A single-center qualitative study evaluating the safety and efficacy of a pharmacist-driven protocol for high-dose methotrexate management.

INTRODUCTION: Delayed methotrexate clearance in several patients admitted to the oncology unit at a regional medical center necessitated the development of a pharmacist-driven protocol for supportive therapy with high-dose methotrexate. This performance improvement project evaluated the impact of the protocol on inpatient length of stay, patient safety, and clinical outcomes. METHODS: Retrospective data were collected over 14 months pre-implementation and prospective data were collected over 19 months post-implementation. Primary outcomes included mean length of stay and incidence of kidney injury. Secondary outcomes included myelosuppression, treatment delays, mucositis, protocol adherence, and pharmacist interventions. Chi-squared and unpaired two sample t-test were used for data analysis. INTERVENTION: A literature review of consensus recommendations for supportive care post high-dose methotrexate administration was conducted to develop the protocol. Education on implementation was provided to involved disciplines. RESULTS: One-hundred ten high-dose methotrexate admissions for 23 patients were analyzed: 24 pre-protocol and 86 post-protocol. Mean length of stay was 5.17 nights pre-protocol and 3.91 nights post-protocol (p = 0.026). Incidence of kidney injury significantly decreased (16.7% pre-protocol versus 3.5% post-protocol; p = 0.0394). Lower incidences of all-grade anemia (83.3% versus 58.1%), neutropenia (62.5% versus 29.1%), and thrombocytopenia (58.3% versus 33.7%) as well as treatment delays (29.2% versus 11.6%; p = 0.036) were reported post protocol. No statistically significant difference in mucositis was detected. Pharmacist adherence to protocol was ≥80% resulting in 348 interventions with 99.4% provider acceptance. CONCLUSION: The implementation of a pharmacist-driven high-dose methotrexate management protocol resulted in a statistically significant decrease in inpatient length of stay and kidney injury. Further studies are needed to assess the impact on additional outcomes.

Modeling the Outcome of Systematic TPMT Genotyping or Phenotyping Before Azathioprine Prescription: A Cost-Effectiveness Analysis.

BACKGROUND: Thiopurine S-methyltransferase (TPMT) testing, either by genotyping or phenotyping, can reduce the incidence of adverse severe myelotoxicity episodes induced by azathioprine. The comparative cost-effectiveness of TPMT genotyping and phenotyping are not known. OBJECTIVE: Our aim was to assess the cost-effectiveness of phenotyping-based dosing of TPMT activity, genotyping-based screening and no screening (reference) for patients treated with azathioprine. METHODS: A decision tree was built to compare the conventional weight-based dosing strategy with phenotyping and with genotyping using a micro-simulation model of patients with inflammatory bowel disease from the perspective of the French health care system. The time horizon was set up as 1 year. Only direct medical costs were used. Data used were obtained from previous reports, except for screening test and admission costs, which were from real cases. The main outcome was the cost-effectiveness ratios, with an effectiveness criterion of one averted severe myelotoxicity episode. RESULTS: The total expected cost of the no screening strategy was €409/patient, the total expected cost of the phenotyping strategy was €427/patient, and the total expected cost of the genotyping strategy was €476/patient. The incremental cost-effectiveness ratio was €2602/severe myelotoxicity averted in using the phenotyping strategy, and €11,244/severe myelotoxicity averted in the genotyping strategy compared to the no screening strategy. At prevalence rates of severe myelotoxicity > 1%, phenotyping dominated genotyping and conventional strategies. CONCLUSION: The phenotype-based strategy to screen for TPMT deficiency dominates (cheaper and more effective) the genotype-based screening strategy in France. Phenotype-based screening dominates no screening in populations with a prevalence of severe myelosuppression due to azathioprine of > 1%.

Economic evaluation of trifluridine and tipiracil hydrochloride in the treatment of metastatic colorectal cancer in Greece.

