Volume Articles

Evaluation and valuation of innovative medicinal products

Mark J C Nuijten^1,2* and Jan Vis³

¹A2M (Ars Accessus Medica), 1546 LG Amsterdam, The Netherlands
²H4V, 1546 LG Amsterdam, The Netherlands
³Talanton, Amsterdam, The Netherlands
⁴RSM, Erasmus University, Rotterdam, The Netherlands

 Rational: Many pharmaceutical companies, especially biotechnology companies, are now commercializing innovative so-called expensive medicinal products, e.g. biologicals, and especially orphan drugs, with an incremental cost-effectiveness ratio (ICER), which will probably exceed threshold values that are commonly regarded as acceptable for reimbursement.

Objective: The goal of this paper is to propose an additional methodology to evaluate and valuate innovative drugs from a broader perspective by applying concepts from business valuation, when the ICER exceeds the threshold.

Methods: Medical innovation relies on the market mechanisms in the finance market of biotechnology including the incentives of the various stakeholders, especially the capital providers, who demand a required return on investment. The justification of the orphan drug price can be based on the Discounted Cash Flow method, which is based on the expected free cash flows and the required cost of capital, and can be used to validate the price of the new drug from a narrow investor’s perspective.

Conclusion: We propose an alternative policy approach for the evaluation of ultra-innovative drugs from a broader perspective by bridging concepts from health economics and the economics of business (economic) valuation. This approach may justify a drug price, especially when ICER exceeds the threshold.

Diagnosing and treatment of Fabry's disease from a neurologic perspective

Michael Y. Soliman, Rima El-Abassi* and John D. England

Department of Neurology, South East Louisiana Veteran Health Care Sysytem (SELVHCS), Louisiana State University, New Orleans, Louisiana, 70112, United States

Parameters of obesity in polycystic ovary syndrome

Di-Fei Lu, and Xiao-Hui Guo*

Peking University First Hospital, Beijing, China

 Polycystic ovary syndrome (PCOS) is a prevalent female endocrine and metabolic disorder, and is typically presented with menstrual irregularity and an excess of androgen production. Obesity is a common comorbidity with PCOS, and accompanying insulin resistance is proved to be a key pathogenesis of PCOS. Several parameters have been applied to evaluate obesity, including body-mass index (BMI), waist circumference (WC), percentage of body fat (PBF) and lipid accumulation product (LAP) index. Accumulating studies were conducted to analyze the association between the markers of obesity and PCOS, as well as the cut-off level of each marker in order to detect higher risk of cardiovascular diseases or rule out metabolic syndrome. However, standards of obesity parameters to screen or diagnose PCOS are yet to be established. Herein we briefly review the association of obesity measuring methods and its diagnostic value with PCOS, which gives insight into the development of standard criteria for obesity in PCOS.

Experimental studies in cytoreductive surgery and hyperthermic intraperitoneal chemotherapy: overview and future directions

David Badrudin, Pierre Dubé and Lucas Sideris*

Maisonneuve-Rosemont Research Center, Maisonneuve-Rosemont Hospital, Université de Montréal, Montréal QC, Canada

 Background: Cytoreductive surgery combined to hyperthermic intraperitoneal chemotherapy (HIPEC) is the standard of care for selected patients with peritoneal surface malignancies. Preclinical studies, especially when performed on animal models, provide a framework for improvement of this treatment. This study aims to present an overview of a single institution's experience in this setting.

Methods/Results: Review of all preclinical studies from a single center was conducted using PubMed and author databases. Multiple experiments were conducted using pig and rat models. These studies examined the impact of different surgical techniques, such as the electrovaporization of tumor nodules and the use of different suture material, in the context of HIPEC. The pharmacokinetics of multiple intraperitoneal cytotoxic agents – namely oxaliplatin, raltitrexed, irinotecan and pemetrexed – were also studied.

