Rescheduling hydrocodone combination products: Impact on patients receiving long-term HCP therapy in a large chain pharmacy-A statewide assessment.

OBJECTIVE: This study aimed to evaluate the rescheduling of hydrocodone combination products (HCPs) from schedule III (CIII) to schedule II (CII) in patients receiving chronic HCP therapy. METHODS: This study was a retrospective cohort analysis of administrative pharmacy data from 118 statewide pharmacies from a retail chain in Tennessee. HCP filling histories were analyzed on patients meeting enrollment criteria from July 1, 2014, to October 1, 2015. The average number of tablets dispensed, daily average of the number of tablets dispensed, and monthly average of morphine milligram equivalents (MME) dispensed were compared for the periods of July 1, 2014, to October 5, 2014 (enrollment period before schedule change) and October 6, 2014, to October 1, 2015 (period following schedule change) using a pooled t test. RESULTS: A total of 4536 patients met the inclusion criteria. Of these 4536 patients, 60.6% were female, and 40.4% were male, with an average age of 58 years (patients included in this study were between the ages of 18 and 99 years). The total number of hydrocodone tablets dispensed in the 12 periods after the schedule change dropped from 467,217 to 259,327, a 45.5% reduction (P < 0.001). Total MME decreased from 4.11 to 2.29 million, a 45.3% reduction (P < 0.001). The number of study participants still receiving an HCP at the end of the study decreased to an average of 2736 across the 12 periods following the schedule change, a 40% reduction. CONCLUSION: HCP dispensing and use decreased among patients receiving chronic opioid treatment from a large corporate statewide community pharmacy in Tennessee after a schedule change from CIII to CII. Monthly sums of total tablets dispensed, average daily tablets dispensed, MME, and average daily MME calculated from July 1, 2014, to October 1, 2015, all experienced statistically significant reductions.

A 24-hour perioperative case study on argatroban use for left ventricle assist device insertion during cardiopulmonary bypass and veno-arterial extracorporeal membrane oxygenation.

A 44-year-old male with ongoing chest pain and left ventricular ejection fraction <20% was transferred from a peripheral hospital with intra-aortic balloon pump placement following a non-ST-elevation myocardial infarction (STEMI). The patient underwent emergent multi-vessel coronary artery bypass grafting requiring veno-arterial (VA) extracorporeal membrane oxygenation (ECMO) on post-operative day (POD)#9 secondary to cardiogenic shock with biventricular failure. Due to clot formation, an oxygenator change-out was necessary shortly after initiation. Following a positive heparin-induced thrombocytopenia (HIT) assay, a total circuit exchange was required to eliminate all heparin coating and argatroban was deemed the anticoagulant of choice due to acute kidney injury. On POD#24, the decision was made to implant a left ventricle assist device (LVAD) as a bridge to heart transplantation. There was difficulty achieving an activated clotting time (ACT) >400 s: multiple argatroban bolus doses were required, along with accelerated up-titration of infusion dosing. Despite maintaining an ACT >484 s, clot formation was observed in the cardiotomy reservoir prior to separation. Subsequently, the patient developed severe disseminated intravascular coagulopathy, with both intra-cardiac and intravascular thrombi, requiring massive transfusion and continuous cell saving due to severe hemorrhage post cardiopulmonary bypass (CPB). The patient received a total of 105 units of plasma, 74 units of packed red cells, 19 units of platelets, 13 bottles of 5% albumin, 6 units of cryoprecipitate and 2 doses of factor VIIa intraoperatively over the course of 24 hours. A total of 19.7 L of washed red blood cells were returned to the patient from the cell saver. With the LVAD in place, the patient developed transfusion-related acute lung injury and acute respiratory distress syndrome with right ventricular dysfunction requiring VA ECMO once again. On POD#30, ECMO was discontinued and the patient was discharged from the intensive care unit (ICU) on POD 66. After a very complex post-operative stay with numerous surgeries and extensive rehabilitation, the patient was discharged home with the LVAD on POD#112.

Use of Optical Imaging Technology in the Validation of a New, Rapid, Cost-Effective Drug Screen as Part of a Tiered In Vivo Screening Paradigm for Development of Drugs To Treat Cutaneous Leishmaniasis.

