Therapeutic drug monitoring of cancer chemotherapy.

Therapeutic drug monitoring is not routinely used for chemotherapy agents. There are Several reasons, but one major drawback is the lack of established therapeutic Concentration ranges. Combination chemotherapy makes the establishment of Therapeutic ranges for individual drugs difficult, the concentration-effect relationship for a single drug may not be the same as when that drug is used in a drug combination. Pharmacokinetic optimization protocols for many classes of cytotoxic compounds exist in specialized centers, and some of these protocols are now part of large multicentre trials. Nonetheless, TDM clearly has the potential to improve the clinical use of chemotherapy gents, most of which have very narrow therapeutic indices and highly variable pharmacokinetics. A substantial body of literature accumulating during the past 15 years demonstrates relationships between systemic exposure to various chemotherapy agents and their toxic or therapeutic effects. This article reviews TDM concepts in addition to tools based on pharmacokinetic modeling of chemotherapy agents. The administered dose of chemotherapy agents is sometimes adjusted individually using either a priori or a posteriori methods. These models can only be applied by using the same dose and schedule as the original study. Bayesian estimation offers more flexibility in blood sampling times and, owing to its precision and to the amount of information provided is the method of choice for ensuring that a given patient benefits from the desired systemic exposure. Moreover, the role and application of Pharmacogenetics as a tool for individualizing chemotherapy is discussed highlighting the agents and mechanisms that have been well studied and defined and their relevance to clinical practice. Finally, this paper address issues critical to the optimal use of TDM in a clinical setting, and the role of clinical pharmacist in this regard. In addition, it discusses future developments in this field that can contribute to improving cancer chemotherapy In terms of patient outcome and survival.     

In Vitro-Induced High Sugar Environments Deteriorate Human Cortical Bone Elastic Modulus and Fracture Toughness

Advanced glycation end-products (AGEs) have been suggested to contribute to bone fragility in type 2 diabetes (T2D). AGEs can be induced through in vitro sugar incubations but there is limited data on the effect of total fluorescent AGEs on mechanical properties of human cortical bone, which may have altered characteristics in T2D. Thus, to examine the effect of AGEs on bone directly in T2D patients with uncontrolled sugar levels, it is essential to first understand the fundamental mechanisms by studying the effects of controlled in vitro-induced AGEs on cortical bone mechanical behavior. Here, human cortical bone specimens from female cadaveric tibias (ages 57–87) were incubated in an in vitro 0.6 M ribose or vehicle solution (n = 20/group) for 10 days at 37°C, their mechanical properties were assessed by microindentation and fracture toughness tests, and induced AGE levels were quantified through a fluorometric assay. Results indicated that ribose-incubated bone had significantly more AGEs (+81%, p ≤ 0.005), lower elastic modulus assessed by traditional microindentation, and lower fracture toughness compared with vehicle controls. Furthermore, based on pooled data, increased AGEs were significantly correlated with deteriorated mechanical properties. The findings presented here show that the accumulation of AGEs allows for lower stiffness and increased ability to initiate a crack in human cortical bone. Statement of clinical significance: High sugar levels as in T2D results in deteriorated bone quality via AGE accumulation with a consequent weakening in bone's mechanical integrity. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 38:972-983, 2020     

Solubilization of Drugs by Physiological Mixtures of Bile Salts

Purpose. The solubilization of a number of steroids was determined in bile salt simple micelles and a bile salt/phospholipid micellar system to provide a better basis to predict the extent of drug solubilization in vivo. Methods. Excess solid drug was dispersed in taurodeoxycholate or mixed micelle solutions prepared with fixed mole ratios of taurocholate, taurodeoxycholate, taurochenodeoxycholate, glycodeoxycholate, glycocholate, and glycochenodeoxycholate with egg phosphatidylcholine. Drug concentrations were determined from the absorbance following centrifugation. Using NMR spectroscopy, the diffusivities of the simple and mixed micelles were 2 × 10^-6 and 8 × 10^-7 cm²/s, respectively. Results. From the change in the concentration of drug in solution with a change in the lipid concentration, the solubilization ratio (SR) was calculated. The SR and aqueous solubility were used to calculate the micelle/aqueous partition coefficients (K_m/w). K_m/w was correlated with octanol/water partition (P_o/w) for the TDC and mixed micelle data sets with correlation lines of logK_m/w = 0.74logP_o/w + 1.55 (r² = 0.91) and logK_m/w = 0.61 logP_o/w + 2.44 (r² = 0.95), respectively. Conclusions. With such data, a refined, predictive relationship between the in vitro and the in vivo solubilization with additional information concerning the bile salt/lipid concentration in the human intestine appears possible.     

Timing of therapeutic intervention determines functional and survival outcomes in a mouse model of late infantile batten disease.

