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Biomedical subjects

M Hibberd

Publications and source records attributed to M Hibberd.

15 recordsLinked to original sources
PubMed2002

A European multicentre study to evaluate the tolerability of apomorphine sublingual administered in a forced dose-escalation regimen in patients with erectile dysfunction.

OBJECTIVE: To determine the risk-benefit ratio of a forced dose-escalation regimen (2 to 3 to 4 mg) in a European clinical study evaluating apomorphine sublingual (SL) in treating erectile dysfunction (ED), by evaluating the overall tolerability and efficacy of the regimen compared with placebo in patients with ED, and evaluating efficacy by assessing the proportion of successful attempts resulting in sexual intercourse. PATIENTS AND METHODS: This randomized, double-blind, two-arm, parallel-group study was conducted in 507 patients enrolled at 34 European sites. After a 1-2 week screening period, patients were treated for 8 weeks with either placebo or apomorphine SL administered as a forced dose-escalation regimen. Heterosexual men (aged 18-70 years) were eligible for participation in the study if they were in stable health, a stable relationship of > or = 6 months duration, had a history of erectile inability, and were diagnosed with ED (successful in fewer than half of attempts to attain and maintain an erection firm enough for intercourse during the 30 days before screening). Patients provided information (recorded on diary cards and reviewed at each study visit) about the frequency and success in achieving erections and of sexual intercourse attempts during both the screening and treatment periods. The dosing regimen required patients to take one tablet of apomorphine SL (2 mg for 2 weeks, then 3 mg for 2 weeks and finally 4 mg for the remaining 4 weeks) or placebo 15-25 min before intercourse, and intercourse was to be attempted at least twice a week. Safety data were collected throughout the 8-week study period, and included recording adverse events, vital signs and changes in laboratory test values for standard haematology and biochemistry variables. The primary efficacy variable was the proportion of successful attempts, defined as an erection rigid enough for sexual intercourse, occurring after dosing (successful intercourse rate). The proportion of erections achieved was a secondary efficacy variable. RESULTS: Of the 507 patients, 254 received apomorphine SL and 253 received placebo; 87% of patients in both groups completed the 8-week treatment period. Of the patients receiving apomorphine SL, 24% had hypertension, 11% had coronary artery disease, 10% had diabetes, and 5.5% had benign prostatic hypertrophy; 62.6% of treated patients received concomitant medications for these maladies. The treatment groups were balanced for demographic and baseline variables, including comorbidity factors. Treatment-emergent adverse events, reported by > 5% of patients in the treated group, were nausea (9.8%), dizziness (7.1%) and headache (6.7%), compared with 0.4%, 2.4% and 4.0%, respectively, in the placebo group. Sixty-six patients withdrew from the study, 16 because of study drug-related adverse events (12 from the apomorphine and four from the placebo group). Six patients (three in each group) reported a total of nine serious treatment-emergent adverse events, all of which resolved by the end of the study. In the intention-to-treat population, the proportion of successful attempts at sexual intercourse and of erections were statistically greater in the apomorphine than in the placebo group (P = 0.001 and 0.021, respectively); analysis of the per-protocol population results confirmed this significant difference. CONCLUSION: This European study supports the safety and tolerability of apomorphine SL despite the forced escalation to a 4-mg dose (exceeding the approved 2-3 mg dose). Adverse effects were not treatment-limiting. These results further support the clinically significant efficacy of apomorphine SL for treating ED at all doses used. The risk/benefit ratio supports apomorphine SL as a safe and effective alternative in managing ED.

Administration, Sublingual↗
PubMed1999

Cellular immune responses to Neisseria meningitidis in children.

