Beta-secretase inhibitors in phase I and phase II clinical trials for Alzheimer’s disease

Introduction: BACE 1 is a protease that cleaves the transmembrane amyloid precursor protein and generates amyloid-β peptides that accumulate in AD brains. No known mutations are identified in the gene encoding BACE1 in AD. However, enzyme levels are elevated in AD and a single residue mutation in amyloid precursor protein protects against protein cleavage by BACE1, suggesting BACE involvement in disease pathogenesis. Drugs that can inhibit BACE1 would theoretically prevent Aβ accumulation and halt AD onset and progression.

Areas covered: This review discusses clinical developments of BACE1 inhibitors and focuses on what is learned about these inhibitors as a potential treatment.

Expert opinion: BACE1 inhibition as a therapeutic strategy to improve cognition in AD has been challening. Brain-penetrant BACE1 inhibitors have been developed and clinical trials are underway, both safety and efficacy are questionable. Several clinical trials suggest that BACE1 inhibition and other immunotherapies to reduce brain Aβ are insufficient to improve cognition in AD. This may be due to the emphasis on the amyloid hypothesis despite big failures. We may have to seriously consider shifting attention to therapeutic strategies other than BACE1 inhibition or reduction of Aβ alone and pay more attention to simultaneous clearance of tau and Aβ.     

Prematurely ended phase III trials in Sweden during the years 2002–2008

Purpose  

The aim of this study was to identify prematurely ended phase III clinical trials (CTs) and the proportion of such trials among all phase III CTs, review the reasons for the premature discontinuation of the CT, determine whether a data monitoring committee (DMC) was involved in this decision-making process, identify the data source on which the decision was based and review the consequences of the premature ending for product development. An additional aim was to identify risk factors for a premature ending.     

Investigational phosphodiesterase inhibitors in phase I and phase II clinical trials for Alzheimer’s disease

Introduction: Phosphodiesterase (PDE) inhibitors improve signaling pathways in brain circuits by increasing intracellular cyclic adenosine monophosphate (cAMP) and/or cyclic guanosine monophosphate (cGMP). In the last decade, the first clinical studies investigating selective PDE inhibitors in Alzheimer’s disease (AD) have been initiated, based on their positive effects on cognitive processes and neuroprotection in numerous animal studies.

Areas covered: This article reviews the clinical studies investigating the pro-cognitive/neuroprotective effects of PDE inhibitors in patients with AD, as well as in age-associated memory impaired elderly and patients with mild cognitive impairment (MCI), the prodromal stage of AD. PDE inhibitors will also be discussed with respect to adverse effects including safety and tolerability.

Expert opinion: The limited available data of clinical studies with PDE inhibitors tested in different populations of AD patients do not allow the drawing of any concrete conclusion yet. Currently, studies with a PDE3 (cilostazol) or PDE9 inhibitor (BI 409,306) are still ongoing in patients with MCI or AD, respectively. Studies with PDE4 inhibitors (HT-0712, roflumilast and BPN14770) in healthy elderly and elderly with age-associated memory impairments indicate that the optimum dose and/or inhibiting the most relevant PDE isoform hold great promise when tested in the appropriate population of patients with MCI or AD eventually.     

Phase I and phase II metabolite identification of rutaecarpine in freshly isolated hepatocytes from male Sprague–Dawley rats

Rutaecarpine, an alkaloid originally isolated from Evodia rutaecarpa, has been used for the treatment of gastrointestinal disorders in Asia. In the present study, the phase I and phase II metabolites of rutaecarpine were investigated in freshly isolated hepatocytes from male Sprague–Dawley rats. The individual metabolites were characterized via liquid chromatography-tandem mass spectrometry. The incubation of rutaecarpine with freshly isolated hepatocytes for 2 h yielded five major phase I metabolites. In addition, three glucuronide conjugates and four sulfate conjugates were observed. Because the majority of metabolites observed in vivo were identified, freshly isolated hepatocytes might be useful for the identification of certain metabolites formed from drug candidates from a reduced number of experimental animals.     

In vitro–in vivo extrapolation of hepatic clearance involving active uptake: Theoretical and experimental aspects

The importance of hepatic uptake transporters in drug clearance is well recognized. The subject is reviewed with the intention of providing an overview of the concepts in order to link the increasing knowledge of transporter-mediated uptake into established models of hepatic clearance. In order to understand and quantify their impact, models of hepatic elimination that incorporate permeability barriers are required. Models that include both active and passive uptake into hepatocytes are discussed and simulations of the influence of active uptake and passive diffusion on hepatic clearance are presented. The advantages and weaknesses of a number of in vitro assays of hepatic uptake are described, and their ability to predict hepatic clearance is reviewed.     

