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Posts Tagged ‘neurotoxicity’


Author: Tilda Barliya PhD

Alzheimer disease (AD) is among the most common brain disorders affecting the elderly population the world over, and is projected to become a major health problem with grave socio-economic implications in the coming decade (1a, 1b). Alzheimer’s disease arises in large part from the body’s inability to clear these naturally occurring proteins. As amyloid beta levels increase, they tend to aggregate and contribute to the brain “plaques” found in Alzheimer’s disease. There are still no effective treatments to prevent, halt, or reverse Alzheimer’s disease, but research advances over the past three decades could change this gloomy picture. Genetic studies demonstrate that the disease has multiple causes (2). Interdisciplinary approaches have been used to reveal the molecular mechanism of the disease including; biochemistry,  molecular and cell biology and transgenic mice models.  Progress in chemistry, radiology, and systems biology is beginning to provide useful biomarkers, and the emergence of personalized medicine is poised to transform pharmaceutical development and clinical trials. However, investigative and drug development efforts should be diversified to fully address the multifactoriality of the disease (2). A nice research review shows  for example, the effects of cancer drugs on AD treatment (3).

Nanotechnology Solutions for Alzheimer

Dr. Amir Nazem and Dr. G. Ali Mansoori described in their paper “Nanotechnology Solutions for Alzheimer’s Disease: Advances in Research Tools, Diagnostic Methods and Therapeutic Agents”
that he development of nanotechnology approaches for early-stage diagnosis of AD is quite promising but acknowledge that scientists are still at the very beginning of the ambitious project of designing effective drugs and methods for the regeneration of the central nervous system (4). Figure 1- Nanotechnology solutions of AD.

Applications of nanotechnology in AD therapy including:

  • Nanodiagnostics including imaging
  • Targeted drug delivery and controlled release
  • Regenerative medicine

These inclued: neuroprotections against oxidative stress anti-amyloid therapeutics, neuroregeneration and drug delivery beyond the blood brain barrier (BBB) are discussed and analyzed.

All of these applications could improve the treatment approach of AD and other neurodegenerative diseases.

Nanotechnology and Diagnostics:

The diagnosis of AD during life remains difficult and a definite diagnosis of AD relies on histopathological confirmation at post-mortem or by cerebral biopsy.  An early clinical diagnosis can be made if patients  are tested by trained neuropsychologists. The great problem is not that mild cognitive impairment  (MCI) cannot be diagnosed, but that the patients do not see doctor until severely affected (5).

During the last decade, research efforts have focused on developing  cerebrospinal fluid (CSF) biomarkers for AD. The diagnostic performance of the CSF  biomarkers: Tau protein, the 42-amino acid form of beta amyloid (Aβ42) and Amyloid  Precursor Protein are of great importance. One possible biomarker for Alzheimer’s is  amyloid beta-derived diffusible ligands (ADDL). The correlation of CSF ADDL levels  with disease state offers promise for improved AD diagnosis and early treatment. Singh et al have developed ADDL-specific monoclonal antibodies with an ultrasensitive,  nanoparticle-based protein detection strategy termed biobarcode amplification (BCA) (5).

The BCA strategy used by Klein, Mirkin and coworkers makes clever use of nanoparticles as DNA carriers to enable millionfold improvements over ELISA sensitivity. CSF is first exposed to monoclonal anti-ADDL antibodies bound to magnetic microparticles. After ADDL binding, the microparticles are separated with a magnetic field and washed before addition of secondary antibodies bound to DNA:Au nanoparticle conjugates. These conjugates conatin covalently bound DNA as well as complementary “barcode” DNA that is attached via hybridization. Unreacted antibody:DNA:Au nanoparticle conjugates are removed during second magnetic separation, after which elevated temperature and low-salt conditions release the barcode DNA for analysis.

“Such a sensor must be able to transmit any biomarker detection event to an external device that records the transmitted signals and reports an estimated amount for the concentration of AD biomarkers in the CSF. Of course, in order to send such biosensor to a place exposing with CSF, it is necessary to design noninvasive approaches.” (4)

Nanotechnology and treatment:

Presently there exist no therapeutic methods available for curing AD [84]. The cure for AD would require therapeutics that will cease the disease progress and will reverse its resultant damages. Today, common medications for AD are symptomatic and aim at the disrupted neurotransmission between the degenerated neurons. Examples of such medications are acetylcholine esterase inhibitors, including tacrine, donepezil, rivastigmine and galantamine (4).

