A Bayesian response-adaptive dose-finding and comparative effectiveness trial.

Combination spinal analgesic chemotherapy: a systematic review.

The value of acetaminophen-ibuprofen combination therapy over single therapy is uncertain in acute pediatric pain management. A model describing the interaction between these two drugs would be useful both for understanding current literature and for future study design. Published pooled time-effect profiles in adults given combination or single therapy after dental extraction were used to construct an interaction model. Pain was measured using pain intensity differences (PRID, 0-10) from zero to eight hours postoperatively. Pharmacodynamic parameter estimates were assumed the same in adults as children. Pediatric pharmacokinetic estimates were scaled using allometric theory. Curve fitting was performed using nonlinear mixed effects models. Pooled data were available in adults given eight single and multiple dose combinations as well as placebo. The ibuprofen dose range was 100-400 mg, and acetaminophen dose range was 500-1000 mg. Pharmacodynamic parameter estimates, expressed using the Hill equation, were maximum effect (E(MAX) ) 4.06 (95% CI: 3.24, 5.51), the concentration of acetaminophen associated with 50% of the maximal drug effect (EC(50,ACET) ) 11.9 (95% CI: 6.0, 49.5) mg·l(-1) , the ibuprofen EC(50) (EC(50,IBU) ) 5.07 (95% CI: 3.50, 8.26) mg·l(-1), and Hill coefficient 2 (95% CI: 1.3, 2.8). An interaction term was fixed at zero (additive interaction). Simulation showed that the addition of acetaminophen to ibuprofen when less than 5 mg·kg(-1) was effective; acetaminophen had minimal effect when given with ibuprofen at doses greater than 5 mg·kg(-1) in the immediate postoperative period. A more sustained analgesic effect was noted at 4-8 h after combination dosing. This drug interaction modeling example is useful to explain combination therapy nuances and impacts on study design. Differences in effect between single drug therapy and combination therapy should be sought at lower doses and beyond the immediate postoperative period. Combination therapy may prolong the duration of analgesia. The maximum effect (E(MAX) ) limits the early additional analgesic gain from combination therapy beyond commonly used doses.

Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related deaths in the US. Treatment most commonly relies on ionizing radiation (IR) and platinum-based DNA damaging agents, but long-term survival is poor and patients tend to suffer chronic side-effects due to the high radiation dose to the surrounding normal tissues. Therefore, new treatments are needed that can be used in combination lower radiation doses. We have recently reported that low, non-cytotoxic doses Poly ADP ribose polymerase inhibitors (PARPi) Talazoparib in combination with DNA methyltransferase inhibitors (DNMTi) Decitabine (DAC) or azacytidine (AZA) significantly increase cytotoxicity in acute myeloid leukemia and breast cancer models in vitro and anti-tumor effects in vivo. Simultaneous administration of both inhibitors result in increased PARP binding in DNA, leading to higher levels of DNA double strand breaks (DSBs), yielding increased cytotoxicity, compared with each agent treatment alone. We first studied the efficacy of Talazoparib and AZA combination therapy in multiple NSCLC cell lines (A549, H358 and H838) in vitro through colony forming assays. Results showed, compared to single agent treatments, combination drug treatment significantly decreased colony formation. Cell viability was also significantly decreased with the drug combination in MTS assays (P<0.05). These results also showed synergistic activity between the two drugs, with a combination index of less than 1 for all tested NSCLC cell lines. Importantly, the drug combination increased PARP trapping in chromatin and DSB formation, as measured by immunofluorescent staining for γH2AX. We next determined whether AZA/Talazoparib in combination with a single dose of radiation (2Gy) had an increased anti-cancer effect compared to each modality alone in in vivo mouse xenografts of NSCLC A549. While the combination of PARPi+DNMTi with radiation treatment decreased tumor growth, compared to PARPi/DNMTi alone or RT alone, no significant enhancement with radiation was observed. We next determined whether low doses of fractionated IR (2Gy 3 fractions) would improve the efficacy of DNTMi and PARPi combination treatment. In vitro studies with colony forming assays of NSCLC cell line A549 show that IR doses in combination with PARPi and DNMTi decrease clonogenicity, compared with non-IR controls. Furthermore, A549 xenografts were treated with the drug combination and then irradiated 1 week later with 2Gy daily for 3 consecutive days. Mice treated with the drug combination followed by IR had significant decreases in tumor volume and survival (P<0.05). This suggests that low doses of PARPi and DNMTi therapy in combination with low dose IR can potentially target NSCLC tumors. This represents a novel treatment approach for NSCLC patients that may reduce chronic side-effects of high dose IR. Citation Format: Christopher Biondi, Daniel Fontaine, Lora Stojanovic, Pratik Nagaria, Rena Lapidus, Eun Yong Choi, Javed Mahmood, Stephen Baylin, Feyruz V. Rassool. Enhancing the therapeutic effects of PARP inhibitors in combination DNA methyl transferase inhibitors, using low doses of ionizing radiation in non small cell lung cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1422. doi:10.1158/1538-7445.AM2017-1422