Classical late infantile neuronal ceroid lipofuscinosis (cLINCL) is a monogenic disorder caused by the loss of tripeptidyl peptidase 1 (TPP1) activity as a result of mutations in CLN2. Absence of TPP1 results in lysosomal storage with an accompanying axonal degeneration throughout the central nervous system (CNS), which leads to progressive neurodegeneration and early death. In this study, we compared the efficacies of pre- and post-symptomatic injections of recombinant adeno-associated virus (AAV) for treating the cellular and functional abnormalities of CLN2 mutant mice. Intracranial injection of AAV1-hCLN2 resulted in widespread human TPP1 (hTPP1) activity in the brain that was 10-100-fold above wild-type levels. Injections before disease onset prevented storage and spared neurons from axonal degeneration, reflected by the preservation of motor function. Furthermore, the majority of CLN2 mutant mice treated pre-symptomatically lived for at least 330 days, compared with a median survival of 151 days in untreated CLN2 mutant controls. In contrast, although injection after disease onset ameliorated lysosomal storage, there was evidence of axonal degeneration, motor function showed limited recovery, and the animals had a median lifespan of 216 days. These data illustrate the importance of early intervention for enhanced therapeutic benefit, which may provide guidance in designing novel treatment strategies for cLINCL patients.     

AAV vector-mediated correction of brain pathology in a mouse model of Niemann-Pick A disease.

Niemann-Pick A disease (NPA) is a fatal lysosomal storage disorder caused by a deficiency in acid sphingomyelinase (ASM) activity. The lack of functional ASM results in cellular accumulation of sphingomyelin and cholesterol within distended lysosomes throughout the brain. In this study, we investigated the potential of AAV-mediated expression of ASM to correct the brain pathology in an ASM knockout (ASMKO) mouse model of NPA. An AAV serotype 2 vector encoding human ASM (AAV2-hASM) was injected directly into the adult ASMKO hippocampus of one hemisphere. This resulted in expression of human ASM in all major cell layers of the ipsilateral hippocampus for at least 15 weeks postinjection. Transduced cells were also present in the entorhinal cortex, medial septum, and contralateral hippocampus in a pattern consistent with retrograde axonal transport of AAV2. There was a substantial reduction of distended lysosomes and an almost complete reversal of cholesterol accumulation in all areas of the brain that were targeted by AAV2-hASM. These findings show that the ASMKO brain is responsive to ASM replacement and that retrograde transport of AAV2 functions as a platform for widespread gene delivery and reversal of pathology in affected brain.     

Intracerebroventricular infusion of acid sphingomyelinase corrects CNS manifestations in a mouse model of Niemann–Pick A disease

Niemann–Pick A (NPA) disease is a lysosomal storage disorder (LSD) caused by a deficiency in acid sphingomyelinase (ASM) activity. Previously, we showed that the storage pathology in the ASM knockout (ASMKO) mouse brain could be corrected by intracerebral injections of cell, gene and protein based therapies. However, except for instances where distal areas were targeted with viral vectors, correction of lysosomal storage pathology was typically limited to a region within a few millimeters from the injection site. As NPA is a global neurometabolic disease, the development of delivery strategies that maximize the distribution of the enzyme throughout the CNS is likely necessary to arrest or delay progression of the disease. To address this challenge, we evaluated the effectiveness of intracerebroventricular (ICV) delivery of recombinant human ASM into ASMKO mice. Our findings showed that ICV delivery of the enzyme led to widespread distribution of the hydrolase throughout the CNS. Moreover, a significant reduction in lysosomal accumulation of sphingomyelin was observed throughout the brain and also within the spinal cord and viscera. Importantly, we demonstrated that repeated ICV infusions of ASM were effective at improving the disease phenotype in the ASMKO mouse as indicated by a partial alleviation of the motor abnormalities. These findings support the continued exploration of ICV delivery of recombinant lysosomal enzymes as a therapeutic modality for LSDs such as NPA that manifests substrate accumulation within the CNS.     

Concomitant natural infection with L. donovani and L. major: A case report from Iraq

Summary This is a case report of kala-azar with cutaneous leishmaniasis. Upon admission, the patient had fever, hepatosplenomegaly and an ulcer on her cheek. The patient responded to Pentostam. Isoenzyme studies of parasite isolates from the the bone marrow and from the cutaneous lesion revealed that these were L. donovani and L. major, respectively. This is the first report in Iraq of a proven concomitant infection with two species of leishmania parasites.

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Simultane Infektion mit L. donovani und L. major: Eine Fallstudie im Irak

Zusammenfassung Wir präsentieren eine Fallstudie von Kala-Azar mit gleichzeitiger kutaner Leishmaniose, Die Patientin hatte Fieber, Hepatosplenomegalie und einen Ulcus an der einen Wange. Sie sprach auf Pentostam an. Die Analyse der Isoenzym-Profile der Parasiten aus einer Knochenmarks-Punktion sowie aus dem Ulcus wiesen nach, dass es sich dabei um L. donovani und um L. major handelte. Diese Studie ist die erste Beschreibung einer simultanen Infektion mit L. donovani und mit L. major im Irak.

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Infection simultanée par L. donovani et L. major: Une étude rapporte en Iraq

Résumé Notre étude rapporte un cas de Kala-Azar accompagné d'une leishmaniose cutanée. La patiente avait la fièvre, une hépatosplénomégalie et un ulcère à une de ses joux. L'infection répondait bien à la Pentostame. L'analyse des isoenzymes montrait que les parasites isolés de la moile osseuse représentaient L. donovani, pendant que ceux de la lésion cutanée représentaient L. major. Notre rapport constitue la première documentation d'un cas d'une infection simultanée par L. donovani et L. major en Iraq.

