Effect of Misalignment between Hospital and Provincial Formularies on Medication Discrepancies at Discharge: PPITS (Proton Pump Inhibitor Therapeutic Substitution) Study

Background

Medication discrepancies may occur on admission, transfer, or discharge from hospital. Therapeutic interchange within a drug class is a common practice in hospitals, and orders for specific proton pump inhibitors (PPIs) are often substituted with the hospital’s formulary PPI through therapeutic interchange protocols. Rabeprazole is the PPI on the formulary of the British Columbia PharmaCare program. However, different PPIs may appear on the formularies of the province’s hospitals. This misalignment and use of therapeutic interchange may lead to increased rates of medication discrepancies at the time of discharge.

Objective

To evaluate the effect of formulary misalignment for PPIs between St Paul’s Hospital in Vancouver and the British Columbia PharmaCare program and use of therapeutic interchange on the occurrence of medication discrepancies at discharge.

Methods

A cohort chart review was performed to compare discharge discrepancy rates for PPI orders between 2 periods: June 2006 to June 2008, when the same PPI appeared on the hospital and provincial formularies, and July 2008 to July 2010, when the designated PPIs differed between the hospital and provincial formularies. Data for the first study period were used to establish the baseline discharge discrepancy rate, and data for the later period represented the discharge discrepancy rate in the presence of misalignment between the hospital and PharmaCare formularies.

Results

The discharge discrepancy rate for PPIs was 27.3% (24/88) when the 2 formularies were aligned and 49.1% (81/165) when the formularies were misaligned. This represents an absolute increase of 21.8 percentage points in the risk of discharge discrepancies (95% confidence interval 9.8–33.9 percentage points; p < 0.001) when the hospital and provincial formularies were misaligned and the hospital’s therapeutic interchange protocol was used.

Conclusions

Misalignment between the PPIs specified in the hospital and provincial formularies, combined with use of therapeutic interchange, was associated with a significant increase in medication discrepancies at discharge.     

A new formulation of tolevamer, a novel nonantibiotic polymer, is safe and well-tolerated in healthy volunteers: a randomized phase I trial

AIMS

To evaluate the safety and tolerability of a new oral solution formulation of tolevamer potassium sodium, a nonantibiotic polymer that binds Clostridium difficile toxins A and B.

METHODS

This phase 1 randomized, double-blind, placebo-controlled study evaluated four doses of tolevamer potassium sodium in 40 healthy volunteers using a sequential dose escalation paradigm and doses of 6, 9, 12 and 15 g day⁻¹ for 9 days. Within each 10 patient cohort, eight patients received active treatment and two matching placebo. Placebo subjects were pooled to provide eight per arm. All subjects received three times daily dosing on days 2–8 as well as a loading dose (a single dose equal to the total daily dose) either on day 1 or day 9.

RESULTS

All 40 subjects completed the study per protocol. Treatment-emergent adverse events (TEAEs) were generally mild, transient, and resolved without sequelae. There were no serious AEs or deaths. There was no relationship detected between dose and the incidence of TEAEs, whether drug-related (all gastrointestinal disorders) or not. No clinically significant changes in laboratory parameters, including serum and urinary potassium concentrations, vital signs, and results of physical examination, were observed. A small but statistically significant reduction in 24 h urine potassium excretion was seen in the 15 g day⁻¹ dose group, and on day 10 in the 6 g day⁻¹ group.

