The Diels–Alder reaction: A powerful tool for the design of drug delivery systems and biomaterials

Click reactions have the potential to greatly facilitate the development of drug delivery systems and biomaterials. These reactions proceed under mild conditions, give high yields, and form only inoffensive by-products. The Diels–Alder cycloaddition is one of the click reactions that do not require any metal catalyst; it is one of the most useful reactions in synthetic organic chemistry and material design. Herein, we highlight possible applications of the Diels–Alder reaction in pharmaceutics and biomedical engineering. Particular focus is placed on the synthesis of polymers and dendrimers for drug delivery, the preparation of functionalized surfaces, bioconjugation techniques, and applications of the Diels–Alder reaction in nanotechnology. Moreover, applications of the reaction for the preparation of hydrogels for drug delivery and tissue engineering are reviewed. A general introduction to the Diels–Alder reaction is presented, along with a discussion of potential pitfalls and challenges. At the end of the article, we provide a set of tools that may facilitate the application of the Diels–Alder reaction to solve important pharmaceutical or biomedical problems.     

Comparison of sandwich enzyme-linked immunoadsorbent assay and radioimmunoassay for determination of exogenous glucagon-like peptide-1(7–36)amide in plasma

A sensitive sandwich enzyme-linked immunoadsorbent assay (ELISA) for determination of exogenous glucagon-like peptide-1(7–36)amide (GLP-1(7–36)amide) in plasma samples from pharmacokinetic studies is described. The assay employs an N-terminally directed antibody and a C-terminally directed antibody. The ELISA has a working range from 10 to 500 pmol 1⁻¹, and can be applied to plasma samples from humans, dogs, pigs, minipigs, cats, rabbits, and rats. The assay was compared to a validated radioimmunoassay (RIA), employing an antibody directed against the mid-region of GLP-1. After s.c. administration of GLP-1(7–36)amide, the plasma immunoreactivity of GLP-1 (P-GLP-1-IR) measured by ELISA was markedly lower than P-GLP-1-IR measured by RIA. After HPLC fractionation of plasma samples with subsequent RIA and ELISA analyses of the fractions, this difference was shown to be due to cross reaction with biologically inactive fragments of GLP-1(7–36)amide in the RIA but not in the ELISA.     

α1-Adrenoceptor subtype mediating contraction of the smooth muscle in the lower urinary tract and prostate of rabbits

Summary The -adrenoceptor subtype mediating contraction of the smooth muscle in the urinary bladder base (trigone), proximal urethra and prostate isolated from male rabbits was investigated by comparing the responsiveness to -adrenoceptor agonists and antagonists under condition where -adrenoceptors and neuronal and extraneuronal uptakes were inhibited. Noradrenaline (non-selective), phenylephrine (₁-selective) and clonidine (₂-selective) caused a dose-dependent contraction in the trigone, urethra and prostate. Phenylephrine acted as a full agonist whereas clonidine was a partial agonist. YM-12617 and prazosin (₁-selective), phentolamine (non-selective) and yohimbine (₂-selective) produced dose-dependent shifts to the right of the dose-response curves for noradrenaline, phenylephrine and clonidine in the all three tissues. YM-12617 (pA₂=9.77, 9.67 and 9.73 for trigone, urethra and prostate, respectively), prazosin (pA₂=8.26, 8.20 and 8.08), phentolamine (pA₂=7.67, 7.62 and 7.45) and yohimbine (pA₂=6.30, 6.30 and 5.94) showed constant pA₂ values irrespective of the agonists and tissues used, suggesting that only a single subclass of -adrenoceptors is present. The actual pA₂ values for these antagonists are comparable to those reported previously in tissues said to contain mainly ₁-adrenoceptors. Thus, we concluded that the postsynaptic -adrenoceptors of the rabbit trigone, urethra and prostate mediating contraction belong to the ₁-subtype.     