Design of each mechanistic therapeutic is for targeting a different stage of the AD pathogenetic process and therefore help to cease the progress of the disease. Currently there are 5 mechanistic therapeutic molecular approaches:

  • Inhibition of Aβ production;
  • Inhibition of Aβ oligomerization,
  • Anti-inflammation,
  • Cholesterol homeostasis modulating;
  • Metal chelation

The nanotechnology approaches are:

  • Drug discovery and monitoring
  • Controlled release
  • Targeted drug delivery

For example: Neuroprotection

Oxidative stress and amyloid induced toxicity are two basic toxicity processes in AD pathogenesis.

Oxidative stress protection:

Fullerene is a nanotechnology building block and can be used to design neuroprotective compounds. It’s chemical structure is known for it’s anti-oxidative and free-scavenger potentials. Applications of functionalized fullerene derivatives including carboxyfullerene and hydroxyfullerene (fullerenols), are promising in discovery of new drugs for AD; however further research on their pharmacodynamic and pharmacokinetic properties is necessary.

Anti-amyloid protections:

Nanotechnology has recently offered some antiamyloid neuroprotective approaches against the cellular and synaptic toxicity of oligomeric and fibrillar (polymeric) Aβ species. The current ongoing nanotechnology research categories on anti-amyloid neuroprotective approaches are the following three:

  1. Prevention from assembly of Aβ monomers
  2. Breaking and resolubilization of the oligomeric or fibrillar (polymeric) Aβ species
  3. Prevention from toxic effects of Aβ

Summary:

AD is a very common disease worldwide,  Solving the major problems of early diagnosis and effective cure for AD requires interdisciplinary research efforts. Research on the basic pathogenetic mechanisms of the disease has provided new insight for designing diagnostic and therapeutic methods. Nanotechnology has great potential in aiding and providing tools for diagnosing and treating AD. However, these research combining nanotechnology is still at very early stages and continuous understanding of the disease, neuronal protection and regeneration are needed in order to alleviate the symptoms of the disease.

Ref.
1a. D. G. Georganopoulou et al., “Nanoparticle-based Detection in Cerebral Spinal Fluid of a Soluble Pathogenic Biomarker for Alzheimer’s Disease”, Proc. Natl Acad Sci., 102 (2005) 2273-2276

1b D.A. Davis, W. Klein and L. Chang, “Nanotechnology-based Approaches to Alzheimer’s Clinical Diagnostics”, Nanoscape, 3 (2006) 13-17.
Read more: http://www.nanowerk.com/spotlight/spotid=23726.php#ixzz2NWlx6jYa

2. Huang Y and Mucke L. Alzheimer mechanisms and therapeutic strategies. Cell. 2012 Mar 16;148(6):1204-22.

http://www.cell.com/abstract/S0092-8674(12)00278-4

http://www.ncbi.nlm.nih.gov/pubmed/22424230

3. Cancer Drug Shows Promise in Alzheimer’s Treatment: Helps clear plaque and improve brain function in mice. Alzheimer’s Disease Research is a program of the American Health Assistance Foundation. http://www.nanowerk.com/spotlight/spotid=5262.php

4. Amir Nazem1, G. Ali Mansoori. Nanotechnology solutions for Alzheimer’s disease: advances in research tools, diagnostic methods and therapeutic agents. J Alzheimers Dis. 2008 Mar;13(2):199-223.  http://www.ncbi.nlm.nih.gov/pubmed/18376062?dopt=Abstract.

Full text: http://www.uic.edu/labs/trl/1.OnlineMaterials/08-Nanotechnology_Solutions_for_Alzheimer’s_Disease.pdf

5. Shinjini Singh, Mritunjai Singh, I. S. Gambhir*. Nanotechnology for Alzheimer’s Disease Detection. Digest Journal of Nanomaterials and Biostructures Vol. 3, No.2, June 2008, p. 75 – 79 .

http://www.chalcogen.infim.ro/Singh-Gambhir.pdf

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Author: Tilda Barliya PhD

In response to the previous post:

Paclitaxel vs Abraxane (albumin-bound paclitaxel)

https://pharmaceuticalintelligence.com/2012/11/17/paclitaxel-vs-abraxane-albumin-bound-paclitaxel/

Pharmacogenomics properties are presented, below.

Paclitaxel is a mitotic inhibitor used in cancer chemotherapy. It was discovered in a U.S. National Cancer Institute program at the Research Triangle Institute (North Carolina)  in 1967 when Monroe E.Wall and Mansukh C.Wani  isolated it from the bark of the Pacific yew tree, Taxus brevifolia and named it taxol. Later it was discovered that endophytic fungi in the bark synthesize paclitaxel.

Paclitaxel is currently being indicated to lung, breast and ovarian cancer as well as  head and neck cancer, and advanced forms of Kaposi’s sarcoma. 

