Community-acquired pneumonia (CAP) hospitalizations and deaths: is there a role for quality improvement through inter-hospital comparisons?

OBJECTIVE: To assess between-hospital variations in standardized in-hospital mortality ratios of community-acquired pneumonia (CAP), and identify possible leads for quality improvement. DESIGN: We used an administrative database to estimate standardized in-hospital mortality ratios for 111 Belgian hospitals, by carrying out a set of hierarchical logistic regression models, intended to disentangle therapeutic attitudes and biases. To facilitate the detection of false-negative/positive results, we added an inconclusive zone to the funnel plots, derived from the results of the study. Data quality was validated by comparison with (i) alternative data from the largest Belgian Sickness Fund, (ii) published German hospital data and (iii) the results of an on-site audit. SETTING: All Belgian hospital discharge records from 2004 to 2007. STUDY PARTICIPANTS: A total of 111 776 adult patients were admitted for CAP. MAIN OUTCOME MEASURE: Risk-adjusted standardized in-hospital mortality ratios. RESULTS: Out of the 111 hospitals, we identified five and six outlying hospitals, with standardized mortality ratios of CAP consistently on the extremes of the distribution, as providing possibly better or worse care, respectively, and 18 other hospitals as having possible quality weaknesses/strengths. At the individuals' level of the analysis, adjusted odds ratios showed the paramount importance of old age, comorbidity and mechanical ventilation. The data compared well with the different validation sources. CONCLUSIONS: Despite the limitations inherent to administrative data, it seemed possible to establish inter-hospital differences in standardized in-hospital mortality ratios of CAP and to identify leads for quality improvement. Monitoring is needed to assess progress in quality.

Determinants of between-country differences in ambulatory antibiotic use and antibiotic resistance in Europe: a longitudinal observational study.

OBJECTIVES: To identify key determinants explaining country-year variations in antibiotic use and resistance. METHODS: Ambulatory antibiotic use data [in defined daily doses per 1000 inhabitants per day (DIDs)] for 19 European countries from 1999 to 2007 were collected, along with 181 variables describing countries in terms of their agriculture, culture, demography, disease burden, education, healthcare organization and socioeconomics. After assessing data availability, overlap and relevance, multiple imputation generalized estimating equations were applied with a stepwise selection procedure to select significant determinants of global antibiotic use (expressed in DIDs), relative use of subgroups (amoxicillin and co-amoxiclav) and resistance of Escherichia coli and Streptococcus pneumoniae. RESULTS: Relative humidity, healthcare expenditure proportional to gross domestic product, feelings of distrust, proportion of population aged >65 years and availability of treatment guidelines were associated with higher total antibiotic use expressed in DIDs. Restrictions on marketing activities towards prescribers, population density, number of antibiotics, educational attainment and degree of atheism were associated with a lower number of total DIDs used. Relative prescribing of amoxicillin and co-amoxiclav was mainly determined by healthcare system choices [e.g. general practitioner (GP) registration and restricted marketing]. Specific antibiotic use was found to be a significant determinant of resistance for some but not all drug/organism combinations. Incentives to stimulate GP gatekeeping were associated with lower levels of resistance, and life expectancy at age 65+ and atheism were associated with more resistance. CONCLUSIONS: Myriad factors influence antibiotic use and resistance at the country level and an important part of these can be modified by policy choices.

The CCK-B agonist, BC264, increases dopamine in the nucleus accumbens and facilitates motivation and attention after intraperitoneal injection in rats.

Although it is known that panic attacks are triggered by the cholecystokinin fragment CCK4, the specific involvement of peripheral or central cholecystokinin CCK receptors in various adaptive processes such as emotion, memory and anxiety has yet to be demonstrated. With this aim, we have investigated the biochemical and pharmacological effects resulting from the administration of BC264, a highly potent and selective CCK-B agonist able to cross the blood-brain barrier. Very low doses of BC264 (microg/kg i.p.), increased the exploration of animals submitted to an unknown territory but were devoid of anxiogenic properties in the elevated plus maze. BC264 increased locomotion and rearings of rats newly placed in an open field and improved their spontaneous alternation in a Y-maze. The use of vagotomized animals showed that the increased alternation induced by BC264 did not require an intact vagus nerve, unlike the locomotor activation. These behavioural effects, prevented by the prior i.p. administration of the CCK-B antagonist L-365,260 but not by the CCK-A antagonist L-364,718, were shown to depend on dopaminergic systems, since they were blocked by D1 (SCH23390, 25 microg/kg i.p.) or D2 (sulpiride, 50 or 100 mg/kg i.p.) antagonists. In addition, bilateral perfusion in freely moving rats of BC264 at pharmacologically active doses, using a newly designed microdialysis system, was found to increase the extracellular levels of DA, DOPAC and HVA in the anterior part of the nucleus accumbens. These results show that activation of CCK-B receptors by BC264 does not produce anxiogenic-like effects but appears to improve motivation and attention, whereas other CCK-B agonists such as BocCCK4 induce anxiogenic responses. Several explanations, including the existence of different sub-sites of the CCK-B receptor, could account for these differential effects.