There is an urgent need for effective vaccines against serogroup B Neisseria meningitidis. Current experimental vaccines based on the outer membrane proteins (OMPs) of this organism provide a measure of protection in older children but have been ineffective in infants. We postulated that the inability of OMP vaccines to protect infants might be due to age-dependent defects in cellular immunity. We measured proliferation and in vitro production of gamma interferon (IFN-gamma), tumor necrosis factor alpha, and interleukin-10 (IL-10) in response to meningococcal antigens by peripheral blood mononuclear cells (PBMCs) from children convalescing from meningococcal disease and from controls. After meningococcal infection, the balance of cytokine production by PBMCs from the youngest children was skewed towards a TH1 response (low IL-10/IFN-gamma ratio), while older children produced more TH2 cytokine (higher IL-10/IFN-gamma ratio). There was a trend to higher proliferative responses by PBMCs from older children. These responses were not influenced by the presence or subtype of class 1 (PorA) OMP or by the presence of class 2/3 (PorB) or class 4 OMP. Even young infants might be expected to develop adequate cellular immune responses to serogroup B N. meningitidis vaccines if a vaccine preparation can be formulated to mimic the immune stimulus of invasive disease, which may include stimulation of TH2 cytokine production.

Adult↗
PubMed1994

Analysis of the peripheral T-cell receptor V beta repertoire in newly diagnosed patients with type I diabetes.

Type I diabetes is an autoimmune disease characterised by a marked activation of peripheral T cells around the time of clinical diagnosis. Studies of T-cell antigen receptor V beta (TCRBV) gene usage in type I diabetes have been conflicting. Using a semi-quantitative polymerase chain reaction technique and flow cytometry we have investigated the TCRBV gene usage of 13 newly diagnosed patients with type I diabetes and 11 normal healthy controls. No preferential TCRBV gene usage was found between patients and controls even after matching for HLA-DR3 and/or -DR4. In addition, no significant differences in TCRBV gene usage were found between sequential samples taken over a period of up to 7 months following diagnosis. These results suggest that the TCR repertoire of these patients is heterogeneous and it is unlikely that a single 'pathogenic' T-cell clone is dominant at the clinical onset of the disease.

Adult↗
PubMed1993

Potential impact of pulmonary artery catheter placement on short-term management decisions in the medical intensive care unit.

The purpose of this study was to examine the potential impact of pulmonary artery (PA) catheter placement on short-term management decisions in the medical intensive care unit (ICU). One hundred three patients were examined over an 18-month period. The predominant indications for PA-catheter placement included refractory congestive heart failure, airspace disease, uncertain cardiac filling pressures, or hypotension. In 58 (56%) of the 103 patients, management recommendations changed as a direct result of knowledge gained by PA catheter placement. These changes involved fluid therapy recommendations in 41 patients, vasopressor use in 17 patients, intravenous vasodilator use in 24 patients, and recommendations for the use of inotropic agents in 15 patients. Although 18 patients experienced early or late complications, major events were limited to a single pneumothorax requiring chest tube insertion and four episodes of bacteremia. No deaths were directly attributable to the catheter insertion. In critically ill patients in the medical intensive care unit, PA-catheter placement leads to changes in recommendations for management in a substantial portion of patients with little risk of life-threatening complications in those who receive such invasive monitoring.

Adolescent↗
PubMed1990

Plasmid-encoded production of coli surface-associated antigen 1 (CS1) in a strain of Escherichia coli serotype O139.H28.

Production of coli surface-associated antigen 1 (CS1) by Escherichia coli strain E24377 of serotype O139.H28 was controlled by a plasmid that also encoded heat stable and heat labile enterotoxins and CS3. The presence of a regulatory sequence was detected on this plasmid by hybridization with the cfaD gene that regulates expression of colonization factor antigen I fimbriae and is at least 96% homologous with the rns sequence controlling production of CS1 or CS2 fimbriae by strains of serotype O6.H16 of appropriate biotype. A separate plasmid, pDEP20, carrying the structural genes for CS1 synthesis was identified and transformed into E. coli strain HB101 or a derivative of strain E24377 without large plasmids. Transformants carrying pDEP20 did not produce CS1 fimbrial antigen, but antigen expression was obtained when a cloned cfaD gene or a wild-type plasmid carrying the rns sequence was introduced. Transposon mutagenesis with Tn1000 identified a 3.7 kbp region of pDEP20 essential for production of CS1 fimbriae. Genes encoding production of CS1 fimbriae were cloned on a 9.9 kbp BamHI fragment and were expressed in the presence of the cfaD sequence. A strain producing both CS1 and CS2 antigens was constructed by introduction of the cloned cfaD gene into a strain of serotype O6.H16 biotype C carrying plasmid pDEP20.