The administration of paclitaxel (Taxol®) through intravenous infusions was achieved by using Cremophor® EL as a vehicle to entrap the drug in micelles and keep it in solution, which affects the disposition of paclitaxel and is responsible for the nonlinear pharmacokinetics of the drug, especially at higher dose levels. (http://www.futuremedicine.com/doi/pdf/10.2217/pgs.10.32)

Although Nonlinear pharmacokinetics (dose-dependented kinetics) may occur in all aspects of pharmacokinetics (absorption, distribution, and/or elimination), it focus on the in the metabolism or MichaelisMenten (MM) kinetics of the drug. http://archive.ajpe.org/legacy/pdfs/aj650212.pdf

Briefly, it is known that some of these adverse effects such as hypersensitivity reactions were diminished with the administration of corticosteroids and H1 and H2 antihistamine premedication, and by reducing the incidence of grade 3/4 neutropenia with the administration of granulocyte colony-stimulating factors (G-CSF) and shortening paclitaxel infusion time from 24 to 3 h. However, the neurotoxicity, which was believed to be caused by either paclitaxel or Cremophor EL, could not be controlled and became the dose-limiting toxicity of the drug. It was later on found that paclitaxel itself was responsible to the neurotoxicity effects (http://annonc.oxfordjournals.org/content/6/7/699.abstract)

Pharmacokinetics and Pharmacodynamics

The selection of pharmacokinetic (PK) parameter end points and basic model types for exposure-toxicity relationships of paclitaxel is usually based on tradition rather than physiological relevance.

pharmacokinetic (PK)-pharmacodynamic (PD) relationships for paclitaxel are still most commonly described with empirically-designed threshold models, which have little or no mechanistic basis and lack usefulness when applied to conditions (eg, schedules, vehicles, or routes of administration) different from those from which they were originally derived. (http://jco.ascopubs.org/content/21/14/2803.long). As such, the AUC of the unbound paclitaxel is highly important as a pharmacokinetic parameter to describe exposure-neutropenia relationships (the unbound ptx was not evaluated yet). (http://clincancerres.aacrjournals.org.rproxy.tau.ac.il/content/1/6/599.full.pdf+html)

The clearance of Cremophor EL in patients was found to be time-dependent, resulting in disproportional increases in systemic exposure being associated with shortening of infusion from 3 hours to 1 hour.

One study (http://clincancerres.aacrjournals.org/content/1/6/599), compare the pharmacokinetics and pharmacodynamics (PD) of paclitaxel between Phase I trials of 3- and 24-h infusions and to determine the most informative pharmacokinetic parameter to describe the PD. The study had 3 main goals

  • (a) to compare the PK and PD of paclitaxel between Phase I studies of 3- and 24-h infusion,
  • (b) to examine the relationship between PK and PD
  • (c) to determine the most informative pharmacokinetic parameter to describe the PD.

Note: Although this study was conducted in ~1993-1995, is has been cited extensively and paved the was to other clinical trials with similar results.

27 patients were treated in a Phase I study of paclitaxel by a 3-h infusion at one of six doses: 105, 135, 180, 210, 240, and 270 mg/m2. Pharmacokinetic data were obtained from all patients. Paclitaxel concentrations were measured in the plasma and urine using HPLC. Similar eligibility criteria were designed for the 24-hr infusion with these doses were 49.5, 75, 105, 135, and 180 mg/m2 . Plasma and urine samples for pharmacokinetic evaluation of paclitaxel were collected.

Pharmacokinetic Analysis: Pharmacokinetic parameters, Cmax, AUC, t112, and MRT were obtained by a noncompartmental moment method. Cmax was actually observed peak concentration. AUC and MRT were computed by trapezoidal integration with extrapolation to infinite time.

Pharmacodynamic Analysis: The pharmacokinetic/pharmacodynamic relationships were modeled with the sigmoid maximum effect

Results:

Pharmacokinetic analysis:

The drug plasma concentration increased throughout the 3-h infusion period and began to decrease immediately upon cessation of the infusion with t112 of 9.9-16.0 h and MRT of 6.47-10.24 h (Fig. 1). Both Cmax and AUC increased with increasing doses (r = 0.865, P <0.001 for Cmax r 0.870, P < 0.001 for AUC), although the pharmacokinetic behavior appeared to be nonlinear (Fig. 2). The mean Cmax and AUC at a dose of 270 mg/m2 were more than 3-fold greater than those at a dose of 135 mg/m2. CL and V, decreased with increasing doses (Table 1). The urinary excretion of paclitaxel over 75 h was less than 15% of the dose administered, which indicated that non-renal excretion is the primary route of drug elimination.

The urinary excretion of paclitaxel over 75 h was less than 15% of the dose administered, which indicated that non-renal excretion is the primary route of drug elimination.

