Modelling to inform next-generation medical interventions for malaria prevention and treatment.

Global progress against malaria has stagnated and novel medical interventions to prevent malaria are needed to fill gaps in existing tools and improve protection against infection and disease. Candidate selection for next-generation interventions should be supported by the best available evidence. Target product profiles and preferred product characteristics play a key role in setting selection criteria requirements and early endorsement by health authorities. While clinical evidence and expert opinion often inform product development decisions, integrating modelling evidence early and iteratively into this process provides an opportunity to link product characteristics with expected public health outcomes. Population models of malaria transmission can provide a better understanding of which, and at what magnitude, key intervention characteristics drive public health impact, and provide quantitative evidence to support selection of use-cases, transmission settings, and deployment strategies. We describe how modelling evidence can guide and accelerate development of new malaria vaccines, monoclonal antibodies, and chemoprevention.

Efficacy of hydroxychloroquine for post-exposure prophylaxis to prevent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection among adults exposed to coronavirus disease (COVID-19): a structured summary of a study protocol for a randomised controlled trial.

OBJECTIVES: Primary Objective • To test the efficacy of Hydroxychloroquine (HCQ) (400 mg orally daily for 3 days then 200 mg orally daily for an additional 11 days, to complete 14 days) to prevent incident SARS-CoV-2 infection, compared to ascorbic acid among contacts of persons with SARS-CoV-2 infection Secondary objectives • To determine the safety and tolerability of HCQ as SARS-CoV-2 Post-exposure Prophylaxis (PEP) in adults • To test the efficacy of HCQ (400 mg orally daily for 3 days then 200 mg orally daily for an additional 11 days, to complete 14 days) to prevent incident SARS-CoV-2 infection 2 weeks after completing therapy, compared to ascorbic acid among contacts of persons with SARS-CoV-2 infection • To test the efficacy of HCQ to shorten the duration of SARS-CoV-2 shedding among those with SARS-CoV-2 infection in the HCQ PEP group • To test the efficacy of HCQ to prevent incident COVID-19 TRIAL DESIGN: This is a randomized, multi-center, placebo-equivalent (ascorbic acid) controlled, blinded study of HCQ PEP for the prevention of SARS-CoV-2 infection in adults exposed to the virus. PARTICIPANTS: This study will enroll up to 2000 asymptomatic adults 18 to 80 years of age (inclusive) at baseline who are close contacts of persons with polymerase chain reaction (PCR)-confirmed SARS-CoV-2 or clinically suspected COVID-19 and a pending SARS-CoV-2 PCR test. This multisite trial will be conducted at seven sites in Seattle (UW), Los Angeles (UCLA), New Orleans (Tulane), Baltimore (UMB), New York City (NYU), Syracuse (SUNY-Upstate), and Boston (BMC). Inclusion criteria Participants are eligible to be included in the study only if all of the following criteria apply: 1.Men or women 18 to 80 years of age inclusive, at the time of signing the informed consent2.Willing and able to provide informed consent3.Had a close contact of a person (index) with known PCR-confirmed SARS-CoV-2 infection or index who is currently being assessed for COVID-19 Close contact is defined as: a.Household contact (i.e., residing with the index case in the 14 days prior to index diagnosis or prolonged exposure within a residence/vehicle/enclosed space without maintaining social distance)b.Medical staff, first responders, or other care persons who cared for the index case without personal protection (mask and gloves)4.Less than 4 days since last exposure (close contact with a person with SARS-CoV-2 infection) to the index case5.Access to device and internet for Telehealth visits6.Not planning to take HCQ in addition to the study medication Exclusion criteria Participants are excluded from the study if any of the following criteria apply: 1.Known hypersensitivity to HCQ or other 4-aminoquinoline compounds2.Currently hospitalized3.Symptomatic with subjective fever, cough, or shortness of breath4.Current medications exclude concomitant use of HCQ5.Concomitant use of other anti-malarial treatment or chemoprophylaxis, including chloroquine, mefloquine, artemether, or lumefantrine.6.History of retinopathy of any etiology7.Psoriasis8.Porphyria9.Known bone marrow disorders with significant neutropenia (polymorphonuclear leukocytes <1500) or thrombocytopenia (<100 K)10.Concomitant use of digoxin, cyclosporin, cimetidine, amiodarone, or tamoxifen11.Known moderate or severe liver disease12.Known long QT syndrome13.Severe renal impairment14.Use of any investigational or non-registered drug or vaccine within 30 days preceding the first dose of the study drugs or planned use during the study period INTERVENTION AND COMPARATOR: Households will be randomized 1:1 (at the level of household), with close contact participants receiving one of the following therapies: •HCQ 400 mg orally daily for 3 days then 200 mg orally daily for an additional 11 days •Placebo-like control (ascorbic acid) 500 mg orally daily for 3 days then 250 mg orally daily for 11 days MAIN OUTCOMES: The primary outcome of the study is the incidence of SARS-CoV-2 infection through day 14 among participants who are SARS-CoV-2 negative at baseline by randomization group. RANDOMISATION: Participants will be randomized in a 1:1 ratio to HCQ or ascorbic acid at the level of the household (all eligible participants in 1 household will receive the same intervention). The randomization code and resulting allocation list will be generated and maintained by the Study Statistician. The list will be blocked and stratified by site and contact type (household versus healthcare worker). BLINDING (MASKING): This is a blinded study. HCQ and ascorbic acid will appear similar, and taste will be partially masked as HCQ can be bitter and ascorbic acid will be sour. The participants will be blinded to their randomization group once assigned. Study team members, apart from the Study Pharmacist and the unblinded statistical staff, will be blinded. Laboratory staff are blinded to the group allocation. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): The sample size for the study is N=2 000 participants randomized 1:1 to either HCZ (n=1 000) and ascorbic acid (n=1 000). TRIAL STATUS: Protocol version: 1.2 05 April 2020 Recruitment is ongoing, started March 31 and anticipated end date is September 30, 2020. TRIAL REGISTRATION: ClinicalTrials.gov, Protocol Registry Number: NCT04328961 Date of registration: April 1, 2020, retrospectively registered FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.