CONCLUSIONS

Tolevamer oral solution administered for 9 days at total daily doses up to 15 g, with loading doses of up to 15 g, was generally safe and well-tolerated in healthy volunteers.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• Clostridium difficile-associated diarrhoea (CDAD), which affects about 1% of hospitalized patients whose intestinal flora have been altered by the administration of antimicrobial agents such as the cephalosporins, accounts for 10% to 20% of all cases of antibiotic-associated diarrhoea.
• The incidence and severity of CDAD is rising in a number of countries, including the United States, United Kingdom, and Canada, where recent outbreaks of CDAD have been associated with increased mortality.
• Since both antibiotics that are currently used for treating CDAD (vancomycin, the only treatment approved by the US Food and Drug Administration for this indication, and metronidazole, the most widely recommended first-line therapy) have serious limitations, including recurrence rates of about 20%, systemic adverse events, and the emergence of drug resistance, there is a large unmet need for the development of novel therapeutic modalities with unique mechanisms of action for the prevention of the disease and/or management of patients with CDAD.

WHAT THIS STUDY ADDS

• The results of the phase I study demonstrate that a new phase III formulation of tolevamer, a novel, high-molecular weight, anionic polymer with a unique mechanism of action based on noncovalent binding to C. difficile toxins A and B, may eliminate the increased risk of hypokalaemia observed with the phase II formulation and allow further clinical development of an alternative therapeutic approach to antibiotics for this antibiotic-induced disease.
• The results demonstrate that a potassium sodium oral liquid formulation of tolevamer given over a 9 day treatment period is generally safe and well-tolerated.
• The information contained herein provides a basis for selection of the appropriate dosing and scheduling of this formulation of tolevamer in future trials.

     

Cardiovascular outcomes associated with concomitant use of clopidogrel and proton pump inhibitors in patients with acute coronary syndrome in Taiwan

AIMS

Our study aimed to examine the impact of concomitant use of proton pump inhibitors (PPIs) with clopidogrel on the cardiovascular outcomes of patients with acute coronary syndrome (ACS). Furthermore, we sought to quantify the effects of five individual PPIs when used concomitantly with clopidogrel.

METHODS

We conducted a retrospective cohort study of patients who were newly hospitalized for ACS between 1 January 2006 and 31 December 2007 retrieved from the Taiwan National Health Insurance Research Database (NHIRD) and who were prescribed clopidogrel (n= 37 099) during the follow-up period. A propensity score technique was used to establish a matched cohort in 1:1 ratio (n= 5173 for each group). The primary clinical outcome was rehospitalization for ACS, while secondary outcomes were rehospitalization for percutaneous transluminal coronary angioplasty (PTCA) with stent, PTCA without stent and revascularization (PTCA or coronary artery bypass graft surgery) after the discharge date for the index ACS event.

RESULTS

The adjusted hazard ratio of rehospitalization for ACS was 1.052 (95% confidence interval, 0.971–1.139; P= 0.214) in the propensity score matched cohort. Among all PPIs, only omeprazole was found to be statistically significantly associated with an increased risk of rehospitalization for ACS (adjusted hazard ratio, 1.226; 95% confidence interval, 1.066–1.410; P= 0.004). Concomitant use of esomeprazole, pantoprazole, rabeprazole and lansoprazole did not increase the risk.

CONCLUSIONS

Our study indicated no statistically significant increase in the risk of rehospitalization for ACS due to concurrent use of clopidogrel and PPIs overall. Among individual PPIs, only omeprazole was found to be statistically significantly associated with increased risk of rehospitalization for ACS.     

Influences of different proton pump inhibitors on the anti-platelet function of clopidogrel in relation to CYP2C19 genotypes

AIMS

The efficacy of clopidogrel is influenced by CYP2C19 genotypes and substrates of CYP2C19, such as proton pump inhibitors (PPIs). We assessed the influence of three different PPIs on the anti-platelet function of clopidogrel in relation to CYP2C19 genotype status.

METHODS

Thirty-nine healthy volunteers with different CYP2C19 genotypes took clopidogrel 75 mg with or without omeprazole 20 mg, lansoprazole 30 mg or rabeprazole 20 mg in the morning for 7 days. The influence of the three PPIs on the anti-platelet function of clopidogrel was determined. A less than 30% inhibition of platelet aggregation (IPA) during clopidogrel dosing was defined as a ‘low responder’. We also examined whether evening dosing of omeprazole could prevent the interaction with clopidogrel dosed in the morning.