Structure-based design of new constrained cyclic agonists of the cholecystokinin CCK-B receptor.

New constrained cyclic pseudopeptide cholecystokinin-B (CCK-B) agonists have been designed on the basis of conformational characteristics of the potent and selective CCK-B agonist Boc-Trp-(NMe)Nle-Asp-Phe-NH2 (Ki = 0.8 nM, selectivity ratio CCK-A/CCK-B > 6000) (Goudreau et al. Biopolymers, 1994, 34, 155-169). These compounds are among the first successful examples of macrocyclic constrained CCK4 analogs endowed with agonist properties and as such may be of value for the development of nonpeptide CCK-B agonists. The affinities and selectivities of these compounds for CCK-B and CCK-A receptors have been determined in vitro by measuring the displacement of [3H]pCCK8 binding to guinea pig cortex and pancreas membranes, respectively. The most potent compound, 8b, N-(cycloamido)-alpha-Me(R)Trp-[(2S)-2-amino-9- ((cycloamido)carbonyl)nonanoyl]-Asp-Phe-NH2, has a Ki value of 15 +/- 1 nM for guinea pig cortex membranes with a good CCK-B selectivity ratio (CCK-A/CCK-B = 147). Furthermore, 8b behaved as a potent and full agonist in a functional assay which measures the stimulation of inositol phosphate accumulation in CHO cells transfected with the rat CCK-B receptor (EC50 = 7 nM). The in vivo affinity of 8b for mouse brain CCK-B receptors was determined following intracerebroventricular injection (ID50 approximately 29 nmol/kg). 8b was also shown to cross the blood-brain barrier (0.16%), after intravenous administration in mice. 8b also increased gastric acid secretion measured in anesthetized rats after intravenous injection. Therefore, 8b appears to be an interesting pharmacological tool and is currently under investigation as a lead for further development of nonpeptide CCK-B agonists.

Role of N- and C-terminal substituents on the CCK-B agonist-antagonist pharmacological profile of Boc-Trp-Phg-Asp-Nal-NH2 derivatives.

Among the CCK derivatives, the tetrapeptide Boc-Trp-Phg-Asp-Nal-NH2 (1) behaves as a short potent CCK-B agonist which led to the development of an efficient peptidase-resistant CCK-B antagonist by bismethylation of its terminal CONH2 group. Further modifications of the N- and C-terminal moieties of 1 have been performed and are described in this paper, together with the pharmacological profile of the novel synthetized compounds. Introduction of more bulky substituents than NalNH2 on the C-terminal part decreased the CCK-B receptor binding affinity. In the series of N-protected tetrapeptides X30-Phg31-Asp32-Nal33-N(CH3)2, the Boc-substituent was shown to be optimal among the N-protecting groups Boc, 2Adoc, propionyl or acetyl when X = Trp. On the other hand, when X = alpha MeTrp, its optimal N-protecting group was 2Adoc and its configuration was preferentially D. In the newly synthesized compounds, 13: 2Adoc-D-alpha MeTrp-Phg-Asp-NalN(CH3)2 and 16: 2Adoc-D-alpha MeTrp-Phg-Asp-NalNH2 had the best CCK-B receptor affinities (KI = 3.5 and 3.4 nM, respectively) and were selected for further biological evaluation. Interestingly, when tested for their capacity to influence inositol phosphate formation, induced by CCK8 in CHO cells transfected with the rat CCK-B receptor, compound 13 behaved as a full CCK-B antagonist with an IC50 value of 18 +/- 1 nM, being as potent as the antagonist L-365,260 and PD-134,308 (IC50 values respectively, 39 +/- 17 and 30 +/- 2 nM), whereas compound 16 was found to behave as a partial CCK-B agonist. Indeed 16 behaved as an antagonist on the firing rate of rat CA1 hippocampal neurons and acted as an agonist in the pentagastrin stimulated gastric acid secretion (EC50 = 12 nmol/kg) in anesthetized rats. Compound 13 in contrast, was found to inhibit the pentagastrin action at a dose (ID50 = 0.56 mumol/kg) similar to the potent antagonist PD-134,308 (ID50 = 0.4 mumol/kg). The antagonist/agonist properties of compounds 13 and 16 show that both N- and C-terminal substituents modulate the pharmacological properties in the Boc-CCK4 derivatives presented here.