Adverse events and blinding in two randomized trials of hyperbaric oxygen for persistent post-concussive symptoms.

Safety monitoring and successful blinding are important features of randomized, blinded clinical trials. We report chamber- and protocol-related adverse events (AEs) for participants enrolled in two randomized, double-blind clinical trials of hyperbaric oxygen (HBO2) for persistent post-concussive symptoms clinicaltrials.gov identifiers NCT01306968, HOPPS, and NCT01611194, BIMA), as well as the success of maintaining the blind with a low-pressure sham control arm. In both studies, participants were randomized to receive HBO2 (1.5 atmospheres absolute, >99% oxygen) or sham chamber sessions (1.2 atmospheres absolute, room air). In 143 participants undergoing 4,245 chamber sessions, chamber-related adverse events were rare (1.1% in the HOPPS study, 2.2% in the BIMA study). Minor, non-limiting barotrauma was the most frequently reported. Rarely, some participants experienced headache with chamber sessions. No serious adverse events were associated with chamber sessions. An allocation questionnaire completed after intervention revealed that the sham control arm adequately protected the blind in both trials. Participants based allocation assumptions on symptom improvement or lack of symptom improvement and could not discern intervention arm by pressure, smell, taste, or gas flow.

Comparative ophthalmic assessment of patients receiving tafenoquine or chloroquine/primaquine in a randomized clinical trial for Plasmodium vivax malaria radical cure.

PURPOSE: Ophthalmic safety observations are reported from a clinical trial comparing tafenoquine (TQ) efficacy and safety versus sequential chloroquine (CQ)/primaquine (PQ) for acute Plasmodium vivax malaria. METHODS: In an active-control, double-blind study, 70 adult subjects with microscopically confirmed P. vivax malaria were randomized (2:1) to receive 400 mg TQ × 3 days or 1500 mg CQ × 3 days then 15 mg PQ × 14 days. MAIN OUTCOME MEASURES: clinically relevant changes at Day 28 and Day 90 versus baseline in the ocular examination, color vision evaluation, and corneal and retinal digital photography. RESULTS: Post-baseline keratopathy occurred in 14/44 (31.8%) patients with TQ and 0/24 with CQ/PQ (P = 0.002). Mild post-baseline retinal findings were reported in 10/44 (22.7%) patients receiving TQ and 2/24 (8.3%) receiving CQ/PQ (P = 0.15; treatment difference 14.4%, 95% CI - 5.7, 30.8). Masked evaluation of retinal photographs identified a retinal hemorrhage in one TQ patient (Day 90) and a slight increase in atrophy from baseline in one TQ and one CQ/PQ patient. Visual field sensitivity (Humphrey™ 10-2 test) was decreased in 7/44 (15.9%) patients receiving TQ and 3/24 (12.5%) receiving CQ/PQ; all cases were < 5 dB. There were no clinically relevant changes in visual acuity or macular function tests. CONCLUSIONS: There was no evidence of clinically relevant ocular toxicity with either treatment. Mild keratopathy was observed with TQ, without conclusive evidence of early retinal changes. Eye safety monitoring continues in therapeutic studies of low-dose tafenoquine (300 mg single dose). CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT01290601.

