Public acceptance of peramivir during the 2009 H1N1 influenza pandemic: implications for other drugs or vaccines under emergency use authorizations.

OBJECTIVE: The Centers for Disease Control and Prevention estimated that up to 88 million H1N1 influenza cases, 398,000 hospitalizations, and up to 18,050 related deaths, including significant racial and ethnic disparities, occurred between April 2009 and March 13, 2010. The Food and Drug Administration (FDA) approved emergency use authorizations (EUAs), which allowed the distribution of unapproved drugs or the off-label use of approved drugs. In late 2009, peramivir was granted an EUA for patients with severe disease. This study examined factors associated with willingness to take peramivir. METHODS: In 2010 we conducted a nationally representative survey with 2079 respondents randomly drawn from the Knowledge Networks research panel. Our completion rate was 56%. Respondents received information about peramivir from a fact sheet and then answered questions about their willingness to take the drug. RESULTS: Overall, 48% of participants indicated that they would probably or definitely take peramivir. Seventy-nine percent definitely would take the drug if their doctor recommended it and there were no alternative treatments. There were significant racial differences in willingness. The term experimental to refer to the drug decreased willingness to accept peramivir among both whites and blacks. CONCLUSIONS: Trust in the FDA was important for peramivir acceptance. Particular care must be taken to ensure that patients and their families understand the complex nature of EUA drugs. Lessons learned can inform communication about future EUAs. (Disaster Med Public Health Preparedness. 2015;9:166-174).

Pharmacokinetic assessment of peramivir in a hospitalized adult undergoing continuous venovenous hemofiltration.

OBJECTIVE: To report a sieving coefficient for peramivir in a patient receiving continuous venovenous hemofiltration (CVVH). CASE SUMMARY: An 18-year-old male presented with chills, myalgias, and dyspnea and was hospitalized. Nasal secretions were positive for influenza by rapid antigen test at an outside facility and oseltamivir was commenced. Oral absorption was predicted to be unreliable, and intravenous peramivir was accessed as an emergency investigational new drug applicaiton (eIND). CVVH was initiated after the development of acute renal failure, with blood samples collected to determine peramivir concentrations. DISCUSSION: Peramivir, an intravenous investigational neuraminidase inhibitor with activity against influenza viruses, has limited data for dosing in the setting of CVVH. A single patient received 600 mg of peramivir intravenously and had blood and ultrafiltrate concentrations measured serially. A sieving coefficient of approximately 0.9 was identified. CONCLUSIONS: Peramivir is well cleared by CVVH, and drug exposure is potentially predictable based on flow rates. Further study is necessary.

Economic model for emergency use authorization of intravenous peramivir.

OBJECTIVES: To develop 3 computer simulation models to determine the potential economic effect of using intravenous (IV) antiviral agents to treat hospitalized patients with influenza-like illness, as well as different testing and treatment strategies. STUDY DESIGN: Stochastic decision analytic computer simulation model. METHODS: During the 2009 influenza A(H1N1) pandemic, the Food and Drug Administration granted emergency use authorization of IV neuraminidase inhibitors for hospitalized patients with influenza, creating a need for rapid decision analyses to help guide use. We compared the economic value from the societal and third-party payer perspectives of the following 4 strategies for a patient hospitalized with influenza-like illness and unable to take oral antiviral agents: Strategy 1: Administration of IV antiviral agents without polymerase chain reaction influenza testing. Strategy 2: Initiation of IV antiviral treatment, followed by polymerase chain reaction testing to determine whether the treatment should be continued. Strategy 3: Performance of polymerase chain reaction testing, followed by initiation of IV antiviral treatment if the test results are positive. Strategy 4: Administration of no IV antiviral agents. Sensitivity analyses varied the probability of having influenza (baseline, 10%; range, 10%-30%), IV antiviral efficacy (baseline, oral oseltamivir phosphate; range, 25%-75%), IV antiviral daily cost (range, $20-$1000), IV antiviral reduction of illness duration (baseline, 1 day; range, 1-2 days), and ventilated vs nonventilated status of the patient. RESULTS: When the cost of IV antiviral agents was no more than $500 per day, the incremental cost-effectiveness ratio for most of the IV antiviral treatment strategies was less than $10,000 per quality-adjusted life-year compared with no treatment. When the cost was no more than $100 per day, all 3 IV antiviral strategies were even more cost-effective. The order of cost-effectiveness from most to least was strategies 3, 1, and 2. The findings were robust to changing risk of influenza, influenza mortality, IV antiviral efficacy, IV antiviral daily cost, IV antiviral reduction of illness duration, and ventilated vs nonventilated status of the patient for both societal and third-party payer perspectives. CONCLUSION: Our study supports the use of IV antiviral treatment for hospitalized patients with influenza-like illness.

