Chlorisondamine, a quarternary nicotinic antagonist, was given in a dose that crosses the blood-brain barrier, is taken up and concentrated intracellularly by dopaminergic neurons, and induces long-term blockade of the locomotor stimulant and rewarding effects of nicotine. This treatment had no effect on the rewarding effects of lateral hypothalamic brain stimulation, failing to shift the function that relates reward strength to rate of responding (rate-frequency function). That the treatment regimen was sufficient to block nicotinic receptors in the reward system was confirmed by the fact that it completely blocked the ability of normally effective nicotine to potentiate the rewarding effects of stimulation (shift this function to the left). These data add evidence that the direct, endogenous cholinergic contribution to brain stimulation reward is muscarinic and fit with other evidence that the potentiation of brain stimulation reward by exogenous nicotine involves actions on nicotinic receptors native to dopaminergic neurons.

Animals↗

PubMed1998

Reference ranges for serum prostate-specific antigen in black and white men without cancer.

OBJECTIVES: To determine the age- and race-specific prostate-specific antigen (PSA) distributions in healthy men in central South Carolina and to compare these to data from other studies. METHODS: Two thousand ninety-two black men aged 40 to 69 years and white men aged 50 to 69 years from the general population in 11 counties of central South Carolina participated in a prostate cancer educational program. Seventy-two percent of the participants were black-about double the proportion in the general population-and 63% of the men (1319 of 2092) subsequently obtained a PSA determination from their own physician. The distribution of serum PSA was compared with distributions from the Olmsted County study and from the Walter Reed Army Medical Center/Center for Prostate Disease Research study. RESULTS: Older men without cancer had higher PSA levels. Regression analyses yielded an associated increase of about 3.3% per year. Reference ranges for normal PSA in men without cancer (based on their sample 95th percentiles) were zero to 1.9, 3.8, and 5.7 ng/mL in black men aged 40 to 49, 50 to 59, and 60 to 69 years, and zero to 2.7 and 4.9 mg/mL in white men aged 50 to 59 and 60 to 69 years, respectively. CONCLUSIONS: Reference ranges for normal serum PSA levels should take into account the population from which they are derived and to which they will be applied. Reference ranges that are useful in the general population can differ from those that are appropriate in a hospital setting. For the general population in central South Carolina, reference ranges for serum PSA levels are lower than previously published reference ranges, particularly among black men.

Adult↗

PubMed1998

Advances in the macrolides and quinolones.

The widespread, frequent clinical use of the macrolides and quinolones has led to resistance in several species. With the prevailing increase of resistance, new developmental compounds with improved spectra, pharmacokinetics, and reduced adverse effects are required, coupled with logical use of the current armamentarium.

4-Quinolones↗

PubMed1998

Chlamydia pneumoniae infection and ethnic origin.

OBJECTIVES: To test the association of Chlamydia pneumoniae infection with ethnic origin. DESIGN: A prospective study by micro-immunofluorescence of antibodies to C. pneumoniae in patients admitted to one hospital with a variety of non-pulmonary, non-cardiovascular disorders. SETTING: A large district general hospital serving a multi-ethnic inner-city population in Birmingham, UK. SUBJECTS: There were 1518 patients, 1061 of whom were Caucasian, 290 Asian and 167 Afro-Caribbean. Each of 169 Asians and 141 Afro-Caribbeans was matched with two Caucasians for age, sex, smoking habit, steroid medication and date of admission, and logistic regression methods were used to compare the effects on C. pneumoniae antibody levels of ethnic origin, these confounding variables, diabetes mellitus and social deprivation. OUTCOME MEASURES: Serological evidence of acute C. pneumoniae infection or reinfection (defined by titres of IgM > or = 8, a four-fold rise in IgG or IgG > or = 512) and previous infection (IgG 64-256 or IgA > or = 8). RESULTS: Results showed 4.8% of Caucasians, 6.6% of Asians and 10.2% of Afro-Caribbeans had antibody titres suggesting acute (re)infection; and 11.2% of Caucasians, 13.4% of Asians and 21.0% of Afro-Caribbeans had titres suggesting previous infection. On chi 2 analysis, the distributions of the three possible serological outcomes (acute, previous and no infection) differed significantly (p < 0.05) between the Afro-Caribbean and Caucasian groups, but not between Asians and Caucasians or between Afro-Caribbeans and Asians. After adjusting for possible confounding variables, odds ratios for Afro-Caribbean versus Caucasian origin were 5.5 (95% confidence intervals 2.0-15.0) for acute (re)infection and 1.9 (1.0-3.7) for previous infection. CONCLUSIONS: Our results suggest that C. pneumoniae infection may be more prevalent among Afro-Caribbean than among Caucasian people, and that Asians may lie somewhere between them in this respect. The behaviour of this pathogen in different ethnic groups deserves further investigation. Future studies of this organism should give due attention to the ethnic origins of patients.