A randomized, double-blind, active-control trial to evaluate the efficacy and safety of a three day course of tafenoquine monotherapy for the treatment of Plasmodium vivax malaria.

BACKGROUND: Tafenoquine is an investigational 8-aminoquinoline for the prevention of Plasmodium vivax relapse. Tafenoquine has a long half-life and the potential for more convenient dosing, compared with the currently recommended 14-day primaquine regimen. METHODS: This randomized, active-control, double-blind trial was conducted in Bangkok, Thailand. Seventy patients with microscopically confirmed P. vivax were randomized (2:1) to tafenoquine 400 mg once daily for 3 days or 2500 mg total dose chloroquine phosphate (1500 mg chloroquine base) given over 3 days plus primaquine 15 mg daily for 14 days. Patients were followed to day 120. RESULTS: Day 28 adequate clinical response rate in the per-protocol population was 93% (40/43) (90%CI 83-98%) with tafenoquine, and 100% (22/22) (90%CI 87-100%) with chloroquine/primaquine. Day 120 relapse prevention was 100% (35/35) with tafenoquine (90%CI 92-100%), and 95% (19/20) (90%CI 78-100%) with chloroquine/primaquine. Mean (SD) parasite, gametocyte and fever clearance times with tafenoquine were 82.5 h (32.3), 49.1 h (33.0), and 41.1 h (31.4) versus 40.0 h (15.7), 22.7 h (16.4), and 24.7 h (17.7) with chloroquine/primaquine, respectively. Peak methemoglobin was 1.4-25.6% (median 7.4%, mean 9.1%) in the tafenoquine arm, and 0.5-5.9% (median 1.5%, mean 1.9%) in the chloroquine/primaquine arm. There were no clinical symptoms of methemoglobinemia in any patient. DISCUSSION: Although there was no difference in efficacy in this study, the slow rate of parasite, gametocyte and fever clearance indicates that tafenoquine should not be used as monotherapy for radical cure of P. vivax malaria. Also, monotherapy increases the potential risk of resistance developing to this long-acting agent. Clinical trials of single-dose tafenoquine 300 mg combined with standard 3-day chloroquine or artemisinin-based combination therapy are ongoing. TRIAL REGISTRATION: Clinicaltrials.gov NCT01290601.

Simple and Procedural Reaction Time for Mild Traumatic Brain Injury in a Hyperbaric Oxygen Clinical Trial.

Simple reaction time (SRT) and procedural reaction time (PRT) are speed-of-processing tasks in the Automated Neuropsychological Assessment Metrics (ANAM) that may be sensitive to mild traumatic brain injury (mTBI). The investigators measured SRT and PRT throughput (correct responses per minute) at baseline, 6 weeks, and 13 weeks in military personnel with mTBI randomized to local care or 40 chamber sessions (sham-1.2 atmospheres absolute [ATA] air, hyperbaric oxygen-1.5 ATA O2). Scores were assessed at baseline using univariate analysis of variance and across time with repeated measures methods. Data reported as throughput standard scores (mean = 100, SD = 15). Seventy-two participants with ongoing symptoms after mTBI enrolled in the study (three female, median age 31 years, mean three lifetime concussion events, most recent mTBI 23 months prior). Sixty-four had Automated Neuropsychological Assessment Metrics data at 13 weeks. SRT and PRT throughput standard scores were comparable across groups at baseline. Over time, SRT scores did not change in the hyperbaric oxygen or sham groups and decreased in the local care group. PRT throughput standard scores increased from baseline to mid-intervention and decreased from mid-intervention to postintervention in all groups. Repeated measures change over time in SRT (p = 0.23), and PRT (p = 0.17) scores were not different among groups. This study may be underpowered to detect statistically significant change.

Operation United Assistance: infectious disease threats to deployed military personnel.