RESULTS

In rapid metabolizers (RMs, *1/*1, n = 15) of CYP2C19, omeprazole and rabeprazole significantly attenuated the anti-platelet function of clopidogrel. In decreased metabolizers (DMs, carriers of *2 and/or *3, n = 24), there was a large variation in IPA and there was a trend but no significant decrease in IPA when placed on a concomitant PPI. Some DMs became ‘low-responders’ when placed on a concomitant PPI. Evening omeprazole dose in RMs did not seem to cause a significant decrease in IPA in contrast to morning dosing, but did so in DMs.

CONCLUSIONS

The three PPIs affected the efficacy of clopidogrel to different degrees. Both omeprazole and rabeprazole significantly decreased IPA in RMs but not DMs, although there was a trend towards lower IPA in DMs. Morning and evening dosing of omeprazole were both associated with lower IPA in DMs.     

Growing a "positive culture" of antimicrobial stewardship in a community hospital

Background:

Promoting the appropriate use of antimicrobials is a core value of antimicrobial stewardship. Prospective audit and feedback constitute an effective strategy for reducing the cost and use of antimicrobials, as well as their adverse effects, such as infection with Clostridium difficile.

Objective:

To evaluate the antimicrobial stewardship program in the intensive care unit at the authors’ hospital, in order to determine the cost and utilization of antimicrobials, as well as the rate of nosocomially acquired C. difficile infection.

Methods:

An infectious diseases team, consisting of a physician and a pharmacist, performed prospective audit and feedback during a pilot study (April to June 2010). The team met with the intensive care unit team daily to discuss optimization of therapy. The cost and utilization of antimicrobial drugs, as well as rates of C. difficile infection, were compared between the pilot period and the same period during the previous year (April to June 2009). For 3 months after the pilot phase (i.e., July to September 2010), the strategy was continued 3 days per week.

Results:

After introduction of the antimicrobial stewardship program, there was a significant reduction in the cost of antimicrobial drugs: $27 917 less than during the same period in the previous year, equivalent to a reduction of $15.45 (36.2%) per patient-day ($42.63 versus $27.18). Utilization of broad-spectrum antipseudomonal antimicrobial agents was also significantly lower, declining from 63.16 to 38.59 defined daily doses (DDDs) per 100 patient-days (reduction of 38.9%). After the pilot period, the rate declined further, to 28.47 DDDs/100 patient-days. During the pilot period, there were no cases of C. difficile infection, and in the post-pilot period, there was 1 case (overall rate 0.42 cases/1000 patient-days). This rate was lower than (but not significantly different from) the rate for April to September 2009 (1.87 cases/1000 patient-days). There were no differences in mortality rate or severity of illness.

Conclusion:

The antimicrobial stewardship program in this community hospital was associated with significant decreases in antimicrobial costs and in utilization of antipseudomonal antimicrobial agents and a nonsignificant decrease in the rate of C. difficile infection. Knowledge exchange, peer-to-peer communication, and decision support, key factors in this success, will be applied in implementing the antimicrobial stewardship program throughout the hospital.     

Inhibition of CYP2D6-mediated tramadol O-demethylation in methadone but not buprenorphine maintenance patients

AIMS

To compare the O- (CYP2D6 mediated) and N- (CYP3A4 mediated) demethylation metabolism of tramadol between methadone and buprenorphine maintained CYP2D6 extensive metabolizer subjects.

METHODS

Nine methadone and seven buprenorphine maintained subjects received a single 100 mg dose of tramadol hydrochloride. Blood was collected at 4 h and assayed for tramadol, methadone, buprenorphine and norbuprenorphine (where appropriate) and all urine over 4 h was assayed for tramadol and its M1 and M2 metabolites.

