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Biomedical subjects

M Connolly

Publications and source records attributed to M Connolly.

At least 19 recordsLinked to original sources
PubMed2000

Pharmacokinetics of levamisole in cancer patients treated with 5-fluorouracil.

PURPOSE: To investigate the pharmacokinetics of levamisole and a metabolite, p-hydroxylevamisole in patients with colorectal cancer treated with 5-fluorouracil (5-FU). METHODS: Following an intravenous bolus dose of 5-FU, 20 patients with colorectal cancer received oral doses of 50 mg levamisole every 8 h for 3 days. Immediately after the last dose, blood and urine samples were collected over at least an 8-h period. Samples were assayed for levamisole and p-hydroxylevamisole by GC/MS. The levamisole plasma and urine data were subjected to pharmacokinetic analysis using NONMEM software. RESULTS: Substantial interpatient variability was observed in the levamisole plasma concentration-time curves. Patients with cardiovascular or gastrointestinal complications demonstrated altered absorption of levamisole. Pharmacokinetic parameter values for levamisole were similar to those obtained previously in healthy subjects and other cancer patients. CONCLUSIONS: There is no evidence that the pharmacokinetics of levamisole are altered by 5-FU administered immediately prior to levamisole administration. The relationship between the substantial intersubject variability in levamisole plasma concentration-time curves and clinical outcome following 5-FU/levamisole adjuvant chemotherapy should be examined.

Adjuvants, Immunologic↗
PubMed2000

Pediatric peri-insular hemispherotomy.

A number of surgical procedures are available for patients with epilepsy associated with diffuse hemispheric disorders. In this report, 16 pediatric patients had hemispherectomy: 5 underwent hemidecortication and 11 had peri-insular hemispherotomy. The clinical records were retrospectively reviewed, and the results and complications of the procedures were documented. The procedure was feasible in very young children and in the absence of ventriculomegaly.

Adolescent↗
PubMed1999

Comment

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Journal Article↗
PubMed1999

Analogues of 1-(3,10-dibromo-8-chloro-6,11-dihydro-5H-benzo-[5,6]-cyclohepta [1,2-b]pyridin-11-yl)piperidine as inhibitors of farnesyl protein transferase.

The synthesis of several 4-pyridylacetyl N-oxide derivatives of 4-(3-bromo-6,11-dihydro-5H-benzo[5,6]-cyclohepta[1,2-b]-pyridin-11-yl)pi perazine/piperidine 3 is described. This study was aimed at identifying fomesyl protein transferase (FPT) inhibitors in these two series of tricycles containing different phenyl ring substituents. The in vitro activity profile of the initial group of compounds 7a-7g led to the synthesis of the 8-methyl-10-methoxy and 8-methyl-10-bromo analogues 7i, 13i, and 13j. The 11R(-) enantiomers of these compounds were found to exhibit potent in vitro FPT inhibition activity.

Alkyl and Aryl Transferases↗
PubMed1999

Is group C meningococcal disease increasing in Europe? A report of surveillance of meningococcal infection in Europe 1993-6. European Meningitis Surveillance Group.

A surveillance system to assess the impact and changing epidemiology of invasive meningococcal disease in Europe was set up in 1987. Since about 1991, contributors from national reference laboratories, national communicable disease surveillance centres and institutes of public health in 35 European countries provided information on all reported cases of meningococcal disease in their country. We describe some trends observed over the period 1993-6. The main findings were: the overall incidence of meningococcal disease was 1.1 per 100000 population but there was some evidence of a slow increase over time and with northern European countries tending to have a higher incidence (Kendall correlation 0.5772, P < 0.001), an increasing predominance of serogroup C, and a shift in the age distribution towards teenagers and away from younger children (chi2 test for trend 44.56, P < 0.0001), although about half of the cases were under 5 years of age. The overall case fatality rate was 8.3% and the most common serosubtypes were B:15:P1.7,16 and C:2a:P1.2,5.

Adolescent↗
PubMed1999

Teaching a research-based approach to the management of breathlessness in patients with lung cancer.