Involvement of α1- and α2-adrenoceptors in the responses of proximal and distal segments of the canine saphenous vein to exogenous and endogenous noradrenaline

Summary In the present study the relationship between adrenergic nerve terminals and postjunctional -adrenoceptors mediating the responses to the endogenous transmitter was compared at proximal and distal levels of the canine saphenous vein.Concentration-response curves to noradrenaline and to tyramine as well as frequency-response curves to electrical stimulation were compared at both levels of the vessel, in the absence and presence of either prazosin (100nmol·l^–1) or yohimbine (100nmol·l^–1) The influence of inhibition of neuronal uptake by cocaine (12 µmol·l^–1) on the responses to noradrenaline in the presence of prazosin (56 nmol·l^–1) or yohimbine (20 nmol·l^–1) was compared at the proximal level. The results show that, at the proximal level, the maximal responses to electrical stimulation and tyramine reached 80.1±2.2 (n = 18) and 74.2±1.9 (n = 18)%, respectively, of the maximal responses to noradrenaline, and 70.3±0.8 (n = 15) and 53.1 ± 1.2 (n = 14) %, respectively, at the distal level. Furthermore, the proximal strips were more sensitive to electrical stimulation than the distal ones. Prazosin had a much greater inhibitory effect on the contractile responses to noradrenaline than on those to electrical stimulation, at both levels. At proximal level, the shifts (to the right) of the concentration (frequency)-response curves (at EC₅₀) amounted to 0.58±0.02 (n = 16) and 0.18±0.02 (n = 8) log units, respectively (P<0.05), but, at the distal level, to 1.12±0.03 (n = 16) and 0.28±0.08 (n = 8) log units, respectively (P< 0.05). At the proximal level, yohimbine antagonizes about equally the responses to noradrenaline and the responses to electrical stimulation. However, at the distal level, the shift of the concentration-response curve to noradrenaline was much larger than that of the frequency-response curve to electrical stimulation [1.12±0.07 and 0.80±0.10 (n = 6) log units at EC₅₀, respectively (P<0.05)]. The leftward shift of the concentration-response curve to noradrenaline caused by cocaine was more pronounced in the presence of prazosin than in the presence of yohimbine: 0.95±0.15 and 0.69±0.12 (n = 12) log units, respectively (P<0.05).We conclude that, in the canine saphenous vein: 1) noradrenaline released from the adrenergic nerve terminals by electrical stimulation and by tyramine preferentially activates ₂-adrenoceptors at both proximal and distal levels; 2) the effectiveness of ₂-adrenoceptor stimulation is greater at the proximal than at the distal level; 3) ₁-adrenoceptors at the distal level seem to be different from those at the proximal one. Send offprint requests to S. Guimarães at the above address     

A multi-centre general practice clinical evaluation of pivmecillinam plus pivampicillin (‘Miraxid’) and co-trimoxazole (‘Septrin’) in respiratory tract infections

Summary

Seven-day courses of either 200?mg pivmecillinam plus 250?mg pivampicillin or co-trimoxazole (800?mg sulphamethoxazole plus 160?mg trimethoprim) given twice daily were compared in a multi-centre general practice study in 318 patients with signs and symptoms of upper or lower respiratory tract infection. Patients were stratified into four diagnostic groups (sinusitis, otitis media, throat infections, and acute bronchitis) and randomly allocated to treatment within these groups. Assessments at Day 7 showed that both treatments were equally effective clinically, 154 (91%) patients in the pivmecillinam plus pivampicillin group showing clinical cure or improvement and 142 (88%) patients in the co-trimoxazole group. Side-effects were reported by 19 (11.9%) patients in the pivmecillinam plus pivampicillin group and by 24 (15.8%) patients in the co-trimoxazole group. Two patients in the pivmecillinam plus pivampicillin group and 4 patients in the co-trimoxazole group stopped treatment.     

Cardiovascular and ocular safety of α1-adrenoceptor antagonists in the treatment of male lower urinary tract symptoms

Introduction: α₁-Adrenoceptor antagonists (α-blockers) represent first-line drug treatment for male lower urinary tract symptoms. Their adverse events (AEs) include asthenia, dizziness, nasal congestion, arterial (orthostatic) hypotension and intraoperative floppy iris syndrome (IFIS).

Areas covered: This report focuses on cardiovascular and ocular AEs of α-blockers as related to their mechanism of action and subtype selectivity.

Expert opinion: The incidence of hypotension differs between α-blockers. It is greatest with doxazosin or terazosin, but others including tamsulosin can also lead to hypotension especially upon treatment initiation. Concomitant antihypertensive medication increases the incidence of hypotension with some α-blockers. Use of α_1A-selective blockers, evening dosing and drug intake after a meal can reduce the risk of hypotension. IFIS can occur with all drugs exerting α₁-adrenoceptor antagonist properties and has especially been reported for tamsulosin. It makes cataract surgery more challenging but does not constitute a health risk to patients. IFIS seems to result from inhibition of iris dilator muscle contraction and occurs in men or women, even after α-blockers have been discontinued. To reduce the risk of IFIS, the authors suggest taking a careful drug history, postponing α-blocker treatment for patients with scheduled cataract surgery and careful counseling of patients taking α-blockers.     