AIM: To evaluate the cost-effectiveness of trifluridine and tipiracil hydrochloride (FTD/TPI) compared with best supportive care (BSC) or regorafenib for the treatment of patients with metastatic colorectal cancer who have been previously treated with or are not considered candidates for available therapies including fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapies, anti-VEGF agents and anti-EGFR agents in Greece. METHODS: A partitioned survival model was locally adapted from a third-party payer perspective over a 10 year time horizon. Efficacy data and utility values were extracted from published studies. Resource consumption data were obtained from local experts using a questionnaire developed for the purpose of the study and was combined with unit costs obtained from official sources. All costs reflect the year 2017 in euros. Primary outcomes were patients' life years (LYs), quality-adjusted life years (QALYs), total costs and incremental cost-effectiveness ratios (ICERs) per QALY and LYs gained. RESULTS: Total life time cost per patient for FTD/TPI, BSC and regorafenib was estimated to be €10,087, €1,879 and €10,850, respectively. In terms of health outcomes, FTD/TPI was associated with 0.25 and 0.11 increment in LYs compared with BSC and regorafenib, respectively. Furthermore, FTD/TPI was associated with 0.17, and 0.07 increment in QALYs compared with BSC and regorafenib, resulting in ICERs of €32,759 per LY gained and €49,326 per QALY gained versus BSC. Moreover, FTD/TPI was a dominant alternative over regorafenib. CONCLUSION: The results indicate that FTD/TPI may represent a cost-effective treatment option compared with other alternative therapies as a third-line treatment of metastatic colorectal cancer in Greece.

Eficacia y seguridad de mifamurtida en pacientes com diagnóstico de osteosarcoma osteoblástico no metastásico sin tratamiento sistémico previo, en el contexto de neoadyuvancia con quimioterapia mapi (metotrexate, doxorrubicina, cisplatino e ifosfamida) / Efficacy and safety of mifamurtide in patients with diagnosis of non-metastatic osteoblastic osteosarcoma without previous systemic treatment, in the context of neoadjuvant chemotherapy with mapi (methotrexate, doxorubicin, cisplatin and ifosfamide)