Weak tolerance to the antinociceptive effect induced by the association of a peptidase inhibitor and a CCKB receptor antagonist.

We have recently shown that CCKB receptor antagonists such as PD-134,308, 4-([2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[tricyclo[3.3.1.1]dec - 2-yloxy)carbonyl]amino]propyl]amino]-1-phenylethyl]amino)-4-oxo[R- (R*,R*)]-butanoate-N-methyl-D-glucamine, are able to strongly potentiate antinociception induced by endogenous enkephalins, protected from degrading enzymes by the mixed inhibitor RB 101, N-[(R,S)-2-benzyl-3[(S)-(2-amino-4- methylthio)butyldithio]-1-oxopropyl)-L-phenylalanine benzyl ester, at both spinal and supraspinal levels. In this study, the duration of this facilitatory response and the possible development of tolerance to this synergistic effect were investigated in the rat tail-flick test after acute and chronic treatment with PD-134,308 and RB 101. PD-134,308 facilitated and prolonged the antinociceptive responses induced by RB 101 (20 mg/kg, i.v.). The duration of the effect induced by PD-134,308 was also investigated by injecting this compound at different times before RB 101 administration. In the case of the tail-flick test, the improvement of RB 101 antinociceptive response was still significant 6 h after PD-134,308 (3 mg/kg, i.p.), whereas in the hot-plate test, this enhancement was only effective for 3 h after CCKB receptor antagonist administration. In the case of a repeated administration of RB 101, the potentiation induced by PD-134,308 on the antinociceptive effect produced by the first injection of RB 101 (20 mg/kg, i.v.), was found almost identical after a second administration of RB 101 performed 190 min later. Chronic administration of RB 101 (20 mg/kg, i.v.) plus PD-134,308 (3 mg/kg, i.p.) administered for 5 days both once or twice per day, did not induce the development of tolerance to antinociception at the peak effect time. However, a decrease in the duration of the antinociceptive response was observed. These results indicate that the potent and long-lasting antinociceptive response induced by the coadministration of the peptidase inhibitor and the CCKB receptor antagonist could have interesting perspectives in the clinical treatment of pain.

Inhibition of morphine withdrawal by the association of RB 101, an inhibitor of enkephalin catabolism, and the CCKB antagonist PD-134,308.

1. The effects induced in rats on naloxone-precipitated morphine withdrawal syndrome by the new mixed inhibitor of enkephalin catabolism able to cross the blood-brain barrier RB 101 (N-((R,S)-2-benzyl-3[(S)(2-amino-4-methylthio)butyl dithio]-1-ox-opropyl-L-phenylalanine benzyl ester) given alone or associated with the selective CCKB antagonist, PD-134,308, were investigated. 2. The systemic administration of RB 101 (5, 10 and 20 mg kg-1, i.v.) elicited a significant decrease in 8 of the 14 withdrawal signs evaluated. PD-134,308 (3 mg kg-1, i.p.) did not modify the expression of morphine abstinence when given alone, but induced a strong facilitation of RB 101 responses (12 of 14 withdrawal signs were decreased). This potentiation was particularly intense in peripherally mediated withdrawal signs. 3. In order to clarify the biochemical mechanisms implicated in these responses, the effects induced by the association of RB 101 and PD-134,308 on the occupation of brain opioid receptors by endogenous enkephalins were also investigated in mice. PD-134,308, as well as RB 101, inhibited [3H]-diprenorphine binding to opioid receptors. These results suggest that an increase in endogenous enkephalin levels induced by PD-134,308 could participate in the facilitation of RB 101 behavioural responses. 4. RB 101 has a promising potential role in the management of the opiate withdrawal syndrome. CCKB antagonists, such as PD-134,308 may be useful in potentiating this anti-withdrawal effect.

A selective CCKB receptor antagonist potentiates, mu-, but not delta-opioid receptor-mediated antinociception in the formalin test.