RESULTS

The urinary metabolic ratio [median (range)] for O-demethylation (M1) was significantly lower (P= 0.0002, probability score 1.0) in the subjects taking methadone [0.071 (0.012–0.103)] compared with those taking buprenorphine [0.192 (0.108–0.392)], but there was no significant difference (P= 0.21, probability score 0.69) in N-demethylation (M2). The percentage of dose [median (range)] recovered as M1 was significantly lower in subjects taking methadone compared with buprenorphine (0.069 (0.044–0.093) and 0.126 (0.069–0.187), respectively, P= 0.04, probability score 0.19), M2 was significantly higher in subjects taking methadone compared with buprenorphine (0.048 (0.033–0.085) and 0.033 (0.014–0.049), respectively, P= 0.04, probability score 0.81). Tramadol was similar (0.901 (0.635–1.30) and 0.685 (0.347–1.04), respectively, P= 0.35, probability score 0.65).

CONCLUSIONS

Methadone inhibited the CYP2D6-mediated metabolism of tramadol to M1. Hence, as the degree of opioid analgesia is largely dependent on M1 formation, methadone maintenance patients may not receive adequate analgesia from oral tramadol.     

Proton pump inhibitors do not impair the effectiveness of metformin in patients with diabetes

Aims

In order to exert its pharmacodynamic effect, the diabetes drug metformin needs to be taken up into hepatocytes by the organic cation transporter (OCT) system. A recent in vitro study found that proton pump inhibitors (PPIs) inhibit OCT1, OCT2 and OCT3, suggesting that PPIs might reduce metformin''s effectiveness. This pharmacoepidemiologic study looked for evidence of a clinical effect of such an interaction.

Methods

This was an observational cohort study examining changes in glycosylated haemoglobin (HbA1c) with exposure to metformin and to PPIs as single agents and in combination. The aim was to assess evidence of a deleterious drug−drug interaction.

Results

PPIs did not reduce the effectiveness of metformin, and indeed were associated with a minimally better glycaemic response by − 0.06 HbA1c percentage points (95% confidence interval, −0.10, −0.01) in metformin initiators.

Conclusions

Despite a mechanistic basis for a potential drug–drug interaction, we found no evidence of a deleterious interaction between PPIs and metformin.     

Urinary Tract Infections: Leading Initiatives in Selecting Empiric Outpatient Treatment (UTILISE)

Background

Overuse of fluoroquinolone antibiotics is associated with outbreaks of methicillin-resistant Staphylococcus aureus and of Clostridium difficile–associated diarrhea and increasing resistance in gram-negative organisms. Over the past decade, resistance of Escherichia coli to ciprofloxacin has increased in the Regina Qu’Appelle Health Region. In August 2011, an exploratory audit of the Regina General Hospital (RGH) emergency department showed that 20% of new antibiotic orders were for fluoroquinolones, and 60% of these new fluoroquinolone orders were for ciprofloxacin. It was postulated that ciprofloxacin was predominantly prescribed for outpatients with urinary tract infection.

Objective:

To develop, implement, and evaluate a best-practice algorithm for the empiric treatment of uncomplicated urinary tract infection in the RGH emergency department, as part of an educational initiative for emergency physicians.

Methods:

A literature review was conducted and local antibiogram data were analyzed to establish a best-practice algorithm for treatment of uncomplicated urinary tract infection in outpatients seen in the emergency department. A chart review was conducted from January to March 2011 to establish a baseline of empiric antibiotic use. An educational strategy targeting emergency physicians described changes in antibiotic resistance patterns in the health region, principles of antimicrobial stewardship, drivers of resistance, and the results of a literature review of best practice for urinary tract infection in outpatients. A post-intervention audit was conducted from January to March 2012 to determine changes in practice.