As part of the international response to control the recent Ebola outbreak in West Africa, the Department of Defense has deployed military personnel to train Liberians to manage the disease and build treatment units and a hospital for health care volunteers. These steps have assisted in providing a robust medical system and augment Ebola diagnostic capability within the affected nations. In order to prepare for the deployment of U.S. military personnel, the infectious disease risks of the regions must be determined. This evaluation allows for the establishment of appropriate force health protection posture for personnel while deployed, as well as management plans for illnesses presenting after redeployment. Our objective was to detail the epidemiology and infectious disease risks for military personnel in West Africa, particularly for Liberia, along with lessons learned from prior deployments.

Effects of hyperbaric oxygen on symptoms and quality of life among service members with persistent postconcussion symptoms: a randomized clinical trial.

IMPORTANCE: Improvement has been anecdotally observed in patients with persistent postconcussion symptoms (PCS) after mild traumatic brain injury following treatment with hyperbaric oxygen (HBO). The effectiveness of HBO as an adjunctive treatment for PCS is unknown to date. OBJECTIVES: To compare the safety of and to estimate the efficacy for symptomatic outcomes from standard PCS care alone, care supplemented with HBO, or a sham procedure. DESIGN, SETTING, AND PARTICIPANTS: Multicenter, double-blind, sham-controlled clinical trial of 72 military service members with ongoing symptoms at least 4 months after mild traumatic brain injury enrolled at military hospitals in Colorado, North Carolina, California, and Georgia between April 26, 2011, and August 24, 2012. Assessments occurred before randomization, at the midpoint, and within 1 month after completing the interventions. INTERVENTIONS: Routine PCS care was provided in specialized clinics. In addition, participants were randomized 1:1:1 to 40 HBO sessions administered at 1.5 atmospheres absolute (ATA), 40 sham sessions consisting of room air at 1.2 ATA, or no supplemental chamber procedures. MAIN OUTCOMES AND MEASURES: The Rivermead Post-Concussion Symptoms Questionnaire (RPQ) served as the primary outcome measure. A change score of at least 2 points on the RPQ-3 subscale (range, 0-12) was defined as clinically significant. Change scores from baseline were calculated for the RPQ-3 and for the total RPQ. Secondary measures included additional patient-reported outcomes and automated neuropsychometric testing. RESULTS: On average, participants had sustained 3 lifetime mild traumatic brain injuries; the most recent occurred 23 months before enrollment. No differences were observed between groups for improvement of at least 2 points on the RPQ-3 subscale (25% in the no intervention group, 52% in the HBO group, and 33% in the sham group; P = .24). Compared with the no intervention group (mean change score, 0.5; 95% CI, -4.8 to 5.8; P = .91), both groups undergoing supplemental chamber procedures showed improvement in symptoms on the RPQ (mean change score, 5.4; 95% CI, -0.5 to 11.3; P = .008 in the HBO group and 7.0; 95% CI, 1.0-12.9; P = .02 in the sham group). No difference between the HBO group and the sham group was observed (P = .70). Chamber sessions were well tolerated. CONCLUSIONS AND RELEVANCE: Among service members with persistent PCS, HBO showed no benefits over sham compressions. Both intervention groups demonstrated improved outcomes compared with PCS care alone. This finding suggests that the observed improvements were not oxygen mediated but may reflect nonspecific improvements related to placebo effects. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01306968.

Field detection of Tembusu virus in western Thailand by rt-PCR and vector competence determination of select culex mosquitoes for transmission of the virus.

Tembusu virus (TMUV; Ntaya serocomplex) was detected in two pools of mosquitoes captured near Sangkhlaburi, Thailand, as well as from sera from sentinel ducks from the same area. Although TMUV has been isolated from several mosquito species in Asia, no studies have ever shown competent vectors for this virus. Therefore, we allowed mosquitoes captured near Sangkhlaburi to feed on young chickens that had been infected with TMUV. These mosquitoes were tested approximately 2 weeks later to determine infection, dissemination, and transmission rates. Culex vishnui developed high viral titers after feeding on TMUV-infected chicks and readily transmitted virus to naïve chickens. In contrast, Cx. fuscocephala seemed less susceptible to infection, and more importantly, zero of five fuscocephala with a disseminated infection transmitted virus by bite, indicating a salivary gland barrier. These results provide evidence for the involvement of Culex mosquitoes in the transmission of TMUV in the environment.