In cancer treatment, the development of combination therapies requires demonstrating the contribution of each individual drug and optimizing the dose during early-phase trials. This necessitates a large sample size, presenting formidable obstacles for drug developers. To address this issue, we propose a 2-stage randomized phase II design that seamlessly integrates combination dose optimization with component contribution assessment. In stage 1, the optimal combination dose is determined by maximizing the risk-benefit tradeoff across multiple candidate combination doses. In stage 2, a multi-arm randomized phase is initiated to evaluate the contribution of each component within the combination therapy. To increase trial efficiency and reduce the sample size, efficacy data from both stages are adaptively combined using a Bayesian logistic regression model with a spike-and-slab prior. The sample size and decision cutoffs of the proposed design are systematically determined based on a novel calibration procedure to achieve desired operating characteristics. Extensive simulation studies show that the proposed design achieves the dual goals of dose optimization and contribution assessment, while yielding substantial sample size savings compared to competing designs.

The time is right for the use of Bayesian Adaptive Designs (BAD) in comparative effectiveness trials. For example, Patient Centered Outcomes Research Institute has joined the Food and Drug Administration and National Intitutes of Health in adopting policies/guidelines encouraging their use. There are multiple aspects to BAD that need to be considered when designing a comparative effectiveness design. First, the adaptation rules can determine the expected size of the trial. Second, a utility function can be used to combine extremely important co-endpoints (e.g., efficacy and tolerability) and is a valuable tool for incorporating clinical expertise and potentially patient preference. Third, accrual rate is also very, very important. Specifically, there is a juxtaposition related to accrual and BAD. If accrual rate is too fast we never gain efficient information for adapting. If accrual rate is too slow we never finish the clinical trial. We propose methodology for finding the 'sweet spot' for BAD that addresses these as design parameters. We demonstrate the methodology on a comparative effectiveness BAD of pharmaceutical agents in cryptogenic sensory polyneuropathy. The study has five arms with two endpoints that are combined with a utility function. The accrual rate is assumed to stem from multiple sites. We perform simulations from which the composite accrual rates across sites result in various piecewise Poisson distributions as parameter inputs. We balance both average number of patients needed and average length of time to finish the study.

We appreciate the opportunity to clarify and refute the serious issues raised by Dr. Chou in the rebuttal to our response to his letter. The main question he posed is how a probabilistic/statistical approach can lead to a quantitative/deterministic equation based on the mass-action law. He also

Rhabdomyosarcoma (RMS) is a highly metastatic soft-tissue sarcoma that often develops resistance to current therapies, including vincristine. Since the existing treatments have not significantly improved survival, there is a critical need for new therapeutic approaches for RMS patients. FOXM1, a known oncogene, is highly expressed in RMS, and is associated with the worst prognosis in RMS patients. In the present study, we found that the combination treatment with specific FOXM1 inhibitor RCM1 and low doses of vincristine is more effective in increasing apoptosis and decreasing RMS cell proliferation in vitro compared to single drugs alone. Since RCM1 is highly hydrophobic, we developed innovative nanoparticle delivery system containing poly-beta-amino-esters and folic acid (NPFA), which efficiently delivers RCM1 to mouse RMS tumors in vivo. The combination of low doses of vincristine together with intravenous administration of NPFA nanoparticles containing RCM1 effectively reduced RMS tumor volumes, increased tumor cell death and decreased tumor cell proliferation in RMS tumors compared to RCM1 or vincristine alone. The combination therapy was non-toxic as demonstrated by liver metabolic panels using peripheral blood serum. Using RNA-seq of dissected RMS tumors, we identified Chac1 as a uniquely downregulated gene after the combination treatment. Knockdown of Chac1 in RMS cells in vitro recapitulated the effects of the combination therapy. Altogether, combination treatment with low doses of vincristine and nanoparticle delivery of FOXM1 inhibitor RCM1 in a pre-clinical model of RMS has superior anti-tumor effects and decreases CHAC1 while reducing vincristine toxicity.

