Drug-Induced Phase Separation in Polyelectrolyte Microgels

Polyelectrolyte microgels may undergo volume phase transition upon loading and the release of amphiphilic molecules, a process important in drug delivery. The new phase is “born” in the outermost gel layers, whereby it grows inward as a shell with a sharp boundary to the “mother” phase (core). The swelling and collapse transitions have previously been studied with microgels in large solution volumes, where they go to completion. Our hypothesis is that the boundary between core and shell is stabilized by thermodynamic factors, and thus that collapsed and swollen phases should be able to also coexist at equilibrium. We investigated the interaction between sodium polyacrylate (PA) microgel networks (diameter: 400–850 µm) and the amphiphilic drug amitriptyline hydrochloride (AMT) in the presence of NaCl/phosphate buffer of ionic strength (I) 10 and 155 mM. We used a specially constructed microscopy cell and micromanipulators to study the size and internal morphology of single microgels equilibrated in small liquid volumes of AMT solution. To probe the distribution of AMT micelles we used the fluorescent probe rhodamine B. The amount of AMT in the microgel was determined by a spectrophotometric technique. In separate experiments we studied the binding of AMT and the distribution between different microgels in a suspension. We found that collapsed, AMT-rich, and swollen AMT-lean phases coexisted in equilibrium or as long-lived metastable states at intermediate drug loading levels. In single microgels at I = 10 mM, the collapsed phase formed after loading deviated from the core-shell configuration by forming either discrete domains near the gel boundary or a calotte shaped domain. At I = 155 mM, single microgels, initially fully collapsed, displayed a swollen shell and a collapsed core after partial release of the AMT load. Suspensions displayed a bimodal distribution of swollen and collapsed microgels. The results support the hypothesis that the boundary between collapsed and swollen phases in the same microgel is stabilized by thermodynamic factors.

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High frequency of NAT2 slow acetylator alleles in the Malay population of Indonesia: an awareness to the anti-tuberculosis drug induced liver injury and cancer

Medical Journal of Indonesia ◽

10.13181/mji.v26i1.1563 ◽

2017 ◽

Vol 26 (1) ◽

pp. 7-13 ◽

Cited By ~ 4

Author(s):

Retno W. Susilowati ◽

Kinasih Prayuni ◽

Intan Razari ◽

Syukrini Bahri ◽

Rika Yuliwulandari

Keyword(s):

Direct Sequencing ◽

Bimodal Distribution ◽

Acetylator Phenotype ◽

Sequencing Data ◽

Drug Induced ◽

Slow Acetylator ◽

Nat2 Genotype ◽

Nat2 Polymorphism ◽

Specific Allele ◽

Malay Population

Background: Arylamine N-acetyltransferase 2 (NAT2) polymorphism was previously reported to have association with the risk of drug toxicities and the development of various diseases. Previous research on the Indonesian population, especially Javanese and Sundanese, showed that there were 33% NAT2 slow acetylator phenotype. The aim of this study was to map the NAT2 variation in the Malay ethnic to gain a deeper insight into NAT2 haplotypic composition in this ethnic.Methods: 50 healthy samples from the Indonesian Malay ethnic were obtained. They were interviewed about their ethnic backgrounds for the last three generations. DNA was extracted from peripheral blood and NAT2 genotyping was done using the PCR direct Sequencing. Data were compiled according to the genotype and allele frequencies estimated from the observed numbers of each specific allele. Haplotype reconstruction was performed using PHASE v2.1.1 software.Results: We found 7 haplotypes consisting of 6 SNPs and 14 NAT2 genotype variations in Indonesian Malay population. The most frequent allele was NAT2*6A (38%) which was classified as a slow acetylator allele. According to bimodal distribution, the predicted phenotype of the Malay population was composed of 62% rapid acetylator and 38% slow acetylator. According to trimodal distribution, the predicted phenotypes for rapid, intermediate and slow acetylators were 10%, 52% and 38% respectively.Conclusion: Our result indicates the presence of the allelic distribution and revealed the most frequent acetylator status and phenotype for the Indonesian Malay population. The result of this study will be helpful for future epidemiological or clinical studies and for understanding the genetic basis of acetylation polymorphism in Indonesia.

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Early Development of Drug-Induced Hepatic Necrosis

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100066942 ◽

1971 ◽

Vol 29 ◽

pp. 576-577

Author(s):

F. G. Zaki ◽

E. Detzi ◽

C. H. Keysser

Keyword(s):

