An N-Acetylgalactosamino Dendron-Clearing Agent for High-Therapeutic-Index DOTA-Hapten Pretargeted Radioimmunotherapy

This review summarizes the epigenetic mechanisms of deoxyribonucleic acid (DNA) methylation, histone modifications in cancer and the epigenetic modifications in cancer therapy. Due to their undesired side effects, the use of epigenetic drugs as chemo-drugs in cancer therapies is limited. The drug delivery system opens a door for minimizing these side effects and achieving greater therapeutic benefits. The limitations of current epigenetic therapies in clinical cancer treatment and the advantages of using drug delivery systems for epigenetic agents are also discussed. Combining drug delivery systems with epigenetic therapy is a promising approach to reaching a high therapeutic index and minimizing the side effects.

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Proline prodrug of melphalan, prophalan-l, demonstrates high therapeutic index in a murine melanoma model

European Journal of Pharmaceutics and Biopharmaceutics ◽

10.1016/j.ejpb.2007.03.024 ◽

2007 ◽

Vol 67 (3) ◽

pp. 752-758 ◽

Cited By ~ 8

Author(s):

Sachin Mittal ◽

Yasuhiro Tsume ◽

Christopher P. Landowski ◽

Kyung-Dall Lee ◽

John M. Hilfinger ◽

...

Keyword(s):

Therapeutic Index ◽

Murine Melanoma ◽

Melanoma Model ◽

High Therapeutic Index

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Balanoposthitis: issues of classification, diagnosis and approaches to therapy

Medical alphabet ◽

10.33667/2078-5631-2021-34-39-44 ◽

2021 ◽

pp. 39-44

Author(s):

A. V. Ignatovsky

Keyword(s):

Therapeutic Index ◽

Therapy Options ◽

Human Papillomavirus Infection ◽

Papillomavirus Infection ◽

Choice Of Treatment ◽

High Therapeutic Index ◽

Modern Classification ◽

Aerobic And Anaerobic

Objective. To present a variant of the modern classification of the processes occurring with lesions of the genitals, to draw specialists’ attention to the peculiarities and variety of causes leading to inflammation of the glans and foreskin, as well as to discuss topical issues of external therapy of balanopostitis.Material and methods. Data from modern studies and clinical guidelines were used in the preparation of the publication.Results. The variety of variants of lesions of the glans and foreskin can be due to a number of reasons and can be either an independent local process or a fragment of dermatosis, where it is possible to be affected in the form of balanoposthitis. Also, when examining and selecting therapy options, it is important to consider the possible role of microorganisms, whose spectrum as a cause of balanoposthitis varies from aerobic and anaerobic, to viral and fungal microflora. Treatment approaches are determined by the etiological factors.Conclusions. Balanoposthitis is a heterogeneous group of nosologies. The choice of treatment is based on the identified cause or empirically when possible. External therapy and hygiene constitute an essential part of treatment. When choosing drugs for topical glucocorticosteroids, preferenceshould be given to drugs with a high therapeutic index and low atrophogenic potential. Dysplastic processes of the penis are associated with human papillomavirus infection, the treatment of which can be both conservative and destructive.

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Anti-anxiety activity of Eucalyptus tereticornis n-hexane extract in Wistar albino rats

International Journal of Basic & Clinical Pharmacology ◽

10.18203/2319-2003.ijbcp20170816 ◽

2017 ◽

Vol 6 (3) ◽

pp. 577

Author(s):

Shyamjith Manikkoth ◽

Sheeba Damodar ◽

Melinda Sequeira ◽

Kevin Samuel

Keyword(s):