Organic solvents vapor pressure and relative humidity effects on the phase transition rate of α and β forms of tegafur

The objective of this work was to investigate the relative humidity (RH) and solvent vapor pressure effects on the phase transition dynamics between tegafur polymorphic forms that do not form hydrates and solvates. The commercially available α and β modifications of 5-fluoro-1-(tetrahydro-2-furyl)-uracil, known as the antitumor agent tegafur, were used as model materials for this study. While investigating the phase transitions of α and β tegafur under various partial pressures of methanol, n-propanol, n-butanol, and water vapor, it was determined that the phase transition rate increased in the presence of solvent vapors, even though no solvates were formed. By increasing the relative air humidity from 20% to 80%, the phase transition rate constant of α and β tegafur was increased about 60 times. After increasing the partial pressure of methanol, n-propanol, or n-butanol vapor, the phase transition rate constant did not change, but the extent of phase transformation was increased. In the homologous row of n-alcohols, the phase transition rate constant decreased with increasing carbon chain length. The dependence of phase transformation extent versus the RH corresponded to the polymolecular adsorption isotherm with a possible capillary condensation effect.     

Effects of atorvastatin on systemic and renal NO dependency in patients with non-diabetic stage II–III chronic kidney disease

Aims

Clinical trials suggest that statins have beneficial effects on the cardiovascular system independent from their cholesterol lowering properties. In patients with chronic kidney disease stage II–III, we tested the hypothesis that atorvastatin increased systemic and renal nitric oxide (NO) availability using L-N^G-monomethyl arginine (L-NMMA) as an inhibitor of NO production.

Methods

In a randomized, placebo-controlled, crossover study patients were treated with atorvastatin for 5 days with standardized diet and fluid intake. Glomerular filtration reate (GFR), fractional excretions of sodium (FE_Na), urinary excretion of aquaporin-2 (u-AQP2) and epithelial sodium channels (u-ENaC_γ), vasoactive hormones (renin, angiotensin II, aldosterone, arginine vasopressin, endothelin-1 and brain natriuretic peptide) and central blood pressure (BP) estimated by applanation tonometry were measured before and after systemic administration of the NO inhibitor L-NMMA.

Results

Atorvastatin caused a significant reduction in U-ENaC_γ, but sodium excretion, , FE_Na and u-AQP2 were not changed by atorvastatin. L-NMMA reduced renal effect variables, including GFR, FE_Na and u-ENaC_γ and increased brachial BP and central BP to a similar extent during both treatments. Vasoactive hormones were changed in the same way by L-NMMA during atorvastatin and placebo treatment.

Conclusion

During, atorvastatin and placebo treatment, inhibition of nitric oxide synthesis induced the same response in brachial and central blood pressure, GFR, renal tubular function and vasoactive hormones. Thus, the data do not support that atorvastatin changes nitric oxide availability in patients with mild nephropathy. The reduced u-ENaC may reflect changes in sodium absorption in the nephron induced by atorvastatin.     

Rimonabant Dimorphism and Its Pressure–Temperature Phase Diagram: A Delicate Case of Overall Monotropic Behavior

Crystalline polymorphism occurs frequently in the solid state of active pharmaceutical ingredients, and this is problematic for the development of a suitable dose form. Rimonabant, an active pharmaceutical ingredient developed by Sanofi and discontinued because of side effects, exhibits dimorphism; both solid forms have nearly the same melting temperatures, melting enthalpies, and specific volumes. Although the problem may well be academic from an industrial point of view, the present case demonstrates the usefulness of constructing pressure–temperature phase diagrams by direct measurement as well as by topological approach. The system is overall monotropic and form II is the more stable solid form. Interestingly, the more stable form does not possess any hydrogen bonds, whereas the less stable one does. © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 102:2311–2321, 2013     

Organic solvents vapor pressure and relative humidity effects on the phase transition rate of α and β forms of tegafur

The objective of this work was to investigate the relative humidity (RH) and solvent vapor pressure effects on the phase transition dynamics between tegafur polymorphic forms that do not form hydrates and solvates. The commercially available α and β modifications of 5-fluoro-1-(tetrahydro-2-furyl)-uracil, known as the antitumor agent tegafur, were used as model materials for this study. While investigating the phase transitions of α and β tegafur under various partial pressures of methanol, n-propanol, n-butanol, and water vapor, it was determined that the phase transition rate increased in the presence of solvent vapors, even though no solvates were formed. By increasing the relative air humidity from 20% to 80%, the phase transition rate constant of α and β tegafur was increased about 60 times. After increasing the partial pressure of methanol, n-propanol, or n-butanol vapor, the phase transition rate constant did not change, but the extent of phase transformation was increased. In the homologous row of n-alcohols, the phase transition rate constant decreased with increasing carbon chain length. The dependence of phase transformation extent versus the RH corresponded to the polymolecular adsorption isotherm with a possible capillary condensation effect.     