INTRODUCCIÓN: El presente informe expone la evaluación de tecnología sobre la eficacia y seguridad de mifamurtida, para el tratamiento de pacientes con osteosarcoma (OS) osteoblástico no metastásico sin tratamiento sistémico previo, en el contexto de neoadyuvancia com quimioterapia MAPI (metotrexato, doxorrubicina, cisplatino e ifosfamida). El osteosarcoma (OS) es un tumor maligno primario del esqueleto y la neoplasia primaria más común del hueso en niños y adultos jóvenes. Representa aproximadamente el 20% de todos los tumores óseos primarios malignos y el 0.2% de todos los tumores malignos. Su curva de distribución en cuanto a la edad es bimodal, con un primer pico en la adolescencia y otro después de los 65 años. La adición de quimioterapia agresiva adyuvante o neoadyuvante a la cirugía há mejorado considerablemente el pronóstico de los pacientes con enfermedad localizada, incrementando la tasa de curación de pacientes con OS en las extremidades y sin enfermedad metastásica evidente de 10-15% a 50-70%. OBJETIVO: El presente dictamen preliminar expone la evaluación de la tecnología sanitaria de la eficacia y seguridad de mifamurtida, para el tratamiento de pacientes com osteosarcoma (OS) osteoblástico no metastásico sin tratamiento sistémico previo, en el contexto de neoadyuvancia con quimioterapia MAPI (metotrexato, doxorrubicina, cisplatino e ifosfamida). TECNOLOGIA SANITARIA DE INTERES: La mifamurtida (Mepact, Takeda) es un compuesto químico biológicamente activo con actividad inmunomoduladora, clasificándose como un adyuvante biológico y perteneciente al grupo farmacoterapéutico de los inmunoestimulantes (36,37) . El compuesto es un derivado totalmente sintético del muramil dipéptido (MDP), el estimulante inmunológico natural más pequeño de las paredes celulares de micobacterias (37) . Al igual que la MDP, la mifamurtida es reconocida por el receptor de reconocimiento de patrones NOD2, localizado en varios tipos de glóbulos blancos, principalmente monocitos y macrófagos. De tal manera, mifamurtida simula una infección bacteriana, resultando en una activación de los macrófagos y un incremento en la producción de TNF-alfa, interleuquina 1, 6, 8 y 12, y moléculas de adhesión (e.g., ICAM-1 y LFA-1). METODOLOGÍA: Se llevó a cabo una búsqueda sistemática de la literatura con respecto a la eficacia y seguridad del uso de mifamurtida para el tratamiento de pacientes con osteosarcoma osteoblástico no metastásico sin tratamiento sistémico previo, en el contexto de neoadyuvancia con quimioterapia MAPI (metotrexato, doxorrubicina, cisplatino e ifosfamida). La búsqueda se realizó utilizando las bases de datos: National Library of Medicine (PubMed, 09/2017), Web of Science (WoS, 09/2017), y Centre for Reviews and Dissemination (CRD, 09/2017). Adicionalmente, se amplió la búsqueda revisando la evidencia generada por grupos internacionales que realizan revisiones sistemáticas (RS), evaluaciones de tecnologías sanitarias (ETS) y guías de práctica clínica (GPC), tales como The Cochrane Library (09/2017), The National Institute of Health and Care Excellence (NICE, 08/2017) del Reino Unido, The National Guidelines of Clearinghouse (NGC, 08/2017) de los Estados Unidos, The Scottish Intercollegiate Guidelines Network (SIGN, 08/2017) de Escocia, Australian Clinical Practice Guidelines (08/2017), The Royal Children's Hospital Melbourne Practice Guidelines de Australia (08/2017), CMA Infobase de la Canadian Medical Association (08/2017), American College of Physicians Clinical Practice Guidelines and Recommendations (08/2017) de los Estados Unidos, Guidelines International Network (GIN, 08/2017), New Zealand Guidelines Group (NZGG, 08/2017) de Nueva Zelanda, Guía Salud de España (08/2017, 08/2017), y el Centro Nacional de Excelencia Tecnológica en Salud (CENETEC) de México. Esta búsqueda se completo revisando publicaciones de grupos dedicados a la educación, investigación y mejora de la práctica clínica oncológica dentro de América y Europa, como The National Comprehensive Cancer Network (NCCN, 09/2017) de los Estados Unidos, y The European Society for Medical Oncology (ESMO, 08/2017). Por último, se completó la búsqueda ingresando a la página web www.clinicaltrials.gov, para así poder identificar ensayos clínicos en elaboración o que no hayan sido publicados aún, y así disminuir el riesgo de sesgo de publicación. RESULTADOS: se llevó a cabo una búsqueda bibliográfica y de evidencia científica hasta setiembre de 2017 relacionada al uso de mifamurtida en el tratamiento de pacientes con osteosarcoma (OS) osteoblástico no metastásico sin tratamiento sistémico previo, en el contexto de neoadyuvancia con quimioterapia MAPI (metotrexato, doxorrubicina, cisplatino e ifosfamida). Según las guías consultadas para pacientes con OS no metastásico resecable, referentes al uso de mifamurtida como parte del régimen quimioterapéutico MAPI neoadyuvante (pre-operatorio), no existen recomendaciones generales, unicamente algunas hacen mención al uso de mifamurtida en un contexto de adyuvancia (post-operatorio). El único ensayo clínico que evalúa el uso de mifamurtida dentro del régimen quimioterapéutico MAPI, lo hace en un contexto adyuvante, el cual reporta que no hubo una mejora estadísticamente significativa en relación a la sobreviva libre de eventos (HR 0.78, IC 95%: 0.54 ­ 1.2; p=0.22). Por otro lado, si bien se observó una aparente mejora en relación a la sobrevida global (HR 0.71; IC 95%, 0.52 ­ 0.96, valor p no reportado), es de notar que el límite superior del intervalo de confianza es marginal con respecto al valor nulo de no significancia estadística y que el valor p no ha sido reportado. Asimismo, estos resultados son invalidados por i) interacción observada entre mifamurtida y quimioterapia, afectando el análisis marginal del ensayo, ii) falta de poder estadístico para comparar individualmente los cuatro regímenes quimioterapéuticos evaluados, y iii) aparente falta de poder estadístico para evaluar el efecto de mifamurtida a los regímenes quimioterapéuticos sobre la sobrevida global. Actualmente, no se ha identificado ningún estudio publicado o en proceso dirigido a evaluar los efectos de la mifamurtida neoadyuvante en población con diagnóstico de OS no metastásico. Por lo tanto, no existe evidencia respecto a la eficacia y seguridad de mifamurtida en un contexto pre-operatorio. Se requiere de un ensayo clínico que evalúe la administración de mifamurtida, prévio a la resección del tumor, en la población de interés del presente dictamen. CONCLUSIÓN: El Instituto de Evaluación de Tecnologías en Salud e Investigación-IETSI no aprueba el uso de mifamurtida para el manejo de los pacientes com diagnóstico de osteosarcoma (OS) osteoblástico no metastásico sin tratamento sistémico en el contexto de neoadyuvancia con quimioterapia MAPI.