Adolescent↗

PubMed1998

Pharmacodynamic properties of HMR 3647, a novel ketolide, on respiratory pathogens, enterococci and Bacteroides fragilis demonstrated by studies of time-kill kinetics and postantibiotic effect.

The pharmacodynamic properties of a novel ketolide (a new class of macrolide), HMR 3647, were investigated by studying time-kill kinetics and postantibiotic effect (PAE). The time-kill kinetics were studied at two inocula against three strains each of Staphylococcus aureus, Haemophilus influenzae, Moraxella catarrhalis, Streptococcus pneumoniae, Streptococcus pyogenes, Enterococcus faecalis, Enterococcus faecium and Bacteroides fragilis. The PAEs of HMR 3647 were also investigated on these organisms at concentrations equivalent to 1, 4 and 10 x MIC. The time-kill kinetic data demonstrated that HMR 3647 is predominantly bacteriostatic and only slowly bactericidal at higher concentrations. HMR 3647 exhibited a significant PAE with all strains studied, ranging from 1.2 h to 8.2 h at 10 x MIC. The bacteriostatic activity and significant PAE demonstrated by HMR 3647 are similar to those previously obtained with other macrolides.

Anti-Bacterial Agents↗

PubMed1998

Comparison of the modified Stokes' method of susceptibility testing with results obtained using MIC methods and British Society of Antimicrobial Chemotherapy breakpoints.

The majority of clinical microbiology laboratories in the UK use comparative disc diffusion methods based on the Stokes' method to determine antibiotic susceptibility. The technical validity of the results obtained from the modified Stokes' method of disc testing and how they relate to MIC data are not known. We studied susceptibility testing using a modified Stokes' disc diffusion method for a wide range of clinical isolates against which MICs had been determined by collaborators not involved with the disc testing evaluation. Results indicated that for 1301 organism-antibiotic combinations the number of major errors (where resistant strains were reported as sensitive) was 21/468 (4.4%) and the number of minor errors (where sensitive strains were reported as resistant) was 14/713 (1.9%) using ciprofloxacin breakpoints of 0.5 and 2 mg/L. There was good correlation between the disc susceptibility test and the MIC for 119 isolates of Enterobacteriaceae tested with the exception of Serratia spp. Excluding Serratia spp. the number of major errors for Enterobacteriaceae was 1/200 (0.5%). Data revealed 2/25 (8%) major errors for Pseudomonas aeruginosa and 1/45 (2.2%) for Acinetobacter spp. Haemophilus influenzae showed a number of unexpected categorization errors. The modified Stokes' method performed accurately for Staphylococcus aureus and coagulase-negative staphylococci when tested for susceptibility to gentamicin, erythromycin, teicoplanin and vancomycin. No major errors were reported for Streptococcus pneumoniae and beta-haemolytic streptococci. Problems occurred with the detection of antibiotic resistance in Enterococcus spp. Major errors were seen for ampicillin (2/12 strains), teicoplanin (5/6 strains) and vancomycin (5/13 strains) using a 30 microg disc but only 1/13 strains using a 5 microg disc. Overall, from our data, the modified Stokes' disc diffusion antibiotic susceptibility test showed an unacceptable number of major errors but an acceptable number of minor errors.

Anti-Bacterial Agents↗

PubMed1998

The in-vitro activity of HMR 3647, a new ketolide antimicrobial agent.

The in-vitro activity of HMR 3647, a novel ketolide, was investigated in comparison with those of erythromycin A, roxithromycin, clarithromycin (14-membered ring macrolides), amoxycillin-clavulanate and ciprofloxacin against 719 recent clinical Gram-positive, Gram-negative and anaerobic isolates and type cultures. HMR 3647 generally demonstrated greater activity than the other compounds with MIC90s of < or =0.5 mg/L, except for Staphylococcus epidermidis (MIC90 > 128 mg/L), Haemophilus influenzae (MIC90 = 2 mg/L), Enterococcus faecalis (MIC90 = 2 mg/L), Enterococcus faecium (MIC90 = 1 mg/L) and the anaerobes, Bacteroides fragilis (MIC90 = 2 mg/L) and Clostridium difficile (MIC90 = 1 mg/L). In general, an increase in the size of the inoculum from 10(4) to 10(6) cfu on selected strains had little effect on the MICs of HMR 3647. Additionally, the in-vitro activity of HMR 3647 was not affected by the presence of either 20 or 70% (v/v) human serum. The antichlamydial activity of HMR 3647 was generally greater than that of commonly used antichlamydial antimicrobials.