Breathlessness is a common but complex symptom experienced by patients with lung cancer. Corner and colleagues have developed a therapeutic nursing intervention for the management of breathlessness. The Macmillan Practice Development Unit (MPDU) have recently undertaken a multi-centre evaluation of the intervention. The authors were involved in this multi-centre study as clinical practitioners offering the intervention in a randomised control trial. There is strong evidence to suggest that much research fails to influence clinical practice. A commitment to practice development led us to explore the reasons for this research-practice gap. This paper considers the factors that facilitate implementation of research and, in particular, how this applies to the breathlessness intervention. Practitioners need to feel competent in the skills described in the intervention to implement the research findings into their practice. Therefore, we developed a course to teach the breathlessness intervention. A description of the course is presented, together with the theoretical basis for the course design and the tools used to evaluate it.

Clinical Competence↗
PubMed1998

(+)-4-[2-[4-(8-Chloro-3,10-dibromo-6,11-dihydro-5H-benzo[5, 6]cyclohepta[1,2-b]- pyridin-11(R)-yl)-1-piperidinyl]-2-oxo-ethyl]-1-piperidinecarboxamid e (SCH-66336): a very potent farnesyl protein transferase inhibitor as a novel antitumor agent.

We have previously shown that appropriate modification of the benzocycloheptapyridine tricyclic ring system can provide potent farnesyl protein transferase (FPT) inhibitors with good cellular activity. Our laboratories have also established that incorporation of either pyridinylacetyl N-oxide or 4-N-carboxamidopiperidinylacetyl moieties results in pharmacokinetically stable inhibitors that are orally efficacious in nude mice. We now demonstrate that further elaboration of the tricyclic ring system by introducing a bromine atom at the 7- or the 10-position of the 3-bromo-8-chlorotricyclic ring system provides compounds that have superior potency and selectivity in FPT inhibition. These compounds have good serum levels and half-lives when given orally to rodents and primates. In vitro and in vivo evaluation of a panel of these inhibitors has led to identification of 15 (SCH 66336) as a highly potent (IC50 = 1.9 nM) antitumor agent that is currently undergoing human clinical trials.

Alkyl and Aryl Transferases↗
PubMed1998

Inhibitors of farnesyl protein transferase. Synthesis and biological activity of amide and cyanoguanidine derivatives containing a 5,11-dihydro[1]benzthiepin, benzoxepin, and benzazepin [4,3-b]pyridine ring system.

Bioisosteric replacement of the C-6 carbon atom in piperidine I and piperazine II with S, O, and N heteroatoms is described. Amide and cyanoguanidine derivatives of these compounds were evaluated in vitro and found to be good inhibitors of farnesyl-protein transferase. An improved method of preparing the 5,11-dihydro-[1]-benzthiepin nucleus 6 was accomplished in high yield and with excellent regioselectivity using an AlCl3 melt protocol.

Alkyl and Aryl Transferases↗
PubMed1998

Novel H3 receptor antagonists. Sulfonamide homologs of histamine.

Sulfonamides derived from 4(5)-(omega-aminoalkyl)-1H-imidazoles containing chain lengths of three- to five-carbons were synthesized. Good to moderate H3 receptor binding affinities were observed for several butyl and pentyl homologs, whereas binding affinities were considerably weaker in the propyl series. Separation of the imidazole ring and the sulfonamide unit by a four- or five-carbon tether afforded potent H3 receptor antagonists.

Animals↗
PubMed1998

Cardiac operations in patients with cirrhosis.

