Alper Okyar

Istanbul University · Department of Pharmacy (Institute of Health Sciences)

Introduction: In oral and maxillofacial surgery, hard tissue augmentation is provided by materials that accelerate the healing, act as a template for reconstructing bony defects, and stimulate bone production and growth. This study investigated the effects of biocompatible carriers containing active vitamin D and platelet-rich plasma (PRP) on bone...

Introduction The 24-hour variations in drug absorption, distribution, metabolism, and elimination, collectively known as pharmacokinetics, are fundamentally influenced by rhythmic physiological processes regulated by the molecular clock. Recent advances have elucidated the intricacies of the circadian timing system and the molecular interplay betwe...

Background Everolimus is an oral mammalian target of rapamycin (mTOR) inhibitor used as an immunosuppressant and anticancer. Its pharmacokinetics is highly variable, it has a narrow therapeutic window and shows chronotoxicity with the best time at ZT13 and worst time at ZT1 (ZT; Zeitgeber time, time after light onset) in the preclinical setting. O...

This study reports a rapid and sensitive reversed‐phase high‐performance liquid chromatography method with ultraviolet detection for the determination of regorafenib (REG) in rat plasma. For the extraction of REG from plasma and the precipitation of plasma proteins, a rapid one‐step precipitation method was performed with methanol. The separation w...

TW68, cryptochromes stabilizer, regulates fasting blood glucose levels in diabetic ob/ob and high fat-diet-induced obese mice, Biochemical Pharmacology (2023), doi: https://doi. Abstract Cryptochromes (CRYs), transcriptional repressors of the circadian clock in mammals, inhibit cAMP production when glucagon activates G-protein coupled receptors. Th...

Essential for survival and reproduction, the circadian timing system (CTS) regulates adaptation to cyclical changes such as the light/dark cycle, temperature change, and food availability. The regulation of energy homeostasis possesses rhythmic properties that correspond to constantly fluctuating needs for energy production and consumption. Adipose...

Citation: Ulbegi Polat, H.; Abaci, I.; Tas Ekiz, A.; Aksoy, O.; Oktelik, F.B.; Yilmaz, V.; Tekin, S.; Okyar, A.; Oncul, O.; Deniz, G. Therapeutic Effect of C-Vx Substance in K18-hACE2 Transgenic Mice Infected with SARS-CoV-2. Int. Abstract: C-Vx is a bioprotective product designed to boost the immune system. This study aimed to determine the antivi...

Cryptochromes (CRYs), transcriptional repressors of the circadian clock in mammals, inhibit cAMP production when glucagon activates G-protein coupled receptors. Therefore, molecules that modulate CRYs have the potential to regulate gluconeogenesis. In this study, we discovered a new molecule called TW68 that interacts with the primary pockets of ma...

Everolimus is an oral mTOR inhibitor used as an immunosuppressant and anticancer. Its pharmacokinetics is highly variable, it has a narrow therapeutic window, and shows chronotoxicity with best time at ZT13 and worst time at ZT1 in preclinical setting. In the present study, we aimed to investigate whether the pharmacokinetics of everolimus vary acc...

The circadian timing system controls absorption, distribution, metabolism, and elimination processes of drug pharmacokinetics over a 24-h period. Exposure of target tissues to the active form of the drug and cytotoxicity display variations depending on the chronopharmacokinetics. For anticancer drugs with narrow therapeutic ranges and dose-limiting...

A discovered molecule increases CRY stability and inhibits glucagon-mediated glucogenesis by inhibiting the transcription of Pck1 and G6pc, gluconeogenetic genes. Results signify a CRY stabilizer, can be used as a therapeutic agent to control hunger blood glucose levels in diabetic patients.

Cryptochromes are negative transcriptional regulators of the circadian clock in mammals. It is not clear how reducing the level of endogenous CRY1 in mammals will affect circadian rhythm and the relation of such a decrease with apoptosis. Here, we discovered a molecule (M47) that destabilizes Crypto-chrome 1 (CRY1) both in vitro and in vivo. The M4...