Aim To evaluate the real-world comparative effectiveness and the cost-effectiveness, from a UK National Health Service perspective, of natalizumab versus fingolimod in patients with rapidly evolving severe relapsing-remitting multiple sclerosis (RES-RRMS). Methods Real-world data from the MSBase Registry were obtained for patients with RES-RRMS who were previously either naive to disease-modifying therapies or had been treated with interferon-based therapies, glatiramer acetate, dimethyl fumarate, or teriflunomide (collectively known as BRACETD). Matched cohorts were selected by 3-way multinomial propensity score matching, and the annualized relapse rate (ARR) and 6-month–confirmed disability worsening (CDW6M) and improvement (CDI6M) were compared between treatment groups. Comparative effectiveness results were used in a cost-effectiveness model comparing natalizumab and fingolimod, using an established Markov structure over a lifetime horizon with health states based on the Expanded Disability Status Scale. Additional model data sources included the UK MS Survey 2015, published literature, and publicly available sources. Results In the comparative effectiveness analysis, we found a significantly lower ARR for patients starting natalizumab compared with fingolimod (rate ratio [RR] = 0.65; 95% confidence interval [CI], 0.57–0.73) or BRACETD (RR = 0.46; 95% CI, 0.42–0.53). Similarly, CDI6M was higher for patients starting natalizumab compared with fingolimod (hazard ratio [HR] = 1.25; 95% CI, 1.01–1.55) and BRACETD (HR = 1.46; 95% CI, 1.16–1.85). In patients starting fingolimod, we found a lower ARR (RR = 0.72; 95% CI, 0.65–0.80) compared with starting BRACETD, but no difference in CDI6M (HR = 1.17; 95% CI, 0.91–1.50). Differences in CDW6M were not found between the treatment groups. In the base-case cost-effectiveness analysis, natalizumab dominated fingolimod (0.302 higher quality-adjusted life-years [QALYs] and £17,141 lower predicted lifetime costs). Similar cost-effectiveness results were observed across sensitivity analyses. Conclusions This MSBase Registry analysis suggests that natalizumab improves clinical outcomes when compared with fingolimod, which translates to higher QALYs and lower costs in UK patients with RES-RRMS.

We propose a rule-based statistical design for combination dose-finding trials with two agents. The Ci3 + 3 design is an extension of the i3 + 3 design with simple up-and-down decision rules comparing the observed toxicity rates and equivalence intervals that define the maximum tolerated dose combination. Ci3 + 3 consists of two stages to allow fast and efficient exploration of the dose-combination space. Statistical inference is restricted to a beta-binomial model for dose evaluation, and the entire design is built upon a set of fixed rules. We show via simulation studies that the Ci3 + 3 design exhibits similar and comparable operating characteristics to more complex designs utilizing model-based inferences. Implementation of Ci3 + 3 for practical trials is simple for the first stage, where the up-and-down decisions may be carried out using a decision table based on the preselected escalation path and i3 + 3. The second stage is not simpler than model-based designs, however, since it also requires computation of posterior probabilities based on a Bayesian model. We believe that the Ci3 + 3 design may provide an alternative choice to help simplify the design and conduct of combination dose-finding trials in practice.