In any drug discovery and development effort, a reduction in the time of the lead optimization cycle is critical to decrease the time to license and reduce costs. In addition, ethical guidelines call for the more ethical use of animals to minimize the number of animals used and decrease their suffering. Therefore, any effort to develop drugs to treat cutaneous leishmaniasis requires multiple tiers of in vivo testing that start with higher-throughput efficacy assessments and progress to lower-throughput models with the most clinical relevance. Here, we describe the validation of a high-throughput, first-tier, noninvasive model of lesion suppression that uses an in vivo optical imaging technology for the initial screening of compounds. A strong correlation between luciferase activity and the parasite load at up to 18 days postinfection was found. This correlation allows the direct assessment of the effects of drug treatment on parasite burden. We demonstrate that there is a strong correlation between drug efficacy measured on day 18 postinfection and the suppression of lesion size by day 60 postinfection, which allows us to reach an accurate conclusion on drug efficacy in only 18 days. Compounds demonstrating a significant reduction in the bioluminescence signal compared to that in control animals can be tested in lower-throughput, more definitive tests of lesion cure in BALB/c mice and Golden Syrian hamsters (GSH) using Old World and New World parasites.

Whole body perfusion for hybrid aortic arch repair: evolution of selective regional perfusion with a modified extracorporeal circuit.

BACKGROUND: Patients undergoing hybrid aortic arch reconstruction require careful protection of vital organs. We believe that whole body perfusion with tailored dual circuitry may help to achieve optimal patient outcomes. METHODS: Our circuit has evolved from a secondary circuit utilizing a cardioplegia delivery device for lower body perfusion to a dual-oxygenator circuit. This allows individually controlled regional perfusion with ease of switching from secondary to primary circuit for total body flow. The re-design allows for separate flow and temperature regulation with two oxygenators in parallel. All patients underwent a single-stage operation for simultaneous treatment of arch and descending aortic pathology via a sternotomy, using a hybrid frozen elephant trunk technique. RESULTS: We report six consecutive patients undergoing hybrid arch and frozen elephant trunk reconstruction using a dual-oxygenator circuit. Five patients underwent elective surgery and one was emergent. One patient had an acute dissection while three underwent concomitant procedures, including a Ross procedure and two valve-sparing root reconstructions. Three cases were redo sternotomies. The mean pump time was 358 ± 131 min, the aortic cross clamp time 243 ± 135 min, the cardioplegia volume of 33,208 ml ± 16,173, cerebral ischemia 0 min, lower body ischemia 76 ± 34 min and the average lower body perfusion time was 142 min. Two patients did not require any donor blood products. The median intensive care unit (ICU) and hospital lengths of stay (LOS) were two days and 10 days, respectively. The average peak serum lactate on CPB was 7.47 mmol/L and, at admission to the ICU, it was 3.37 mmol/L. Renal and respiratory failure developed in the salvage acute type A dissection patient. No other complications occurred in this series. CONCLUSIONS: Whole body perfusion as delivered through individually controlled dual-oxygenator circuitry allows maximum flexibility for hybrid aortic arch reconstruction. A modified circuit perfusion strategy may help to limit intra-operative metabolic derangements, providing improved clinical outcomes.

Interactive Care Model: A Framework for More Fully Engaging People in Their Healthcare.

Transformation of care delivery requires rethinking the relationship between the person and clinician. The model described provides a process to more fully engage patients in their care. Five encounters include assessing capacity for engagement, exchanging information and choices, planning, determining interventions, and evaluating the effectiveness of engagement interventions. Created by researchers and validated by experts, implications for practice, education, and policy are explored.

Rapid, high-fluence multi-pass q-switched laser treatment of tattoos with a transparent perfluorodecalin-infused patch: A pilot study.