Therapeutic Index ◽

Antioxidant Property ◽

Hexane Extract ◽

Albino Rats ◽

Group Iii ◽

Group I ◽

Plus Maze ◽

High Therapeutic Index ◽

Group Ii ◽

Wistar Albino Rats

Background: To find out a new agent with a high therapeutic index for the treatment of anxiety, an indigenous medicinal plant Eucalyptus terteticornis was screened for its effect on anxiety in experimental animal model.Methods: Thirty six adult Wistar albino rats of both sexes weighing 175-200g were divided into three groups: Group I: DMSO 10% (0.1ml/200g), Group II: hexane extract of leaves of Eucalyptus terteticornis (ETHE) (100mg/kg/body weight), Group III: Diazepam (1mg/kg orally). All test compounds were administered orally for ten days. On tenth day, after one hour of test compounds administration, Wistar rats were taken for elevated plus maze (EPM) and light dark arena (LDA) tests. Statistical comparisons among the groups were performed by One-way analysis of variance (ANOVA) followed by Tukey Krammer test.Results: The results showed that ETHE treated animals (Group II) significantly (p <0.001) increased the time spent in open arms of EPM and in bright arena of LDA on comparing with normal (Group I).Conclusions: The anti-anxiety activity of Eucalyptus terteticornis can be due to its effect on brain neurotransmitters or due to antioxidant property.

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Do Benzodiazepines Still Deserve a Major Role in The Treatment of Psychiatric Disorders? A Critical Reappraisal

European Psychiatry ◽

10.1016/j.eurpsy.2011.11.003 ◽

2013 ◽

Vol 28 (1) ◽

pp. 7-20 ◽

Cited By ~ 114

Author(s):

B. Dell’osso ◽

M. Lader

Keyword(s):

Psychiatric Disorders ◽

Critical Appraisal ◽

Randomized Clinical Trials ◽

Treatment Guidelines ◽

Scientific Evidence ◽

Family Physicians ◽

Therapeutic Index ◽

The Elderly ◽

High Therapeutic Index

AbstractDiscovered in the late 1950s by Leo Sternbach, the first benzodiazepine (BZD) chlordiazepoxide was followed by several congeners, which rapidly constituted one of the largest and most widely prescribed classes of psychotropic compounds. After 50 years, BZDs are still routinely utilized not only in psychiatry but, more generally, in the whole of medicine. Despite their high therapeutic index which makes BZDs safer than other compounds like barbiturates, as well as their rapidity of onset, psychiatrists and family physicians are well aware about the controversy that surrounds the wide use – often not adequately based on scientific evidence – of BZDs in many psychiatric disorders. In this overview of international treatment guidelines, systematic reviews and randomized clinical trials, the aim was to provide a critical appraisal of the current use and role of BZDs in psychiatric disorders and their disadvantages, with specific emphasis on anxiety and affective disorders, sleep disorders, alcohol withdrawal, violent and aggressive behaviours in psychoses, and neuroleptic-induced disorders. In addition, specific emphasis has been given to the extent of usage of BZDs and its appropriateness through the assessment of available international surveys. Finally, the entire spectrum of BZD-related adverse effects including psychomotor effects, use in the elderly, paradoxical reactions, tolerance and rebound, teratologic risk, dependence, withdrawal and abuse issues was examined in detail.

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A phase I and biodistribution study of ABT-806i, an 111indium-labeled conjugate of the tumor-specific anti-EGFR antibody ABT-806.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.15_suppl.2520 ◽

2013 ◽

Vol 31 (15_suppl) ◽

pp. 2520-2520 ◽

Cited By ~ 13

Author(s):

Hui Kong Gan ◽

Matthew E. Burge ◽

Benjamin J. Solomon ◽

Kyle D. Holen ◽

Yumin Zhang ◽

...

Keyword(s):