Objectives: In this preliminary study, the in vitro effect of C-Vx in human PBMCs and the in vivo effect of C-Vx in rats were investigated. Methods: The human part was analyzed in PBMCs isolated from healthy subjects. Apoptotic index, cytotoxic activity of CD8+ T and NK cells, and cell proliferation of CD3+, CD4+, CD8+ T and NK cells in response to...

Cryptochromes are negative transcriptional regulators of the circadian clock in mammals. It is not clear how reducing the level of endogenous level of the CRY1 in mammals will affect circadian rhythm and the relation of such a decrease with apoptosis is unknown. Here, we discovered a molecule that destabilizes Cryptochrome 1 (CRY1) both in vitro an...

The circadian timing system controls many biological functions in mammals including drug metabolism and detoxification, cell cycle events, and thus may affect pharmacokinetics, target organ toxicity and efficacy of medicines. Selective mTOR (mammalian target of rapamycin) inhibitor everolimus is an immunosuppressant and anticancer drug that is effe...

P-glycoprotein (P-gp) is an efflux protein that forms a tissue barrier and plays a role in the pharmacokinetics of drugs, limiting the influx of them and other xenobiotics into the cells, as expressed in various tissues such as liver, brain, intestinal mucosa and kidneys. Circadian clock controls many biological functions in mammals including xenob...

Objective: Gastric cancer is the second leading cause of cancer-related deaths worldwide. 5-Fluorouracil (5-FU) is one of the most commonly used drugs to treat cancer, but 5-FU and its forms are characterized by wide inter-individual pharmacokinetic variability. ABCC5 and ABCC11 are members of the ABC transporter superfamily and play a role in the...

Despite strict measures taken by many countries, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to be an issue of global concern. Currently, there are no clinically proven pharmacotherapies for coronavirus disease 2019, despite promising initial results obtained from drugs such as azithromycin and hydroxychloroquine. Therefo...

Acetamiprid, a selective agonist of nicotinic acetylcholine recetors, is one of the most widely used neonicotinoids. There is limited data about toxicity of acetamiprid on male reproductive system. Therefore, the study aimed to investigate the reproductive toxic potential of acetamiprid in male rats orally treated with acetamiprid with low (12.5 mg...

div>We performed repurposing of FDA approved drugs against SARS-CoV-2 3 chymotrypsin like protease and RNA-dependent RNA polymerase. During the screening, 3948 drugs approved by the U.S. Food and Drug Administration (FDA) to target the active site of 3CLpro and nsp8 binding sites of RdRp and, in turn, disturb SARS-CoV-2 life cycle in host cell. As...

In this study, we aimed to determine the drug-drug interaction potential between atorvastatin (ATOR), and talinolol (TAL). Concentration-dependent effects of ATOR on the intestinal permeability of TAL were investigated by an in situ intestinal perfusion method. Dose-dependent effects of ATOR on TAL exposure were evaluated by measuring plasma concen...

Proper function of many physiological processes requires a robust circadian clock. Disruptions of the circadian clock can result in metabolic diseases, mood disorders, and accelerated aging. Therefore, identifying small molecules that specifically modulate regulatory core clock proteins may potentially enable better management of these disorders. I...

Acetamiprid, a selective agonist of type-2 nicotinic acetylcholine receptors, is one of the most widely used neonicotinoids. The hepato- and nephrotoxic potential of acetamiprid has not been clarified although it is known to be toxic to other several organ systems, including the nervous, respiratory and immune systems. The present study aimed to in...

P-glycoprotein (P-gp) largely influences the pharmacokinetics (PK) and toxicities of xenobiotics in a patient-specific manner so that personalized drug scheduling may lead to significant patient’s benefit. This systems pharmacology study investigated P-gp activity in mice according to organ, sex, feeding status, and circadian time. Sex-specific cir...

