In vivo drug-drug interaction studies--a survey of all new molecular entities approved from 1987 to 1997

Ninety-eight new molecular entities applications approved between 1987 to 1991 (period I) and 193 applications for new molecular entities between 1992 to 1997 (period II) were surveyed for drug-drug interaction studies. In period I (used as a comparator), 32 applications contained drug-drug interaction studies for a total of 117 studies. In period II, 106 applications reported drug-drug interaction studies, and the number of studies per new molecular entity ranged from 0 to 15. Most studies (77%) were performed in healthy subjects, with 44% using crossover designs, 7% using parallel designs, and the remaining using fixed sequence designs. The most common dosing scheme for new molecular entities/interacting drug was multiple dose (47%), whereas single dose/multiple dose was used in 31% of studies, and single dose/single dose was used in 18% of studies. Of the 540 drug-drug interaction studies submitted in period II, 80 (15%) resulted in clinically significant labeling statements. Submissions for new molecular entities to the Center for Drug Evaluation and Research divisions most likely to include drug-drug interaction studies were neuropharmacology, cardiorenal, antiviral, and antiinfective drugs. Some drug classes such as oncology drug products and radioimaging products were least likely to include drug-drug interaction studies in their submissions. We conclude that the use of drug-drug interaction studies in the drug development process has increased between the two periods.     

Why and how to prepare biodegradable, monodispersed, polymeric microparticles in the field of pharmacy?

Pharmaceutical cocrystals are emerging as a new class of solid drugs with improved physicochemical properties, which has attracted increased interests from both industrial and academic researchers. In this paper a brief and systematic overview of pharmaceutical cocrystals is provided, with particular focus on cocrystal design strategies, formation methods, physicochemical property studies, characterisation techniques, and recent theoretical developments in cocrystal screening and mechanisms of cocrystal formations. Examples of pharmaceutical cocrystals are also summarised in this paper.     

The impact of angiotensin-converting enzyme inhibitors and angiotensin-receptor blockers in patients with Clostridium difficile infection

There is increasing frequency and severity of disease due to Clostridium difficile infection (CDI). In addition, failure of initial antibiotic therapy is increasing. Angiotensin-converting enzyme inhibitors (ACEI) and angiotensin-receptor blockers (ARBs) may have local and systemic anti-inflammatory properties to reduce severity of disease in CDI. We performed a retrospective study of 306 patients with CDI over 23 months at a single center in Detroit, Michigan. Patient outcomes (death, death due to CDAD and relapse rates) were compared based on the use of ACEI or ARB during an episode of CDI. A total of 116 (37.9%) patients received an ACEI/ARB and 190 (62.1%) did not. The groups were similar except ACEI/ARB patients were older (71.9 vs. 64.3, P<0.0005) and had a higher frequency of congestive heart failure (50.9% vs. 30.2%, P<0.0005) and chronic obstructive pulmonary diseases (44.8% vs. 30.2%, P<0.010). ACEI/ARB patients had lower overall mortality rates (9.5% vs. 23.3%, P<0.002) as well as mortality due to CDI (2.6% vs. 8.6%, P<0.036). The rate of CDI relapse was not significantly different between the groups (5.2% in ACEI/ARB vs. 10.0%, P=0.135). Logistic regression analysis demonstrated that ACEI/ARB use was associated with lower overall mortality rate (OR 0.26; 95% CI, 0.12-0.55) and mortality due to CDI (OR 0.29; 95% CI, 0.08-1.02). Our findings suggest that ACEI/ARBs may have a role as an adjuvant therapy to antibiotics in patients with CDI. Prospective studies are needed to confirm these results.     

CC2D2A mutations in Meckel and Joubert syndromes indicate a genotype–phenotype correlation

Meckel-Gruber syndrome (MKS) is a lethal fetal disorder characterized by diffuse renal cystic dysplasia, polydactyly, a brain malformation that is usually occipital encephalocele, and/or vermian agenesis, with intrahepatic biliary duct proliferation. Joubert syndrome (JBS) is a viable neurological disorder with a characteristic “molar tooth sign” (MTS) on axial images reflecting cerebellar vermian hypoplasia/dysplasia. Both conditions are classified as ciliopathies with an autosomal recessive mode of inheritance. Allelism of MKS and JBS has been reported for TMEM67/MKS3, CEP290/MKS4, and RPGRIP1L/MKS5. Recently, one homozygous splice mutation with a founder effect was reported in the CC2D2A gene in Finnish fetuses with MKS, defining the 6th locus for MKS. Shortly thereafter, CC2D2A mutations were also reported in JBS. The analysis of the CC2D2A gene in our series of MKS fetuses, identified 14 novel truncating mutations in 11 cases. These results confirm the involvement of CC2D2A in MKS and reveal a major contribution of CC2D2A to the disease. We also identified three missense CC2D2A mutations in two JBS cases. Therefore, and in accordance with the data reported regarding RPGRIP1L, our results indicate phenotype–genotype correlations, as missense and presumably hypomorphic mutations lead to JBS while all null alleles lead to MKS. Hum Mutat 30:1–9, 2009. © 2009 Wiley-Liss, Inc.     