Avaliação da eficácia do mmp® com 5-fluoracil versus mmp® sem medicação versus injeção subcutânea de 5-fluoracil para tratamento de leucodermias solares: ensaio clínico randomizado, monocego / Efficacy assessment of mmp® with 5-fluoracil versus drug-free mmp® versus subcutaneous injection of 5-fluoracil for the treatment of solar leukoderma: a randomized, single-blind clinical trial

INTRODUÇÃO: Leucodermias solares geram preocupações estéticas para os pacientes e nenhum tratamento é primeira escolha na literatura. MÉTODOS: Ensaio clínico randomizado, monocego. Foram selecionados nove pacientes, com presença de pelo menos 10 lesões de leucodermia em cada antebraço, totalizando 180 lesões. Avaliou-se a eficácia de 2 sessões do MMP® com 5-Fluoracil comparado com MMP® sem medicação e 5-Fluoracil intralesional para tratamento das leucodermias de antebraços. RESULTADOS: Das lesões avaliadas segundo a eficácia, todas apresentaram repigmentação, o que indica melhora clínica com qualquer dos 3 tratamentos. O 5-FU isolado foi o mais eficaz, com significância estatística, seguido do MMP®+5-FU. O MMP® sem medicação foi o menos eficaz. Dentre os efeitos adversos, hiperpigmentação, ardor, prurido e dor não tiveram significância estatística ao fim do estudo. O eritema do MMP®+5-FU foi significativamente superior na maioria das visitas. Todos os pacientes relataram melhora clínica após os procedimentos. Maior relato de dor com a técnica de MMP® com ou sem medicação. DISCUSSÃO: A melhor eficácia do 5-FU em relação ao MMP®+5-Fluoracil poderia ser explicada pela diferente técnica de aplicação da medicação. Supõe-se que o MMP® foi o menos eficaz devido a não utilização do 5-FU. Não existem na literatura trabalhos com o uso de 5-FU intralesional ou MMP®+5-FU ou MMP® isolado para tratar leucodermias solares. O eritema persistente do MMP®+5-FU seria resultado do trauma somado a reação inflamatória induzida pelo 5-FU. CONCLUSÃO: Após 2 sessões de tratamento, o 5-FU mostrou-se o mais eficaz e com maior tolerabilidade pelos pacientes. Descritores: Leucodermia solar; 5-Fluoracil; MMP®; Dermatologia

D-Cycloserine acts via increasing the GluN1 protein expressions in the frontal cortex and decreases the avoidance and risk assessment behaviors in a rat traumatic stress model.

D-cycloserine (DCS), an FDA approved anti-tuberculosis drug has extensively been studied for its cognitive enhancer effects in psychiatric disorders. DCS may enhance the effects of fear extinction trainings in animals during exposure therapy and hence we investigated the effects of DCS on distinct behavioral parameters in a predator odor stress model and tested the optimal duration for repeated daily administrations of the agent. Cat fur odor blocks were used to produce stress and avoidance and risk assessment behavioral parameters were used where DCS or saline were used as treatments in adjunct to extinction trainings. We observed that DCS facilitated extinction training by providing further extinction of avoidance responses, risk assessment behaviors and increased the contact with the cue in a setting where DCS was administered before extinction trainings for 3 days without producing a significant tolerance. In amygdala and hippocampus, GluN1 protein expressions decreased 72h after the fear conditioning in the traumatic stress group suggesting a possible down-regulation of NMDARs. We observed that extinction learning increased GluN1 proteins both in the amygdaloid complex and the dorsal hippocampus of the rats receiving extinction training or extinction training with DCS. Our findings also indicate that DCS with extinction training increased GluN1 protein levels in the frontal cortex. We may suggest that action of DCS relies on enhancement of the consolidation of fear extinction in the frontal cortex.

Response assessment in Waldenström macroglobulinaemia: update from the VIth International Workshop.