BACKGROUND: A retrospective review was performed to determine the outcome after cardiac operations in patients with a documented history of noncardiac cirrhosis. METHODS: The charts of patients admitted to the cardiothoracic surgical service between 1990 and 1996 were reviewed, and 13 patients with a preoperative history of cirrhosis were identified. The severity of preoperative liver disease was graded according to the criteria of Child. RESULTS: Most of the cases of cirrhosis were alcohol-related. Eight patients were classified as having Child class A and 5 as having Child class B cirrhosis. One hundred percent of patients with Child class B and 25% of those with Child class A cirrhosis had major complications. The postoperative chest tube output and transfusion requirements of these patients were approximately three times higher than average. The overall perioperative mortality rate was 31%. In patients with Child class B cirrhosis, the mortality rate was 80%. No patient with Child class A cirrhosis died. Deaths were related to gastrointestinal and septic complications, and not to cardiovascular failure. CONCLUSIONS: These findings suggest that patients with minimal clinical evidence of cirrhosis can tolerate cardiopulmonary bypass and cardiac surgical procedures, whereas those with more advanced liver disease should not be offered operation.

Aged↗
PubMed1998

Synthesis of isomeric 3-piperidinyl and 3-pyrrolidinyl benzo[5,6]cyclohepta[1,2-b]pyridines: sulfonamido derivatives as inhibitors of Ras prenylation.

Blocking farnesylation of oncogenic Ras proteins is a mechanism based therapeutic approach that is of current interest for the development of antitumor agents to treat ras associated tumors. As part of a SAR study on the lead farnesyl protein transferase (FPT) inhibitor I, we report here the synthesis of novel geometric isomers II and III and the FPT inhibition activity of their N-acyl and N-sulfonamido derivatives 15-65. The N-acyl derivatives are markedly less active than the lead inhibitor I thereby demonstrating that the spatial location of the N-acyl group in I is critical for binding of the compound to FPT. In contrast to I, the N-sulfonamido-II series is a novel lead of non-sulfhydryl, nonpeptidic compounds that are dual FPT/GGPT inhibitors. In light of recent reports on the alternative prenylation of N- and K-Ras, dual FPT/GGPT inhibitors may be required to control cell proliferation in tumors containing activated Ras.

Alkyl and Aryl Transferases↗
PubMed1998

Tuberculosis control in refugee populations: a challenge to both relief agencies and national programs.

Today's worldwide tuberculosis epidemic and the movement of a growing number of refugees overlap geographically and have made tuberculosis control in refugee populations an issue of increasing importance. However, in developing countries, where both of these problems are concentrated, tuberculosis control in refugee populations remains a largely unmet need. Experience shows that despite difficult field conditions, tuberculosis control programs can be managed successfully in this setting. The range of outcome results reported for treatment completion and defaulting is, however, wide. Analyzing possible determinants for observed variation in treatment outcome results, this paper outlines prerequisites for establishing a tuberculosis control program in a refugee setting. An attempt is made to formulate a general strategy for the main policies which, if applied consistently, will reduce morbidity, mortality and transmission of tuberculosis among refugee populations living in camps. Criteria for the evaluation and monitoring of such a program are discussed.

Communicable Disease Control↗
PubMed1997

[Control of tuberculosis in refugees and displaced].

As a result of national and international conflicts, the number of refugees and displaced persons in various countries of the world is increasing. The complex and protracted nature of these conflicts often forces refugees to remain away from their countries for long periods, living in refugee camps. Many refugees come from countries where tuberculosis is endemic and, once the immediate problems of establishing a camp are overcome, this disease becomes the principal problem affecting refugee camps. In order to advise the persons in charge of refugee camps on how to set up tuberculosis control programs, this document details the general requirements and specific recommendations of WHO for the implementation of such programs, as well as guidelines for their evaluation and monitoring, including criteria that would justify camp closure.

Humans↗
PubMed1996

The N terminus of bradykinin when bound to the human bradykinin B2 receptor is adjacent to extracellular Cys20 and Cys277 in the receptor.

