A Cost-Utility Analysis of Remote Pulse-Oximetry Monitoring of Patients With COVID-19.

OBJECTIVES: Since 2020, COVID-19 has infected tens of millions and caused hundreds of thousands of fatalities in the United States. Infection waves lead to increased emergency department utilization and critical care admission for patients with respiratory distress. Although many individuals develop symptoms necessitating a ventilator, some patients with COVID-19 can remain at home to mitigate hospital overcrowding. Remote pulse-oximetry (pulse-ox) monitoring of moderately ill patients with COVID-19 can be used to monitor symptom escalation and trigger hospital visits, as needed. METHODS: We analyzed the cost-utility of remote pulse-ox monitoring using a Markov model with a 3-week time horizon and daily cycles from a US health sector perspective. Costs (US dollar 2020) and outcomes were derived from the University Hospitals' real-world evidence and published literature. Costs and quality-adjusted life-years (QALYs) were used to determine the incremental cost-effectiveness ratio at a cost-effectiveness threshold of $100 000 per QALY. We assessed model uncertainty using univariate and probabilistic sensitivity analyses. RESULTS: Model results demonstrated that remote monitoring dominates current standard care, by reducing costs ($11 472 saved) and improving outcomes (0.013 QALYs gained). There were 87% fewer hospitalizations and 77% fewer deaths among patients with access to remote pulse-ox monitoring. The incremental cost-effectiveness ratio was not sensitive to uncertainty ranges in the model. CONCLUSIONS: Patient with COVID-19 remote pulse-ox monitoring increases the specificity of those requiring follow-up care for escalating symptoms. We recommend remote monitoring adoption across health systems to economically manage COVID-19 volume surges, maintain patients' comfort, reduce community infection spread, and carefully monitor needs of multiple individuals from one location by trained experts.

Myoelectric Activation Pattern Changes in the Involved Limb of Individuals With Transtibial Amputation During Locomotor State Transitions.

OBJECTIVE: To investigate whether lower extremity muscle activation patterns differ in the strides leading to locomotive state transitions in the involved limb of individuals with transtibial amputation. It is hypothesized that all transitions elicit activation differences between strides as the subjects move toward the transition event. DESIGN: Single-sample, observational study. SETTING: University research center. PARTICIPANTS: Volunteer sample of persons with unilateral transtibial amputation (N=9; mean age, 48.8±12.1y; mean height, 1.74±0.09m; mean weight, 86.1±24.7kg) were recruited by posting flyers in local prosthetics clinics. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Surface electromyography was used to measure muscle activation from 7 muscles of the involved limb. Subjects walked across 8 different terrain conditions transitioning from level-ground to ramp/stair locomotion and vice versa. Statistical Parametric Mapping analysis of variance (α<.05) was used to assess muscle activation differences in the 3 pretransition gait cycles as subjects moved toward the terrain change. RESULTS: No muscle activation changes were observed in ramp transitions. All stair transitions elicited a myoelectric difference in at least 2 muscles. The transition from stair descent to level ground elicited change in the greatest number of muscles. Tibialis anterior activation was unchanged in all transitions. CONCLUSIONS: Muscle activation differences were observed in the involved limb of individuals with transtibial amputation during stair transitions, suggesting that those patterns may be successfully used in transition detection algorithms. It remains unknown whether ramp transitions can be successfully identified pretransition using electromyography.

Children referred for evaluation for ADHD: comorbidity profiles and characteristics associated with a positive diagnosis.

BACKGROUND: The symptoms of attention-deficit/hyperactivity disorder (ADHD) are non-specific, and a range of possible causes and comorbidities need to be considered in children referred for assessment. OBJECTIVE: To examine the factors associated with ADHD diagnosis following multidisciplinary assessment. METHODS: Children underwent multidisciplinary evaluation including parent and teacher questionnaires; semi-structured interview to screen for internalizing and externalizing diagnoses; paediatric, psychology and special education assessments; and case conference. Predictors of ADHD diagnosis were examined in univariable and multivariable logistic regression models. RESULTS: Data from 190 assessments (82% male, mean age 6.8 years) were included. ADHD was diagnosed in 132 (70%) cases, of which 77% had one or more comorbidities. In children not diagnosed with ADHD, 60% had one or more alternate diagnosis made. Teacher-reported ADHD symptom severity and learning difficulties were the strongest predictors of ADHD diagnosis. The pattern of comorbid/alternative diagnoses was similar between those diagnosed with ADHD and those not diagnosed with ADHD. CONCLUSIONS: Direct report from teachers is the most critical element of the clinical dataset for the evaluation for ADHD. These findings emphasize the importance of cross-situational impairment to ADHD diagnosis. The frequency and similarity of diagnoses in both groups highlight the overlapping nature of childhood developmental disorders, and the importance of evaluating for comorbid disorders regardless of the primary diagnosis.

