 95% CI 0.15 to 0.62), as well as in meningitis caused by other bacteria than H. influenzae (RR 0.42, 95%CI 0.20 to 0.89). In adults there was a reduction in case-fatality (RR 0.38, 95% CI 0.18 to 0.78), however there were few data. Adverse events were not increased significantly with the use of corticosteroids. REVIEWER'S CONCLUSIONS: Adjuvant corticosteroids are beneficial in the treatment of children with acute bacterial meningitis. The limited data available in adults shows a trend in favour of adjuvant corticosteroids but a definite recommendation must await more studies. ERRATUM: During the review process of this systematic review the results of the European Dexamethasone in Adulthood Bacterial Meningitis Trial were published. (De Gans 2002) In this prospective, randomised, double-blind, multicenter trial, which included 301 adults with bacterial meningitis, treatment with dexamethasone was associated with a reduction in mortality (relative risk of death, 0.48; 95 CI 0.24 to 0.96; p = 0.04). Therefore, dexamethasone should be given to all adults with bacterial meningitis and should be initiated before or with the first dose of antibiotics.

Adolescent↗
PubMed2002

Editorial.

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Journal Article↗
PubMed2002

The emergence of resistant pneumococcal meningitis--implications for empiric therapy.

BACKGROUND: Following the emergence of penicillin and cephalosporin resistant pneumococcal meningitis in the United States, inclusion of vancomycin in empiric therapy for all suspected bacterial meningitis was recommended by the American Academy of Pediatrics. Few data are available to evaluate this policy. AIMS: To examine the management and clinical course in relation to antibiotic therapy of a large unselected cohort of children with pneumococcal meningitis in a geographic area where antibiotic resistance has recently increased. METHODS: Retrospective review of all cases of pneumococcal meningitis in a defined population (Sydney, Australia), 1994-99. RESULTS: A total of 104 cases without predisposing illnesses were identified; timing of lumbar puncture (LP) was known in 103. Resistance to penicillin increased from 0 to 20% over the study period. Only 57 (55%) had an early LP (prior to parenteral antibiotics); 55 (96%) had organisms on Gram stain. Severe disease (intensive care admission or death) increased significantly from 57 cases with early LP (28%) to 33 with delayed LP (42%) to 13 with no LP (62%). Evidence of pneumococcal infection was available within 24 hours in 85% of those with delayed or no LP. Outcome was not related to empiric vancomycin use, which increased from 5% prior to 1998 to 48% in 1999. CONCLUSION: LP is frequently delayed in pneumococcal meningitis. Based on disease severity, empiric vancomycin is most justified when LP is deferred. If an early LP is done, vancomycin can be withheld if Gram positive diplococci are not seen.

Adolescent↗
PubMed2001

Pharmacological differences between the human and rat vanilloid receptor 1 (VR1).

Vanilloid receptors (VR1) were cloned from human and rat dorsal root ganglion libraries and expressed in Xenopus oocytes or Chinese Hamster Ovary (CHO) cells. Both rat and human VR1 formed ligand gated channels that were activated by capsaicin with similar EC(50) values. Capsaicin had a lower potency on both channels, when measured electrophysiologically in oocytes compared to CHO cells (oocytes: rat=1.90+/-0.20 microM; human=1.90+/-0.30 microM: CHO cells: rat=0.20+/-0.06 microM; human=0.19+/-0.08 microM). In CHO cell lines co-expressing either rat or human VR1 and the calcium sensitive, luminescent protein, aequorin, the EC(50) values for capsaicin-induced responses were similar in both cell lines (rat=0.35+/-0.06 microM, human=0.53+/-0.03 microM). The threshold for activation by acidic solutions was lower for human VR1 channels than that for rat VR1 (EC(50) pH 5.49+/-0.04 and pH 5.78+/-0.09, respectively). The threshold for heat activation was identical (42 degrees C) for rat and human VR1. PPAHV was an agonist at rat VR1 (EC(50) between 3 and 10 microM) but was virtually inactive at the human VR1 (EC(50)>10 microM). Capsazepine and ruthenium red were both more potent at blocking the capsaicin response of human VR1 than rat VR1. Capsazepine blocked the human but not the rat VR1 response to low pH. Capsazepine was also more effective at inhibiting the noxious heat response of human than of rat VR1.