Conclusion: Experimental studies help guide future directions for the treatment of peritoneal surface malignancies with hyperthermic intraperitoneal chemotherapy.

Long-term weekly adrenocorticotropic hormone therapy for relapsed infantile spasms

Takeo Kato^1*, Minako Ide¹ and Masatoshi Nakata²

¹Department of Pediatrics, Hyogo Prefectural Amagasaki General Medical Center, Hyogo, Japan
²Department of Pediatrics, Graduate School of Medicine, Kyoto University, Kyoto Japan

 Infantile spasms (IS) is the most recognized epileptic encephalopathy in early infancy, resulting in poor cognitive outcome. Adrenocorticotropic hormone (ACTH) therapy is the first-line therapy for IS, but the relapse rate is high. Relapse after initial ACTH therapy is a poor prognostic factor for long-term seizure control and outcome of cognitive function. Recently, several studies have reported on the long-lasting maintenance of the positive effects produced by an initial course of ACTH by using long-term weekly ACTH therapy for relapsed IS. Here, we review the clinical characteristics of five previously reported cases. Epileptic spasms and hypsarrhythmia remained completely resolved during the extended ACTH therapy and did not recur after ACTH discontinuation in all cases. Furthermore, no cognitive or neurodevelopment deterioration was observed, and no serious adverse events occurred in any patient. In conclusion, this therapy appears safe and may lead to improved psychomotor development. We believe that it may be a good alternative therapy when frequent relapses occur after a favorable response to an initial course of conventional ACTH therapy. However, further studies are required to examine the risks and benefits of this therapy for relapsed IS in a large population and in countries in addition to Japan.

Ataxia-Telangiectasia mutated kinase: Role in myocardial remodeling

Patsy Thrasher¹, Mahipal Singh¹ and Krishna Singh^1,2*

¹Department of Biomedical Sciences, James H Quillen College of Medicine, East Tennessee State University, Johnson City, TN, USA
²James H Quillen Veterans Affairs Medical Center, Mountain Home, TN, USA

 Ataxia-telangiectasia mutated kinase (ATM) is a serine/threonine kinase. Mutations in the ATM gene cause a rare autosomal multisystemic disease known as Ataxia-telangiectasia (AT). Individuals with mutations in both copies of the ATM gene suffer from increased susceptibility to ionizing radiation, predisposition to cancer, insulin resistance, immune deficiency, and premature aging. Patients with one mutated allele make-up ~1.4 to 2% of the general population. These individuals are spared from most of the symptoms of the disease. However, they are predisposed to developing cancer or ischemic heart disease, and die 7-8 years earlier than the non-carriers. DNA double-strand breaks activate ATM, and active ATM is known to phosphorylate an extensive array of proteins involved in cell cycle arrest, DNA repair, and apoptosis. The importance of ATM in the regulation of DNA damage response signaling is fairly well-established. This review summarizes the role of ATM in the heart, specifically in cardiac remodeling following β-adrenergic receptor stimulation and myocardial infarction.

The evidence to date: A redox-inactive analogue of tocotrienol as a new anti-mesothelioma agent

Ayami Sato^1,2, Nantiga Virgona², Yuko Sekine¹ and Tomohiro Yano^2*

¹Graduate School of Medical and Pharmaceutical Sciences, Chiba University, Chiba, Japan
²Research Institute of Life Innovation, Toyo University, Gunma, Japan

 Malignant mesothelioma (MM) is an aggressive cancer associated with exposure to asbestos. In recent years, despite restrictions on the use of asbestos, the incidence of MM has been increasing due to its long latency period. Owing to its poor prognosis, the treatment of MM requires innovative therapies. Tocotrienol (T3), one of the vitamin E analogues, has powerful antioxidant properties and anti-cancer effects. However, these effects have not been fully understood, and are mediated independent of its antioxidant activity. Therefore, we have synthesized a new redox-inactive derivative of T3 (T3E) that has shown a stronger anti-MM effect than its redox-sensitive mother compound. In this review, we discuss the potential for anti-MM effect of T3E as non-antioxidant functions of T3 by introducing our previous reports.