A microdialysis profile of β-endorphin and catecholamines in the rat nucleus accumbens following alcohol administration

Rationale Alcohol stimulates the release of dopamine in the nucleus accumbens (NACB) of rats, mice and humans. There is evidence to suggest that the activation of beta-endorphin (β-EP) in the mesolimbic pathway by alcohol and other drugs of abuse may be associated with the rise in dopamine levels in the NACB. Objectives The present studies investigate whether the release of β-EP in the NACB is (1) dependent on the dose of alcohol that is administered, and (2) associated with changes in the extracellular concentrations of the catecholamines dopamine and norepinephrine, and the dopamine metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), in the NACB. Methods Male Sprague-Dawley rats were implanted with a microdialysis probe positioned in the shell region of the NACB. Artificial cerebrospinal fluid was pumped at a rate of 2.3 μl/min in awake and freely moving animals and the dialysate was collected at 30-min intervals. After a baseline period, rats were injected intraperitoneally with either physiological saline or one of three doses of alcohol: 0.8, 1.6, or 2.4 g ethanol/kg body weight. The dialysates collected were analyzed with radioimmunoassay, to estimate the content of β-EP; and high performance liquid chromatography, to estimate the content of dopamine, norepinephrine, DOPAC and HVA. Results Alcohol induced a dose-dependent increase in the extracellular levels of β-EP and dopamine. However, elevations in the extracellular levels of norepinephrine, DOPAC and HVA did not reach significance. The largest increase in β-EP and dopamine was observed with the 2.4 g/kg dose. Conclusion The alcohol-induced release of β-EP and dopamine in the NACB is dose-dependent, where the highest dose resulted in more pronounced concentrations in the dialysate. Furthermore, the increase in the extracellular levels of dopamine appeared to occur at an earlier time point following alcohol administration, than for β-EP. These results suggest that alcohol stimulates dopamine and β-EP in the NACB, but probably does so via independent mechanisms.     

Efficacy of a paracetamol–pseudoephedrine combination for treatment of nasal congestion and pain-related symptoms in upper respiratory tract infection

ABSTRACT

Objective: This study compared the efficacy of 1000?mg of paracetamol combined with 60?mg of pseudoephedrine, with that of either paracetamol or pseudoephedrine alone and placebo for the treatment of symptomatic URTI.

Research design and methods: A double‐blind, parallel group study was performed on 305 patients with URTI (nasal airflow resistance [NAR] of > 0.25 Pa cm³ s and a global pain score of at least moderate intensity). NAR and pain relief/intensity scores were measured over 4?h after initial dose. Patients then dosed up to three times daily for 3 days and recorded nasal congestion and pain intensity scores.

Main outcome measures: Nasal airflow conductance (NAC) and pain relief after the initial dose were primary objectives. NAC was calculated from NAR. Pain relief was measured on a 5‐point verbal rating scale (VRS) and pain intensity and nasal congestion on a 4‐point VRS. Data were analysed using analysis of covariance. Safety was assessed by adverse events.

Results: A single dose of the combination was superior to paracetamol and placebo for NAC (?p = 0.0001) and was superior to pseudoephedrine and placebo for pain relief (?p ≤ 0.048). Multiple doses of the combination were also superior to paracetamol and placebo for decongestion (?p ≤ 0.021) and were superior to pseudoephedrine and placebo for pain reduction (?p ≤ 0.0057). All treatments were well tolerated.

Conclusions: The combination treatment provided a greater decongestant effect than either paracetamol or placebo and better pain relief than either pseudoephedrine or placebo. The additive effect of the combination was apparent for both single and multiple doses.     