Amino Acid Sequence↗
PubMed2001

Comment.

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Journal Article↗
PubMed2001

Palliative care by family physicians in the 1990s. Resilience amid reform.

OBJECTIVE: To explore issues family physicians face in providing community-based palliative care to their patients in the context of a changing health care system. DESIGN: Focus groups. SETTING: Small (< 10,000 population), medium-sized (10,000 to 50,000), and large (> 50,000) communities in Nova Scotia. PARTICIPANTS: Twenty-five men and women physicians with varying years of practice experience in both solo and group practices. METHOD: A semistructured approach was used, asking physicians to reflect on recent palliative care experiences in order to explore issues of care. MAIN FINDINGS: Five themes emerged from the discussions: resources needed, availability of family support, time and money supporting physicians' activities, symptom control for patients, and physicians' emotional reactions to caring for dying patients. CONCLUSION: With downsizing of hospitals and greater emphasis on community-based care, the issues identified in this study will need attention, particularly in designing an integrated service delivery model for palliative care.

Adult↗
PubMed2000

Single blind, randomised trial of efficacy and acceptability of oral picolax versus self administered phosphate enema in bowel preparation for flexible sigmoidoscopy screening.

OBJECTIVE: To compare the acceptability and efficacy of two methods of self administered bowel preparation for flexible sigmoidoscopy screening: a single phosphate enema and a single sachet of Picolax. DESIGN: Single blind, randomised trial. SETTING: Endoscopy units of two general hospitals. PARTICIPANTS: 1442 men and women aged 55-64 years who had agreed to be screened by flexible sigmoidoscopy. MAIN OUTCOME MESURESs: Attendance rates, compliance with allocated preparations, adverse effects, quality of bowel preparation, procedure time, and yield of neoplasia. RESULTS: Compliance with the enema was higher than with the Picolax (608 (84%) v 566 (79%); difference 6%, 95% confidence interval 2% to 10%). Almost half of those who refused Picolax used an enema at home. Wind, incontinence, and sleep disturbance were more frequent in the Picolax group than the enema group; bottom soreness was more frequent in the enema group. Around 30% (187) found the diet restriction required by Picolax difficult; 78% (471) found the enema easy to administer. The quality of preparation was better with the enema; the proportion of procedures complete to the descending colon was greater and the mean duration of the procedure was shorter. There was no significant difference in polyp detection rates. CONCLUSION: A single phosphate enema self administered around one hour before leaving home is a more acceptable and effective method of preparing the distal bowel for flexible sigmoidoscopy than Picolax.

Administration, Oral↗
PubMed2000

Regulation of bradykinin receptor gene expression in human lung fibroblasts.

In WI-38 human fibroblasts, interleukin-1 beta and tumour necrosis factor-alpha (TNF-alpha) increased bradykinin B(1) receptor mRNA, which peaked between 2 and 4 h, remaining elevated for 20 h. Binding of the bradykinin B(1) receptor selective ligand [3H]des-Arg(10)-kallidin, also increased, peaking at 4 h and remaining elevated for 20 h. The B(max) value for [3H]des-Arg(10)-kallidin rose from 280+/-102 fmol/mg (n=3) to 701+/-147 fmol/mg (n=3), but the K(D) value remained unaltered (control, 1.04+/-0.33 nM (n=3); interleukin-1 beta, 0.88+/-0.41 nM (n=3)). The interleukin-1 beta-induced [3H]des-Arg(10)-kallidin binding sites were functional receptors, as bradykinin B(1) receptor agonist-induced responses increased in treated cells. Bradykinin B(2) receptor mRNA and [3H]bradykinin binding were upregulated by interleukin-1 beta, but not TNF-alpha. The effect of interleukin-1 beta on bradykinin B(2) receptors was smaller than for bradykinin B(1) receptors. Cycloheximide prevented interleukin-1 beta-mediated increases in B(1) and B(2) binding, but not mRNA suggesting that de novo synthesis of a transcriptional activator was unnecessary.