Antiphosphatidylethanolamine antibodies are associated with an increased odds ratio for thrombosis. A multicenter study with the participation of the European Forum on antiphospholipid antibodies

A multicenter study was set up to evaluate the prevalence, clinical and biological significance of antiphosphatidylethanolamine antibodies (aPE) in thrombotic patients with or without the main known clinical and biological risk factors for thrombosis. APE and antibodies, defined as the laboratory criteria of antiphospholipid syndrome (APS) -lupus anticoagulant, anticardiolipin and anti-beta(2)-GPI antibodies were measured in 270 patients with thrombosis (234 venous and 37 arterial) and 236 matched controls. APE were found in 15% of thrombotic patients compared to 3% of controls (p < 0.001) with no predominant isotype, no association with the main known clinical or biological risk factors for thrombosis neither with a type of thrombosis, arterial or venous. In a multivariate logistic regression analysis of antibodies, aPE showed the highest association with thrombosis (odds ratio [OR]: 4.2, p < 0.001). Moreover, using a multivariate analysis in a case-control subgroup study on 158 patients, IgGaPE were found to be significantly associated with venous thrombosis (OR:6;p = 0.005). Interestingly, 25 of the 40 aPE-positive patients (63%) were negative for the APS laboratory criteria. Most of them (21/25) had venous thrombosis, recurrent in ten of them. Four patients also suffered from early or late miscarriages. Our results underline the strength of the association between the presence of aPE and thrombosis and suggest their measurement in thrombotic patients, especially when lupus anticoagulant, anticardiolipin or anti-beta(2)-GPI antibodies are absent.     

PTEN Contributes to Profound PI3K/Akt Signaling Pathway Deregulation in Dystrophin-Deficient Dog Muscle