Objectives: Type 2 diabetes (T2DM) is one of the most serious challenges of the 21th century with life-threatening complications and excessive health care costs. In diabetic patients, the main goal in T2DM treatment is the regulation of both blood glucose and lipid levels. For that, Gliclazide (GLZ), an oral antidiabetic, and Atorvastatin (ATV), a...

The circadian timing system controls many biological functions in mammals including xenobiotic metabolism, detoxification, cell proliferation, apoptosis and immune functions. Everolimus is a mammalian target of rapamycin inhibitor, whose immunosuppressant properties are both desired in transplant patients and unwanted in cancer patients, where it i...

Circadian clock largely modifies efficacy and toxicity of many anticancer agents. An efflux transporter P-glycoprotein (encoded by abcb1a/abcb1b genes in rodents) is a well-known mechanism causing multidrug resistance in cancer patients by extruding anticancer drugs out of tumor cells and its expression is under the control of circadian clock. We a...

The circadian timing system (CTS) controls various biological functions in mammals including xenobiotic metabolism and detoxification, immune functions, cell cycle events, apoptosis and angiogenesis. Although the importance of the CTS is well known in the pharmacology of drugs, it is less appreciated at the clinical level. Genome-wide studies highl...

Mucosal vaccination stimulates both mucosal and systemic immunity. However, mucosal applications of vaccine antigens in their free form generally result in poor systemic immune responses and need adjuvantation. In this study, bovine serum albumin loaded, new hybridised poly(β-amino ester)-poly(d,l-lactide-co-glycolide) nanoparticles were prepared b...

A coordinated network of molecular circadian clocks in individual cells generates 24-hour rhythms in liver metabolism and proliferation. Circadian disruption through chronic jet lag or Per2 clock gene mutation was shown to accelerate hepatocarcinoma development in mice. Since divergent effects were reported for clock genes Per and Cry regarding xen...

Background The molecular circadian clock regulates mTOR activity, the main target of EV. EV use is hampered by adverse events in MBC patients (pts). Knowing the optimal timing of EV oral intake could improve tolerability, thus compliance and treatment efficacy. Objective: To assess the relevance of EV timing for side effects in MBC pts, and to dete...

Concomitant administration of P-glycoprotein substrates and inhibitors may cause pharmacokinetic drug interactions leading to increased concentrations associated with serious side effects and toxicities. Barnidipine is a longacting calcium-channel blocker and potent inhibitor of P-glycoprotein in vitro, and talinolol is a beta-blocker and probe sub...

Purpose The aim of this study was to evaluate safety and toxicity of chronomodulated capecitabine administered in the morning and at noon according to a specific time schedule (Brunch Regimen: Breakfast and Lunch) as a part of first-line XELOX chemotherapy in patients with metastatic colorectal cancer. Methods A total of 30 treatment-naïve colorect...

Daily rhythms in physiology significantly modulate drug pharmacokinetics and pharmacodynamics according to the time-of-day, a finding that has led to the concept of chronopharmacology. The importance of biological clocks for xenobiotic metabolism has gained increased attention with the discovery of the molecular circadian clockwork. Mechanistic und...

Background: Because reactive oxygen species (ros) contribute to the pathogenesis of various acute and chronic liver diseases, dietary antioxidants and drugs from herbal origins have been proved to be beneficial as therapeutic agents in reversing hepatotoxicity and oxidative stress. The objective of this study was to investigate the protective effec...

Background: Because reactive oxygen species (ros) contribute to the pathogenesis of various acute and chronic liver diseases, dietary antioxidants and drugs from herbal origins have been proved to be beneficial as therapeutic agents in reversing hepatotoxicity and oxidative stress. The objective of this study was to investigate the protective effec...

Dimenhydrinate (DMH)-loaded buccal bioadhesive films for the prevention and treatment of motion sickness were prepared and optimized. This study examines the rate of drug release from the films for prolonged periods of time to reduce or limit the frequency of DMH administration. Based on preliminary studies using various polymers and concentrations...