Mini-review on "Molecular diagnosis of 65 families with mucopolysaccharidosis type II (Hunter syndrome) characterized by 16 novel mutations in the IDS gene: Genetic, pathological, and structural studies on iduronate-2-sulfatase".

Ryuichi Mashima^1* and Torayuki Okuyama^1,2

¹Department of Clinical Laboratory Medicine, National Center for Child Health and Development, 2-10-1 Okura, Setagaya-ku, Tokyo 157-8535, Japan
²Center for Lysosomal Storage Disorders, National Center for Child Health and Development, 2-10-1 Okura, Setagaya-ku, Tokyo 157-8535, Japan

Lenz-Majewski syndrome: How a single mutation leads to complex changes in lipid metabolism

Mira Sohn and Tamas Balla*

Section on Molecular Signal Transduction, Program for Developmental Neuroscience, Eunice Kennedy Shriver NICHD, National Institutes of Health, Bethesda, Maryland 20892, USA

 Lenz-Majewski syndrome (LMS) is a rare disease presenting with complex physical and mental abnormalities. Whole exome sequencing performed on five LMS-affected individuals has identified gain-of-function mutations in the PTDSS1 gene encoding phosphatidylserine synthase 1 (PSS1) enzyme. These mutations all rendered PSS1 insensitive to PS-mediated product inhibition. In a recent study we showed that uncontrolled PS production by these mutant PSS1 enzymes lead to the accumulation of PS in the ER where it is not detected in normal cells. This increased PS in the ER in turn, activated the Sac1 phosphatase, which is responsible for the dephosphorylation of the minor lipid, phosphatidylinositol 4-phosphate (PI4P) in the ER. Increased Sac1 activity decreased PI4P levels both in the Golgi and the plasma membrane thereby dissipating the PI4P gradients set up by PI 4-kinase enzymes (PI4Ks) between these membranes and the ER. Such PI4P gradients at membrane contact sites have been shown to support the transports of structural lipids such as cholesterol and PS out of the ER by non-vesicular lipid transfer. Therefore, uncontrolled production of PS not only affects the PS status of cells but also initiates an avalanche of changes in the metabolism of other membrane lipids via affecting PI4P gradients throughout the cell. Recognition of the close metabolic interaction between PS synthesis and PI4P metabolism provided a new clue to better understand the molecular underpinning of this rare and severe disease.

Idiopathic systemic capillary leak syndrome in childhood: A Literature Review

Tu-Anh Tran^1*, Anne Filleron¹, Mathieu Simonin² and Pierre Corbeau³

¹Department of Pediatrics, Nîmes University Hospital, INSERM U 1183, Montpellier-Nîmes University, Nîmes, France
²Institut Gustave Roussy, Department of Pediatric Oncology, 114 Rue Paul Vaillant, 94800 Villejuif, France
³Department of Immunology, Nîmes university hospital, Montpellier-Nîmes university, Nîmes, France

 Systemic capillary leak syndrome (SCLS), is a rare condition characterized by a recurrent stereotypical triad: hypovolemic shock, generalized edema, paradoxical hemoconcentration and hypoalbuminemia. It is caused by massive fluid extravasation into the interstitial space. Mortality may result from hemodynamic failure in the acute phase or cardiac failure due to reflex circulatory overload in the sub-acute phase. To date, twenty-one pediatric cases were reported in the literature. Sex ratio (M/F) was 0.32 with a median age at disease onset of 5.7 years and at diagnosis of 6 years. The disease was recurrent in 81% of patients with a median of three attacks. Severe complications were possible involving central nervous system (n=2) or rhabdomyolysis, with a compartment syndrome needing fasciotomy (n=5). The median time to clinical recovery was five days. Although the clinical manifestations of pediatric and adult SCLS were similar; in the opposite of adult SCLS, none of the children showed evidence of monoclonal gammopathy and three pediatric cases had a family history of SCLS. Seventy five percent of the patients were treated with prophylactic treatment (mainly immunoglobulins, theophylline plus verapamil). Several inflammatory cytokines were suspected to be involved in the pathophysiology of SCLS, especially interleukin-17 and tumor necrosis factor -alpha.