Most hypolipidemic drugs can not normalize plasma cholesterol and LDL levels in type II hyperlipoproteinemia (HLP) when used alone. Furthermore, combinations of many hypolipidemic agents can have additive effects.In this study, we investigated the effects of niceritrol-probucol combination therapy on serum lipid and apoprotein concentrations in type II HLP.Thirty one type II HLP (28; IIa, 3; IIb) patients were treated with probucol (500mg/day) for more than 12 weeks, then niceritrol (500-1, 500mg/day) was added to the treatment regimen. In six patients, medication of niceritrol was ferminated after combined treatment.Total cholesterol (TC) was reduced from 307mg/dl to 273mg/dl (10% of reduction) by probucol alone and further reduced to 235mg/dl (14% of further reduction) by combination therapy with niceritrol. Total reduction rate of TC was 23% by combination therapy. Additionally, LDL-c was reduced 9% by probucol alone and a further 14% by combination treatment. Total reduction rate of LDL-c was 23% by combination therapy. HDL-c was reduced 23% by probucol alone, but no further reduction was observed in the combination period. Hence, the atherogenic Index (AI) was reduced 16% by combination therapy. Serum TG did not show significant change by probucol alone, but was reduced 9% by combination therapy. Serum concentration of apoB was reduced 11% by combination therapy.These data indicated that combined niceritrolprobucol therapy for type II HLP is very useful.

ObjectiveTo develop a microsimulation model for type 2 diabetes using population-level real-world data. Such a model allows for the synthesis of multiple data sources for comparative effectiveness analysis related to a variety of correlated outcomes. ApproachThe model was built using health state features including sex, age, diabetes duration, laboratory test results, and a history of major acute events. Features update using a cycle length of one month. Events modelled include myocardial infarction, stroke, heart failure, amputation and death. Model outputs include counts of events, lifetime healthcare costs and quality-adjusted life-years (QALYs). We then used the model to calculate the number of events that could be averted if a population with type 2 diabetes achieved treatment targets for HbA1c, blood pressure and LDL-cholesterol for 10 years. ResultsBringing all 60-year-olds with type 2 diabetes into target for 10 years would result in annual event reductions of 87.0 per 100,000 person-years for myocardial infarction, 49.4 for stroke, and 166.8 for heart failure. QALYs would improve by 1,155 per 100,000 patients. For 75-year-olds, annual event reductions would be 178.2, 56.8 and 261.6 per 100,000 person-years, respectively, and QALYs would improve by 2,121 per 100,000 patients. ConclusionsPopulation-level real-world data can be used to develop microsimulation models for type 2 diabetes that estimate long-term event risks, mortality and healthcare costs. This model is capable of comparative effectiveness and cost-effectiveness analysis of novel therapies in diabetes.

Background: Stroke designation has become increasingly important for administrators and physicians of stroke facilities in recent years. Designation (accreditation, recognition) as a stroke center implies to the community tangible evidence of quality, yet no study has assessed the comparative effectiveness of outcomes for designation in stroke. Methods: Using 2004 to 2009 for all patients treated for acute ischemic stroke across all 547 hospitals in Texas, we perform a comparative effectiveness analysis. Ischemic strokes include only ICD-9 codes 433-436. De-identified data were obtained from the Texas Health Care Information Collection data files. Hospitals were categorized in three groups: 1) recognition from the American Heart Association Get With the Guidelines Stroke program; 2) accreditation from the Joint Commission as a Primary Stroke Center (PSC), or 3) non-accredited from either of these programs. We compared each of these three subgroups employing various tests for differences and logistic regressions for odds ratios at 95% CI. Outcome measures assessed include mortality rate, average length of stay (ALOS), treatment costs, and use of thrombolysis. We adjusted mortality rates and lytics utilization based on risk mortality, illness severity, and patient age to control for mix and acuity. We calculated lytics rates dividing total cases where lytics were utilized by total ischemic strokes. We adjusted hospital reported charges using a standard cost-charge ratio. Results: 41 hospitals (7.5%) are recognized by the GWTG Gold or Silver levels, and 77 (14%) were recognized as a Primary Stroke Center. The remainder had neither designation. Of the 275,163 total strokes, 86% were ischemic. ALOS for all patients was 5.3 days, and average hospital costs were $36,529. Average mortality rate was 3.5% and mean lytics utilization was 1.6% across all cases. KW median test confirms that PSC hospitals had significantly lower ALOS compared to the non-accredited group (5.1 days vs. 5.5) and lower costs ($34,428 vs. $38,952). Logistics regressions showed significantly higher lytics rate (OR=3.3) as well as marginally higher mortality rates (OR=1.1). The GWTG subgroup had similar statistically significant results with ALOS (5.1) and costs ($34,792) both being significantly less than the non-accredited group. The odds ratio for lytics usage was exactly twice that of the non-accredited group. Mortality rates however were not significantly different between the two groups. Conclusion: Accreditation or designation of stroke facilities is associated with more efficient practice of care and improved processes (shorter stays, lower costs, and improved lytics use). Mortality rate however was marginally higher in one of the two accredited subgroups, but not in the other. Results suggest expansion of strengthening and expansion of designation programs.

