Bryostatin-1: pharmacology and therapeutic potential as a CNS drug

Bryostatin-1 is a powerful protein kinase C (PKC) agonist, activating PKC isozymes at nanomolar concentrations. Pharmacological studies of bryostatin-1 have mainly been focused on its action in preventing tumor growth. Emerging evidence suggests, however, that bryostatin-1 exhibits additional important pharmacological activities. In preclinical studies bryostatin-1 has been shown at appropriate doses to have cognitive restorative and antidepressant effects. The underlying pharmacological mechanisms may involve an activation of PKC isozymes, induction of synthesis of proteins required for long-term memory, restoration of stress-evoked inhibition of PKC activity, and reduction of neurotoxic amyloid accumulation and tau protein hyperphosphorylation. The therapeutic potential of bryostatin-1 as a CNS drug should be further explored.     

Transgenic mouse models of Alzheimer disease: developing a better model as a tool for therapeutic interventions

Alzheimer disease (AD) is the leading cause of dementia among elderly. Currently, no effective treatment is available for AD. Analysis of transgenic mouse models of AD has facilitated our understanding of disease mechanisms and provided valuable tools for evaluating potential therapeutic strategies. In this review, we will discuss the strengths and weaknesses of current mouse models of AD and the contribution towards understanding the pathological mechanisms and developing effective therapies.     

Integrating pharmacogenetics and therapeutic drug monitoring: optimal dosing of imatinib as a case-example

Purpose

To illustrate the interface of pharmacogenetics and therapeutic drug monitoring and to estimate target blood level for imatinib in the treatment of chronic myelogenous leukemia

Methods

A literature review to provide the evidence and necessary data to support the case for the interface, and quantitative analysis of the data to estimate the target blood level for imatinib using receiver operating curve (ROC; signal detection theory) analysis.

Results and discussion

One study estimated the optimum target level of imatinib in chronic myelogenous leukaemia as 1002 ng/mL (1.70 µM) through ROC analysis. Using individual-patient level data reported in another study and the same methodology, we estimated the target level as 0.95 µM. This is consistent with the results of other observational studies where dose–response was not the primary research objective. The available evidence suggests considerable inter-individual variability in dose–blood level response. In addition to the pharmacogenetics of metabolic enzymes and transporters, genetic mutations in genes participating in the signalling pathways may also account for the wide inter-individual variability in dose–blood level and dose–clinical response relationships.

Conclusion

A single-dose regimen for all pharmacogenetically eligible patients is not the optimum strategy for prescribing imatinib to patients with chronic myelogenous leukaemia. We suggest that therapeutic drug monitoring aimed at ensuring a trough target level of 1 µM would reduce the incidence of pseudo-resistance and hence personalize treatment and optimise response to imatinib. Persistent resistance can then be probed further for other causes.     

alpha1-Microglobulin as a promising marker of cadmium-induced tubular dysfunction, possibly better than beta2-microglobulin

The purpose of the present study was to evaluate the validity of alpha1-microglobulin (alpha1-MG) in comparison with popularly used beta2-microglobulin (beta2-MG). A database on 8975 cases of never-smoking adult women was revisited; the data were based on spot urine samples from the women in 10 prefectures all over Japan. The validity of alpha1-MG was examined following essentially the same protocol as beta2-MG was examined in a previous study. Comparisons were made for alpha1-MG as observed (e.g. alpha1-MG(ob)), as corrected for creatinine (CR or cr) (e.g. alpha1-MGcr) and as corrected for a specific gravity (SG or sg) of 1.016 (e.g. alpha1-MGsg). A cut-off value of 5.0 mg alpha1-MG/g cr or l was deduced from 400 microg beta2-MG/g cr taking advantage of the regression equation between alpha1-MG and beta2-MG. The prevalence of alph1-microglobulinuria as corrected for a specific gravity of 1.016 (or alpha1-MGsg-uria in short) was essentially unchanged irrespective of SG, except for in very dense or very thin urine samples. alpha1-MGcr-uria prevalence decreased at higher CR. Comparison of the present observation with previous findings on beta2-MG-uria prevalence showed that the variation in prevalence of MG-uria as a function of urine density was smaller for alpha1-MGsg whereas it was substantially larger for beta2-MGcr, and thus it appeared prudent to consider alpha1-MGsg rather than beta2-MGcr as a marker of tubular dysfunction.     