Binding, Competitive↗
PubMed2000

Differing serologic responses to an haemophilus influenzae type b polysaccharide-neisseria meningitidis outer membrane protein conjugate (PRP-OMPC) vaccine in australian aboriginal and caucasian infants - implications for disease epidemiology.

This study compared Hib antibody responses to a single lot of PRP-OMPC vaccine given at 2, 4 and 12 months to 57 Aboriginal infants in rural areas of the Northern Territory and 56 Caucasian infants in Sydney, Australia. The Aboriginal infants had lower levels of antibody in cord blood (P>0.05), which were significantly lower (P<0.02) by 2 months of age. Antibody responses to one or two doses of vaccine, measured at 4 and 12 months of age, were similar but the geometric mean titre following the booster dose in Aboriginal infants was significantly lower (1.98 vs. 6.04 mcg/ml, P = 0.002). Low preimmunisation antibody is consistent with the early onset of Hib disease in Aboriginal infants before immunisation. Lower responses to boosting could correlate with persistence of Hib colonisation in indigenous populations.

Age Factors↗
PubMed2000

The CD44v7/8 epitope as a target to restrain proliferation of fibroblast-like synoviocytes in rheumatoid arthritis.

CD44 is a receptor for the glycosaminoglycan hyaluronan. It exists in a large range of isoforms because of variability in the pattern of glycosylation (both N- and O-linked) and of multiple splice variants. Human fibroblast-like synoviocytes derived from patients with rheumatoid arthritis express certain CD44 splice variants and we have investigated the functional implications of their expression. We found that the rate of proliferation of fibroblast-like synoviocytes expressing the CD44v7/8 epitope (average doubling time 55 hours) exceeds those obtained from the same synovial specimen but lacking this particular epitope (69 hours). Antibodies against CD44v7/8, but not against other exons, inhibit cell proliferation with concomitant induction of the cell cycle inhibitors GADD45, GADD153 and the cyclin-dependent protein-kinase inhibitors p21Waf/Cip. These data show that expression of CD44v7/8 contributes to the transformed phenotype of fibroblast-like synoviocytes. More importantly, they reveal the presence of a target that might be amenable to pharmacological intervention in the treatment of rheumatoid arthritis.

Arthritis, Rheumatoid↗
PubMed2000

Bradyzide, a potent non-peptide B(2) bradykinin receptor antagonist with long-lasting oral activity in animal models of inflammatory hyperalgesia.

Bradyzide is from a novel class of rodent-selective non-peptide B(2) bradykinin antagonists (1-(2-Nitrophenyl)thiosemicarbazides). Bradyzide has high affinity for the rodent B(2) receptor, displacing [(3)H]-bradykinin binding in NG108-15 cells and in Cos-7 cells expressing the rat receptor with K(I) values of 0.51+/-0.18 nM (n=3) and 0.89+/-0.27 nM (n=3), respectively. Bradyzide is a competitive antagonist, inhibiting B(2) receptor-induced (45)Ca efflux from NG108-15 cells with a pK(B) of 8.0+/-0.16 (n=5) and a Schild slope of 1.05. In the rat spinal cord and tail preparation, bradyzide inhibits bradykinin-induced ventral root depolarizations (IC(50) value; 1.6+/-0.05 nM (n=3)). Bradyzide is much less potent at the human than at the rodent B(2) receptor, displacing [(3)H]-bradykinin binding in human fibroblasts and in Cos-7 cells expressing the human B(2) receptor with K(I) values of 393+/-90 nM (n=3) and 772+/-144 nM (n=3), respectively. Bradyzide inhibits bradykinin-induced [(3)H]-inositol trisphosphate (IP(3)) formation with IC(50) values of 11.6+/-1.4 nM (n=3) at the rat and 2.4+/-0.3 microM (n=3) at the human receptor. Bradyzide does not interact with a range of other receptors, including human and rat B(1) bradykinin receptors. Bradyzide is orally available and blocks bradykinin-induced hypotension and plasma extravasation. Bradyzide shows long-lasting oral activity in rodent models of inflammatory hyperalgesia, reversing Freund's complete adjuvant (FCA)-induced mechanical hyperalgesia in the rat knee joint (ED(50), 0.84 micromol kg(-1); duration of action >4 h). It is equipotent with morphine and diclofenac, and 1000 times more potent than paracetamol, its maximal effect exceeding that of the non-steroidal anti-inflammatory drugs (NSAIDs). Bradyzide does not exhibit tolerance when administered over 6 days. In summary, bradyzide is a potent, orally active, antagonist of the B(2) bradykinin receptor, with selectivity for the rodent over the human receptor. British Journal of Pharmacology (2000) 129, 77 - 86