A Novel Approach for Toe Off Estimation During Locomotion and Transitions on Ramps and Level Ground.

Identification of the toe off event is critical in many gait applications. Accelerometer threshold-based algorithms lack adaptability and have not been tested for transitions between locomotion states. We describe a new approach for toe off identification using one accelerometer in over ground and ramp walking, including transitions. The method uses invariant foot acceleration features in the segment of gait, where toe off is probable. Wavelet analysis of foot acceleration is used to derive a unique feature in a particular frequency band, yielding estimated toe off occurrence. We tested the new method for five conditions: over ground walking (W), ramp ascending (RA), ramp descending (RD); transitions between states (W-RA, W-RD). Mean absolute estimation error was 17.4 ± 12.5, 13.8 ± 8.5, and 22.0 ± 16.4 ms for steady states W, RA, and RD, 20.1 ± 15.5, and 17.1 ± 13.7 ms for transitions W-RA and W-RD, respectively. Algorithm performance was equivalent across all pairs of transition and locomotion state except between RA and RD ( p = 0.03), demonstrating adaptability. The db1 wavelet outperformed db2 across states and transitions (p < 0.01). The presented algorithm is a simple, robust approach for toe off detection.

High energy spectrogram with integrated prior knowledge for EMG-based locomotion classification.

Electromyogram (EMG) signal representation is crucial in classification applications specific to locomotion and transitions. For a given signal, classification can be performed using discriminant functions or if-else rule sets, using learning algorithms derived from training examples. In the present work, a spectrogram based approach was developed to classify (EMG) signals for locomotion mode. Spectrograms for each muscle were calculated and summed to develop a histogram. If-else rules were used to classify test data based on a matching score. Prior knowledge of locomotion type reduced class space to exclusive locomotion modes. The EMG data were collected from seven leg muscles in a sample of able-bodied subjects while walking over ground (W), ascending stairs (SA) and the transition between (W-SA). Three muscles with least discriminating power were removed from the original data set to examine the effect on classification accuracy. Initial classification error was <20% across all modes, using leave one out cross validation. Use of prior knowledge reduced the average classification error to <11%. Removing three EMG channels decreased the classification accuracy by 10.8%, 24.3%, and 8.1% for W, W-SA, and SA respectively, and reduced computation time by 42.8%. This approach may be useful in the control of multi-mode assistive devices.

12-Month comorbidity patterns and associated factors in Europe: results from the European Study of the Epidemiology of Mental Disorders (ESEMeD) project.

OBJECTIVE: Comorbidity patterns of 12-month mood, anxiety and alcohol disorders and socio-demographic factors associated with comorbidity were studied among the general population of six European countries. METHOD: Data were derived from the European Study of the Epidemiology of Mental Disorders (ESEMeD), a cross-sectional psychiatric epidemiological study in a representative sample of adults aged 18 years or older in Belgium, France, Germany, Italy, the Netherlands and Spain. The diagnostic instrument used was the Composite International Diagnostic Interview (WMH-CIDI). Data are based on 21 425 completed interviews. RESULTS: In general, high associations were found within the separate anxiety disorders and between mood and anxiety disorders. Lowest comorbidity associations were found for specific phobia and alcohol abuse-the disorders with the least functional disabilities. Comorbidity patterns were consistent cross-nationally. Associated factors for comorbidity of mood and anxiety disorders were female gender, younger age, lower educational level, higher degree of urbanicity, not living with a partner and unemployment. Only younger people were at greater risk for comorbidity of alcohol disorder with mood, anxiety disorders or both. CONCLUSION: High levels of comorbidity are found in the general population. Comorbidity is more common in specific groups. To reduce psychiatric burden, early intervention in populations with a primary disorder is important to prevent comorbidity.

Sampling and methods of the European Study of the Epidemiology of Mental Disorders (ESEMeD) project.