Growth Factor Receptor ◽

Therapeutic Index ◽

Whole Body ◽

Extension Study ◽

Antibody Drug Conjugate ◽

Minor Response ◽

Normal Tissues ◽

Specific Tumor ◽

High Therapeutic Index ◽

A Minor

2520 Background: ABT-806 is a humanized antibody targeting a conformationally exposed epitope only available when tumor Epidermal Growth Factor Receptor (EGFR) is overexpressed or (EGFRvIII) mutated. A prior trial treated 8 patients (pts) with a chimeric homologue (single-dose 5-40 mg/kg), with a minor response in one squamous cell carcinoma of skin pt. A prior phase 1A study of ABT-806 treated 26 pts (2-24 mg/kg IV q2w), with prolonged SD in one head and neck (H&N) cancer pt. No pt had a typical EGFR-inhibitor rash. The current study gathers further ABT-806 clinical data, assesses ABT-806i dosimetry in normal and malignant tissues and examines its relationship to clinical and PK/PD data. Methods: Pts with advanced tumors likely to express EGFR, ECOG 0-2, measurable disease and adequate organ function were enrolled. ABT-806i scans comprised ABT-806i 5-7mCi injection followed by whole body and regional SPECT scans over one week. Cohort (C) 1 pts (n=6) had ABT-806i scans alone. C2 pts (n=12) had ABT-806i scans at baseline and at week 6 (after 3 fortnightly doses of ABT-806; 6 pts at 18 mg/kg and 6 at 24 mg/kg). Subjects with PR/SD could receive ABT-806 on an extension study until progression. Results: 18 pts (M:F 11:7; median age 57 yrs) with tumors of H&N (6), colon (3), lung (2), brain (2), bladder (1), cervical (1) and other (3) were treated. An H&N pt had a confirmed PR whilst 5 pts had SD (lasting 37 and 24 wks in an adrenal carcinoma and H&N pt respectively). Two potential toxicities were seen at 24mg/kg on the extension study: equivocal rash (G1; three transient lesions on nose) and allergic reaction (Sweet’s syndrome, G2). Dosimetry in C1 pts confirmed safe radiation exposure levels to normal tissues. Many pts showed high, specific tumor uptake of ABT-806i, including 1 pt with an intracranial tumor. ABT-806i uptake was not significantly affected by concurrent ABT-806 treatment. Ongoing analyses of how ABT-806i uptake correlates with tumor EGFR and clinical response may inform the recommended phase 2 dose of ABT-806. Conclusions: The high therapeutic index and specificity of ABT-806 merits further investigation as monotherapy or an antibody-drug conjugate. ABT-806i may have utility as a bioimaging agent. Clinical trial information: NCT01472003.

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Bioactivities and analysis of peptides from Sumbawa horse milk generated by Bacillus thuringiensis protease

Jurnal Ilmu Ternak dan Veteriner ◽

10.14334/jitv.v21i4.1627 ◽

2018 ◽

Vol 21 (4) ◽

pp. 244 ◽

Cited By ~ 3

Author(s):

Eni Kusumaningtyas ◽

R. Widiastuti ◽

H. D. Kusumaningrum ◽

M. T. Suhartono

Keyword(s):

Bacillus Thuringiensis ◽

Milk Protein ◽

Antioxidant Activities ◽

Protein Hydrolysate ◽

Chemical Properties ◽

Therapeutic Index ◽

Gastrointestinal Disorder ◽

Bioactive Peptide ◽

Peptide Fraction ◽

High Therapeutic Index

Sumbawa horse milk is claimed to cure some diseases such as asthma, hypertension, diabetes and gastrointestinal disorder but its potential bioactive peptide has not been explored. The aims of this study are to evaluate bioactivities peptides from Sumbawa horse milk protein hydrolysate and to analyzethe physio-chemical properties of selected peptides. The milk protein was hydrolyzed by Bacillus thuringiensis protease, the peptide produced were sequential fractionated and then analyzed for antibacterial and antioxidant activities. The peptide fraction <3 kDa was then sequenced using LCMS-MS and the physio-chemical properties of the peptides were analyzed. The result showed that peptides fraction <3 kDa from the 30 min hydrolysis was the most active as antibacterial and more active to Gram negative bacteria. For antioxidant, scavenging activity of the fraction per µg protein/mL were 83% to ABTS and 31% to DPPH radicals. The values were similar with vitamin C 12.5 µg/mL for ABTS and 14.5 µg/mL for DPPH. Peptide <tt>HPYFYAPELLYYANK with molecular weight prediction </tt>1887.92 Da and isoelectric point 7.47 has high therapeutic index prediction (64.75). The result showed that peptides from Sumbawa horse milk hydrolyzed by Bacillus thuringiensis protease was active as antibacterial and antioxidant. Peptide <tt>HPYFYAPELLYYANK from fraction <3 kDa was potential as antibacterial.</tt>Key Words: Bacillus thuringiensis, Bioactive Peptide, Horse Milk