Antigens, Bacterial↗
PubMed1990

Characterization of a new putative colonization factor (CS17) from a human enterotoxigenic Escherichia coli of serotype O114:H21 which produces only heat-labile enterotoxin.

Enterotoxigenic Escherichia coli (ETEC) of serotype O114:H21, which produced only heat-labile enterotoxin (LT), gave mannose-resistant hemagglutination (MRHA) with bovine erythrocytes. One strain, E20738A, was shown to possess fimbriae of approximately 7.5 nm diameter. On SDS-PAGE two possible fimbrial polypeptides of molecular masses 17.5 and 15.5 kDa were seen; the 17.5-kDa band was the most prominent. Loss of LT and MRHA together from strain E20738A was associated with loss of a 100-MDa plasmid. An absorbed anti-strain E20738A serum reacted specifically with the 17.5- and 15.5-kDa polypeptides and bound to the intact fimbriae. This antiserum reacted positively in an ELISA with LT-positive E. coli strains of serogroups O8, O15, O48, O114, and O146. The antiserum did not react with ETEC carrying known colonization factors. The term coli-surface-associated antigen (CS) 17 has been used to describe the fimbriae.

Antigens, Bacterial↗
PubMed1990

Clinical efficacy and safety of a new leuprorelin acetate depot formulation in patients with advanced prostatic cancer.

A depot preparation of leuprorelin acetate was assessed in 52 patients with advanced prostatic cancer. Patients received 3.75 mg, or occasionally 7.5 mg, leuprorelin acetate depot subcutaneously every 28 +/- 3 days for up to 2 years. Following treatment, there was one complete remission and 29 partial remissions; in other patients the disease was stable and in five it was progressive, with an estimated median time to progression of 500 days. Significant improvement in performance status, micturition problems and general well-being were reported. Suppression of serum testosterone and luteinizing hormone concentrations was maximal after 28 days and castration levels were maintained for up to 96 weeks. Tumour flare occurred in 15 (29%) patients during the first week of therapy but only one event was serious; sweating and flushing also occurred occasionally during the study. Of all administrations, 97% were free from any adverse local effect, the remaining events being mild in severity. It is concluded that once-monthly administration of leuprorelin acetate depot is effective in the management of advanced prostatic cancer and has an acceptable side-effect profile.

Acid Phosphatase↗
PubMed1989

Characterization of a putative colonization factor (PCFO166) of enterotoxigenic Escherichia coli of serogroup O166.

Enterotoxigenic Escherichia coli (ETEC) of serogroup O166 gave mannose-resistant haemagglutination (MRHA) with bovine and human erythrocytes. The strains did not react with antisera prepared against the known colonization factors CFA/I, CFA/II, CFA/III, CFA/IV and PCFO159:H4. Strain E7476 of serotype O166:H27, which produced heat-stable enterotoxin (ST), was examined initially. It produced fimbriae about 7 nm in diameter. On SDS-PAGE two possible fimbrial polypeptides of molecular mass 15.5 and 17.0 kDa were seen. When variants of strain E7476 were isolated, loss of ST and MRHA together was associated with loss of a 98 MDa plasmid, while loss of ST alone correlated with plasmid deletion. An absorbed anti-strain E7476 antiserum reacted specifically with the 15.5 and 17.0 kDa polypeptides in Western immunoblotting and bound to the intact fimbriae by immuno-electron microscopy. When this antiserum was used in an ELISA to examine other strains of serogroup O166, a positive reaction was obtained with all the ST- and MRHA-positive strains. One strain of serotype O71:H27 and two strains of serotype O98:H- also reacted with the absorbed anti-strain E7476 antiserum. The antiserum did not react with ETEC carrying known colonization factors. E. coli K12 and a number of E. coli of different serotypes carrying a plasmid coding for ST transferred from strain E7476, all gave MRHA and reacted with the absorbed anti-strain E7476 antiserum. The term putative colonization factor O166 (PCFO166) is proposed to describe the adhesive factor(s) on ETEC of serogroup O166 because of the similarity of properties with those of known colonization factors.