The emergency use authorization of peramivir IV: a view from the manufacturer.

The 2009 H1N1 influenza pandemic prompted the US Food and Drug Administration (FDA) to issue an emergency use authorization (EUA) for the intravenous antiviral peramivir, an unapproved neuraminidase inhibitor (NAI) currently under development. Peramivir use was limited to patients for whom other NAI therapy had failed or in whom oral or inhalational drug absorption was believed to be unreliable. This introduced a patient selection bias that precluded safety and efficacy assessment. Despite the challenges and risks, there was a compelling public health need for an intravenous agent during the 2009 H1N1 pandemic.

The role of clinical pharmacology in supporting the emergency use authorization of an unapproved anti-influenza drug, peramivir.

On 23 October 2009, the commissioner of the US Food and Drug Administration (FDA) issued an Emergency Use Authorization (EUA) for peramivir for intravenous injection, an unapproved neuraminidase inhibitor used for treating certain hospitalized adult and pediatric patients infected with 2009 H1N1 influenza. This was the first EUA of an unapproved drug product. This report summarizes the critical contributions of the clinical pharmacology review team in support of the peramivir EUA.

Assessment of pandemic and seasonal influenza A (H1N1) virus susceptibility to neuraminidase inhibitors in three enzyme activity inhibition assays.

The neuraminidase inhibitors (NAIs) zanamivir and oseltamivir are currently the only antiviral drugs effective for the treatment and prophylaxis of 2009 pandemic influenza A (H1N1) virus infections. The proven potential of these viruses to acquire NAI resistance during treatment emphasizes the need to assess their NAI susceptibility. The 50% inhibitory concentrations (IC(50)s) are known to vary depending on the neuraminidase inhibition (NI) test used; however, few side-by-side comparisons of different NI assays have been done. In the present study, a panel of 11 isolates representing 2009 seasonal and pandemic influenza H1N1 viruses, including oseltamivir-resistant H275Y variants, were tested in three functional NI assays: chemiluminescent (CL), fluorescent (FL), and colorimetric (CM). The sensitivities of the viruses to zanamivir, oseltamivir, and three investigational NAIs (peramivir, R-125489, and A-315675) were assessed. All isolates with the exception of H275Y variants were sensitive to all five NAIs by all three NI assays. The H275Y variants showed substantially elevated IC(50)s against oseltamivir and peramivir. The three NI assays generally yielded consistent results; thus, the choice of NI assay does not appear to affect conclusions based on drug susceptibility surveillance. Each assay, however, offers certain advantages compared to the others: the CL assay required less virus volume and the FL assay provided the greatest difference in the IC(50)s between the wild type and the variants, whereas the IC(50)s obtained from the CM assay may be the most predictive of the drug concentrations needed to inhibit enzyme activity in humans. It would be desirable to develop an NI assay which combines the advantages of all three currently available assays but which lacks their shortcomings.

Pharmacological assessment of netobimin as a potential anthelmintic for use in horses: plasma disposition, faecal excretion and efficacy.

This study aimed to determine the plasma disposition and faecal excretion of netobimin (NTB) and its respective metabolites as well as the efficacy against strongyles in horses following oral administration. Netobimin (10mg/kg) was administered orally to 8 horses. Blood and faecal samples were collected from 1 to 120h post-treatment and analysed by high performance liquid chromatography (HPLC). Using a chiral phase-based HPLC, plasma disposition of ABZSO enantiomers produced was also determined. Faecal strongyle egg counts (EPG) were performed by a modified McMaster's technique before and after the treatment. Neither NTB nor ABZ were present and only albendazole sulphoxide (ABZSO) and sulphone metabolites (ABZSO(2)) were detected in the plasma samples. Maximum plasma concentration of ABZSO (0.53+/-0.14microg/ml) and ABZSO(2) (0.36+/-0.09microg/ml) were observed at (t(max)) 10.50 and 19.50h, respectively following administration of NTB. The area under the curve (AUC) of the two metabolites was similar to each other. Netobimin was not detected, and ABZ was predominant in faecal samples. The maximum plasma concentration (C(max)) of (-)ABZSO was significantly higher than (+)ABZSO, but the area under the curves (AUCs) of the enantiomer were not significantly different each other in plasma samples. The enantiomers of ABZSO were close to racemate in the faecal samples analyzed. Netobimin reduced the EPG by 100%, 100%, 77%, 80% and 75% 2, 4, 6, 8 and 10 weeks post-treatment, respectively. The specific behaviour of the two enantiomers probably reflects different enantioselectivity of the enzymatic systems of the liver which are responsible for sulphoxidation and sulphonation of ABZ. Considering the pharmacokinetic and efficacy parameters NTB could be used as an anthelmintic in horses.