Preparation and characterization of recombinant human growth hormone–Zn2+-dextran nanoparticles using aqueous phase–aqueous phase emulsion

An effective and simple method was developed to prepare spherical and uniform-sized recombinant human growth hormone (rhGH)–Zn²⁺-dextran nanoparticles (NPs) for a variety of delivery applications of the delicate protein. The results showed that the prepared rhGH-Zn²⁺-dextran particles were spherical, glassy, and uniform in size. rhGH recovered from the NPs maintained its structural integrity and its bioactivity well, as suggested by the Nb₂-11 cell proliferation assay. Using polyethylene glycol and polysaccharide to mediate Zn²⁺-induced precipitation has proved to be a promising method to prepare spherical protein-loaded NPs with desired sizes and preserved protein stability.From the Clinical EditorThis basic science paper discusses a simple yet effective method to prepare spherical and uniform-sized recombinant human growth hormone (rhGH)-Zn²⁺-dextran nanoparticles for a variety of delivery applications.     

Development of a linear dual column HPLC–MS/MS method and clinical genetic evaluation for tramadol and its phase I and II metabolites in oral fluid

Tramadol is a centrally acting synthetic opioid analgesic and has received special attention due to its abuse potential and unexpected responses induced by CYP2D6 polymorphism. Oral fluid is an advantageous biofluid for drug analysis due to non-invasive sampling and high correlation of drug concentrations with plasma. However, few studies have been performed on distribution of tramadol and its metabolites in oral fluid. In the present study, a linear dual column HPLC–MS/MS method was developed and fully validated for the simultaneous determination of tramadol and its phase I [O-desmethyltramadol (ODMT), N-desmethyltramadol (NDMT) and N,O-didesmethyltramadol (NODMT)] and II metabolites in oral fluid. Furthermore, the distribution of tramadol and its metabolites, in relation to CYP2D6 genetic variations, in oral fluid was investigated following a clinical study including 23 subjects with CYP2D6*wt/*wt, CYP2D6*10/*10 or CYP2D6*5/*5. The validation results of selectivity, matrix effect, linearity, precision and accuracy were satisfactory. Pharmacokinetic parameters, such as C_ss,max and AUC_0–τ of tramadol, NDMT and NODMT, in the CYP2D6*10/*10 group were significantly higher than those in the CYP2D6*wt/*wt group. Moreover, the ratios of ODMT/tramadol, NDMT/tramadol and NODMT/NDMT correlated well with the CYP2D6 genotypes. We demonstrated that oral fluid is a promising biofluid for pharmacokinetic evaluation in relation to genetic variations.     

Decision Making from Phase II to Phase III and the Probability of Success: Reassured by “Assurance”?

With Phase III failure rates of 50%, better ways of predicting late-stage success are needed. One concept that has been used is “assurance.” Rather than conventional power calculations hypothesizing a known effect of a drug, assurance provides an expected power calculation based on some prior distribution for the treatment effect. It therefore has appeal in Phase III planning and decision making, especially when the prior is based on Phase II data. However, assurance has counterintuitive properties that can serve to confuse and concern the nonstatistician. Appreciation of these properties is helpful to ensure an informed use of assurance in strategic drug development.     

Gas–plasma sterilization: relative efficacy of the hydrogen peroxide phase compared with that of the plasma phase

Recent modifications specified in the European Pharmacopoeia IIIrd Edition (1 January 1997) have led us to investigate the sensitivity of Bacillus stearothermophilus ATCC 7953, a sporulated bacterial species now used instead of Bacillus subtilis var niger ATCC 9372 as a reference in peroxide sterilization. Inactivation kinetic studies have shown that this choice is well founded and also indicate that inherent efficacy of the STERRAD^® 100 gas–plasma process is above all due to hydrogen peroxide. The ionization obtained during the plasma phase is validated in its role of a residue detoxifying process, without any sporicidal effect.     

Curcumin–Zn(II) complex for enhanced solubility and stability: an approach for improved delivery and pharmacodynamic effects

Objective: The aim of present investigation was to prepare Curcumin–Zn(II) complex in a view to enhance solubility, stability and pharmacodynamic effect in experimentally induced ulcerative colitis.