Administration, Oral↗
PubMed2000

Pertussis antibody levels in infants immunized with an acellular pertussis component vaccine, measured using whole-cell pertussis ELISA.

A commercially available whole-cell pertussis IgG ELISA was used to test the response of 137 2-month-old infants to immunization with a trivalent acellular pertussis vaccine. The pre-immunization geometric mean (GM) IgG index was 6.96 (95% confidence interval (CI) 5.88-8.04) and the postimmunization GM index was 13.16 (95% CI 12. 20-14.11), P < 0.001. Eighty percent of subjects (110/137) had a significant 1.5-fold increase of pertussis IgG index (97/137, 71%) or a postimmunization IgG index > 10 (93/137, 68%). In single antigen ELISA, 83% showed at least a fourfold increase in pertussis toxin-specific IgG (PT-IgG) and 91% showed an increase in IgG specific for filamentous haemagglutinin (FHA-IgG). Four percent had high pre- immunization antibody levels (index > 20), likely to reflect recent maternal exposure to pertussis. This correlated with a smaller increase in pertussis IgG index. A decline in pertussis IgG index postimmunization occurred in 17/24 infants (71%) whose pre-immunization IgG index was > 10. This postimmunization pertussis IgG index was not significantly different to that of infants with a low pre-immunization index. A similar trend was noted with PT-IgG and FHA-IgG results. The whole-cell ELISA can detect a response to acellular pertussis vaccination in most infants if both antibody index and degree of seroconversion are calculated and at least one criterion is satisfied.

Antibodies, Bacterial↗
PubMed2000

Abnormal spinal curvature and its relationship to pelvic organ prolapse.

OBJECTIVE: Intra-abdominal vector forces have been implicated in the development of genital prolapse. Because the normal spinal curvature appears to protect the pelvic cavity from direct upper abdominal forces, variations in spinal curvature may alter these vector forces and possibly potentiate the development of pelvic organ prolapse. This study was undertaken to evaluate the relationship of spinal curvature and pelvic organ prolapse, specifically, the loss of lumbar lordosis or pronounced thoracic kyphosis. STUDY DESIGN: A total of 363 patients referred for various complaints of urinary incontinence or pelvic organ prolapse were included in this multicenter, prospective, case-control study. All patients underwent a detailed history with site-specific examinations; pelvic organ prolapse was quantitatively assessed according to the POPQ (pelvic organ prolapse quantitation) staging system. Spinal curvature was measured with a flexi-curve malleable rod when patients were in a fully erect position. Spinal curvature was then transferred to graph paper by tracing the flexi-curve. Thoracic and lumbar curvatures were determined by measuring thoracic and lumbar lengths and widths, respectively. RESULTS: Ninety-two patients had abnormal spinal curvature according to the study criteria. Complete loss of lumbar lordosis was found in 69 patients. Of the 92 patients with an abnormal curvature, 84 currently had or previously had pelvic organ prolapse (sensitivity, 91%). When compared with patients with a normal curvature, patients with an abnormal spinal curvature were 3. 2 times more likely to have development of pelvic organ prolapse (odds ratio, 3.18; 95% confidence interval, 1.46 to 6.93; P =.002). There was no difference in the number of vaginal deliveries, weight of largest vaginally delivered infant, or body mass index. Only 11% (8/72) of patients with stage 0 prolapse had an abnormal spinal curvature, which increased to 30% (28/99) in patients with stage III prolapse (P =.042). CONCLUSION: An abnormal change in spinal curvature, specifically, a loss of lumbar lordosis, appears to be a significant risk factor in the development of pelvic organ prolapse.