Validation of 4β-hydroxycholesterol and evaluation of other endogenous biomarkers for the assessment of CYP3A activity in healthy subjects

AimsThis study aimed to assess changes in the plasma concentrationss of 4β-hydroxycholesterol (4βHC) against intravenous (i.v.) and oral midazolam (MDZ) pharmacokinetics (PK) after administration of a potent CYP3A inhibitor [ketoconazole (KETO)] and inducer [rifampicin (RIF)].MethodsThirty-two healthy subjects (HS) were allocated into three groups of 12 each in KETO and RIF and 10 in a placebo group (PLB). All HS were randomized to receive oral and i.v. MDZ on day 1 or 2 and on day 15 or 16 after receiving RIF (600 mg once daily), KETO (400 mg once daily) or PLB for 2 weeks. Subjects were followed until day 30. The effect of treatments on 4βHC was assessed by analyzing % change from baseline using a linear spline mixed effects model.ResultsCompared with PLB, KETO decreased 4βHC mean values up to 13% (P = 0.003) and RIF increased 4βHC mean values up to 220% (P < 0.001). Within 14 days of stopping KETO and RIF, 4βHC had either returned to baseline (KETO) or was still returning to baseline (RIF). Compared with baseline, mean oral MDZ AUC increased by 11-fold (90% CI ranging from 9-fold to 13-fold increase) and decreased by 92% (90% CI ranging from 90% to 95% decrease) after KETO and RIF, respectively. Similar trends were observed for 6β-hydroxycortisol : cortisol (6βHCL : CL) urinary ratios.ConclusionsChanges in plasma 4βHC can be utilized as a surrogate for MDZ PK after multiple doses of potent CYP3A inducers. There is a more limited dynamic range for 4βHC for assessment of potential CYP3A inhibitors. 4βHC is a valuable tool for the assessment of potential CYP3A inducers in early drug development.     

Compaction and measurement of tablets in liquids with different dielectric constants for determination of bonding mechanisms—Evaluation of the concept

In order to study bonding mechanisms in tablets, liquids with increasing dielectric constants have been used to filter out weak long range distance forces. The aim of this study was to further critically evaluate this concept.Tablets of sodium chloride, sodium bicarbonate, Avicel®, Emcompress®, lactose and sucrose were compacted in media with dielectric constants from 1 to 24 and the remaining tensile strength of tablets compacted in liquid was calculated. With increasing dielectric constant a continuos decrease in tensile strength was obtained and at a dielectric constant above approximately 10–15, a plateau level was reached for all materials except for Avicel®. This level was assumed to reflect the proportion of solid bridges in the compact and the values were consistent with previous data reported from our laboratory.The results also showed that by compacting particles suspended in a liquid a more effective reduction of long range distance forces was obtained, than if tablets were compacted in air followed by a soaking process in liquid.Compaction in liquids may be unsuitable for some materials due to swelling or changes in volume reduction behaviour. Nevertheless, the method appears to be favourable for studying bonding mechanisms, especially for tablets with a low porosity.     

Immunomodulatory effect of pleuran (β-glucan from Pleurotus ostreatus) in children with recurrent respiratory tract infections

ObjectivesRecurrent respiratory tract infections (RRTIs) represent a very important problem in daily clinical practice because of their significant contribution to morbidity in children. Several natural nutritional supplements have been used in the prevention of RRTIs, but the clinical efficacy of only a few preparations is supported by scientific evidence.Materials and methodsIn a double-blind, placebo-controlled, randomised, multicentre study, we have observed a group of 175 children (aged 5.65 ± 2.39 years) with more than 5 respiratory infections that occurred during the 12 months prior to the beginning of the study. Children were randomised into an active group, treated with Imunoglukan P4H® syrup (with pleuran-β-glucan from Pleurotus ostreatus and vitamin C), or a placebo group (vitamin C only). During the 3 visits, within a 12-month period, questionnaires were completed, and blood samples were examined for immune parameters.ResultsIn the active group, 36% of the children did not suffer from any respiratory infections throughout the treatment, compared to 21% in the placebo group (p < 0.05). Imunoglukan P4H® also significantly decreased the frequency of flu and flu-like disease and the number of lower respiratory tract infections. Imunoglukan P4H® treatment resulted in a statistically significant modulation of humoral and cellular immunity.ConclusionsResults from this study demonstrate that Imunoglukan P4H® is effective in the prevention of RRTIs in children. Furthermore, our results also revealed complex immunomodulatory activity of this product. This is the first double-blind, placebo-controlled study in children with RRTIs that has addressed the preventive effects of pleuran on morbidity caused by respiratory infections.     

Persistent (current) in the face of adversity … A new class of cardiac anti-ischaemic compounds on the horizon?