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Ameliorative Role of Nutraceutical Quercetin and its Derivatives Against Cognitive Impairment Process Induced by Lead Exposure in Drosophila melanogaster(Fruit Fly)

Iraqi Journal of Pharmaceutical Sciences ( P-ISSN 1683 - 3597 E-ISSN 2521 - 3512) ◽

10.31351/vol30iss2pp135-142 ◽

2021 ◽

Vol 30 (2) ◽

pp. 135-142

Author(s):

Abubakar lema Abdullahi ◽

A. A. Lema ◽

K. Jibrin ◽

W. Nuraddeen ◽

E. M. Alexander

Keyword(s):

Drosophila Melanogaster ◽

Molecular Docking ◽

Therapeutic Index ◽

Fruit Fly ◽

Acetylcholinesterase Activity ◽

Docking Studies ◽

Pharmacokinetic Studies ◽

Glutathione S Transferase ◽

High Therapeutic Index ◽

In Silico Toxicity

Cumulative lifetime lead (Pb) exposure has been associated with accelerated declines in cognition through the free radical generation and epigenetic effects. Several pieces of literature have identified a correlation between exposure to lead and neurodegenerative disorders. Harwich strain Drosophila melanogaster was exposed to lead acetate for two weeks, and changes in pulse transmission by acetylcholinesterase and systemic redox were evaluated. Besides, molecular docking studies of acetylcholinesterase against Quercetin and its most common derivatives contained in food have been performed. Pharmacokinetic studies on Quercetin and its derivatives have also been performed in silico toxicity. The data obtained showed alterations in antioxidant enzymes and molecules such as catalase, glutathione-S-transferase, and glutathione. Upregulation of acetylcholinesterase activity was observed after treatment with Quercetin. In molecular docking tests, Quercetin and its derivatives were found to bind to acetylcholinesterase's active and peripheral pockets. Pharmacokinetic studies demonstrate moderate solubility, high therapeutic index, excellent absorption potential, hepatoprotective and non-mutagenic properties. With other antioxidant molecules, Quercetin may also play a crucial role in avoiding the development of Alzheimer's and associated antioxidant disorders.

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High Cell Selectivity and Bactericidal Mechanism of Symmetric Peptides Centered on d-Pro–Gly Pairs

International Journal of Molecular Sciences ◽

10.3390/ijms21031140 ◽

2020 ◽

Vol 21 (3) ◽

pp. 1140

Author(s):

Boyan Jia ◽

Yiming Wang ◽

Ying Zhang ◽

Zi Wang ◽

Xue Wang ◽

...

Keyword(s):

Antibiotic Resistance ◽

Geometric Mean ◽

Therapeutic Index ◽

Helical Structure ◽

Gram Negative Bacteria ◽

Gram Negative ◽

Membrane Mimetic ◽

High Therapeutic Index ◽

Low Toxicity ◽

Conventional Antibiotics

Antimicrobial peptides (AMPs) have a unique action mechanism that can help to solve global problems in antibiotic resistance. However, their low therapeutic index and poor stability seriously hamper their development as therapeutic agents. In order to overcome these problems, we designed peptides based on the sequence template XXRXXRRzzRRXXRXX-NH2, where X represents a hydrophobic amino acid like Phe (F), Ile (I), and Leu (L), while zz represents Gly–Gly (GG) or d-Pro–Gly (pG). Showing effective antimicrobial activity against Gram-negative bacteria and low toxicity, designed peptides had a tendency to form an α-helical structure in membrane-mimetic environments. Among them, peptide LRpG (X: L, zz: pG) showed the highest geometric mean average treatment index (GMTI = 73.1), better salt, temperature and pH stability, and an additive effect with conventional antibiotics. Peptide LRpG played the role of anti-Gram-negative bacteria through destroying the cell membrane. In addition, peptide LRpG also exhibited an anti-inflammatory activity by effectively neutralizing endotoxin. Briefly, peptide LRpG has the potential to serve as a therapeutic agent to reduce antibiotic resistance owing to its high therapeutic index and great stability.

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