Objective- Venous malformations (VMs) arise from developmental defects of the vasculature and are characterized by massively enlarged and tortuous venous channels. VMs grow commensurately leading to deformity, obstruction of vital structures, bleeding, and pain. Most VMs are associated with the activating mutation L914F in the endothelial cell (EC) tyrosine kinase receptor TIE2. Therapeutic options for VM are limited and ineffective while therapy with the mammalian target of rapamycin inhibitor rapamycin shows moderate efficacy. Here, we investigated novel therapeutic targets promoting VM regression. Approach and Results- We performed an unbiased screen of Food and Drug Administration-approved drugs in human umbilical vein ECs expressing the TIE2-L914F mutation (HUVEC-TIE2-L914F). Three ABL (Abelson) kinase inhibitors prevented cell proliferation of HUVEC-TIE2-L914F. Moreover, c-ABL, common target of these inhibitors, was highly phosphorylated in HUVEC-TIE2-L914F and VM patient-derived ECs with activating TIE2 mutations. Knockdown of c-ABL/ARG in HUVEC-TIE2-L914F reduced cell proliferation and vascularity of murine VM. Combination treatment with the ABL kinase inhibitor ponatinib and rapamycin caused VM regression in a xenograft model based on injection of HUVEC-TIE2-L914F. A reduced dose of this drug combination was effective in this VM murine model with minimal side effects. The drug combination was antiproliferative, enhanced cell apoptosis and vascular channel regression both in vivo and in a 3-dimensional fibrin gel assay. Conclusions- This is the first report of a combination therapy with ponatinib and rapamycin promoting regression of VM. Mechanistically, the drug combination enhanced AKT inhibition compared with single drug treatment and reduced PLCγ (phospholipase C) and ERK (extracellular signal-regulated kinase) activity.

Background: AST-008 is a novel spherical nucleic acid configuration of a toll-like receptor 9 (TLR9) agonist oligonucleotide, designed to trigger anti-tumor immune responses. Here we focus on immune activation upon AST-008 injection in the phase 1b/2 study in patients with advanced solid tumors (NCT03684785). Materials and Methods: AST-008 was injected intratumorally (IT) into one or more tumors QW for 8 doses, then Q3W thereafter, at doses from 2 to 32 mg. Starting at week 3, pembrolizumab was administered per label until toxicity or progression. Peripheral blood immune cell profiling and cytokine/chemokine analyses were performed before and 24 hours after both the first AST-008 dose (week 1) and the first combination dose (week 3). Serial tumor biopsies of lesions were collected from both AST-008-injected lesions and non-injected (“witness”) lesions at baseline, after IT AST-008 monotherapy, and after combination therapy. Results: Seventeen patients have been enrolled in the dose escalation cohort: median age 66 [range: 30-86], 82% male, median ECOG 1 [0-1]. Dose dependent lymphocyte activation was observed after IT AST-008. AST-008 dosing alone (16 mg cohort, n = 3) increased activated fractions of CD4+ (33%) and CD8+ T cells (64%), monocytes (97%) and NK cells (94%), compared to baseline (15%, 22%, 4%, and 37%, respectively). At AST-008 doses of 8 and 16 mg, the cell activation response within a dose level was generally similar in the presence or absence of pembrolizumab. In addition, the cytokines/chemokines IL-12p40, IL-1RA, IP-10, and MCP-1 were induced in a dose-proportional manner after IT AST-008 mono- or combination therapy. IT AST-008 resulted in average fold increase of 5, 12, and 16 for doses of 2, 4, and 8 mg dose cohorts, respectively, in IP-10 concentration from baseline (n = 11). Generally, combination therapy with pembrolizumab and AST-008 at doses of 2 and 4 mg produced a cytokine/chemokine response that was smaller than AST-008 alone (n = 5), but 8 mg dose responses were similar after monotherapy or combination therapy (n = 3). Preliminary analysis of serial biopsies by Nanostring revealed increased T cells and cytotoxic cells in the injected lesion after AST-008 dosing (n = 4) and in the non-injected witness lesion after combination therapy (n = 6). Combination therapy produced increases in B cells, T cells, cytotoxic cells and macrophages the AST-008 injected lesions (n = 6). Further PD data are being collected. The emerging safety profile consists mostly of grade (G) 1 and 2 injection site reactions and flu-like symptoms, reflecting local and systemic immune activation. One G3 lymphocytopenia has been observed, with no clinical consequences. No AST-008-related serious AEs or DLTs have been reported. Conclusions: IT AST-008 is well tolerated at the doses administered and is associated with dose-proportional systemic immune activation. Gene expression analysis suggests increased lymphocytes in the injected tumor after IT AST-008 and in both injected and witness tumors after combination therapy. Citation Format: Mohammed M. Milhem, Cesar A. Perez, Glenn J. Hanna, Trisha M. Wise-Draper, Shailender Bhatia, Alice S. Bexon, Weston L. Daniel, Steven J. O'Day. Phase 1b/2 study of an intratumoral TLR9 agonist spherical nucleic acid (AST-008) and pembrolizumab: Evidence of immune activation [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr LB-140.