OBJECTIVE: The European Study of Epidemiology of Mental Disorders (ESEMeD) project was designed to evaluate the prevalence, the impact and the treatment patterns in Europe. This paper presents an overview of the methods implemented in the project. METHOD: ESEMeD is a cross-sectional study in a representative sample of 21 425 adults, 18 or older, from the general population of Belgium, France, Germany, Italy, the Netherlands and Spain. The Composite International Diagnostic Interview (WMH-CIDI) was administered by home interviews from January 2001 to August 2003 using Computer Assisted Personal Interview (CAPI) technology. Data quality was controlled to ensure reliability and validity of the information obtained. RESULTS: Response rate varied from 78.6% in Spain to 45.9% in France. Less than 4% of the individuals had errors in the checking procedures performed. CONCLUSION: The sampling methodologies, comprehensive psychiatric instruments and quality control procedures used have rendered the ESEMeD database a unique and important source of information about the prevalence, the disability burden and unmet medical needs of mental disorders within Europe.

Prevalence of mental disorders in Europe: results from the European Study of the Epidemiology of Mental Disorders (ESEMeD) project.

OBJECTIVE: To describe the 12-month and lifetime prevalence rates of mood, anxiety and alcohol disorders in six European countries. METHOD: A representative random sample of non-institutionalized inhabitants from Belgium, France, Germany, Italy, the Netherlands and Spain aged 18 or older (n = 21425) were interviewed between January 2001 and August 2003. DSM-IV disorders were assessed by lay interviewers using a revised version of the Composite International Diagnostic Interview (WMH-CIDI). RESULTS: Fourteen per cent reported a lifetime history of any mood disorder, 13.6% any anxiety disorder and 5.2% a lifetime history of any alcohol disorder. More than 6% reported any anxiety disorder, 4.2% any mood disorder, and 1.0% any alcohol disorder in the last year. Major depression and specific phobia were the most common single mental disorders. Women were twice as likely to suffer 12-month mood and anxiety disorders as men, while men were more likely to suffer alcohol abuse disorders. CONCLUSION: ESEMeD is the first study to highlight the magnitude of mental disorders in the six European countries studied. Mental disorders were frequent, more common in female, unemployed, disabled persons, or persons who were never married or previously married. Younger persons were also more likely to have mental disorders, indicating an early age of onset for mood, anxiety and alcohol disorders.

Disability and quality of life impact of mental disorders in Europe: results from the European Study of the Epidemiology of Mental Disorders (ESEMeD) project.

OBJECTIVE: This manuscript examines the impact of mental health state and specific mental and physical disorders on work role disability and quality of life in six European countries. METHOD: The ESEMeD study was conducted in: Belgium, France, Germany, Italy, the Netherlands and Spain. Individuals aged 18 years and over who were not institutionalized were eligible for an in-home computer-assisted interview. Common mental disorders, work loss days (WLD) in the past month and quality of life (QoL) were assessed, using the WMH-2000 version of the CIDI, the WHODAS-II, and the mental and physical component scores (MCS, PCS) of the 12-item short form, respectively. The presence of five chronic physical disorders: arthritis, heart disease, lung disease, diabetes and neurological disease was also assessed. Multivariate regression techniques were used to identify the independent association of mental and physical disorders while controlling for gender, age and country. RESULTS: In each country, WLD and loss of QoL increased with the number of disorders. Most mental disorders had approximately 1.0 SD-unit lower mean MCS and lost three to four times more work days, compared with people without any 12-month mental disorder. The 10 disorders with the highest independent impact on WLD were: neurological disease, panic disorder, PTSD, major depressive episode, dysthymia, specific phobia, social phobia, arthritis, agoraphobia and heart disease. The impact of mental vs. physical disorders on QoL was specific, with mental disorders impacting more on MCS and physical disorders more on PCS. Compared to physical disorders, mental disorders had generally stronger 'cross-domain' effects. CONCLUSION: The results suggest that mental disorders are important determinants of work role disability and quality of life, often outnumbering the impact of common chronic physical disorders.

Use of mental health services in Europe: results from the European Study of the Epidemiology of Mental Disorders (ESEMeD) project.