Cancer chronotherapy aims at enhancing tolerability and efficacy of anticancer drugs through their delivery according to circadian clocks. However, mouse and patient data show that lifestyle, sex, genetics, drugs and cancer itself can modify both host circadian clocks and metabolism pathways dynamics, thus the optimal timing of drug administration....

This study was designed to evaluate the protective effect of water extract of Amaranthus lividus L. (A. lividus) (Amaranthaceae) on carbon tetrachloride (CCl4)-induced toxicity in kidneys of rats. For this purpose, male albino Wistar rats were pretreated with A. lividus (250 and 500 mg/kg body weight (b.w.)) daily for 9 days and a single dose of CC...

Environmental disruption of molecular clocks promoted liver carcinogenesis and accelerated cancer progression in rodents. We investigated the specific role of clock gene Period 2 (Per2) for liver carcinogenesis and clock-controlled cellular proliferation, genomic instability and inflammation. We assessed liver histopathology, and determined molecul...

Purpose: The aim of this study was to evaluate efficacy and safety of chronomodulated capecitabine administered according to a specific time schedule (Brunch Regimen: Breakfast and Lunch) as a part of neoadjuvant chemoradiation therapy in patients with locally advanced rectal cancer. Methods: Eighty-five patients with stage II and III rectal can...

The protective effect of an aqueous extract of the shoots and leaves of Smilax excelsa L. against acute carbon tetrachloride (CCl4)induced toxicity and the changes in antioxidative defense activities in kidney of rats were investigated. Female Wistar rats were supplied with S. excelsa shoots and leaves aqueous extract once a day for 9 days (orally...

Objective: To evaluate the possible effect of methotrexate (MTX) on rat ovaries by measuring serum antimullerian hormone (AMH), the novel marker of the ovarian reserve. Methods: Pretreatment serum AMH levels were measured in 15 Wistar albino rats. MTX was given in 1 mg/kg dose in days 1, 3, 5, and 7. Serum AMH levels were measured twenty-four ho...

The relevance of P-glycoprotein (P-gp) for irinotecan chronopharmacology was investigated in female B6D2F1 mice. A three-fold 24 h change in the mRNA expression of Abcb1b was demonstrated in ileum mucosa, with a maximum at Zeitgeber Time (ZT) 15 (p < 0.001). No rhythm was found for abcb1a in ileum mucosa, or for Abcb1a/b in Glasgow osteosarcoma (GO...

The circadian timing system (CTS) governs the 24-h rhythm of the organism and, hence, also main pathways responsible for drug pharmacokinetics. P-glycoprotein (P-gp) is a drug transporter that plays a pivotal role in drug absorption, distribution, and elimination, and temporal changes in its activity may affect input, output, activity, and toxicity...

Chronotherapeutics aims at the adjustment of treatments to ∼ 24 h rhythms, which result from the moderation of most biological functions by the circadian timing system (CTS). The integration of CTS-related knowledge in drug delivery concepts challenges most current views, where steady-state constant drug levels are synonymous to enhanced tolerabili...

Supporting information concerning Materials and Methods and parameter estimation. (PDF)

Circadian timing largely modifies efficacy and toxicity of many anticancer drugs. Recent findings suggest that optimal circadian delivery patterns depend on the patient genetic background. We present here a combined experimental and mathematical approach for the design of chronomodulated administration schedules tailored to the patient molecular pr...

ATP-binding cassette transporter abcc2 is involved in the cellular efflux of irinotecan. The drug is toxic for mouse ileum, where abcc2 is highly expressed. Here, we investigate whether circadian changes in local abcc2 expression participate in the circadian rhythm of irinotecan toxicity for ileum mucosa, and further assess whether genetic backgrou...