Triangular test design to evaluate tinidazole in the prevention of Plasmodium vivax relapse.

BACKGROUND: There are very few drugs that prevent the relapse of Plasmodium vivax malaria in man. Tinidazole is a 5-nitroimidazole approved in the USA for the treatment of indications including amoebiasis and giardiasis. In the non-human primate relapsing Plasmodium cynomolgi/macaque malaria model, tinidazole cured one of six macaques studied with an apparent mild delay to relapse in the other five of 14-28 days compared to 11-12 days in controls. One study has demonstrated activity against P. vivax in man. Presented here are the results of a pilot phase II, randomized, open-label study conducted along the Thai-Myanmar border designed to evaluate the efficacy of tinidazole to prevent relapse of P. vivax when administered with chloroquine. METHODS: This study utilized a modified triangular test sequential analysis which allows repeated statistical evaluation during the course of enrolment while maintaining a specified power and type 1 error and minimizing recruitment of subjects. Enrolment was to be halted when a pre-specified success/failure ratio was surpassed. The study was designed to have a 5% type 1 error and 90% power to show whether tinidazole would produce a relapse rate of less than 20% or greater than 45% through Day 63 of weekly follow-up after initiation of treatment and initial parasite clearance with 3 days of an oral weight based dosing of chloroquine and five days of 2 grams/day of tinidazole. RESULTS: All subjects cleared their parasitaemia by Day 3. Six of the first seven subjects treated with tinidazole relapsed prior to Day 63 (average Day 48.3 (range 42-56)). This exceeded the upper boundary of the triangular test and enrolment to receive tinidazole was halted. A concurrent cohort of five subjects definitively treated with standard doses of primaquine and chloroquine (historically 100% effective) showed no episodes of recurrent P. vivax parasitaemia during the 63-day protocol specified follow-up period. CONCLUSIONS: Tinidazole is ineffective in preventing relapse of P. vivax at the dose used. The macaque relapsing model appeared to correctly predict outcome in humans. Use of the modified triangular test allowed minimal enrolment and limited unnecessary exposure to the study drug and reduced costs. This adds weight to the ethical and economic advantages of this study design to evaluate similarly situated drugs. TRIAL REGISTRATION: ClinicalTrials.gov NCT00811096.

A simplified intravenous artesunate regimen for severe malaria.

BACKGROUND: We compared a conventional empirically derived regimen with a simplified regimen for parenteral artesunate in severe malaria. METHODS: This was a randomized, double-blind, placebo-controlled comparison to assess the noninferiority of a simplified 3-dose regimen (given at 0, 24, and 48 hours) compared with the conventional 5-dose regimen of intravenous artesunate (given at 0, 12, 24, 48, and 72 hours) in African children with Plasmodium falciparum malaria with a prespecified delta of 0.2. The total dose of artesunate in each group was 12 mg/kg. The primary end point was the proportion of children clearing ≥ 99% of their admission parasitemia at 24 hours. Safety data, secondary efficacy end points, and pharmacokinetics were also analyzed. RESULTS: In 171 children (per protocol), 78% of the recipients (95% confidence interval [CI], 69%-87%) in the 3-dose group achieved ≥ 99% parasite clearance 24 hours after the start of treatment, compared with 85% (95% CI, 77%-93%) of those receiving the conventional regimen (treatment difference, -7.2%; 95% CI, -18.9% to 4.4%). Dihydroartemisinin was cleared slightly more slowly in those children receiving the higher 3-dose regimen (7.4 vs 8.8 L/h for a 13-kg child; P 5 .008). CONCLUSIONS: Pharmacodynamic analysis suggests that 3 doses of artesunate were not inferior to 5 doses for the treatment of severe malaria in children. CLINICAL TRIALS REGISTRATION: NCT00522132.

Prolonged protection provided by a single dose of atovaquone-proguanil for the chemoprophylaxis of Plasmodium falciparum malaria in a human challenge model.