Chemical cross-linking combined with site-directed mutagenesis was used to evaluate the role of extracellular cysteines and their positions relative to the binding site for the agonist bradykinin (BK) in the human BK B2 receptor. All extracellular cysteines, Cys20, Cys103, Cys184, and Cys277, in the receptor were mutated to serines, and single and double mutants were transfected into COS-7 cells. The Ser20 and Ser277 single mutants and the Ser20/Ser277 double mutant bound [3H]BK and the antagonist [3H]NPC17731 with pharmacological profiles identical to the wild-type B2 receptor. In contrast, the Ser103 and Ser184 single mutants were unable to bind either of the two radioligands. However, these mutants were still expressed as determined by immunoblotting with anti-B2 receptor antibodies. Previous studies on the bovine B2 receptor showed that bifunctional reagents, which are reactive to amines at one end and to free sulfhydryls in the opposite end, cross-link the N terminus of receptor-bound BK to a sulfhydryl in the receptor (Herzig, M. C. S., and Leeb-Lundberg, L. M. F. (1995) J. Biol. Chem. 270, 20591-20598). Here, we show that m-maleimidobenzoyl-N-hydroxysuccinimide ester and 1,5-difluoro-2, 4-dinitrobenzene cross-linked BK to the wild-type human B2 receptor and the Ser20 and Ser277 single mutant receptors, whereas these reagents were unable to cross-link BK to the Ser20/Ser277 double mutant. These results show that Cys103 and Cys184 are both required for expression of high affinity agonist and antagonist binding sites in the human B2 receptor, while Cys20 and Cys277 are not required. Furthermore, the results provide direct biochemical evidence that the N terminus of BK, when bound to the B2 receptor, is adjacent to Cys277 in extracellular domain 4 and Cys20 in extracellular domain 1 of the receptor.

Animals↗
PubMed1996

Synthesis and characterization of pseudopeptide bradykinin B2 receptor antagonists containing the 1,3,8-triazaspiro[4.5]decan-4-one ring system.

A series of pseudopeptides containing alkyl-, cycloalkyl-, aryl-, and aralkyl-substituted 1,3,8-triazaspiro[4.5]decan-4-one-3-acetic acids as amino acid surrogates to replace the Pro2-Pro3-Gly4-Phe5 section of the peptide bradykinin B2 receptor antagonist [Pro3, Phe5]HOE 140 (D-Arg0-Arg1-Pro2-Pro3-Gly4-Phe5-Ser6-D-Tic7+ ++-Oic8-Arg9) were prepared. These psuedopeptides were examined in vitro for their B2 receptor affinities as well as for their ability to block bradykinin mediated actions in vivo. Two compounds in particular, NPC 18521 (I) and NPC 18688 (V) were quite potent in these latter assays, indicating that a significant portion of this prototypical second generation decapeptide antagonist can be replaced with a more compact nonpeptide molecule.

Amino Acid Sequence↗
PubMed1996

Tuberculosis in Siberia: 1. An epidemiological and microbiological assessment.

SETTING: Siberia, Russian Federation. OBJECTIVE: To assess the situation regarding tuberculosis as a paradigm for the Russian Federation. DESIGN: Data was obtained from official sources and through visits to dispensaries and hospitals in 1994. RESULTS: The downward trend in notifications of tuberculosis throughout Russia reversed in 1990/91, the rate increasing from 34/100,000 to 42.9/100,000 in 1993. Incidence rates are higher in Siberia, varying from approximately 43 to 108/100,000; prevalence is 250-300/100,000. The tuberculosis service is centralized and based on specialized polyclinics and dispensaries. An extensive surveillance system employs regular fluorography and tuberculin testing: half of the cases diagnosed are detected by fluorography, against 1% through contact tracing. Patients are classified principally on clinical and radiological grounds. Bacille Calmette-Guérin immunisation is performed at birth and at age 7, and again at 13, 21, and 28 years if Mantoux test is negative. Microscopy and culture services are organisationally separate, and direct comparison of smear and culture data is not possible. Drug resistance to isoniazid and streptomycin is probably high and resistance to rifampicin low, but data on susceptibility of isolates from new cases are not available. CONCLUSION: Tuberculosis is increasing in Siberia. Homelessness, unemployment and alcoholism are important factors, but concurrent human immunodeficiency virus (HIV) infection appears to be uncommon. Prisons probably form a significant reservoir of infectious cases.

Adult↗