Comparison of PD between 3-h and 24-h Infusion

Groups. AUC and duration of plasma concentration (h) above (7>) 0.05-0.1 LM correlated with the % D in granulocytes with p values less than 0.05. The best parameter predicting granulocytopenia was T> 0.09 pM with the minimum of the Akaike Information Criterion. In the 24-h schedule, dose, AUC, and T > 0.04-0.07 pM were demonstrated to correlate with the % D in granulocytes. The best parameter predicting granulocytopenia in the 24-h schedule was T > 0.05 p.M.

Nonhematological toxicities such as peripheral neuropathy, hypotension, and arthralgialmyalgia mainly observed in the 3-h infusion group had no relationship with Cm or AUC which are much higher in the 3-h infusion group, although peripheral neuropathy and musculoskeletal toxicity have been suggested to be associated with AUC on a 6- (12) or 24-h (29) schedule.

Pharmacogenomics:

In the past, the major adverse effects encountered with Taxol were severe hypersensitivity reactions, mainly attributed to Cremophor EL; hematologic toxicity, primarily appearing in the form of severe neutropenia; and neurotoxicity, mainly seen as cumulative sensory peripheral neuropathy. The mechanism for the neurotoxicity has been demonstrated to involve ganglioneuropathy and axonopathy caused by dysfunctional microtubules in dorsal root ganglia, axons and Schwann cells.

Variability in paclitaxel pharmacokinetics has  been associated with the adverse effects of the  drug. Thus, polymorphisms in genes encoding  paclitaxel-metabolizing enzymes, transporters and therapeutic targets have been suggested  to contribute to the interindividual variability in toxicity and response.

Further characterization of  genes involved in paclitaxel elimination and drug  response was performed, including the identification of their most relevant genetic variants. The organic anion transporting polypeptide (OATP)  1B3 was identified as a key protein for paclitaxel hepatic uptake and polymorphisms in the genes encoding for paclitaxel metabolizing enzymes and transporters (CYP2C8, CYP3A4) CYP3A5, P-glycoprotein and OATP1B3) (http://www.futuremedicine.com/doi/pdf/10.2217/pgs.10.32)

***It is important to note that  the allele frequencies for many of these polymorphisms are subject to important ethnicity  specific differences, with some alleles exclusively present in specific populations (e.g., the Caucasian CYP2C8*3).

For the CYP2C8 gene, two alleles common in Caucasians that result in amino acid changes CYP2C8*3 (R139K; K399R) and CYP2C8*4 (I264M), were described. The former has been shown to possess an altered activity, while the latter does not seem to have functional
consequences. In addition, two CYP2C8 haplotypes were recently shown to confer an increased and reduced metabolizing activity, respectively.

CYP3A5 was found to be highly polymorphic owing to CYP3A5*3, CYP3A5*6 and CYP3A5*7 , with the latter two being African-specific polymorphisms.

Pharmacogenetic studies comparing the most relevant polymorphisms in these genes and paclitaxel pharmacokinetics have rendered contradictory results, with some studies finding no associations while others reported an effect for ABCB1, CYP3A4 or CYP2C8 polymorphisms on specific pharmacokinetic parameters.

Again, with respect to paclitaxel neurotoxicity risk, some studies have rendered positive results for ABCB1 , CYP2C8  and CYP3A5  polymorphisms, while others found no significant associations.

Note: These differences might be caused by underpowered studies and by differences in the patients under study.

Changes affecting microtubule  structure and/or composition have been shown to affect paclitaxel efficacy, probably by reducing drug–target affinity. Mainly, resistance to tubulin-binding agents has been associated with an overexpression of b-tubulin isotype III,
which seems to be caused by a deregulation of the microRNA family 200.

However, the clinical utility of these findings remains to be established; furthermore, the identification of biomarkers that could be used to individualize paclitaxel treatment remains a challenge.

In summary,

  1. Pharmacokinetics: Paclitaxel seems to have a non-linear (=dose-dependent) PK parameters.
  2. Pharmcokinetics- Pharmacodynamics: Previous clinical trials did NOT take into account the unbound concentrations of Ptx and therefore in the PK analysis, therefore newly designed clinical trials should take that into consideration. This is very important since the neurotoxicity is attributed to ptx and not its vehicle Cremophor (as shown in the PD analysis)
  3. Difficult to compare between the 3hr and 24hr infusion schedule as most clinical trials did NOT used similar dose-regime making the comparison very hard.
  4. Pharmacogenetics: Different polymorphisms seems to attribute to the been suggested  to contribute to the interindividual variability in toxicity and response.
  5. Prospective pharmacogenetic-guided clinical trials will be required in order to accurately establish the utility of the identified markers/strategies for patients and healthcare systems.

 

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