Duchenne muscular dystrophy is the most common and severe form of muscular dystrophy, and although the genetic basis of this disease is well defined, the overall mechanisms that define its pathogenesis remain obscure. Alterations in individual signaling pathways have been described, but little information is available regarding their putative implications in Duchenne muscular dystrophy pathogenesis. Here, we studied the status of various major signaling pathways in the Golden Retriever muscular dystrophy dog that specifically reproduces the full spectrum of human pathology. Using antibody arrays, we found that Akt1, glycogen synthase kinase-3β (GSK3β), 70-kDa ribosomal protein S6 kinase (p70S6K), extracellular signal-regulated kinases 1/2, and p38δ and p38γ kinases all exhibited decreased phosphorylation in muscle from a 4-month-old animal with Golden Retriever muscular dystrophy, revealing a deep alteration of the phosphatidylinositol 3-kinase (PI3K)/Akt and mitogen-activated protein kinase pathways. Immunohistochemistry analysis revealed the presence of muscle fibers exhibiting a cytosolic accumulation of Akt1, GSK3β, and phosphatidylinositol-3,4,5-trisphosphate 3-phosphatase (PTEN), an enzyme counteracting PI3K-mediated Akt activation. Enzymatic assays established that these alterations in phosphorylation and expression levels were associated with decreased Akt and increased GSK3β and PTEN activities. PTEN/GSK3β-positive fibers were also observed in muscle sections from 3- and 36-month-old animals, indicating long-term PI3K/Akt pathway alteration. Collectively, our data suggest that increased PTEN expression and activity play a central role in PI3K/Akt/GSK3β and p70S6K pathway modulation, which could exacerbate the consequences of dystrophin deficiency.Duchenne muscular dystrophy (DMD) is an X-linked neuromuscular disorder that affects 1 newborn boy in 3500. This recessive disease is caused by mutations in the dystrophin gene, resulting in total lack of the protein,^1,2,3 and is characterized by severe degeneration of muscle fibers, progressive paralysis, and death. Dystrophin is located under the sarcolemma of muscle fibers, and is associated with a complex comprising several integral, peripheral membrane and cytoplasmic proteins: the dystrophin-glycoprotein complex (DGC).^4,5,6,7 By providing a strong physical link between the cytoskeleton network and the extracellular matrix, the DGC ensures the integrity of skeletal muscle fibers. In the absence of dystrophin, the complex is destabilized and this integrity is lost.^5,8 However, the impaired structural role of the DGC alone may not be sufficient to account for the massive degenerative process observed in DMD muscles. Numerous observations suggest that signaling pathway alterations may also participate in DMD pathogenesis.Dystrophin and various DGC proteins have been demonstrated to interact with a number of signaling proteins, including growth factor receptor-bound protein 2,⁹ neuronal nitric oxide synthase,¹⁰ calmodulin,¹¹ focal adhesion kinase,¹² and caveolin-3.^13,14,15 Moreover, studies of the X chromosome-linked muscular dystrophy (mdx) mouse¹⁶ revealed modulations in mitogen-activated protein kinase (MAPK) signaling cascades, as dystrophic animals exhibited increased phosphorylation of extracellular signal-regulated kinases 1 and 2 (ERK1/2)^17,18 and c-jun N-terminal kinases 1 and 2 (JNK1/2),^19,20,21 and decreased phosphorylation of p38.¹⁸ Also, the phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway has been shown to be affected in the mdx mouse, with increased synthesis and phosphorylation of Akt.^22,23In addition to the limited information related to the origin of signal perturbations in dystrophic muscle, almost no information is available regarding signaling pathways in clinically relevant animal models or human tissue samples.²³ It is noteworthy that the mdx mouse model of DMD is characterized by successive degeneration/regeneration processes, but does not exhibit the progressive muscle wasting and accumulation of connective tissue observed during the development of the human disease.^24,25,26 The Golden Retriever muscular dystrophy (GRMD) dog, characterized by rapidly progressive clinical dysfunction, severe muscle weakness, and abundant fiber necrosis, displays a disease progression that is far more similar to human DMD.^27,28In this study, we used antibody arrays to assess the global phosphorylation status of key proteins of the PI3K/Akt and MAPK signaling pathways in skeletal muscles of 4-month-old healthy and GRMD dogs. Our data indicated that Akt1, glycogen synthase kinase-3β (GSK3β) and p70S6K, as well as ERK1/2 and p38δ and γ kinases all displayed a decreased phosphorylation level in GRMD muscle. Western immunoblot, immunohistochemistry analysis, and enzymatic assays allowed us to confirm these results and demonstrated that they were associated with a reduction in Akt activity and with enhanced GSK3β expression and activity. Analysis of key enzymes involved in Akt regulation revealed that phosphatidylinositol-3,4,5-trisphosphate 3-phosphatase (PTEN) was present at a much higher level and was more active in GRMD muscle. Moreover, immunohistochemistry analysis showed that all of the GSK3β-positive fibers observed in GRMD muscle sections exhibited a strong cytosolic labeling of PTEN, suggesting that the accumulation of the phosphatase could play a central role in PI3K/Akt signaling pathway deregulation. The observation of PTEN/GSK3β-positive fibers in muscle sections from 3- and 36-month-old GRMD dogs further demonstrated that both the early and late stages of the disease share deregulation of the pathway. Collectively, our findings highly suggest that alterations in PTEN exist in GRMD muscle, which leads to long-term and deep modulation of the PI3K/Akt signaling pathway.     

Effects of phonological and semantic cuing on encoding and retrieval processes in adolescent psychosis

The aim of this study was to investigate the effects of cuing on encoding and retrieval processes in adolescent psychosis. Patients and controls were instructed to learn word lists under three conditions: no cue, phonological cue, and semantic cue. Memory performance was measured with free and cued recalls. In free recall, both groups showed higher performance with semantic than with phonological encoding cues, but patients had no advantage from semantic cuing relative to no cue, contrary to controls. Patients' performance improved from free to cued recall, but this was not sufficient to normalize their performance. Impaired strategic processes may lead to encoding and retrieval difficulties in patients.     

Utilisation of pharmacokinetic-pharmacodynamic modelling and simulation in regulatory decision-making.

Modelling and simulation (M&S) play an important role in regulatory decision-making that affects both the public and industry. Technological advances in various fields related to drug development call for more focus on ways to optimise current drug development practices. Recognition of the potential of M&S by regulatory agencies inevitably has a substantial impact on drug development. The objective of the current review is to present the various regulatory initiatives for application of M&S to clinical drug development. The relevant parts of the various recommendations issued by the US Food and Drug Administration (FDA), via guidance documents and advisory committee meeting proceedings, are highlighted. Application of M&S to a variety of activities, such as integrating pharmacokinetic-pharmacodynamic knowledge across a new drug application and designing efficient trials, is discussed. Some of the challenges that pharmaceutical institutions currently face when implementing M&S projects, such as team structure, communication with regulators, training and time constraints, are also presented, and solutions are proposed.