Seliciclib, a cyclin-dependent kinase inhibitor, is a promising candidate to treat a variety of cancers. Pharmacokinetic studies have shown high oral bioavailability but limited brain exposure to the drug. This study shows that seliciclib is a high-affinity substrate of ATP-binding cassette B1 (ABCB1) because it activates the ATPase activity of the...

Tiaprofenic acid is a potent analgesic and nonsteroidal anti-inflammatory drug (NSAID) and like any other nonsteroidal anti-inflammatory drug, oral administration of the conventional dosage forms of tiaprofenic acid invariably causes gastrointestinal side effects. In an effort to eliminate these side effects while enhancing the drug concentration a...

A number of 2-arylidene-2H-1,4-benzoxazin-3(4H)-ones were synthesized and evaluated for CNS activity. Some of the tested compounds exhibited marked CNS depressant activity in mice.

The aim of this study was to prepare ondansetron-loaded biodegradable microspheres as a nasal delivery system. Microspheres were prepared with emulsification/spray-drying technique using poly(d,l-lactide) (PLA) and two different types of poly(d,l-lactide-co-glycolide) (PLGA). The effect of the type of organic solvent (dichloromethane (DCM) or a mix...

The aim of this study was to evaluate ciprofloxacin hydrochloride-loaded chitosan microspheres for nasal administration. Microspheres were prepared by spray drying method and evaluated with respect to the particle size, morphological properties, drug-polymer interaction, production yield, drug content, encapsulation efficiency, in vitro drug releas...

The circadian timing system is composed of molecular clocks, which drive 24-h changes in xenobiotic metabolism and detoxification, cell cycle events, DNA repair, apoptosis, and angiogenesis. The cellular circadian clocks are coordinated by endogenous physiological rhythms, so that they tick in synchrony in the host tissues that can be damaged by an...

The aim of this study was to develop chitosan microspheres for nasal delivery of ondansetron hydrochloride (OND). Microspheres were prepared with spray-drying method using glutaraldehyde as the crosslinking agent. Microspheres were characterized in terms of morphology, particle size, zeta potential, production yield, drug content, encapsulation eff...

Many secondary plant metabolites have been reported to possess lipid-lowering properties. Aloe vera which has been extensively used for medical and cosmetic purposes contains multiple constituents with potential biological activities. This study was undertaken to investigate the beneficial effects of Aloe vera extracts in comparison to glibenclamid...

Tiaprofenic acid (TA) a nonsteroidal antiinflammatory agent that lipophilic character and widely used in rheumatoid arthritis via oral route. TA has various side-effects like other prostaglandine inhibitors in gastrointestinal system and these effects limit its use e.g., active stomach ulcer patients. Hence, local application of the drug as importa...

Etodolac, a highly lipophilic anti-inflammatory drug, is widely used in rheumatoid arthritis usually at an oral dose of 200 mg twice daily. The commonest side effects during therapy with etodolac is generally gastrointestinal disturbances these are usually mild and reversible but in some patients are peptic ulcer and severe gastrointestinal bleedin...

In this study, heparin-loaded microspheres having smooth surface and small particle size were designed in order to provide the absorption of heparin through nasal mucosa. For this purpose, microspheres at different polymer/drug ratios (1:10, 1:2.5 and 1:1) and at different concentrations of polyvinyl alcohol, emulsifying agent (1.5% and 2.5% w/v) w...

In this study, the effects of cetirizine, a second generation H1-receptor antagonist, on psychomotor functions were assessed by using subjective and objective psychometric tests and the results were compared to those obtained with placebo and the positive control pheniramine. 10 healthy volunteers orally received placebo, cetirizine (10 mg) and phe...

The aim of this work was to investigate the effects of Aloe vera leaf pulp and gel extracts on the liver tissue of neonatal streptozotocin (n0STZ)-induced type-II diabetic rats. The diabetic rats were separated into four groups and each group was given the following samples by gavage, daily for 15 d: phosphate buffered saline (PBS; diabetic control...