BACKGROUND: We conducted a randomized, placebo-controlled, double-blind trial to establish the efficacy of atovaquone-proguanil to prevent malaria with the goal of simulating weekly dosing in a human Plasmodium falciparum challenge model. METHODS: Thirty volunteers randomly received 1 of the following dose regimens: (1) 250 milligrams of atovaquone and 100 milligrams of proguanil (250/100 milligrams) 1 day prior to infectious mosquito challenge (day -1), (2) 250/100 milligrams on day 4 after challenge, (3) 250/100 milligrams on day -7, (4) 500 milligrams of atovaquone and 200 milligrams of proguanil (500/200 milligrams) on day -7 or, (5) 1000 milligrams of atovaquone and 400 milligrams of proguanil (1000/400 milligrams) on day -7. All regimens included matching placebo such that all volunteers received identical pill numbers. Six volunteers served as open-label infectivity controls. Volunteers underwent mosquito sporozoite challenge with P. falciparum 3D7 strain. Follow-up consisted of serial microscopy and close clinical monitoring for 90 days. RESULTS: Six of 6 infectivity controls developed parasitemia as expected. Two of 5 evaluable volunteers receiving 250/100 milligrams 7 days prior to challenge and 1 of 6 volunteers receiving 1000/400 milligrams 7 days prior to challenge were microscopically diagnosed with malaria. All other volunteers were protected. Atovaquone exposure (area under the curve) during liver stage development was low in 2 of 3 volunteers with prophylactic failure (423 and 199 ng/mL × days compared with a mean for protected volunteers of 1903 ng/mL × days), as was peak concentration (165 and 81 ng/mL compared with a mean of 594 ng/mL in volunteers with prophylactic success). Elimination half-life was short in volunteers with prophylactic failure (2.4, 2.0, and 3.3 days compared with a mean of 4.1 days in volunteers with prophylactic success). CONCLUSIONS: Single-dose atovaquone-proguanil provides effective malaria chemoprophylaxis against P. falciparum challenge at dosing intervals supportive of weekly dosing. Postexposure prophylaxis 4 days after challenge was 100% effective.

Plasmodium falciparum infection during suppressive prophylaxis with mefloquine does not induce an antibody response to merozoite surface protein-1(42).

A sensitive biomarker of malaria infection would obviate the need for placebo control arms in clinical trials of malaria prophylactic drugs. Antibodies to the 42-kDa fragment of merozoite surface protein-1 (MSP1(42)) have been identified as a potential marker of malaria exposure in individuals receiving prophylaxis with mefloquine. We conducted an open-label trial to determine the sensitivity of seroconversion to MSP1(42), defined as a fourfold rise in enzyme-linked immunosorbant assay (ELISA) titer, among 23 malaria naïve volunteers receiving mefloquine prophylaxis and 6 controls after Plasmodium falciparum sporozoite challenge. All members of the control cohort but none of the mefloquine cohort developed patent parasitemia. Four of six controls but zero of the mefloquine cohort seroconverted to MSP1(42). We conclude that malaria infection during suppressive prophylaxis does not induce antibody response to the blood-stage antigen MSP1(42) in a malaria-naïve study population.

Pharmacokinetic profiles of artesunate after single intravenous doses at 0.5, 1, 2, 4, and 8 mg/kg in healthy volunteers: a phase I study.

The pharmacokinetics of good manufacturing process injection of artesunate (AS) were evaluated after single doses at 0.5, 1, 2, 4, and 8 mg/kg with a 2-minute infusion in 40 healthy subjects. Drug concentrations were analyzed by validated liquid chromatography and mass spectrometry system (LC-MS/MS) procedures. The drug was immediately converted to dihydroartemisinin (DHA), with elimination half-lives ranging 0.12-0.24 and 1.15-2.37 hours for AS and DHA, respectively. Pharmacokinetic model-dependent analysis is suitable for AS, whereas DHA fits both model-dependent and -independent methods. Although DHA concentration was superior to that of AS with a 1.12-1.87 ratio of area under the curve (AUC)(DHA/AS), peak concentration of AS was much higher than that of DHA, with a 2.80- to 4.51-fold ratio of peak concentration (C(max AS/DHA)). Therefore, AS effectiveness has been attributed not only to its rapid hydrolysis to DHA, but also to itself high initial C(max).

Disseminated Mycobacterium marinum infection in a patient with rheumatoid arthritis receiving infliximab therapy.

Tumor necrosis factor-alpha inhibitors are important adjunctive therapies for rheumatologic diseases. These agents increase the risk for granulomatous disease. We present a case of a woman with severe rheumatoid arthritis on infliximab who developed multiple nodular skin lesions. Biopsies grew Mycobacterium marinum. New lesions developed through therapy, necessitating surgical debulking.