OBJECTIVE: Comprehensive information about access and patterns of use of mental health services in Europe is lacking. We present the first results of the use of health services for mental disorders in six European countries as part of the ESEMeD project. METHOD: The study was conducted in: Belgium, France, Germany, Italy, the Netherlands and Spain. Individuals aged 18 years and over who were not institutionalized were eligible for an computer-assisted interview done at home. The 21 425 participants were asked to report how frequently they consulted formal health services due to their emotions or mental health, the type of professional they consulted and the treatment they received as a result of their consultation in the previous year. RESULTS: An average of 6.4% of the total sample had consulted formal health services in the previous 12 months. Of the participants with a 12-month mental disorder, 25.7% had consulted a formal health service during that period. This proportion was higher for individuals with a mood disorder (36.5%, 95% CI 32.5-40.5) than for those with anxiety disorders (26.1%, 95% CI 23.1-29.1). Among individuals with a 12-month mental disorder who had contacted the health services 12 months previously, approximately two-thirds had contacted a mental health professional. Among those with a 12-month mental disorder consulting formal health services, 21.2% received no treatment. CONCLUSION: The ESEMeD results suggest that the use of health services is limited among individuals with mental disorders in the European countries studied. The factors associated with this limited access and their implications deserve further research.

Psychotropic drug utilization in Europe: results from the European Study of the Epidemiology of Mental Disorders (ESEMeD) project.

OBJECTIVE: To assess psychotropic drug utilization in the general population of six European countries, and the pattern of use in individuals with different DSM-IV diagnoses of 12-month mental disorders. METHOD: Data were derived from the European Study of the Epidemiology of Mental Disorders (ESEMeD/MHEDEA 2000), a cross-sectional psychiatric epidemiological study in a representative sample of 21 425 adults aged 18 or older from six European countries (e.g. Belgium, France, Germany, Italy, the Netherlands and Spain). Individuals were asked about any psychotropic drug use in the past 12 months, even if they used the drug(s) just once. A colour booklet containing high-quality pictures of psychotropic drugs commonly used to treat mental disorders was provided to help respondents recall drug use. RESULTS: Psychotropic drug utilization is generally low in individuals with any 12-month mental disorder (32.6%). The extent of psychotropic drug utilization varied according to the specific DSM-IV diagnosis. Among individuals with a 12-month diagnosis of pure major depression, only 21.2% had received any antidepressants within the same period; the exclusive use of antidepressants was even lower (4.6%), while more individuals took only anxiolytics (18.4%). CONCLUSION: These data question the appropriateness of current pharmacological treatments, particularly for major depression, in which under-treatment is coupled with the high use of non-specific medications, such as anxiolytics.

The interaction of saquinavir (soft gelatin capsule) with ketoconazole, erythromycin and rifampicin: comparison of the effect in healthy volunteers and in HIV-infected patients.

OBJECTIVE: The aim of this study was to compare the effect of ketoconazole, erythromycin and rifampicin on the pharmacokinetics of saquinavir soft-gelatin formulation (Fortovase; FTV) in healthy volunteers with that in HIV-infected patients at steady state after administration of 1200 mg three times daily. METHODS: In two open-labelled, randomised, crossover studies pharmacokinetic parameters were calculated in healthy volunteers who received on one occasion multiple doses of 1200 mg FTV three times daily alone and on the other occasion in combination with multiple doses of either 400 mg ketoconazole once daily or 600 mg rifampicin once daily. In another open-labelled, multicentre study, 33 HIV-infected patients underwent a pharmacokinetic assessment after 36-51 weeks of treatment with FTV and were then given additionally multiple doses of either 200 mg ketoconazole once daily, 250 mg erythromycin four times daily or 600 mg rifampicin once daily. Pharmacokinetic parameters of saquinavir were determined again at the end of the combination treatment. RESULTS: In healthy volunteers, coadministration of ketoconazole increased saquinavir area under the curve from time 0 to 8 h (AUC0-8 h) by 190% (95% CI: 90-343) whereas coadministration with rifampicin resulted in a decrease for AUC0-8 h by 70% (95% CI: 50-82). In HIV-infected patients, coadministration of ketoconazole and erythromycin increased AUC0-8 h of saquinavir by 69% (95% CI: 14-150) and 99% (95% CI: 33-198), respectively. When saquinavir was given together with rifampicin, exposure of saquinavir in terms of AUC0-8 h was decreased by 46% (95% CI: 18-65) compared with the baseline assessment. CONCLUSION: Interactions of saquinavir with ketoconazole, erythromycin and rifampicin were observed in healthy volunteers as well as patients. The effects observed in patients, however, appear to be less pronounced. The enzyme induction caused by rifampicin might lead to subtherapeutic levels of saquinavir and this finding appears to be of clinical relevance.