The endogenous peptides enkephalins and cholecystokinin appear to play an opposite role in the control of pain. In this work, the effect of the selective CCKB receptor antagonist PD-134,308 on antinociceptive effects induced by morphine or by a complete inhibitor of enkephalin-metabolizing enzymes, RB 101, was studied using the formalin test. In mice, s.c. injection of formalin into the dorsal surface of the hindpaw had a biphasic effect: an early nociceptive response followed by a late response. Morphine (2 mg/kg i.p.) caused naloxone (0.5 mg/kg s.c.) but not naltrindole (0.5 mg/kg s.c.) reversible antinociceptive responses in the early and late phases of the assay, suggesting a preferential involvement of mu-opioid receptors in these responses. In contrast, RB 101 (50 mg/kg i.p.) produced antinociceptive effects in the early and late phases which were both antagonized by the delta-selective opioid receptor antagonist naltrindole (0.5 mg/kg s.c.). The antinociceptive response elicited by morphine on the late but not the early phase of the formalin test was potentiated by the CCKB antagonist PD-134,308 (1 mg/kg i.p.). This compound was unable to facilitate the analgesic effects produced by RB 101 on both phases, in contrast to what was observed in the hot plate test with mice and the tail flick test with rats. Therefore, in the formalin test with mice, the facilitating effects of opiate-induced analgesia by CCKB receptor antagonists seem to be restricted to mu-opioid receptor-mediated responses.

The selective CCK-B agonist, BC 264, impairs socially reinforced memory in the three-panel runway test in rats.

The role of CCK-B receptor activation in memory processes has been reassessed using the three-panel runway task, under conditions which avoid the effects of CCK on satiety and reduce emotional responses. For this purpose the food reinforcement usually used was replaced by a social reinforcement. The results show that learning and memory can be assessed using this procedure. Moreover, under these experimental conditions, drugs such as scopolamine, amphetamine or kinurenic acid injected into the nucleus accumbens produced behavioral deficits. BC 264, a highly selective CCK-B agonist, peripherally administered or infused into the anterolateral part of the nucleus accumbens also impaired memory. These effects were suppressed by L-365,260 supporting the involvement of CCK-B receptors and of the nucleus accumbens in memory processes.

Cholecystokinin peptidomimetics as selective CCK-B antagonists: design, synthesis, and in vitro and in vivo biochemical properties.

Antagonists of cholecystokinin-B (CCK-B) receptors have been shown to alleviate CCK4-induced panic attacks in humans and to potentiate opioid effects in animals. The clinical use of these compounds is critically dependent on their ability to cross the blood-brain barrier. In order to improve this property, new, peptoid-derived CCK-B antagonists, endowed with high affinity, selectivity, and increased lipophilicity have been developed. The affinity and selectivity of these compounds have been characterized in vitro and in vivo using guinea pig, rat, and mouse. Most of these compounds proved to be selective for the CCK-B receptor, the most potent analog, N-[N-[(2-adamantyloxy)carbonyl]-D-alpha- methyltryptophanyl]-N-[2-(4-chlorophenyl)ethyl]glycine (26A), having a Ki value of 6.1 nM for guinea pig cortex membranes in vitro and a good selectivity ratio (Ki CCK-A/Ki CCK-B = 174). Furthermore, the in vivo affinity of 26A for mouse brain CCK-B receptors, following intracerebroventricular injection at different concentrations, was found to be 10 nmol. Using competition experiments with the specific CCK-B ligand [3H]pBC 264, compound 26A was shown to cross the blood-brain barrier (0.2%) after intraperitoneal administration in mice. This compound is therefore an interesting pharmacological tool to further elucidate the physiopathological role of endogenous CCK.

Hybrid cholecystokinin-A antagonists based on molecular modeling of lorglumide and L-364,718.

A series of novel nonpeptide cholecystokinin-A (CCK-A) antagonists have been synthesized. Designed on the basis of the structural homology between lorglumide and L-364,718, as investigated with molecular modeling, these compounds constitute a link between the N-acylglutamic acid and 3-amino-5-phenyl-1,4-benzodiazepin-2-one derived antagonists. The prepared compounds were tested in vitro as antagonists of the binding of [3H]-(+/-)-L-364,718 and [3H]-CCK-8(S) to rat pancreas and guinea pig brain membranes, respectively. All compounds proved to be selective for the (peripheral) CCK-A receptor, the most potent analogue, 6, having a Ki value of 90 nM. The structure-activity profile of the series of hybrid compounds relates closest to that of the N-acylglutamic acid derived antagonists.