Product selection, bioequivalence, and therapeutic equivalence: the generic drug market

Pharmacists are continually faced with drug product selection decisions. When is a generic drug product equivalent to the innovator product and, thus, a suitable candidate for generic substitution? The FDA policy has been that only drug products that are therapeutic equivalents are candidates for product selection decisions. This paper outlines the regulatory and scientific framework for the FDA's policies and requirements for generic drug products. The history and current status of the Drug Efficacy Study Implementation (DESI) project is described. Originally begun in 1966 as a review of about 3,400 drug products, the review in mid-1983 is more than 90% complete, but its impact has already affected more than 7,000 marketed drug products. The therapeutic equivalence policy and the manner in which decisions on therapeutic equivalence are communicated are reviewed. Regulatory policies for the approval of generic drug products are reviewed and specific litigation challenging the rights of generic drug manufacturers to produce generic "look-alikes" and challenging the FDA's policy that a generic drug product is a new drug requiring an approved New Drug Application for marketing is discussed. The conclusion reached is that the evaluation of regulatory requirements and science is leading to a point where all generic drug products will be known to be safe, effective and therapeutically equivalent, and pharmacists can be optimistic about the quality of products in the generic drug market.     

Cimetidine as an inhibitor of drug metabolism: therapeutic implications and review of the literature

Cimetidine has been reported to decrease the biotransformation of drugs metabolized by the MFOE system. Additionally, cimetidine decreases liver blood flow and increases the bioavailability of drugs with high hepatic extraction ratios. Patients receiving cimetidine in conjunction with drugs known to interact with cimetidine in conjunction with drugs known to interact with cimetidine are at risk of experiencing toxicity. When appropriate, reducing the dosage of these agents or switching to an alternative drug will minimize the incidence of side effects. Clinicians should be suspicious if patients experience exaggerated drug effects when cimetidine therapy is begun.     

Nucleic acids in the drug discovery process: aptamers as therapeutic and as active ingredients for drugs

Kombinatorische biochemische Methoden erm?glichen die Identifikation von Nukleins?uren, so genannten Aptameren, die hoch affin und spezifisch an Zielmoleküle binden und deren biologische Funktionen effektiv inhibieren. Deshalb repr?sentieren Aptamere eine viel versprechende Klasse neuartiger Therapeutika. Untermauert wird dies vor allem durch die Zulassung von Pegaptanib (Macugen) zur Behandlung der altersbedingten Makuladegeneration (AMD), dem ersten Aptamer-basierten Medikament. Die Aptamertechnologie er?ffnet vielf?ltige Applikationsm?glichkeiten und neuere Arbeiten zeigen, dass sie auch bei der Identifikation niedermolekularer Wirkstoffe einen wertvollen Beitrag leisten kann.     

Multi-faceted aspects of gamma-hydroxybutyric acid: a neurotransmitter, therapeutic agent and drug of abuse

Gamma hydroxybutyric acid (GHB), an endogenous constituent of the mammalian brain, acts as i) a neurotransmitter or neuromodulator, ii) a medicine used for the treatment of narcolepsy and alcoholism, and iii) a drug illicitly used for its psychotropic effects. GHB is thought to act as a specific GHB receptor agonist as well as a weak gamma-aminobutyric acid type B (GABA(B)) receptor agonist. Here, I review the in vivo and in vitro pharmacological properties of GHB and its interaction with GHB and GABA(B) receptors. When exogenously administered, GHB is rapidly absorbed, crosses the blood-brain barrier, penetrates into the brain and exerts a number of pharmacological effects including anxiolysis, sedation/hypnosis and anesthesia. Due to its effects on the central nervous system, GHB has been used for the treatment of narcolepsy and as an anesthetic adjuvant. More recently, a role for GHB in the pharmacotherapy of alcohol dependence has been described. In this review, I also focus on the abuse liability and reinforcing properties of GHB in humans and laboratory animals.     