The leftward cradling bias and hemispheric asymmetry for speech prosody.

Most women prefer to cradle an infant to the left side. It has been suggested that this bias is due to the specialisation of the right hemisphere for emotion, but investigations of visual asymmetries found no empirical support for this proposal. In a recent article, Sieratzki and Woll (1996) suggested that more emphasis should be placed on the auditory, rather than the visual, modality. Using a dichotic listening procedure we investigated whether ear preference for the perception of emotion in speech was related to the lateral cradling bias. Although the findings of both a leftward lateral cradling bias and a left ear emotion perception advantage were replicated, we found no association between the two variables--and thus fail to support the recent suggestions of a possible cause for the lateral cradling bias.

Evidence that the inhibition of cartilage proteoglycan breakdown by mannosamine is not mediated via inhibition of glycosylphosphatidylinositol anchor formation.

The effect of mannosamine, an inhibitor of glycosylphosphatidylinositol (GPI) anchor formation, on chondrocyte-mediated cartilage proteoglycan breakdown was investigated using cartilage explant cultures. Mannosamine inhibited interleukin 1alpha-, tumour necrosis factor alpha- and retinoic acid-stimulated proteoglycan release from bovine nasal and articular cartilage, and retinoic acid-stimulated proteoglycan release from human cartilage. Its effects on two GPI-anchored proteins [the urokinase receptor, which binds urokinase-type plasminogen activator (uPA) to cell surfaces, and alkaline phosphatase] were also studied using bovine chondrocytes. Enzyme histochemistry and zymography demonstrated cell-associated uPA-like serine proteinase activity and PA activity respectively which was not reduced by treatment of chondrocytes with mannosamine at concentrations effective at inhibiting cartilage proteoglycan breakdown. Similarly, the activity of cell-associated alkaline phosphatase was not reduced, except at mannosamine concentrations much higher than those used to inhibit proteoglycan breakdown. These results demonstrate that inhibition of proteoglycan breakdown by mannosamine is too potent to be explained by an effect on GPI-anchor formation.

A serine proteinase inactivator inhibits chondrocyte-mediated cartilage proteoglycan breakdown occurring in response to proinflammatory cytokines.

The role played by serine proteinases with trypsin-like specificity in chondrocyte-mediated cartilage proteoglycan breakdown was investigated by use of a selective proteinase inactivator, 7-amino-4-chloro-3-(-3-isothiureidopropoxy)isocoumarin, in explant culture systems. This compound was a rapid inactivator of urokinase-type plasminogen activator. It potently inhibited interleukin 1- and tumor necrosis factor-stimulated proteoglycan release from both nasal and articular cartilage. Its less potent inhibition of basal and retinoic acid-stimulated release appeared to be due to cytotoxic effects. The functional half-life of the inactivator in culture medium was 95 min, and its concentration in cartilage was 2.5-fold higher than in the surrounding medium. Following spontaneous hydrolysis the breakdown products of the inactivator were unable to inhibit proteoglycan release. Trypsin-like activity was demonstrated by enzyme histochemistry to be chondrocyte-associated and inhibited by the serine proteinase inactivator. Cell-associated and secreted plasminogen activator activity was detected by zymography. These results suggest the involvement of a serine proteinase(s) with trypsin-like specificity, possibly urokinase-type plasminogen activator, in chondrocyte-mediated cartilage proteoglycan breakdown occurring as a result of stimulation with proinflammatory cytokines. Basal proteoglycan breakdown may occur via a different pathway. Our findings point to a pathological role for serine proteinase(s) in the development of cartilage diseases such as arthritis, possibly in a cascade which results in the activation of the enzyme(s) directly responsible for proteoglycan breakdown. It remains to be shown whether the target serine proteinase is urokinase-type plasminogen activator.

Cisatracurium besilate. A review of its pharmacology and clinical potential in anaesthetic practice.