BACKGROUND AND OBJECTIVES: Perfluorodecalin (PFD) has previously been shown to rapidly dissipate the opaque, white micro-bubble layer formed after exposure of tattoos to Q-switched lasers [1]. The current pilot study was conducted to qualitatively determine if the use of a transparent PFD-infused silicone patch would result in more rapid clearance of tattoos than conventional through-air techniques. MATERIALS AND METHODS: Black or dark blue tattoos were divided into two halves in a single-site IRB-approved study with 17 subjects with Fitzpatrick skin types I-III. One half of each tattoo served as its own control and was treated with one pass of a standard Q-switched Alexandrite laser (755 nm). The other half of the tattoo was treated directly through a transparent perfluorodecalin (PFD) infused patch (ON Light Sciences, Dublin, CA). The rapid whitening reduction effect of the Patch routinely allowed three to four laser passes in a total of approximately 5 minutes. Both sides were treated at highest tolerated fluence, but the optical clearing, index-matching, and epidermal protection properties of the PFD Patch allowed significantly higher fluence compared to the control side. Standard photographs were taken at baseline, immediately prior to treatment with the PFD Patch in place, and finally before and after each treatment session. Treatments were administered at 4- to 6-week intervals. RESULTS: In a majority of subjects (11 of 17), tattoos treated through a transparent PFD-infused patch showed more rapid tattoo clearance with higher patient and clinician satisfaction than conventional treatment. In no case did the control side fade faster than the PFD Patch side. No unanticipated adverse events were observed. CONCLUSIONS: Rapid multi-pass treatment of tattoos with highest tolerated fluence facilitated by a transparent PFD-infused patch clears tattoos more rapidly than conventional methods.

Interactive Care Model: A Framework for More Fully Engaging People in Their Healthcare.

Transformation of care delivery requires rethinking the relationship between the person and clinician. The model described provides a process to more fully engage patients in their care. Five encounters include assessing capacity for engagement, exchanging information and choices, planning, determining interventions, and evaluating the effectiveness of engagement interventions. Created by researchers and validated by experts, implications for practice, education, and policy are explored.

Innovation in prediction planning for anterior open bite correction.

This study applies recent advances in 3D virtual imaging for application in the prediction planning of dentofacial deformities. Stereo-photogrammetry has been used to create virtual and physical models, which are creatively combined in planning the surgical correction of anterior open bite. The application of these novel methods is demonstrated through the surgical correction of a case.

Assessment of the prophylactic activity and pharmacokinetic profile of oral tafenoquine compared to primaquine for inhibition of liver stage malaria infections.

BACKGROUND: As anti-malarial drug resistance escalates, new safe and effective medications are necessary to prevent and treat malaria infections. The US Army is developing tafenoquine (TQ), an analogue of primaquine (PQ), which is expected to be more effective in preventing malaria in deployed military personnel. METHODS: To compare the prophylactic efficacy of TQ and PQ, a transgenic Plasmodium berghei parasite expressing the bioluminescent reporter protein luciferase was utilized to visualize and quantify parasite development in C57BL/6 albino mice treated with PQ and TQ in single or multiple regimens using a real-time in vivo imaging system (IVIS). As an additional endpoint, blood stage parasitaemia was monitored by flow cytometry. Comparative pharmacokinetic (PK) and liver distribution studies of oral and intravenous PQ and TQ were also performed. RESULTS: Mice treated orally with three doses of TQ at 5 mg/kg three doses of PQ at 25 mg/kg demonstrated no bioluminescence liver signal and no blood stage parasitaemia was observed suggesting both drugs showed 100% causal activity at the doses tested. Single dose oral treatment with 5 mg TQ or 25 mg of PQ, however, yielded different results as only TQ treatment resulted in causal prophylaxis in P. berghei sporozoite-infected mice. TQ is highly effective for causal prophylaxis in mice at a minimal curative single oral dose of 5 mg/kg, which is a five-fold improvement in potency versus PQ. PK studies of the two drugs administered orally to mice showed that the absolute bioavailability of oral TQ was 3.5-fold higher than PQ, and the AUC of oral TQ was 94-fold higher than oral PQ. The elimination half-life of oral TQ in mice was 28 times longer than PQ, and the liver tissue distribution of TQ revealed an AUC that was 188-fold higher than PQ. CONCLUSIONS: The increased drug exposure levels and longer exposure time of oral TQ in the plasma and livers of mice highlight the lead quality attributes that explain the much improved efficacy of TQ when compared to PQ.

The semantics of time and space: a thematic analysis.

Three empirical studies and one analysis of pre-existing data were performed to determine the everyday meanings of time, a major component of phenomenological analyses of human experience. To this end, participants in Studies 1 and 2 sorted time related words into groups having similar meanings, with these groups then evaluated by hierarchical clustering procedures. Results of Studies 1 and 2 produced similar clustering patterns suggesting it was possible to define the everyday meanings of time in terms of experiences of change and continuity, linear organization, tempo, and boundaries. Results of Study 3 indicated little or no effect on clustering patterns of time words when space words also were included in the set of items to be sorted. Concerns about the size and representativeness of the words used as stimuli in Studies 1, 2 and 3 led to an analysis of over 2,000 words falling under the general heading of Time in Roget's Thesaurus. Results of this analysis revealed that clusters comparable to those obtained in the other three studies also appeared in these data. These results were discussed in terms of their implications for the way in which "invisible" concepts such as time are thought about and used, particularly as related to figurative expression.