Update on the fluorometric measurement of enzymatic activities for Lysosomal Storage Disorder detection: The example of MPS VI.

Paula G. Franco^1,2, Ana M. Adamo^1,2, Patricia Mathieu^1,2, María J. Pérez^1,2, Patricia C. Setton-Avruj^1,2 and Lucas Silvestroff^1,2*

¹Universidad de Buenos Aires, Facultad de Farmacia y Bioquímica, Cátedra de Química Biológica Patológica. Buenos Aires, Argentina
²Universidad de Buenos Aires, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Instituto de Química y Fisicoquímica

Biológicas (IQUIFIB) Profesor Alejandro C. Paladini, Facultad de Farmacia y Bioquímica, Argentina

 Lysosomal Storage Disorders (LSD) are rare diseases that as a whole have a combined incidence ranging from 1:1500 to 1:7000 live births. One of such diseases is Mucopolysaccharidosis VI (MPS VI), or Maroteaux Lamy Syndrome. MPS VI patients undergo devastating and irreversible skeletal alterations and multisystemic failure as from early childhood due to reduced Arylsulfatse B (ARSB) enzyme activity.

Reaching a final diagnosis is not always a short cut path, but rather a years-long battle against uncertainty and unnecessary medical interventions. Our aim is to contribute from the bench table with different approaches that could serve as alternatives to pre-existing assays for screening and diagnosing MPS VI and other LSD.

The present work is based on our research article authored by Franco et al.1 where we studied the effect of blood-derived hemoglobin, and other blood components, on the fluorescence of 4-Methylumbelliferone when measuring ARSB enzyme activity from dried blood spot (DBS) samples.

Our experience indicates that to date there are plenty of different approaches for measuring ARSB enzyme activity, although the sample type required or the assay in itself often make them more adaptable for either high throughput screening or small scale diagnostics.

As a whole, the fluorometric determinations seem to be the most accessible to low budget laboratories with equally valuable performances as a sophisticated mass spectrometry analysis for this disease. Furthermore, the DBS serves as an attractive sample type for screening the disease in large populations.

Mini Review on "Winning the battle against the scourge of poliomyelitis in the African Region"

Matshidiso Moeti*

WHO regional office for Africa, Brazzaville, Congo

 This mini review on my previous article entitled, ‘Winning the battle against the scourge of poliomyelitis in the African Region’ published in Vaccine 34 (2016) 5142–5143 takes another look at the optimism expressed in that article about the success in eradicating poliomyelitis (Polio) from the African Region. Polio is a deadly and painful disease that afflicts mostly children less than 5 years. The struggle to eradicate it and get the African Region polio-free has been tortuous. The struggle has been protracted with a series of public health emergencies and political strife compromising the efforts of global partnership comprising of WHO and its key partners such as the United Nations Children’s Fund, the United States Centres for Disease Control and Prevention, Rotary International, and Bill and Melinda Gates Foundation, among others, as well as other stakeholders and national governments in the African Region. In a renewed effort, the partnership generated a huge amount of resources and skills deployed to interrupt polio transmission in the Region. For the first time since the struggle began in the early 80s, the Region reported no wild polio virus for two years. However, the recent success of the military campaign in Northeast Nigeria brought to the open the realities of reservoirs of transmission isolated in security compromised areas. Thus, after two years new cases of wild polio virus were reported in previously unreachable areas. The lesson here is in understanding the impact of political activities on the realization of health for all in our Region.