Results:

Comparison of results from the post-intervention audit with baseline data showed that adherence to best practice increased significantly, from 41% (39/96) before the intervention to 66% (50/76) after the intervention (odds ratio [OR] 2.81, 95% confidence interval [CI] 1.51–5.25; p < 0.001). There was also a significant change in overall antibiotic selection (OR 0.25, 95% CI 0.11–0.58; p < 0.001). Further analysis suggested that this significant change was driven by a decrease in use of ciprofloxacin, from 32% (31/96) to 11% (8/76).

Conclusion:

Creation of a best-practice algorithm and education focused on emergency physicians significantly increased adherence to best practice and optimized antibiotic prescribing for outpatients with uncomplicated urinary tract infection by limiting overuse of fluoroquinolones, primarily ciprofloxacin.     

Involvement of decreased muscarinic receptor function in prepulse inhibition deficits in mice reared in social isolation

BACKGROUND AND PURPOSE

We have previously reported that galantamine, a weak acetylcholinesterase inhibitor, improves prepulse inhibition (PPI) deficits in mice reared in social isolation. ACh receptors are involved in the underlying mechanism of PPI, but whether rearing in social isolation causes dysfunction of the cholinergic system is unknown. In this study, we examined the involvement of muscarinic receptors in the improvement of PPI deficits induced by galantamine, and whether the cholinergic system is altered in mice reared in isolation.

EXPERIMENTAL APPROACH

Three-week-old male ddY mice were housed in isolated cages for 6 weeks before the initiation of experiments to create PPI deficits. Cholinergic functions were determined by measuring the behavioural and neurochemical responses to nicotinic and muscarinic receptor agonists.

KEY RESULTS

The improvement by galantamine of social isolation-induced PPI deficits was blocked by scopolamine, a non-selective muscarinic antagonist, and telenzepine, a preferential M₁ receptor antagonist. Activation of M₁ receptors improved social isolation-induced PPI deficits. Social isolation did not affect choline acetyltransferase and acetylcholinesterase activities in the prefrontal cortex and hippocampus, but it reduced the locomotor-suppressive response to muscarinic agonist oxotremorine, but not to nicotine. The isolation also attenuated the M₁ receptor agonist N-desmethylclozapine-induced increase in prefrontal dopamine release.

CONCLUSIONS AND IMPLICATIONS

Galantamine improves PPI deficits of mice reared in social isolation via activation of M₁ receptors. Social isolation reduces the muscarinic, especially M₁, receptor function and this is involved in PPI deficits.     

Kynurenic acid attenuates multiorgan dysfunction in rats after heatstroke

Aim:

To assess whether systemic delivery of kynurenic acid improves the outcomes of heatstroke in rats.

Methods:

Anesthetized rats were divided into 2 major groups and given vehicle solution (isotonic saline 0.3 mL/kg rat weight) or kynurenic acid (30–100 mg in 0.3 mL saline/kg) 4 h before the start of thermal experiments. They were exposed to an ambient temperature of 43 °C for 68 min to induce heatstroke. Another group of rats were exposed to room temperature (26 °C) and used as normothermic controls. Their core temperatures, mean arterial pressures, serum levels of systemic inflammatory response molecules, hypothalamic values of apoptotic cells and neuronal damage scores, and spleen, liver, kidney and lung values of apoptotic cells were determined.

Results:

The survival time values during heatstroke for vehicle-treated rats were decreased from the control values of 475–485 min to new values of 83–95 min. Treatment with KYNA (30–100 mg/kg, iv) 4 h before the start of heat stress significantly and dose-dependently decreased the survival time to new values of 152–356 min (P<0.05). Vehicle-treated heatstroke rats displayed hypotension, hypothalamic neuronal degeneration and apoptosis, increased serum levels of tunor necrosis factor-α (TNF-α), intercellular adhesion molecule-1 (ICAM-1), and interleukin-10 (IL-10), and spleen, liver, kidney, and lung apoptosis. KYNA preconditioning protected against hypotension but not hyperthermia and attenuated hypothalamic neuronal degeneration and apoptosis during heatstroke. KYNA preconditioning attenuated spleen, kidney, liver, and lung apoptosis and up-regulated serum IL-10 levels but down-regulated serum TNF-α and ICAM-1 levels during heatstroke.