Magnitude and persistence of higher estrus-associated temperatures in beef heifers and suckled cows.

Higher estrus-associated temperatures (HEAT) are a hallmark feature in sexually active females. The overarching aim of this study was to characterize the variability, magnitude, and persistence of HEAT in heifers and suckled beef cows as well as identify associated factors when occurring during thermoneutral conditions at the onset of the spring breeding season. In both heifers and cows, estrus was induced using a 7-d controlled internal drug release (CIDR)-PGF2α protocol. Vaginal temperature after prostaglandin F2α administration was recorded every 5 min using a Thermochron iButton affixed to a blank CIDR (containing no progesterone). Estrus was defined as when a heifer first stood to be mounted or when a cow had an Estrotect patch score of 3 or 4. Level of HEAT varied among individual animals. When comparing common HEAT variables using a mixed model with date nested within a year, maximum HEAT (39.9 ±â€…0.1 and 40.0 ±â€…0.1 °C) and duration (15.5 ±â€…0.8 and 15.4 ±â€…0.7) were similar in heifers and cows, respectively. However, the magnitude and persistence of HEAT differed. Total area under the HEAT curve was 117.1 ±â€…13.5 and 158.7 ±â€…12.3 for heifers vs cows, respectively (P = 0.0571). Further, 42.9% of heifers and 49% of cows had maximum HEAT ≥ 40 °C which persisted up to 6.5 and 10 h, respectively. When ambient conditions were predominantly thermoneutral, temperature humidity index had minimal impact on HEAT (mixed model, repeated measures over time). Toward identifying associated factors with different aspects of HEAT using best fit hierarchical linear regression models, baseline vaginal temperature and baseline duration were the most highly associated independent variables. Follicle size, estradiol and progesterone levels, and other available animal-related variables (e.g., age, weight, hair coat score) explained only a small amount of variation in HEAT. In summary, level of HEAT varies in estrus females even under thermoneutral conditions. Because HEAT can persist for an extended time, direct effects on fertility important components are unavoidable. Whether HEAT is a good or bad component of the periovulatory microenvironment is the basis of ongoing and future studies.

When striving for a pregnancy, estrus is a critically important event. Higher estrus-associated temperatures (HEAT) are a hallmark feature in sexually active females. The importance of HEAT for pregnancy, however, remains unclear. Toward filling this critical knowledge gap, efforts described in the current study focused on examining variability of HEAT in individual animals, 2) defining the magnitude and persistence of HEAT, 3) identifying HEAT-associated factors, and 4) examining the similarity of HEAT between heifers and suckled beef cows when occurring at the onset of a spring breeding season. Although the magnitude and persistence of HEAT varied, 42.9% of heifers and 49% of cows reached temperatures ≥ 40 °C which in some cases persisted up to 6.5 and 10 h, respectively. When attempting to identify factors that could explain why some females exhibiting estrus remained hot for an extended time, available animal and environmental data contributed little. Even so, because HEAT can persist for an extended time, direct effects on fertility important components are unavoidable. Whether too much HEAT is good or bad for pregnancy is the basis of ongoing and future studies.

Synthesis and In vitro Efficacy of Tetracyclic Benzothiazepines Against Blood-Stage Plasmodium falciparum and Liver-Stage P. berghei.