Early Development ◽

Hepatic Necrosis ◽

Screening Tests ◽

Dense Matrix ◽

Sprague Dawley ◽

Electron Microscopic ◽

Drug Induced ◽

Hepatocellular Damage ◽

Sprague Dawley Rats ◽

Microscopic Studies

This study represents the first in a series of investigations carried out to elucidate the mechanism(s) of early hepatocellular damage induced by drugs and other related compounds. During screening tests of CNS-active compounds in rats, it has been found that daily oral administration of one of these compounds at a dose level of 40 mg. per kg. of body weight induced diffuse massive hepatic necrosis within 7 weeks in Charles River Sprague Dawley rats of both sexes. Partial hepatectomy enhanced the development of this peculiar type of necrosis (3 weeks instead of 7) while treatment with phenobarbital prior to the administration of the drug delayed the appearance of necrosis but did not reduce its severity.Electron microscopic studies revealed that early development of this liver injury (2 days after the administration of the drug) appeared in the form of small dark osmiophilic vesicles located around the bile canaliculi of all hepatocytes (Fig. 1). These structures differed from the regular microbodies or the pericanalicular multivesicular bodies. They first appeared regularly rounded with electron dense matrix bound with a single membrane. After one week on the drug, these vesicles appeared vacuolated and resembled autophagosomes which soon developed whorls of concentric lamellae or cisterns characteristic of lysosomes (Fig. 2). These lysosomes were found, later on, scattered all over the hepatocytes.

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Effect of piperacillin on morphology and viability of gram-negative bacteria

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100111203 ◽

1984 ◽

Vol 42 ◽

pp. 218-219

Author(s):

R. H. Liss

Keyword(s):

Inhibitory Concentration ◽

Cytoplasmic Membrane ◽

Drug Binding ◽

Gram Negative Bacteria ◽

Bacterial Cells ◽

Drug Induced ◽

Penicillin Binding Proteins ◽

Lactam Antibiotic ◽

Drug Free ◽

Tube Dilution

Piperacillip (PIP) is b-[D(-)-α-(4-ethy1-2,3-dioxo-l-piperzinylcar-bonylamino)-α-phenylacetamido]-penicillanate. The broad spectrum semisynthetic β-lactam antibiotic is believed to effect bactericidal activity through its affinity for penicillin-binding proteins (PBPs), enzymes on the bacterial cytoplasmic membrane that control elongation and septation during cell growth and division. The purpose of this study was to correlate penetration and binding of 14C-PIP in bacterial cells with drug-induced lethal changes assessed by microscopic, microbiologic and biochemical methods.The bacteria used were clinical isolates of Escherichia coli and Pseudomonas aeruginosa (Figure 1). Sensitivity to the drug was determined by serial tube dilution in Trypticase Soy Broth (BBL) at an inoculum of 104 organisms/ml; the minimum inhibitory concentration of piperacillin for both bacteria was 1 μg/ml. To assess drug binding to PBPs, the bacteria were incubated with 14C-PIP (5 μg/0.09 μCi/ml); controls, in drug-free medium.

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Drug Induced Changes in Cell Organelles

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100100299 ◽

1968 ◽

Vol 26 ◽

pp. 110-111

Author(s):

Sarah A. Luse

Keyword(s):

Clinical Medicine ◽

Cell Organelles ◽

Riboflavin Deficiency ◽

Drug Induced ◽

New Era ◽

Health And Disease ◽

In The Beginning ◽

Cellular Pathology ◽

Induced Changes ◽

The Impact

In the mid-nineteenth century Virchow revolutionized pathology by introduction of the concept of “cellular pathology”. Today, a century later, this term has increasing significance in health and disease. We now are in the beginning of a new era in pathology, one which might well be termed “organelle pathology” or “subcellular pathology”. The impact of lysosomal diseases on clinical medicine exemplifies this role of pathology of organelles in elucidation of disease today.Another aspect of cell organelles of prime importance is their pathologic alteration by drugs, toxins, hormones and malnutrition. The sensitivity of cell organelles to minute alterations in their environment offers an accurate evaluation of the site of action of drugs in the study of both function and toxicity. Examples of mitochondrial lesions include the effect of DDD on the adrenal cortex, riboflavin deficiency on liver cells, elevated blood ammonia on the neuron and some 8-aminoquinolines on myocardium.

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Electron microscopy of niobium and tantalum hydrides

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100110362 ◽

1978 ◽

Vol 36 (1) ◽

pp. 644-645

Author(s):

T. Schober

Keyword(s):

Electron Microscopy ◽

Heat Storage ◽

Measurement Techniques ◽

Metal Hydrides ◽

Detailed Understanding ◽

Storage Devices ◽

Unit Cells ◽

Endothermic Reactions ◽

Hydrogen Reactions ◽

New Phase

Nb, Ta and V are prototype substances for the study of the endothermic reactions of H with metals. Such metal-hydrogen reactions have gained increased importance due to the application of metal-hydrides in hydrogen- und heat storage devices. Electron microscopy and diffraction were demonstrated to be excellent methods in the study of hydride morphologies and structures (1). - Figures 1 and 2 show the NbH and TaH phase diagrams (2,3,4). EM techniques have contributed substantially to the elucidation of the structures and domain configurations of phases β, ζ and ε (1,4). Precision length measurement techniques of distances in reciprocal space (5) recently led to a detailed understanding of the distortions of the unit cells of phases ζ and ε (4). In the same work (4) the existence of the new phase η was shown. It is stable near -68 °C. The sequence of transitions is thus below 70 %.