Antibodies, Bacterial↗
PubMed1989

Soft tissue trauma: a randomised controlled trial of the topical application of felbinac, a new NSAID.

Two hundred and thirty-one patients with acute soft tissue injuries were treated in a double-blind placebo-controlled study of felbinac (biphenylacetic acid) gel applied three times daily to the injured site. Those treated with felbinac had significantly greater improvement at Day 4 (p less than 0.001) and Day 7 (p less than 0.02) than those who received placebo. Patients' self-assessment diary cards confirmed superiority of the active treatment as early as Day 2 of the study. Local skin reactions were few (three per cent), mild and recovered spontaneously. Felbinac is an effective management for acute soft tissue injuries and because of its topical application may be safer than oral non-steroidal anti-inflammatory drugs for the treatment of these conditions.

Administration, Topical↗
PubMed1988

Pharmacokinetics of nilvadipine after single oral doses in healthy volunteers.

Forty healthy male Caucasian volunteers were randomly assigned to five treatment groups to receive a placebo or a 4, 8, 12, 16 or 20 mg dose of nilvadipine. The drug was well tolerated by the subjects at all dose levels. Pharmacokinetic parameters for nilvadipine were determined using model-independent methods. There were no significant differences (p greater than 0.05) in the time to the maximum plasma concentration (Cmax) (tmax), the elimination half-life or the mean residence time among the five treatment groups. Up to doses of about 12 mg, there was a linear relationship between dose and Cmax or area under the plasma concentration-time curve (AUCO----infinity). At doses of 16 and 20 mg, the relationship between dose and Cmax or AUCO----infinity was no longer linear, suggesting that the pharmacokinetics of the drug after single oral doses greater than about 12 mg may be dose-dependent, probably due to concentration-dependent first-pass hepatic elimination of the drug.

Administration, Oral↗
PubMedDate not supplied

Mitoxantrone combined with vincristine, cyclophosphamide and fluorouracil for advanced breast cancer. A study of short-term response rate.

50 patients with advanced breast cancer were treated with the combination of Mitoxantrone 10mg/m2 IV day 2, 5-Fluorouracil 400mg/m2 IV and Cyclophosphamide 300mg/m2 IV day 3, 4, 5, 6 of each monthly cycle. 49 patients are evaluable for toxicity and 47 for efficacy after three months of treatment. Hematologic toxicity was substantial and dose-limiting, with one toxic death early in the trial. Other toxicities were moderate and manageable in this short-term study. The response rate after three cycles was 53% +/- 14% with 4 complete remissions, 21 partial remissions, 16 stable disease and 6 progressions. Using the fixed response rate hypothesis of Gehan generalised by Lee and Wesley, with an expected response rate of 60% consistent with the reported response rate of advanced breast cancer to Adriamycin containing regimens, we conclude that the combination studied is not less efficient for the induction of remissions in advanced breast cancer than comparable combinations with Adriamycin. As there is now substantial experimental and clinical evidence of reduced toxicity, mainly on the cardiac muscle, of Mitoxantrone as compared to Adriamycin, we feel that the routine substitution of the latter by the former in chemotherapy for advanced breast cancer is justifiable.

Adult↗