OBJECTIVE: A series of novel, substituted tetracyclic benzothiazepines were designed and prepared in an effort to optimize the potency of this chemical class against drug-resistant strains of the malaria parasite. METHODS: Tetracyclic benzothiazepines bearing structural modification at seven distinct positions within the structure were synthesized in Knoevenagel condensation reactions followed by sequential intermolecular thio-Michael and then intramolecular imine formation reactions. Following purification and chemical characterization, the novel compounds were tested for in vitro efficacy against blood-stage P. falciparum and liver-stage P. berghei and also for in vivo efficacy against P. berghei. RESULTS: Benzothiazepines bearing structural modification at the sulfur atom and at the three carbocycles within the molecule were successfully synthesized. The majority of analogs inhibited bloodstage P. falciparum with submicromolar IC50 values. The potency of an 8-methoxy-substituted analog 12 exceeded that of chloroquine in all three P. falciparum strains tested. The parent benzothiazepine 1 possessed liver-stage activity, inhibiting P. berghei sporozoites infecting HepG2 cells with an IC50 of 106.4 nM and an IC90 of 408.9 nM, but failed to enhance the longevity of P. berghei infected mice compared to the controls. Compounds displayed modest toxicity toward HepG2 cells and were tolerated by mice at the highest dose tested, 640 mg/kg/dose once daily for three days. CONCLUSION: The tetracyclic benzothiazepine described, which inhibits P. berghei infected hepatic cells with an IC50 of 106.4 nM, would appear to warrant further investigation. Optimization of ADME properties may be required since the most active analogs are probably excessively lipophilic.

Ketotifen is an antimalarial prodrug of norketotifen with blood schizonticidal and liver-stage efficacy.

Ketotifen is known to exhibit antimalarial activity in mouse and monkey malaria models. However, the low plasma levels and short half life of the drug do not adequately explain its in vivo efficacy. We synthesized most of the known metabolites of ketotifen and evaluated their antimalarial activity and pharmacokinetics in mice. Norketotifen, the de-methylated metabolite of ketotifen, was a more potent antimalarial in vitro as compared to ketotifen, and exhibited equivalent activity in vivo against asexual blood and developing liver-stage parasites. After ketotifen dosing, norketotifen levels were much higher than ketotifen relative to the IC50s of the compounds against Plasmodium falciparum in vitro. The data support the notion that the antimalarial activity of ketotifen in mice is mediated through norketotifen.

Prescribing recommendations for the treatment of acute pain in dentistry.

Effective acute pain management is an essential but sometimes challenging component of dental practice. Numerous studies have examined the efficacy of various analgesic agents in dental postoperative models. This article combines an evaluation of the available evidence with current prescribing patterns to provide dental practitioners prescribing recommendations for acute pain, based on the anticipated severity of post-procedural pain. An important consideration when prescribing analgesics is to determine for whom opioid analgesics are necessary and appropriate, and if so, the dose and quantity that should be prescribed. This is partly because of the prevalence of substance and alcohol abuse that can be expected to be encountered within the dental patient population, and because substance abusers in the community frequently obtain prescription drugs from friends and family for misuse.

Defining the role of mutations in Plasmodium vivax dihydrofolate reductase-thymidylate synthase gene using an episomal Plasmodium falciparum transfection system.

Plasmodium vivax resistance to antifolates is prevalent throughout Australasia and is caused by point mutations within the parasite dihydrofolate reductase (DHFR)-thymidylate synthase. Several unique mutations have been reported in P. vivax DHFR, and their roles in resistance to classic and novel antifolates are not entirely clear due, in part, to the inability to culture P. vivax in vitro. In this study, we use a homologous system to episomally express both wild-type and various mutant P. vivax dhfr (pvdhfr) alleles in an antifolate-sensitive line of P. falciparum and to assess their influences on the susceptibility of the recipient P. falciparum line to commonly used and new antifolate drugs. Although the wild-type pvdhfr-transfected P. falciparum line was as susceptible to antifolate drugs as the P. falciparum parent line, the single (117N), double (57L/117T and 58R/117T), and quadruple (57L/58R/61M/117T) mutant pvdhfr alleles conferred a marked reduction in their susceptibilities to antifolates. The resistance index increased with the number of mutations in these alleles, indicating that these mutations contribute to antifolate resistance directly. In contrast, the triple mutant allele (58R/61M/117T) significantly reversed the resistance to all antifolates, indicating that 61M may be a compensatory mutation. These findings help elucidate the mechanism of antifolate resistance and the effect of existing mutations in the parasite population on the current and new generation of antifolate drugs. It also demonstrates that the episomal transfection system has the potential to provide a rapid screening system for drug development and for studying drug resistance mechanisms in P. vivax.

Intraoperative techniques to reduce the potential of set-screw loosening in long spinal constructs: a static and fatigue biomechanical investigation.