The suppressive action of various doses of chloroquine, amodiaquine, primaquine, and pyrimethamine on the development of parasitemia in mice infected with Plasmodium berghei was investigated. After the dose-suppression curve was established for each of the four drugs, various combinations of two and three drugs were compared with equivalent doses of single drugs. Test mice were infected intravenously with 1 million parasitized red blood cells. Drugs were administered by stomach tube daily for 5 consecutive days, beginning on the day of infection (day 0). Parasitemia was evaluated from blood smears made on day 6 of infection. Average per cent parasitemia for animals within test groups was used to compare the effect of various drug treatments. By the test procedure employed, combinations of chloroquine, amodiaquine, primaquine, and pyrimethamine were not superior to single drug treatments in suppression of the development of parasitemia in mice infected with P. berghei. The joint suppressive action of combinations of two or three of these drugs was additive, or less than additive, and no evidence of synergism was observed. In the treatment of human malaria various combinations of drugs have been used in an effort to enhance therapeutic effects. Combinations of drugs have been employed to reduce the relapse rate in P. vivax infections through their joint action on both erythrocytic and exoerythrocytic phases of the parasite. Other objectives of combining drugs include (1) suppression of the development of drugresistant strains, (2) reduction of overall toxicity to the host, and (3) enhancement of the suppressive activity, thereby reducing the dosage requirement. In experimental malarial infections the suppressive effect of drug combinations has been compared with the effect of single drugs in order to assess the potency of the combination and also to study the nature of combined drug action. Roehl (1926) demonstrated that in avian malaria pamaquine combined with quiReceived for publication 30 July 1963. * Office of the Director, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda 14, Maryland. tPresent address: Department of Pharmacology, University of Tennessee, School of Medicine, 874 Union Avenue, Memphis 3. nine was more effective than quinine alone in delaying the appearance of parasites. The enhanced action of this combination since has been demonstrated clinically. Proguanil and sulfadiazine, when given concurrently to chicks infected with P. gallinaceum, were found to be synergistic by Greenberg and his associates (1948). The effective dose of proguanil could be reduced to 1/4 if combined with 1/32 to 164 the effective dose of sulfadiazine. Later Greenberg (1949) showed that other compounds are synergistic with proguanil and that these drugs, like sulfadiazine, are all inhibitors of p-aminobenzoic acid. Reilly et al. (1950) studied the action of drug combinations on Plasmodium lophurae in chicks and found the joint suppressive effect of quinine and quinacrine as well as quinacrine and pamaquine to be additive, whereas quinine combined with pamaquine and possibly quinine with pentaquine are synergistic in their joint suppressive effects. Subsequently, Bishop and McConnachie (1952) reported that no synergism was observed between pamaquine and quinine, when tested in combined doses, upon active infections of P. gallinaceum in chicks. Bishop (1956) observed no potentiation of drug action