Method: Curcumin–Zn(II) complex was prepared by stirring curcumin with anhydrous zinc chloride at a molar ratio of 1:1. The prepared curcumin metallocomplex was characterized by TLC, FTIR, UV spectroscopy and ¹H NMR. In vitro kinetic degradation and solubility of Curcumin and Curcumin–Zn(II) complex was analyzed spectrophotometrically. Pharmacodynamic evaluation of curcumin and its metal complex was assessed in ulcerative colitis in mice.

Results: Curcumin showed chelation with zinc ion as confirmed by the TLC, FTIR, UV spectroscopy and ¹H NMR. The results of TLC [R_f value], IR Spectroscopy [shifting of stretching vibrations of υ(C=C) and υ(C=O)], UV spectra [deconvoluted with absorption band at 432–466.4 nm] of Curcumin–Zn(II) complex compared to curcumin confirmed the formation of metallocomplex. ¹HNMR spectra of Curcumin–Zn(II) showed the upfield shift of H_a and H_b. Kinetic stability studies showed metallocomplex with zinc exhibited good stability. In vivo study revealed significant reduction in severity and extent of colonic damage with Curcumin–Zn(II) which were further confirmed by histopathological study.

Conclusion: This study recognizes higher solubility and stability of Curcumin–Zn(II) complex and suggested better pharmacodynamic effects.     

Investigational drugs in phase I and phase II clinical trials targeting interleukin 23 (IL23) for the treatment of Crohn’s disease

Introduction: Medical therapy for Crohn’s disease (CD) is directed at controlling intestinal inflammation to prevent development of disease-related complications. Not all patients will respond to currently available treatments and thus, novel therapies are needed. The interleukin (IL)-23 cytokine axis is implicated in CD pathogenesis and so targeting this pathway has become an important focus for drug development.

Areas covered: This review summarizes the role of the IL23 cytokine pathway in CD pathogenesis and appraises phase I and II clinical trial data for novel IL23p19 specific monoclonal antibodies for the treatment of CD. The evidence for risankizumab (BI655066/ABBV066), brazikumab (MEDI2070, formerly AMG139), guselkumab (CNTO1959), tildrakizumab (MK3222), and mirikizumab (LY3074828) is reviewed; moreover, future applications for these agents are considered.

Expert opinion: Targeting the specific p19 subunit of IL23 is a promising strategy in CD. Two multicenter, randomized, placebo-controlled phase II clinical trials have evaluated risankizumab and brazikumab. Both studies indicate that IL23-specific blockade is likely to be a safe and effective alternative to current biologics, including the TNF antagonists vedolizumab and ustekinumab. Confirmatory Phase 3 studies are underway. Ultimately, comparative effectiveness trials will be necessary to define the role of IL23-specific antagonists in CD treatment algorithms.     

The association between the catechol-O-methyltransferase Val108/158Met polymorphism and hyperactive–impulsive and inattentive symptoms in youth

Rationale

Hyperactivity, impulsivity, and inattention are major symptoms occurring in attention-deficit/hyperactivity disorder. This disorder is highly heritable, multifactorial, polygenic, and associated primarily with dysfunctions of dopaminergic, noradrenergic, and serotonergic systems.

Objectives

The present study tested the possible association of the catechol-O-methyltransferase (COMT) Val108/158Met (rs4680) polymorphism with hyperactive–impulsive and inattentive symptoms in male youth.

Method

Polymorphism COMT Val108/158Met was analyzed in 807 male unrelated Caucasian young subjects: 231 healthy controls, 195 subjects with moderate hyperactive symptoms and 254 subjects with moderate inattentive symptoms, 111 subjects with severe hyperactive symptoms and 90 subjects with severe inattentive symptoms, all evaluated using Swanson, Nolan, and Pelham Questionnaire IV criteria.

Results

The frequency of the COMT genotypes, alleles, and the homozygous Met/Met genotype versus Val carriers (χ ² test with standardized residuals) differed significantly between subjects without and subjects with hyperactive–impulsive and inattentive symptoms. In addition, significantly higher hyperactive–impulsive and inattentive scores were found in subjects with the Met/Met genotype compared to carriers of other COMT genotypes. These significant results were due to the more frequent occurrence of Met/Met genotype or the Met allele in subjects with moderate and severe hyperactive–impulsive and inattentive symptoms compared to matched controls.

Conclusion

These results suggest that the Met/Met genotype or the Met allele of the COMT Val108/158Met, contributing to higher dopaminergic activity, are significantly overrepresented in subjects with moderate or severe hyperactive–impulsive and inattentive symptoms, and that this polymorphism is significantly associated with hyperactive–impulsive and inattentive symptoms in young boys and adolescents.