STUDY DESIGN: The purpose of this study was to investigate the effects of implant selection and set-screw tightening technique on the loosening torques in long scoliosis constructs after long-term biaxial fatigue loading. SUMMARY OF BACKGROUND DATA: Expanded use of pedicle screws in the correction of long scoliotic curves and the mechanical demands on segmental fixation systems requires surgeon awareness of revisiting set screws to ensure full screw/rod engagement and minimize the potential of set-screw loosening and/or rod slippage postoperatively. METHODS: Biomechanical tests were performed to evaluate the effect of set-screw tightening techniques and rod approximation on screw/rod interface strength. RESULTS: Rod reduction test shows the force required to approximate a rod to a pedicle screw is statistically lower with uniplanar or polyaxial screws, when compared with monoaxial screws. This ease of approximation in both polyaxial and uniplanar screws directly correlate to improvement in the axial slippage resistance. In the simulated spinal model construct, rod/screw securement can vary based on the number of tightening torques applied to the system. CONCLUSIONS: Sequential revisiting of sets crews in long scoliosis constructs resulted in a statistically significant increase in loosening torque for monoaxial and polyaxial screw systems. Intraoperative securement assessment of set screws is recommended. The use of polyaxial and uniplanar screws at the distal ends in long constructs is recommended to increase the screw/rod interface strength.

Bringing all the players to the table: the West Virginia Controlled Substance Advisory Board.

Abuse and diversion of controlled substances are well-known problems in West Virginia and nationally. The costs to our society in both dollars and human capital are substantial. These problems touch groups as diverse as law enforcement, medical professionals, government leaders, addiction specialists, pain specialists, social workers, educators and regulatory boards, among others. The issues these groups face are varied and often unique to each profession, often resulting in a lack of communication and collaboration. This problem has been compounded by the fact that each group often makes decisions based on independent data related to substance abuse and diversion, which historically have not been shared due to privacy and other concerns. The West Virginia Controlled Substance Advisory Board was created to address these and other issues involved in drug diversion and substance abuse in West Virginia.

Understanding the cultures of prescription drug abuse, misuse, addiction, and diversion.

Prescription drug abuse, misuse, addiction, and diversion have reached epidemic proportions in the United States. The elimination of the burden of these activities on the healthcare system, the criminal justice system and society as a whole requires a multifaceted approach. Before resolution of these issues around prescription drugs can occur, a clear understanding of the cultures leading to these activities is required.

Multiple origins of resistance-conferring mutations in Plasmodium vivax dihydrofolate reductase.

BACKGROUND: In order to maximize the useful therapeutic life of antimalarial drugs, it is crucial to understand the mechanisms by which parasites resistant to antimalarial drugs are selected and spread in natural populations. Recent work has demonstrated that pyrimethamine-resistance conferring mutations in Plasmodium falciparum dihydrofolate reductase (dhfr) have arisen rarely de novo, but spread widely in Asia and Africa. The origin and spread of mutations in Plasmodium vivax dhfr were assessed by constructing haplotypes based on sequencing dhfr and its flanking regions. METHODS: The P. vivax dhfr coding region, 792 bp upstream and 683 bp downstream were amplified and sequenced from 137 contemporary patient isolates from Colombia, India, Indonesia, Papua New Guinea, Sri Lanka, Thailand, and Vanuatu. A repeat motif located 2.6 kb upstream of dhfr was also sequenced from 75 of 137 patient isolates, and mutational relationships among the haplotypes were visualized using the programme Network. RESULTS: Synonymous and non-synonymous single nucleotide polymorphisms (SNPs) within the dhfr coding region were identified, as was the well-documented in-frame insertion/deletion (indel). SNPs were also identified upstream and downstream of dhfr, with an indel and a highly polymorphic repeat region identified upstream of dhfr. The regions flanking dhfr were highly variable. The double mutant (58R/117N) dhfr allele has evolved from several origins, because the 58R is encoded by at least 3 different codons. The triple (58R/61M/117T) and quadruple (57L/61M/117T/173F, 57I/58R/61M/117T and 57L/58R/61M/117T) mutant alleles had at least three independent origins in Thailand, Indonesia, and Papua New Guinea/Vanuatu. CONCLUSION: It was found that the P. vivax dhfr coding region and its flanking intergenic regions are highly polymorphic and that mutations in P. vivax dhfr that confer antifolate resistance have arisen several times in the Asian region. This contrasts sharply with the selective sweep of rare antifolate resistant alleles observed in the P. falciparum populations in Asia and Africa. The finding of multiple origins of resistance-conferring mutations has important implications for drug policy.