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Acetaminophen: Macula densa hypersecretory activity by induced hepatotoxicity

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s042482010012895x ◽

1987 ◽

Vol 45 ◽

pp. 934-935

Author(s):

S.S. Poolsawat ◽

C.A. Huerta ◽

S.TY. Lae ◽

G.A. Miranda

Keyword(s):

Cell Proliferation ◽

Liver Function ◽

Chronic Inflammation ◽

Foam Cell ◽

Term Effect ◽

Short Term ◽

Drug Induced ◽

Experimental Induction ◽

Tissue Alterations ◽

Toxic Responses

Introduction. Experimental induction of altered histology by chemical toxins is of particular importance if its outcome resembles histopathological phenomena. Hepatotoxic drugs and chemicals are agents that can be converted by the liver into various metabolites which consequently evoke toxic responses. Very often, these drugs are intentionally administered to resolve an illness unrelated to liver function. Because of hepatic detoxification, the resulting metabolites are suggested to be integrated into the macromolecular processes of liver function and cause an array of cellular and tissue alterations, such as increased cytoplasmic lysis, centrilobular and localized necroses, chronic inflammation and “foam cell” proliferation of the hepatic sinusoids (1-4).Most experimentally drug-induced toxicity studies have concentrated primarily on the hepatic response, frequently overlooking other physiological phenomena which are directly related to liver function. Categorically, many studies have been short-term effect investigations which seldom have followed up the complications to other tissues and organs when the liver has failed to function normally.

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The organization of cell surface membrane domains

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100155992 ◽

1989 ◽

Vol 47 ◽

pp. 804-805

Author(s):

Michael Edidin

Keyword(s):

Cell Surface ◽

Membrane Lipids ◽

Surface Membrane ◽

Lateral Diffusion ◽

Cell Types ◽

Membrane Domains ◽

Membrane Biology ◽

Morphological Polarity ◽

Discrete Domains ◽

Membrane Components

Cell surface membranes are based on a fluid lipid bilayer and models of the membranes' organization have emphasised the possibilities for lateral motion of membrane lipids and proteins within the bilayer. Two recent trends in cell and membrane biology make us consider ways in which membrane organization works against its inherent fluidity, localizing both lipids and proteins into discrete domains. There is evidence for such domains, even in cells without obvious morphological polarity and organization [Table 1]. Cells that are morphologically polarised, for example epithelial cells, raise the issue of membrane domains in an accute form.The technique of fluorescence photobleaching and recovery, FPR, was developed to measure lateral diffusion of membrane components. It has also proven to be a powerful tool for the analysis of constraints to lateral mobility. FPR resolves several sorts of membrane domains, all on the micrometer scale, in several different cell types.

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A quantitative image analysis method for the determination of cocontinuity in polymer blends

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100150307 ◽

1993 ◽

Vol 51 ◽

pp. 894-895

Author(s):

William A. Heeschen

Keyword(s):

Image Analysis ◽

Polymer Blends ◽

Quantitative Measurement ◽

Morphological Evolution ◽

Phase Ratio ◽

Irregular Shapes ◽

Quantitative Image ◽

Discrete Domains ◽

A Domains

Two new morphological measurements based on digital image analysis, CoContinuity and CoContinuity Balance, have been developed and implemented for quantitative measurement of morphology in polymer blends. The morphology of polymer blends varies with phase ratio, composition and processing. A typical morphological evolution for increasing phase ratio of polymer A to polymer B starts with discrete domains of A in a matrix of B (A/B < 1), moves through a cocontinuous distribution of A and B (A/B ≈ 1) and finishes with discrete domains of B in a matrix of A (A/B > 1). For low phase ratios, A is often seen as solid convex particles embedded in the continuous B phase. As the ratio increases, A domains begin to evolve into irregular shapes, though still recognizable as separate domains. Further increase in the phase ratio leads to A domains which extend into and surround the B phase while the B phase simultaneously extends into and surrounds the A phase.

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Drug-Induced Movement Disorders

Perspectives on Neurophysiology and Neurogenic Speech and Language Disorders ◽

10.1044/nnsld25.2.70 ◽

2015 ◽

Vol 25 (2) ◽

pp. 70-77

Author(s):

Amy Lustig ◽

Cesar Ruiz

Keyword(s):

Movement Disorders ◽

Medical Management ◽

Disease Process ◽

Underlying Disease ◽

Extrapyramidal Symptoms ◽

Drug Induced ◽

General Overview ◽

Management Approaches ◽

Broad Understanding ◽

Underlying Disease Process

The purpose of this article is to present a general overview of the features of drug-induced movement disorders (DIMDs) comprised by Parkinsonism and extrapyramidal symptoms. Speech-language pathologists (SLPs) who work with patients presenting with these issues must have a broad understanding of the underlying disease process. This article will provide a brief introduction to the neuropathophysiology of DIMDs, a discussion of the associated symptomatology, the pharmacology implicated in causing DIMDs, and the medical management approaches currently in use.

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