Although a persistent component of the sodium current (INaP) was described in cardiac tissue about three decades ago, its physiological role and potential as a therapeutic target was not immediately apparent. Subsequent demonstrations that INaP is enhanced by hypoxia and ischaemia, and that Na⁺ influx via INaP may contribute to cellular damage, diastolic dysfunction and arrhythmias during ischaemia and reperfusion, raised interest in INaP as a target for anti-ischaemic drugs. Several agents have now been developed to clinical stages, which have INaP block as either their main action, or as a useful co-effect. In this issue of the British Journal of Pharmacology, Vacher et al. report the anti-ischaemic actions of {"type":"entrez-nucleotide","attrs":{"text":"F15845","term_id":"1130985","term_text":"F15845"}}F15845, which appears to exhibit the most selective block of INaP yet described. Its efficacy in animal models of angina raises the prospect of new, specific, INaP blockers that may represent a largely unexploited opportunity for a new class of anti-ischaemic compounds.     

Hypothesis-based weight of evidence: A tool for evaluating and communicating uncertainties and inconsistencies in the large body of evidence in proposing a carcinogenic mode of action—naphthalene as an example

Human health risk assessment consists of bringing to bear a large body of in vitro, animal, and epidemiologic studies on the question of whether environmental exposures to a substance are a potential risk to humans. The body of scientific information is typically less than definitive and often contains apparent contradictions. Often various possible conclusions about potential human risks may be drawn from the data and these may vary from very strong to tenuous. The task, therefore, is to communicate the uncertainties in the inferences from the data effectively, giving proper consideration to contrary data and alternative scientifically plausible interpretations. We propose an approach, Hypothesis-Based Weight of Evidence (HBWoE), to organize, evaluate, and communicate the large body of available relevant data on a given chemical, using naphthalene as an example. The goal for our use of the term “weight of evidence” (WoE) is broad in that we express the relative degrees of credence that should be placed in alternative possible interpretations of the naphthalene data and hypothesized carcinogenic modes of action (MoAs), expressed in a way that shows how such credence is tied to specific scientific interpretations, considering consistencies, inconsistencies, and contradictions within the data set.     

Two enzymes for the detoxication of organophosphorus compounds—Sources,similarities, and significance

An enzyme in E. coli that hydrolyzes diisopropylphosphorofluoridate (DFP) has now been found to hydrolyze the nerve gas 1,2,2-trimethylpropylmethylphosphonofluoridate (soman) many times faster. With either substrate the E. coli enzyme is stimulated manyfold by 10⁻³ m Mn²⁺. These criteria are combined and applied to this, and to a superficially similar but distinctly different, enzyme found in squid nerve. The results suggest that while several tissues of the squid contain only this second kind of DFP hydrolyzing enzyme, termed squid type DFPase, many other sources including E. coli contain a mixture of squid type DFPase (the name not strictly indicative of source) and the other DFP hydrolyzing enzyme, now termed Mazur type DFPase. Procedures for the purification of Mazur type DFPase from hog kidney, while increasing the specific activity for DFP hydrolysis may actually have been enriching the purified material in the squid type DFPase. Because E. coli has the highest soman hydrolyzing capacity of any source so far examined, this organism is a promising source for the development of new purification procedures for Mazur type DFPase.     

The use of ceftolozane-tazobactam in the treatment of complicated intra-abdominal infections and complicated urinary tract infections—A meta-analysis of randomized controlled trials

ObjectiveThe aim of this study was to assess the clinical efficacy and safety of ceftolozane-tazobactam in the treatment of complicated intra-abdominal infections (cIAIs) and complicated urinary tract infections (cUTIs) in adult patients through meta-analysis.MethodsPubMed, Embase and Cochrane databases were searched up to June 2019. Only randomized controlled trials (RCTs) that evaluated ceftolozane-tazobactam and comparators for treating cIAIs and cUTIs in adult patients were included. Primary outcome was clinical cure rate; secondary outcomes were clinical failure rate, microbiological eradication rate, and risk of an adverse event (AE).ResultsThree RCTs were included. Overall, ceftolozane-tazobactam had a clinical cure rate similar to comparators in the microbiological intent-to-treat (mITT) population (odds ratio [OR], 0.87; 95% confidence interval [CI], 0.43–1.79; I² = 73%) and in the clinically evaluable (CE) population (OR, 1.22; 95% CI, 0.79–1.88; I² = 0%). Furthermore, ceftolozane-tazobactam had a similar microbiological eradication rate for pathogens (OR, 1.31; 95% CI, 0.42–4.10; I² = 37%). There were no significant differences in the risks of treatment-emergent AEs (OR, 1.04; 95% CI, 0.87–1.23; I² = 0%), serious AEs (OR, 1.16; 95% CI, 0.67–1.99; I² = 37%), discontinuation of study drug due to an AE (OR, 0.77; 95% CI, 0.17–3.47) and mortality (OR, 1.62; 95% CI, 0.69–3.77, I² = 0%) between ceftolozane-tazobactam and comparators.ConclusionsThe clinical efficacy of ceftolozane-tazobactam is as high as that of comparators in the treatment of cIAIs and cUTIs in adult patients, and this antibiotic is well tolerated.     