Cisatracurium besilate (besylate) is a nondepolarising neuromuscular blocking agent with an intermediate duration of action. It is the R-cis, R'-cis isomer of atracurium besilate and is approximately 3-fold more potent than the mixture of isomers that constitute the parent drug. The ED95 for cisatracurium besilate (dose required to produce 95% suppression of twitch response to nerve stimulation) in adults is 0.05 mg/kg during N2O/O2 opioid anaesthesia. As for atracurium besilate, the primary route of elimination of cisatracurium besilate is by spontaneous degradation. Cisatracurium besilate is not associated with dose-related histamine release (at bolus doses of < or = 8 x ED95) and, consistent with this, has demonstrated cardiovascular stability in both healthy patients (< or = 8 x ED95) and those with coronary artery disease (< or = 6 x ED95). In clinical trials, cisatracurium besilate has been used successfully to facilitate intubation (at 2 to 4 x ED95) and as a muscle relaxant during surgery and in intensive care. Compared with vecuronium, cisatracurium besilate was associated with a significantly faster recovery after continuous infusion in patients in intensive care. Relative to atracurium besilate, cisatracurium besilate has a lower propensity to cause histamine release is more potent but has a slightly longer onset time at equipotent doses. It also offers a more predictable recovery profile than vecuronium after prolonged use in patients in intensive care. Thus, comparative data provide some indication of the potential of cisatracurium besilate as an intermediate-duration neuromuscular blocking agent but further comparisons with other like agents are required to define precisely its relative merits.

Nefazodone. A review of its pharmacology and clinical efficacy in the management of major depression.

Nefazodone hydrochloride is a phenylpiperazine antidepressant with a mechanism of action that is distinct from those of other currently available drugs. It potently and selectively blocks postsynaptic serotonin (5-hydroxytryptamine; 5-HT) 5-HT2A receptors and moderately inhibits serotonin and noradrenaline (norepinephrine) reuptake. In short term clinical trials of 6 or 8 weeks' duration, nefazodone produced clinical improvements that were significantly greater than those with placebo and similar to those achieved with imipramine, and the selective serotonin reuptake inhibitors (SSRIs) fluoxetine, paroxetine and sertraline. The optimum therapeutic dosage of nefazodone appears to be between 300 and 600 mg/day. Limited long term data suggest that nefazodone is effective in preventing relapse of depression in patients treated for up to 1 year. Analyses of pooled clinical trial results indicate that nefazodone and imipramine produces similar and significant improvements on anxiety- and agitation-related rating scales compared with placebo in patients with major depression. Short term tolerability data indicate that nefazodone has a lower incidence of adverse anticholinergic, antihistaminergic and adrenergic effects than imipramine. Compared with SSRIs, nefazodone causes fewer activating symptoms, adverse gastrointestinal effects (nausea, diarrhoea, anorexia) and adverse effects on sexual function, but is associated with more dizziness, dry mouth, constipation, visual disturbances and confusion. Available data also suggest that nefazodone is not associated with abnormal weight gain, seizures, priapism or significant sleep disruption, and appears to be relatively safe in overdosage. Nefazodone inhibits the cytochrome P450 3A4 isoenzyme and thus has the potential to interact with a number of drugs. Further long term and comparative studies will provide a more accurate assessment of the relative place of nefazodone in the management of major depression. Nonetheless, available data suggest that nefazodone is a worthwhile treatment alternative to tricyclic antidepressants and SSRIs in patients with major depression.

Fosfomycin tromethamine. A review of its antibacterial activity, pharmacokinetic properties and therapeutic efficacy as a single-dose oral treatment for acute uncomplicated lower urinary tract infections.