Conclusion:

Our results suggest that systemic delivery of kynurenic acid may attenuate multiorgan dysfunction in rats after heatstroke.     

Development of a validated HPLC method for the simultaneous determination of flavonoids in Cuscuta chinensis Lam. by ultra-violet detection

Background

Cuscuta species known as dodder, have been used in traditional medicine of eastern and southern Asian countries as liver and kidney tonic. Flavonoids are considered as the main biologically active constituents in Cuscuta plants especially in C. chinensis Lam.

Objective

In the present study, a fast, simple and reliable method for the simultaneous determination and quantization of C. chinensis flavonols including hyperoside, rutin, isorhamnetin and kaempferol has been developed.

Materials and methods

The chromatographic separation was carried out on a reversed phase ACE 5 C₁₈ with eluting at a flow rate of 1 ml/min using a gradient with O-phosphoric acid 0.25% : acetonitrile for 42 min. UV spectra were collected across the range of 200–900 nm, extracting 360 nm for the chromatograms. The method was validated according to linearity, selectivity, precision, recovery, LOD and LOQ.

Results

The method was selective for determination of rutin, hyperoside, isorhamnetin and kampferol. The calibration graphs of flavonols were linear with r² > 0.999. RSDs% of intra- and inter-day precisions were found 1.3&3.4 for rutin, 1.5&2.8 for hyperoside, 1.3&3.3 for isorhamnetin and 1.7 & 2.9 for kaempferol which were satisfactory. LODs and LOQs were calculated as 1.73 & 8.19 for rutin, 0.09 & 4.19 for hyperoside, 2.09 & 6.3 for isorhamnetin and 0.18 & 0.56 for kaempferol. The recovery averages of above-mentioned flavonols were 90.3%, 97.4%, 98.7% and 90.0%, respectively.

Conclusion

The simplicity of the method makes it highly valuable for quality control of C. chinensis according to quantization of flavonols.     

Apoptosis induced by genipin in human leukemia K562 cells: involvement of c-Jun N-terminal kinase in G₂/M arrest

Aim:

To investigate the effect of genipin on apoptosis in human leukemia K562 cells in vitro and elucidate the underlying mechanisms.

Methods:

The effect of genipin on K562 cell viability was measured using trypan blue dye exclusion and cell counting. Morphological changes were detected using phase-contrast microscopy. Apoptosis was analyzed using DNA ladder, propidium iodide (PI)-labeled flow cytometry (FCM) and Hoechst 33258 staining. The influence of genipin on cell cycle distribution was determined using PI staining. Caspase 3 activity was analyzed to detect apoptosis at different time points. Protein levels of phospho-c-Jun, phosphor-c-Jun N-terminal kinase (p-JNK), phosphor-p38, Fas-L, p63, and Bax and the release of cytochrome c were detected using Western blot analysis.

Results:

Genipin reduced the viability of K562 cells with an IC₅₀ value of approximately 250 μmol/L. Genipin 200–400 μmol/L induced formation of typical apoptotic bodies and DNA fragmentation. Additionally, genipin 400 μmol/L significantly increased the caspase 3 activity from 8–24 h and arrested the cells in the G₂/M phase. After stimulation with genipin 500 μmol/L, the levels of p-JNK, p-c-Jun, Fas-L, Bax, and cytochrome c were remarkably upregulated, but there were no obvious changes of p-p38. Genipin 200–500 μmol/L significantly upregulated the Fas-L expression and downregulated p63 expression. Dicoumarol 100 μmol/L, a JNK1/2 inhibitor, markedly suppressed the formation of apoptotic bodies and JNK activation induced by genipin 400 μmol/L.

Conclusion:

These results suggest that genipin inhibits the proliferation of K562 cells and induces apoptosis through the activation of JNK and induction of the Fas ligand.     