Economic efficacy of anthelmintic treatments in dairy sheep naturally infected by gastrointestinal strongyles.

The aim of the present paper was to assess benefit of strategic anthelmintic treatments on milk production in six commercial dairy sheep farms, located in southern Italy, whose animals were naturally infected with gastrointestinal strongyles. On each farm, two similar groups were formed, one untreated control group and one treated group. In all the treated groups, the strategic anthelmintic schemes were based on: (i) only one treatment with moxidectin in the periparturient period (February, Farm No. 6), or; (ii) two treatments, i.e. the first with moxidectin performed in the periparturient period (February, Farms Nos. 1, 2, 3 and 4) or in the postparturient period (April, Farm No. 5), and the second with netobimin at the mid/end of lactation (June, Farms Nos. 1, 2, 3, 4 and 5). Faecal egg count reduction (FECR) tests were performed on each farm in order to asses the anthelmintic efficacy of the drugs used. In addition, milk yield measurements for each animal fortnightly in each farm for the lactation period were performed. In terms of FECR, both moxidectin and netobimin were effective in all the 6 studied farms. Regarding milk production, overall in the 6 study farms the mean daily milk productions of the treated groups were higher than those of the control group. However, there were important differences between the 6 farms, i.e. the increase of milk production in the treated groups versus the control groups was as follows: +18.9% (Farm 1), +30.4% (Farm 2), +4.0% (Farm 3), +37.0% (Farm 4), +5.5% (Farm 5) and +40.8% (Farm 6). The results of the study showed that the economic efficacy of an anthelmintic treatment is not a cause-effect issue, but is a multifactorial issue which depends upon the quali-quantitative parasitological status of the animals, the pathogenesis of the species of parasites, the virulence of the strains of parasites, the local epidemiology, the timing of treatment, the breed of animal in terms of genetics and production types, nutrient supply.

Post-Amadori AGE inhibition as a therapeutic target for diabetic complications: a rational approach to second-generation Amadorin design.

Aminoguanidine and pyridoxamine (Pyridorintrade mark), two major inhibitors of advanced glycation end product (AGE) formation, have entered clinical trials for diabetic nephropathy. They share no structural similarity and are believed to inhibit AGE formation by entirely different mechanisms. Pyridoxamine is a post-Amadori AGE inhibitor-that is, an "Amadorin"-whereas aminoguanidine primarily scavenges reactive dicarbonyl precursors to AGEs. However, pyridoxamine also has a limited potential to react with dicarbonyls. We thus embarked on an effort to develop second-generation Amadorins with low nucleophilicity. Our hypothesis was that we could improve specificity for inhibiting the post-Amadori pathway by minimizing the potential for scavenging small dicarbonyl intermediates. This mechanism-based strategy has led to a rational drug design program that has successfully produced candidate Amadorins, among them the novel compound BST-4997. This Amadorin has greater post-Amadori potency than pyridoxamine but possess no dicarbonyl scavenging activity. Prototypical inhibitors like BST-4997 provide a unique tool to help identify relevant AGE pathways that contribute to diabetic complications. Targeting AGE inhibition differs significantly from traditional approaches to drug discovery and thus represents a new paradigm for the drug industry that should be recognized.

Influenza treatment with neuraminidase inhibitors: cost-effectiveness and cost-utility in healthy adults in the United Kingdom.

We assessed the cost-effectiveness and cost-utility of treating influenza with neuraminidase inhibitors (oseltamivir and zanamivir) from a health care payer's and societal perspective in the United Kingdom. A simulation model was developed to predict morbidity and mortality due to influenza and its specified complications, comparing neuraminidase inhibitors with usual care in an otherwise healthy adult population. Robustness of the results was tested by one-way and multiway as well as probabilistic sensitivity analyses. Treatment with either neuraminidase inhibitor results in reduced morbidity and faster return to normal activities. However, oseltamivir dominates zanamivir in cost-utility analysis due to its lower costs. Comparing oseltamivir with usual care, the costs are pound14.36 per day of normal activity gained and pound5,600 per quality-adjusted life-year gained from the healthcare payer perspective. Oseltamivir dominates usual care from the societal perspective. Treatment with oseltamivir is a cost-effective strategy for otherwise healthy adults in the UK from both the healthcare payer and societal perspective.