Role of α1- and α2-GABA(A) receptors in mediating the respiratory changes associated with benzodiazepine sedation

BACKGROUND AND PURPOSE

The molecular substrates underlying the respiratory changes associated with benzodiazepine sedation are unknown. We examined the effects of different doses of diazepam and alprazolam on resting breathing in wild-type (WT) mice and clarified the contribution of α1- and α2-GABA_A receptors, which mediate the sedative and muscle relaxant action of diazepam, respectively, to these drug effects using point-mutated mice possessing either α1H101R- or α2H101R-GABA_A receptors insensitive to benzodiazepine.

EXPERIMENTAL APPROACH

Room air breathing was monitored using whole-body plethysmography. Different groups of WT mice were injected i.p. with diazepam (1–100 mg·kg⁻¹), alprazolam (0.3, 1 or 3 mg·kg⁻¹) or vehicle. α1H101R and α2H101R mice received 1 or 10 mg·kg⁻¹ diazepam or 0.3 or 3 mg·kg⁻¹ alprazolam. Respiratory frequency, tidal volume, time of expiration and time of inspiration before and 20 min after drug injection were analysed.

KEY RESULTS

Diazepam (10 mg·kg⁻¹) decreased the time of expiration, thereby increasing the resting respiratory frequency, in WT and α2H101R mice, but not in α1H101R mice. The time of inspiration was shortened in WT and α1H101R mice, but not in α2H101R mice. Alprazolam (1–3 mg·kg⁻¹) stimulated the respiratory frequency by shortening expiration and inspiration duration in WT mice. This tachypnoeic effect was partially conserved in α1H101R mice while absent in α2H101R mice.

CONCLUSIONS AND IMPLICATIONS

These results identify a specific role for α1-GABA_A receptors and α2-GABA_A receptors in mediating the shortening by benzodiazepines of the expiratory and inspiratory phase of resting breathing respectively.     

Comparison of the adverse event profiles of levofloxacin 500 mg and 750 mg in clinical trials for the treatment of respiratory infections

ABSTRACT

Objective: To compare safety data with levofloxacin 500?mg and 750?mg from clinical trials for the treatment of respiratory infections.

Methods: We compared adverse event data for levofloxacin 500?mg and 750?mg from clinical trials in acute bacterial sinusitis, acute bacterial exacerbation of chronic bronchitis, and community-acquired pneumonia. Adverse events occurring after the initiation of therapy were classified as treatment-emergent adverse events (TEAE); drug-related adverse events (DRAE) were TEAE assessed by the clinical investigator as definitely/very likely or probably related to levofloxacin therapy.

Results: Overall, the safety profile of the two doses was similar but not identical. TEAE occurred in 49.0% (1601/3268) of those treated with 500?mg and in 45.5% (519/1141) of those treated with 750?mg (?p = 0.042); the corresponding rates of DRAE were 7.6% (248/3268) and 8.0% (91/1141) (?p = 0.699). There was no statistically significant difference in terms of overall TEAE and DRAE rates within each of the three infectious conditions, but there were in specific events, all of which are expected with levofloxacin therapy. The limitations of this analysis include that it utilized a subset of available safety data, that it includes data only from clinical trials, and that we report primarily on events occurring in ≥ 2% of patients.

Conclusions: Given similar adverse event profiles and the advantages of higher dose therapy, including shorter courses of therapy and potential impact on preventing resistance, clinicians should consider utilizing the 750?mg dose of levofloxacin when choosing between dosage strengths for treatment of indicated infections.