Adult↗
PubMed2000

Surveillance of pneumococcal disease in Australian states and territories.

Information on pneumococcal disease, including immunisation programs, and optimum future surveillance in each Australian State and Territory were discussed at the Pneumococcal Disease in Australia Workshop on 26-27 March 1999. Workshop participants further expanded on the surveillance aspects of the Workshop in this report. Most participants favoured notification by laboratories of pneumococcal isolates from sterile sites, to provide baseline surveillance data before immunisation programs are fully implemented. It was also thought that trends in antimicrobial resistance should be notified.

Australia↗
PubMed2000

Vaccine preventable diseases and vaccination coverage in Australia, 1993-1998.

BACKGROUND: Since the introduction of childhood vaccination for diphtheria in 1932 and the widespread use of vaccines to prevent tetanus, pertussis (whooping cough) and poliomyelitis in the 1950s, deaths in Australia from vaccine preventable diseases (VPDs) have declined by more than 99%. It is important, however, that the downward trend in morbidity and mortality from VPDs is maintained and carefully monitored, and that changes are interpreted in relation to vaccination coverage. AIM: This report aimed to bring together three national sources of routinely collected data on the morbidity and mortality (notifications, hospitalisations and deaths) from VPDs during the period 1993-1998 for the 8 diseases then on the routine childhood vaccination schedule, and for 4 other diseases potentially preventable by childhood vaccination. It also examined vaccination coverage for the same period. METHODS: Data sources included notifications from the National Notifiable Diseases Surveillance System (NNDSS), hospitalisation data from the Australian Institute of Health and Welfare (AIHW) National Hospital Morbidity Database, deaths from the Australian Bureau of Statistics (ABS) Causes of Death Collection and vaccination coverage according to the Australian Childhood Immunisation Register (ACIR). All data sources were expected to have some limitations, the most important being under-reporting for notifications and vaccination encounters, and coding errors in the hospital morbidity data. RESULTS: Notifications for the 8 diseases covered by the routine schedule declined by 42%, from an average of 11,537 cases each year in 1993-1997 to 6700 in 1998, and hospitalisations fell by 12%, from an average of 1745 per year to 1536 in 1997/1998, while deaths remained unchanged at 7 each year over the period of review (Table 1). Tetanus caused 1 or 2 of the deaths each year. However, 6 of the 7 deaths in 1997 were in infants during a major outbreak of pertussis. Pertussis caused most of the notifications, hospitalisations and deaths during the review period. While most of these were in children, 46% of the notifications and 13% of the hospitalisations occurred in persons aged 15 years or more. There were notable declines in the numbers of notifications of invasive Haemophilus influenzae type b (Hib) disease in children under 5 years of age (77%), measles (87%) and rubella (75%), and there were no notifications of diphtheria or poliomyelitis. Vaccination coverage estimated using ACIR data increased during the review period. Coverage for the first 3 doses of diphtheria, tetanus, pertussis and Hib vaccines, assessed at 1 year of age, increased from 75% to 85%, while coverage for measles-mumps-rubella (MMR) vaccine, assessed at 2 years of age, increased from 83% to 86%. It is likely that these data underestimated coverage by 5-10%, and that the increase in coverage partly reflected better reporting to the ACIR by providers.

Adolescent↗