Pharmacology and clinical assessment of cariporide for the treatment coronary artery diseases.

Myocardial protection through pharmacological approaches represents a large therapeutic challenge and is an important therapeutic strategy in patients with coronary artery disease, particularly after myocardial infarction. Extensive animal experiments have repeatedly demonstrated the efficacy of sodium-hydrogen exchange (NHE) inhibition as a potent cardioprotective approach. The heart possesses primarily the NHE1 isoform which has led to the development of NHE1 specific inhibitors for cardiovascular therapeutics. Cariporide (HOE 642) is the first of such agents to have been developed and subjected to clinical trial. Preclinical studies with cariporide revealed excellent protection against necrosis, apoptosis, arrhythmias and mechanical dysfunction in hearts subjected to ischaemia and reperfusion. Cariporide has recently been evaluated in a large dose-finding Phase II/Phase III clinical trial (GUARDIAN) to assess its efficacy in patients with acute coronary syndromes. Overall results failed to demonstrate protection but sub-group analysis revealed significant risk reductions with the highest cariporide dose (120 mg t.i.d.) especially in high risk patients undergoing coronary artery bypass surgery. This suggests that insufficient dosage may have accounted, at least in part, for the less than optimum results. Another NHE1 inhibitor, eniporide, is currently in Phase II clinical trial (ESCAMI) in patients with acute myocardial infarction (MI) who are given angioplasty or thrombolysis. Although the study has not been completed interim findings appear positive. Both drugs were well-tolerated and produced no excess side effects compared with placebo. Further studies are needed to confirm the efficacy of NHE1 inhibitors for the treatment of coronary heart disease, even so initial results are encouraging.

Assessment of pinacidil in patients with primary Raynaud's phenomenon.

In fourteen patients with primary Raynaud's phenomenon we performed a double-blind, controlled study, comparing single doses of 12.5 and 25 mg of the potassium channel opener pinacidil with placebo and the active control nifedipine in randomised order. The main response criterium was the area under the curve (AUC) of the photoelectric plethysmography (PEP) during cooling and rewarming, performed 2-3 hours after administration of the study medication. Single doses of 12.5 and 25 mg pinacidil were shown not to be superior to placebo in respect of the AUC of PEP. Nifedipine, on the contrary, was significantly better than placebo. We conclude that no efficacy can be expected from the potassium channel opener pinacidil in the treatment of primary Raynaud's phenomenon. The efficacy of nifedipine cannot be explained from central rheological effects, as total blood viscosity was the same after pinacidil, nifedipine and placebo.

Influence of gastro-intestinal nematodes on the productivity of dairy cattle in the wet highlands of Sri Lanka.

To study the response and economics of nematode control in cattle, trials with anthelmintics were carried out in the wet season at New Zealand farm in the highlands of Sri Lanka. Three age groups were used: stall fed yearlings, grazing heifers and lactating cows. Groups were treated with ivermectin or febantel and monitored along with control groups for faecal egg counts, growth and milk production. Treatment reduced the trichostrongylid faecal egg counts in yearlings, heifers and cows for six to 10 weeks, for more than 10 weeks and for 140 days respectively. The growth rate of treated yearlings did not increase significantly while treated heifers did grow significantly faster. Treated cows produced an average of 115 kg more milk over 133 days (P less than 0.05). The economic gains in reducing the age at first service and in terms of milk yield far outweighed the cost of anthelmintics used.

[Clinical assessment of anticoagulation therapy during left ventricular assist with artificial heart: induction with protease inhibitor].

Left ventricular assist device was attached to five patients suffered from severe low cardiac output after open heart surgery. In two patients, anticoagulation therapy with heparin started just after the operation. Repeated operations for hemostasis were required because of massive bleeding in these two patients. Anticoagulation therapy was not performed in another one, and thrombus formation in the device was recognized in this patient. In the other two patients, anticoagulation therapy was started with large dose of protease inhibitor (gabexate mesilate or nafamstat mesilate). Heparin infusion was combined with protease inhibitor during the period of weaning from the device. Thrombosis and massive bleeding were not recognized in these two patients, and they were able to wean from the device successfully.