This report represents a further update of the consensus panel criteria for the assessment of clinical response in patients with Waldenström macroglobulinaemia (WM). These criteria have been updated in light of further data demonstrating an improvement in categorical responses with new drug regimens as well as acknowledgement of the fact that such responses are predictive of overall outcome. A number of key changes are proposed but challenges do however remain and these include the variability in kinetics of immunoglobulin M (IgM) reduction with different treatment modalities and the apparent discrepancy between IgM and bone marrow/tissue response noted with some regimens. Planned sequential bone marrow assessments are encouraged in clinical trials.

[Comparative assessment of the methods of treatment of Condylomata acuminata].

The treatment of Condylomata acuminata often causes disappointment to both the physician and the patient since most of the current medical approaches require multiple examines while on the other hand success rates are low and recurrence rates remain high. The treatment approaches include surgical as well as non-surgical methods. The non-surgical treatment includes the application of local agents such as imiquimod, podophyllotoxin, and 5-fluorouracil. Other local agents, used in outpatient treatment settings, include trichloroacetic acid (TCA), podophyllin, or the intralesional application of agents such as interferon and bleomycin. The surgical methods include cryotherapy, electrosurgery, excision and laser therapy. Their major goal is the removal of the visible lesions. The development of the laser systems and the new HPV vaccines are a significant progress in the treatment and prevention of the HPV infections.

Management of hyperuricemia with rasburicase review.

Tumor lysis syndrome (TLS) is a serious complication in patients with hematological malignancies. Massive lysis of tumor cells can lead to hyperuricemia, hyperkalemia, hyperphosphatemia and hypocalcaemia. These metabolic disturbances may result in renal failure, because of precipitation of uric acid crystals and calcium phosphate salts in the kidney. The standard prophylaxis or treatment of hyperuricemia consists of decreasing uric acid production with allopurinol and facilitating its excretion by urinary alkalinization and hyperhydration. By inhibiting the enzyme xanthine oxidase, allopurinol blocks the conversion of hypoxanthine and xanthine into uric acid. An alternative treatment is urate oxidase which oxidates uric acid into allantoin. Allantoin is 5-10 times more soluble than uric acid and is therefore excreted easily. In several clinical trials rasburicase, the recombinant form of urate oxidase, has shown to be very effective in preventing and treating hyperuricemia. Rasburicase, in contrast with the non-recombinant form of urate oxidase uricozyme, is associated with a low incidence of hypersensitivity reactions. In addition to the demonstrated clinical benefit, rasburicase also proved to be a cost-effective option in the management of hyperuricemia.

Cyclosporine minimization and cost reduction in renal transplant recipients receiving a C2-monitored, cyclosporine-based quadruple immunosuppressive regimen.

BACKGROUND: Targeting 2-hr postdose cyclosporine (C2) levels to 1,000 to 1,700 mg/dL during the first 6 months after renal transplantation is recommended for triple immunosuppressive regimens. This trial determines whether lower C2 levels could be targeted safely in de novo kidney transplant recipients under a quadruple regimen compared with a similar cohort monitored with trough (C0) levels. METHODS: This single-center, sequential, cohort-designed trial included patients who received Thymoglobulin, corticosteroids, an antimetabolite, and cyclosporine monitored by C2 (n=50) or C0 (n=50). Cyclosporine was tapered to maintain the C2 between 1,000 and 1,200 ng/mL months 0 to 3 and between 600 and 1,000 ng/mL thereafter and C0 between 250 and 350 ng/mL months 0 to 3 and between 100 and 250 ng/mL thereafter. RESULTS: Baseline patient and donor characteristics were similar. There were no differences in graft survival (100% C2 vs. 100% C0), acute rejection (4% C2 vs. 6% C0), allograft function, or adverse events at 6 months. C2 levels were lower than the suggested guidelines throughout the study (33% lower at 1 month and 48% lower at 6 months). Lower cyclosporine doses were achieved in the C2 arm compared with the C0 arm by 1 month and were sustained throughout the trial, which translated into an average cyclosporine cost savings of USD $773 in the C2 arm during the 6-month period (P<0.001). CONCLUSION: With a quadruple immunosuppressive regimen and lower C2 targets than recommended for triple therapy, safe and effective cyclosporine minimization was achieved. Lower cyclosporine doses were achieved in C2-monitored patients compared with C0-monitored patients, translating into lower immunosuppressive costs.