Anti-Bacterial Agents↗

PubMed1998

The in-vitro activity of linezolid (U-100766) and tentative breakpoints.

The in-vitro activity of linezolid, a novel oxazolidinone, was investigated in comparison with those of amoxycillin, cefuroxime, quinupristin/dalfopristin, trovafloxacin and vancomycin against 420 recent Gram-positive and anaerobic clinical isolates. Linezolid was equally active (MIC90 1 mg/L) against methicillin-susceptible and -resistant Staphylococcus aureus. It demonstrated uniform activity against streptococci and enterococci and no cross-resistance with other agents. The time-kill kinetic data demonstrated that the in-vitro activity of linezolid was predominantly bacteriostatic; slow bactericidal activity was only observed at the higher concentration with streptococci. An increase in inoculum from 10(4) to 10(6) cfu on selected strains had little effect on the MICs (MIC90 within one dilution step) of linezolid and an increase in inoculum from 10(5) to 10(7) cfu/mL had no notable effect on the in-vitro bactericidal activity. A tentative linezolid breakpoint of 2 mg/L was chosen after analysis of distribution of susceptibilities.

Acetamides↗

PubMed1998

Pharmacokinetics and inflammatory fluid penetration of clinafloxacin.

A single 200-mg dose of clinafloxacin was given orally to each of nine healthy male volunteers, and the concentrations of the drug were measured in plasma, cantharidin-induced inflammatory fluid, and urine over the following 24 h (48 h in the case of urine). The mean maximum concentration in plasma was 1.34 microg/ml at a mean time of 1.8 h postdose. The mean maximum concentration in the inflammatory fluid was 1.3 microg/ml at 3.8 h postdose. The mean elimination half-life of clinafloxacin in plasma was 5.65 h. The overall penetration into the inflammatory fluid was 93.1%, as assessed by determining the ratio of area under the concentration-time curves. Recovery of clinafloxacin in urine was 58.8% by 24 h and 71.8% by 48 h postdose.

Adult↗

PubMed1998

Prevalence of a putative efflux mechanism among fluoroquinolone-resistant clinical isolates of Streptococcus pneumoniae.

Twenty-three norfloxacin-selected first-step mutants of Streptococcus pneumoniae showed low-level fluoroquinolone resistance. Their susceptibility to norfloxacin in the presence or absence of reserpine and known efflux pump substrates was determined by an agar dilution method. Five mutants showed four- to eightfold increases in their susceptibility to norfloxacin in the presence of reserpine and four- to eightfold decreases in their susceptibility to acriflavine and ethidium bromide. This phenotype is suggestive of an efflux mechanism of resistance. A representative of these mutants, 1N27, accumulated significantly less ethidium bromide than the parent strain; reserpine abolished these differences. No changes in the quinolone resistance-determining regions of parC, parE, gyrA, or gyrB were found in this mutant. By our validated agar dilution method, the efflux phenotype was sought in clinical isolates of S. pneumoniae. Of 1,037 clinical isolates examined from the United Kingdom, 273 showed reduced susceptibility to norfloxacin or ciprofloxacin. Of these, 45.4% showed the efflux phenotype. Our findings suggest that an efflux mechanism may be a frequent cause of clinically significant fluoroquinolone resistance in pneumococci.

Anti-Infective Agents↗

PubMed1998

Chlamydia pneumoniae and asthma.

BACKGROUND: This study was designed to test the association of Chlamydia pneumoniae infection with asthma in a multi-racial population, after adjustments for several potential confounding variables. METHODS: Antibodies to C pneumoniae were measured by microimmunofluorescence in 123 patients with acute asthma, 1518 control subjects admitted to the same hospital with various non-cardiovascular, non-pulmonary disorders, and 46 patients with severe chronic asthma, including some with "brittle" asthma. Acute infection or reinfection was defined by titres of IgG of > or = 512 or IgM > or = 8 or a fourfold rise in IgG, and previous infection by IgG 64-256 or IgA > or = 8. Logistic regression was used to control for likely confounders, including ethnic origin, age, sex, smoking habit, steroid medication, diabetes mellitus and social deprivation, on antibody levels. RESULTS: Antibody titres consistent with acute C pneumoniae infection were found in 5.7% of patients with acute asthma and 5.7% of control patients, while 14.6% of patients with acute asthma and 12.7% of control patients had titres suggesting previous infection. These two groups did not differ significantly. However, titres suggesting previous infection were found in 34.8% of patients with severe chronic asthma: the difference between this group and the control group was statistically significant with an adjusted odds ratio of 3.99 (95% confidence interval 1.60 to 9.97). CONCLUSIONS: These data raise important questions about the previously demonstrated association of C pneumoniae infection with asthma, and suggest that future studies of this association should give particular attention to the presence or absence of a history of severe chronic asthma.