Arf6 as a therapeutic target: Structure,mechanism, and inhibitors

ADP-ribosylation factor 6(Arf6), a small G-protein of the Ras superfamily, plays pivotal roles in multiple cellular events, including exocytosis, endocytosis, actin remodeling, plasma membrane reorganization and vesicular transport. Arf6 regulates the progression of cancer through the activation of cell motility and invasion. Aberrant Arf6 activation is a potential therapeutic target. This review aims to understand the comprehensive function of Arf6 for future cancer therapy. The Arf6 GEFs, prot...     

Nuclear receptors as drug targets: new developments in coregulators, orphan receptors and major therapeutic areas

Nuclear receptors (NRs) are ideal targets for drug discovery. Not only do they control a myriad of biological and disease processes, but they are also regulated by small lipophilic molecules that can be easily exchanged with a drug of choice. All 48 of the NR genes in the human genome have been identified, many of their structures have been solved and their ligands identified. Their mechanism of action has been elucidated and many of their target genes have been identified. Nonetheless, presentations at the recent conference sponsored by IBC Life Sciences indicated that, while many NRs already have marketable drugs, the latest tools in robotics, genomics, proteomics, and informatics are helping to identify more selective drugs.     

Relationship between HBV markers and heroin as a cause of liver injury in drug addicts

Fifty liver biopsies from heroin addicts on methadone maintenance were studied for histological features. The relationship between hepatic damage, HBV markers and the length of drug abuse was analysed. Infiltration was found in 95.6% of hepatitis B surface antigen (HBsAg) positive patients and in 50% of hepatitis B surface antibody (HBsAb) positive and HBV negative patients. The length of drug abuse showed a strong direct correlation with vacuolar degeneration (P less than 0.001) and an inverse correlation with fibrosis (P less than 0.05).     

Toxicodynamic therapeutic drug monitoring of immunosuppressants: promises, reality, and challenges

Although current immunosuppressive protocols have dramatically decreased acute rejection episodes, there has been less progress in terms of long-term graft survival after kidney transplantation over the last 2 decades. The key to reducing the damage to a transplanted organ as caused by chronic processes is early detection. Modern screening technologies in the fields of genetics, genomics, protein profiling (proteomics), and biochemical profiling (metabolomics) have opened new opportunities for the development of sensitive and specific diagnostic tools. Metabolic profiling appears to be a promising strategy because changes in the cell biochemistry are ultimately responsible for the histologic and pathophysiologic changes of the transplanted kidney and are most likely already detectable before histologic and pathophysiologic changes occur. Using truly no-targeted screening technologies as clinical diagnostic tools is not yet feasible, mostly because of the complexity of the data generated and the lack of algorithms to convert this information into clinically applicable information. A realistic and powerful targeted approach is the development of combinatorial biomarkers. These are biomarker patterns that typically consist of five or more individual parameters. Combined biomarker patterns confer significantly more information than a single measurement and, thus, can be expected to have better specificity and sensitivity. A series of studies in rats and healthy individuals evaluating the effects of immunosuppressants on urine metabolite patterns showed that immunosuppressant-induced changes of metabolite patterns in urine were associated with a combination of changes in glomerular filtration, changes in secretion/absorption by tubulus cells, and changes in kidney cell metabolism. These studies suggested that a combination of biomarkers that can be used for toxicodynamic therapeutic drug monitoring of immunosuppressants should include urine metabolites that constitute valid surrogate markers of these kidney functions.