Anti-pruritic effect of baicalin and its metabolites, baicalein and oroxylin A, in mice Anti-tumorPharmacology

Aim:

To explore whether intestinal microflora plays a role in anti-pruritic activity of baicalin, a main constituent of the rhizome of Scutellaria baicalensis (SB).

Methods:

Baicalin was anaerobically incubated with human fecal microflora, and its metabolites, baicalein and oroxylin A, were isolated. The inhibitory effect of baicalin and its metabolites was accessed in histamine- or compound 48/80-induced scratching behavior in mice.

Results:

Baicalin was metabolized to baicalein and oroxylin A, with metabolic activities of 40.2±26.2 and 1.2±1.1 nmol·h⁻¹·mg⁻¹ wet weight of human fecal microflora, respectively. Baicalin (20, 50 mg/kg) showed more potent inhibitory effect on histamine-induced scratching behavior when orally administered than intraperitoneally. In contrast, baicalein and oroxylin A had more potent inhibitory effect when the intraperitoneally administered. The anti-scratching behavior activity of oral baicalin and its metabolites was in proportion to their inhibition on histamine-induced increase of vascular permeability with oroxylin A more potent than baicalein and baicalin. In Magnus test using guinea pig ileum, oroxylin A is more potent than baicalein and baicalin in inhibition of histamine-induced contraction. The anti-scratching behavioral effect of oral baicalin was significantly reduced when oral antibiotics were simultaneously administered, whereas the effect of baicalein and oroxylin A were not affected.

Conclusion:

Oral baicalin may be metabolized by intestinal microflora into baicalein and oroxylin A, which ameliorate pruritic reactions through anti-histamine action.     

A ketolide antibiotic, telithromycin, inhibits vascular adrenergic neurotransmission in the rat mesenteric vascular bed

Background and purpose:

A ketolide antibiotic, telithromycin, has side effects including temporary loss of consciousness in clinical use, but the underlying mechanisms remain unclear. This study investigated the effects of telithromycin on perivascular nerve function in rat mesenteric arteries, in comparison with those of macrolide (erythromycin and clarithromycin) and new quinolone antibiotics (levofloxacin and gatifloxacin).

Experimental approach:

In vitro, vascular responses and release of noradrenaline induced by periarterial nerve stimulation (PNS) of rat perfused mesenteric vascular beds were measured in the presence of each antibiotic. In vivo blood pressure measurement was performed in Wistar rats.

Key results:

In mesenteric preparations with resting tone, telithromycin (10 nM–10 μM) markedly inhibited PNS (4–12 Hz)-induced adrenergic nerve- and exogenous noradrenaline-mediated vasoconstriction, whereas the other antibiotics slightly inhibited PNS-induced responses without affecting noradrenaline-induced responses. Telithromycin significantly reduced PNS (12 Hz)-evoked noradrenaline release in the perfusate. In pre-constricted preparations with or without endothelium, telithromycin (0.1 nM–10 μM) caused a concentration-dependent vasodilation. Telithromycin (10 nM) inhibited calcium-induced vasoconstriction in high KCl and calcium-free medium. None of the antibiotics used affected PNS (0.5–2 Hz)-induced calcitonin gene-related peptide (CGRP) nerve- and exogenous CGRP-mediated vasodilation. Intravenous injection of telithromycin significantly lowered blood pressure in anaesthetized rats.

Conclusions and implications:

These results suggest that telithromycin causes not only strong inhibition of perivascular adrenergic neurotransmission but also a vasodilator action in mesenteric vascular beds and hypotension. It is thus possible that telithromycin increases visceral blood flow, consequently reducing cerebral blood flow and resulting in a temporary loss of consciousness.     