Acute Disease↗

PubMed1998

Chlamydia pneumoniae antibodies in severe essential hypertension.

Several studies have implied an association between Chlamydia pneumoniae (C. pneumoniae) and cardiovascular disease. Our study was designed to determine whether this organism is associated with severe essential hypertension in a multiracial British population. Antibodies to C. pneumoniae were measured by microimmunofluorescence in 123 patients with chronic severe hypertension and 123 control subjects, matched for ethnic origin, age, sex, and smoking habit, admitted to the same hospital with various noncardiovascular, nonpulmonary disorders. Previous infection was defined by IgG 64 to 256, provided that there was no detectable IgM. Multiple regression analyses of matched and unmatched data were used to investigate the influences of antibody levels and potential confounding factors (ethnic origin, age, sex, smoking habit, diabetes mellitus, and social deprivation) on hypertension. A portion of the hypertensive patients underwent echocardiography, estimation of left ventricular mass index, and measurements of fibrinogen, D-dimer, and von Willebrand factor concentrations. Thirty-five percent of hypertensive patients and 17.9% of matched control subjects had antibody titers consistent with previous C. pneumoniae infection. The hypertensive patients differed significantly from their matched control subjects in their level of previous infection, with an odds ratio of 2.5 (95% confidence interval, 1.3 to 4.7). There were no significant differences in antibody levels between patients with left ventricular hypertrophy and those without it. Fibrinogen, D-dimer, and von Willebrand factor concentrations were not significantly associated with antibody levels. These data support an association of C. pneumoniae with severe essential hypertension. They provide no evidence of a predisposition to develop left ventricular hypertrophy in hypertensive patients with C. pneumoniae infection or of associations with hypercoagulability or endothelial dysfunction.

Antibodies, Bacterial↗

PubMed1998

Chlamydia pneumoniae antibody titers are significantly associated with acute stroke and transient cerebral ischemia: the West Birmingham Stroke Project.

BACKGROUND AND PURPOSE: Several studies have implied an association between Chlamydia pneumoniae and atherosclerosis. Our research was designed to investigate the association of this organism with strokes and transient cerebral ischemia. METHODS: Antibodies to C pneumoniae were measured in 176 patients with stroke or transient cerebral ischemia and 1518 control subjects with noncardiovascular, nonpulmonary disorders. Acute infection or reinfection was defined by IgG > or =512 or IgM > or =8 or fourfold rise in IgG, and previous infection was defined by IgG 64 to 256 or IgA > or =8. Logistic regression was used to examine the influences of ethnic origin, age, sex, smoking habit, diabetes mellitus, steroid medication, and social deprivation on antibody levels. Some patients underwent CT and carotid ultrasound examinations and cholesterol, triglyceride, fibrinogen, and von Willebrand factor estimations. RESULTS: We found that 13.6% of stroke/transient ischemic attack (TIA) patients and 5.7% of control subjects had antibody titers suggesting acute C pneumoniae (re)infection, while 32.4% of stroke/TIA patients and 12.7% of control subjects had titers suggesting previous infection (P<.05). Stroke/TIA patients differed from control subjects in their levels of acute and previous infection, with adjusted odds ratios of 4.2 (95% CI, 2.5 to 7.1) and 4.4 (95% CI, 3.0 to 6.5), respectively. These did not differ notably between strokes resulting from major nonhemorrhagic infarcts, small-vessel infarcts, or hemorrhage. Cholesterol, triglyceride, fibrinogen, and von Willebrand factor concentrations showed no apparent association with titers. CONCLUSIONS: These data support the association of cerebral vascular disease with previous C pneumoniae infection and the association of stroke and transient cerebral ischemia with recrudescence of infection.

Adolescent↗

PubMed1998

A comparison of the activity of ciprofloxacin and levofloxacin with other agents against respiratory tract pathogens.

In a study involving 15 UK hospitals, sequential respiratory tract isolates of Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis were studied. The susceptibility of these strains to two fluoroquinolones, ciprofloxacin and levofloxacin were compared to those of currently used macrolides and beta-lactams. The activity of ciprofloxacin and levofloxacin against S. pneumoniae was not statistically significantly different (geometric mean MIC 0.978 and 0.95 mg/L respectively). Beta-lactam resistance did not affect fluoroquinolone susceptibility. H. influenzae and M. catarrhalis were highly susceptible to both fluoroquinolones.

Anti-Infective Agents↗