Fosfomycin tromethamine is a phosphonic acid bactericidal agent with in vitro activity against most urinary tract pathogens. It is particularly active against Escherichia coli, and Citrobacter, Enterobacter, Klebsiella, Serratia and Enterococcus spp. There appears to be little cross-resistance between fosfomycin and other antibacterial agents, possibly because it differs from other agents in its general chemical structure and site of action. In its new formulation as the oral tromethamine salt, fosfomycin has 34 to 41% oral bioavailability, has a mean elimination half-life of 5.7 hours, and is primarily excreted unchanged in the urine. Following a single 3 g oral dose, peak urinary concentrations occur within 4 hours and remain high (> 128 mg/L) for 24 to 48 hours, which is sufficient to inhibit most urinary tract pathogens. In clinical trials in patients with acute uncomplicated lower urinary tract infection, single-dose fosfomycin tromethamine therapy was effective, and comparable with several other antibacterial agents given either as single-dose or multiple-dose treatments [e.g. beta-lactam and fluoroquinolone agents, cotrimoxazole (trimethoprim-sulfamethoxazole), nitrofurantoin and pipemidic acid]. Bacteriological eradication rates of 75 to 90% were achieved 5 to 11 days after therapy, with eradication rates of 62 to 93% 4 to 6 weeks after therapy. In 3 large double-blind comparisons with ciprofloxacin, cotrimoxazole and nitrofurantoin, 99% of fosfomycin tromethamine recipients and 100% of patients receiving comparator agents were considered clinically cured or improved after therapy. Fosfomycin tromethamine is well tolerated, with a low incidence of adverse events. These comprise mainly gastrointestinal symptoms that are transient, mild and self-limiting. Thus, fosfomycin tromethamine achieves high clinical and bacteriological cure rates in patients with acute uncomplicated lower urinary tract infection and is well tolerated. The single-dose administration regimen and favourable US pregnancy category rating of fosfomycin tromethamine should also encourage its use in this indication.

Sparfloxacin. A review of its antibacterial activity, pharmacokinetic properties, clinical efficacy and tolerability in lower respiratory tract infections.

Sparfloxacin is a fluoroquinolone antibacterial agent with activity against a broad range of Gram-negative and Gram-positive organisms including Streptococcus pneumoniae, one of the main pathogens in community-acquired pneumonia. In this infection, sparfloxacin has shown efficacy similar to that of amoxicillin, erythromycin, roxithromycin, amoxicillin/clavulanic acid and amoxicillin plus ofloxacin, producing clinical cure rates of 80 to 84% assessed by intention-to-treat analyses in European or multinational trials. US studies showed similar results for sparfloxacin to those for erythromycin and cefaclor. Sparfloxacin was also as effective as all other comparator drugs in patients with other lower respiratory tract infections, usually acute exacerbations of chronic obstructive pulmonary disease (COPD). The profile of adverse effects for sparfloxacin is generally similar to that of other quinolones: gastrointestinal discomfort and CNS effects are the most common in clinical trials. Sparfloxacin causes fewer gastrointestinal disturbances than agents such as amoxicillin and erythromycin and doses not interact with theophylline, an important consideration when treating patients with respiratory disease. Its long elimination half-life permits once-daily dosage regimens. On the other hand, there are infrequent reports of prolonged QTc interval (3% increase) during sparfloxacin therapy. Photosensitivity occurs more frequently than with the other fluoroquinolones (2% of patients in an ongoing postmarketing study and 7.9% of those in US trials), and requires ongoing surveillance. In summary, the good activity of sparfloxacin against S. pneumoniae and other respiratory pathogens supports its use in lower respiratory tract infections, particularly community-acquired pneumonia. Its profile of good efficacy, once-daily dosage, good gastrointestinal tolerability and lack of interaction with theophylline are advantageous, but clinicians and patients must be alert to the possibility of photosensitivity reactions. On this basis, sparfloxacin, when appropriately prescribed, can provide the clinician with a useful alternative treatment option for these common infections.

Donepezil.

Donepezil is a specific and potent acetylcholinesterase inhibitor according to in vitro data. It displays primarily noncompetitive inhibitory activity. In vivo, donepezil inhibited acetylcholinesterase activity in human erythrocytes and increased extracellular acetylcholine levels in the cerebral cortex and hippocampus of the rat. Donepezil demonstrated efficacy in tests of reference memory in animals, but had less consistent activity in tests of working memory. Donepezil 5 or 10 mg/day was associated with significant improvements in cognitive function [assessed by the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog)] after 14 and 30 weeks and patient global function (Clinician's Interview-based Impression of Change incorporating caregiver input score) after 30 weeks, compared with placebo, in patients with mild to moderate Alzheimer's disease. After 2 years, donepezil 5 or 10 mg/day was associated with an ADAS-cog score approximately 4 points better than would be expected in untreated patients with mild to moderate Alzheimer's disease. The most common adverse events reported in association with donepezil 5 mg/day were gastrointestinal events (nausea/vomiting, diarrhoea, gastric upset and constipation) and dizziness. No hepatotoxicity was reported after 12 weeks' treatment.