Cost analysis of secondary prophylaxis with oral clodronate versus pamidronate in metastatic breast cancer patients.

OBJECTIVE: We compared the direct medical costs of secondary prophylaxis with bisphosphonates (BPs) in bone metastases (BMs) of breast cancer (BCa) from a payer perspective. PATIENTS AND METHODS: This study adopted an incidence-based chart review of consecutive BCa patients with BMs who received prophylactic treatment with orally administered (po) clodronate (CLODpo group), or intravenously administered (iv) pamidronate (PAM group) in 1997 at two large oncology centers in Toronto, Ontario. We evaluated the difference in costs of management of patients among the CLODpo and PAM groups using an intent-to-treat analysis from diagnosis of BMs to death, or last follow-up. The results are presented as observed mean and average lifetime (including terminal care) costs per patient. RESULTS: The observed mean costs in the PAM and CLODpo groups were 49,472 dollars and 50,307 dollars (2002 Canadian dollars), respectively. The difference in costs between the CLODpo (n=34) and PAM (n=18) groups was not significant (P=0.64), and remained robust after sensitivity analyses. The corresponding average lifetime costs were 65,677 dollars in the CLODpo group and 61,254 dollars in the PAM group. Inpatient and terminal care were the major cost drivers, comprising 45% and 25% of overall costs. Of all hospitalizations, 46% were associated with complications from BMs. CONCLUSIONS: Our analysis, which was based on a convenience sample, failed to reveal a statistically significant difference in the observed mean costs between groups of patients who initiated treatment with po clodronate versus iv pamidronate. The cost estimates from this study can be used for future corroborative economic analyses.

Treating Bowen's disease: a cost-minimization study.

BACKGROUND: In the current economic climate, it is important to justify the cost of treatments used in dermatology, particularly where cheaper alternatives exist. OBJECTIVES: To determine which treatment modality commonly used for Bowen's disease is associated with the lowest cost to the National Health Service. METHODS: A cost-minimization analysis was used to compare the following six treatments for Bowen's disease: cryotherapy, curettage and cautery, excision, laser ablation, photodynamic therapy and 5-fluorouracil. These are all known to have similar recurrence rates. Information regarding use of these treatment modalities was extracted from a literature review. Costs were determined from published data, average wholesale prices of medications, staff salary pay scales and health economics departments. RESULTS: The results show that, if treatment is indeed undertaken, a single lesion of Bowen's disease is most cheaply treated by curettage or excision biopsy under local anaesthetic, and most expensively treated by photodynamic therapy. The usefulness of this information has to be taken in the context of the study design, outcome measurements and base assumptions. CONCLUSIONS: Valid costing studies such as this, in conjunction with evidence of effectiveness and safety, can provide guidance for resource allocation and treatment decisions.

The use of antimetabolites with trabeculectomy: a critical appraisal.

PURPOSE: To examine why most ophthalmologists routinely use mitomycin C or 5-fluorouracil (antimetabolites) in association with filtering surgery for glaucoma. METHODS: Critical analysis of seven medical, social and economic trends. RESULTS: The rapid acceptance of the adjunctive use of antimetabolites at the time of filtration surgery may be explained by reasons other than anticipated increase in the "success" of glaucoma surgery. CONCLUSION: The use of antimetabolites in conjuction with filtering glaucoma surgery may be at least partially a consequence of changing medical-social-economic factors, rather than solely a desire on the part of physicians to improve the "success" of glaucoma surgery. This may indicate a need to reevaluate the proper place of antimetabolites in association with filtration surgery.

Clinical assessment of trough levels for monitoring of rejection in cyclosporine-treated kidney transplant recipients.

We evaluated whether trough cyclosporine (CYA) level monitoring was useful in the diagnosis of rejection within 2 weeks after transplantation. Rejection occurred in 14 out of 17 patients (82.3%) treated with CYA, mizoribine (MZR) and prednisolone (Pred) when trough CYA levels dropped below 70 ng/ml, suggesting the importance of trough level monitoring. When anti-lymphocyte globulin (ALG) was added to the 3 above-mentioned drugs, however, rejection occurred in only 1 patient (6.7%) and 2 patients (13.3%), respectively, within 1 week and 1-2 weeks after transplantation, suggesting that trough level monitoring is less important in patients treated with these 4 drugs.