     

Glycosphingolipids are modulators of disease pathogenesis in amyotrophic lateral sclerosis

Recent genetic evidence suggests that aberrant glycosphingolipid metabolism plays an important role in several neuromuscular diseases including hereditary spastic paraplegia, hereditary sensory neuropathy type 1, and non-5q spinal muscular atrophy. Here, we investigated whether altered glycosphingolipid metabolism is a modulator of disease course in amyotrophic lateral sclerosis (ALS). Levels of ceramide, glucosylceramide, galactocerebroside, lactosylceramide, globotriaosylceramide, and the gangliosides GM3 and GM1 were significantly elevated in spinal cords of ALS patients. Moreover, enzyme activities (glucocerebrosidase-1, glucocerebrosidase-2, hexosaminidase, galactosylceramidase, α-galactosidase, and β-galactosidase) mediating glycosphingolipid hydrolysis were also elevated up to threefold. Increased ceramide, glucosylceramide, GM3, and hexosaminidase activity were also found in SOD1^G93A mice, a familial model of ALS. Inhibition of glucosylceramide synthesis accelerated disease course in SOD1^G93A mice, whereas infusion of exogenous GM3 significantly slowed the onset of paralysis and increased survival. Our results suggest that glycosphingolipids are likely important participants in pathogenesis of ALS and merit further analysis as potential drug targets.Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by selective loss of motor neurons (MNs) within the CNS. Although our understanding of the genetic basis of ALS has advanced greatly in recent years (1), the adverse biological processes that converge on the neuromuscular axis to drive both MN death and neuropathological features in additional cell types remain largely unknown. Glycosphingolipids (GSLs) are a heterogeneous group of membrane lipids formed through the covalent linkage of a glycan moiety to ceramide (Cer; see SI Appendix, Fig. S1 for an overview of GSL metabolism). Glucosylceramide (GlcCer) and galactosylceramide (GalCer) are GSLs with a single sugar residue: glucose and galactose respectively. The successive addition of galactose and sialic acid moieties to GlcCer results in the synthesis of gangliosides (e.g., GM3, GM2, and GM1) (2). GSLs are especially abundant in the CNS and have bioactive roles in metabolism, growth factor signaling, oligodendrocyte differentiation, neuroinflammation, angiogenesis, and pathways of cell death (2–9)—all of which are thought to participate in ALS disease pathogenesis.Several lines of evidence suggest that aberrant changes in GSL homeostasis may contribute to disease pathogenesis in ALS. Evidence includes the detection of unique gangliosides (10), high titer serum auto-antibodies to GM2 and GM1 (11, 12), and elevated GM2 levels within the motor cortex of ALS patients (13). Furthermore, a number of neuromuscular diseases are associated with mutations in genes that regulate the metabolism of Cer and GSLs. For example, hereditary sensory neuropathy type I (HSNT1), a disease that features dorsal root ganglion cell and MN degeneration, is attributed to mutations in serine palmitoyltransferase long chain base subunit-1 (SPTLC1), the rate-limiting enzyme in Cer synthesis. Notably, certain mutations in SPTLC1 associated with HSNT1 result in elevated levels of Cer and GlcCer (14). In addition, mutations in acid ceramidase (ASHA1), an enzyme that mediates the hydrolysis of Cer, are linked to forms of spinal muscular atrophy that are not caused by the more frequent mutations in the survival motor neuron 1 gene (non-5q SMA) (15). Moreover, hereditary spastic paraplegia (HSP), a disease with corticospinal tract and in some cases, spinal cord MN degeneration, is attributed to mutations in GM2 synthase (16) and the nonlysosomal glucosylceramidase, GBA2 (17). Last, patients with adult-onset Tay-Sachs disease (GM2 gangliosidosis), a disease triggered by a deficiency in hexosaminidase (HEX), a lysosomal enzyme that hydrolyzes GM2 to GM3, have been reported in some instances to display a disease phenotype that closely mimics ALS (18–20). Interestingly, HEX mRNA is up-regulated within MNs of transgenic mice expressing the mutant human SOD1 protein (i.e., SOD1^G93A mice), a familial model of ALS (21, 22). Collectively, these findings suggest that titration of GSLs is important to maintaining neuromuscular system homeostasis. Similar to other metabolic aspects thought to influence ALS disease progression (23), GSL bioactivity in the neuromuscular system is likely exerted through an inverted U-shaped dose–response curve (SI Appendix, Fig. S1). Healthy (or eustatic) GSL levels are achieved in the central, optimal range of the curve, whereas GSL levels that promote features of disease (or cacostasis) are associated with either end of the curve (i.e., instances of GSL insufficiency or excess). Here, we investigated whether disrupted GSL homeostasis contributes to neurodegeneration in ALS. We show that altered GSL metabolism is a manifestation of sporadic and familial ALS and that modulation of GSL levels in SOD1^G93A mice significantly affects disease course.