The effect of SLCO1B1 polymorphism on repaglinide pharmacokinetics persists over a wide dose range

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• Organic anion transporting polypeptide 1B1 is an influx transporter expressed on the basolateral membrane of hepatocytes.
• A common single nucleotide polymorphism, c.521T→C (p.Val174Ala), of the SLCO1B1 gene has been associated with increased plasma repaglinide concentrations in healthy volunteers.
• Previous studies at low repaglinide doses have suggested that the effect of SLCO1B1 c.521T→C polymorphism on the pharmacokinetics of repaglinide could be dose-dependent.

WHAT THIS STUDY ADDS

• Repaglinide peak plasma concentration and area under the plasma concentration–time curve increased linearly along with repaglinide dose ranging from 0.25 to 2 mg in both the predominant c.521TT and rare c.521CC genotype group.
• The effect of SLCO1B1 c.521T→C polymorphism on repaglinide pharmacokinetics persists over a wide dose range.

AIMS

To establish whether the effect of SLCO1B1[encoding organic anion transporting polypeptide 1B1 (OATP1B1)] c.521T→C (p.Val174Ala) polymorphism on the pharmacokinetics of repaglinide is dose-dependent.

METHODS

Twelve healthy volunteers with the SLCO1B1 c.521TT genotype (controls) and eight with the c.521CC genotype ingested a single 0.25-, 0.5-, 1- or 2-mg dose of repaglinide in a dose-escalation study with a wash-out period of ≥1 week.

RESULTS

The mean area under the plasma concentration–time curve from time 0 to infinity (AUC_0–∞) of 0.25, 0.5, 1 or 2 mg repaglinide was 82% (95% confidence interval 47, 125), 72% (24, 138), 56% (24, 95) or 108% (59, 171) (P ≤ 0.001) larger in participants with the SLCO1B1 c.521CC genotype than in those with the c.521TT genotype, respectively. Repaglinide peak plasma concentration and AUC_0–∞ increased linearly along with repaglinide dose in both genotype groups (r > 0.88, P < 0.001). There was a tendency towards lower blood glucose concentrations after repaglinide administration in the participants with the c.521CC genotype than in those with the c.521TT genotype.

CONCLUSIONS

The effect of SLCO1B1 c.521T→C polymorphism on the pharmacokinetics of repaglinide persists throughout the clinically relevant dose range.     

Protective effect of Bu-7, a flavonoid extracted from Clausena lansium, against rotenone injury in PC12 cells

Aim:

To investigate the protective effect and underlying mechanisms of Bu-7, a flavonoid isolated from the leaves of Clausena lansium, against rotenone-induced injury in PC12 cells.

Methods:

The cell viability was evaluated using MTT assay. The cell apoptosis rate was analyzed using flow cytometry. JC-1 staining was used to detect the mitochondrial membrane potential (MMP). Western blotting analysis was used to determine the phosphorylation of c-Jun N-terminal kinase (JNK), p38 mitogen-activated protein kinase (p38), tumor protein 53 (p53), Bcl-2–associated X protein (Bax), B-cell lymphoma 2 (Bcl-2), and caspase 3.

Results:

Treatment of PC12 cells with rotenone (1–20 μmol/L) significantly reduced the cell viability in a concentration-dependent manner. Pretreatment with Bu-7 (0.1 and 10 μmol/L) prevented PC12 cells from rotenone injury, whereas Bu-7 (1 μmol/L) had no significant effect. Pretreatment with Bu-7 (0.1 and 10 μmol/L) decreased rotenone-induced apoptosis, attenuated rotenone-induced mitochondrial potential reduction and suppressed rotenone-induced protein phosphorylation and expression, whereas Bu-7 (1 μmol/L) did not cause similar effects. Bu-7 showed inverted bell-shaped dose-response relationship in all the effects.

Conclusion:

Bu-7 protects PC12 cells against rotenone injury, which may be attributed to MAP kinase cascade (JNK and p38) signaling pathway. Thus, Bu-7 may be a potential bioactive compound for the treatment of Parkinson''s disease.