Mefenamic acid prodrugs and codrugs - two decades of development

prodrugs are bioreversible derivatives of drug molecules that undergo intermolecular or intramolecular reactions by enzymatic or chemical biotransformation in the human body to give the corresponding active parent drugs and a non-toxic promoiety. Prodrugs have been extensively and successfully used as a chemical tool for modification of the physicochemical, pharmacokinetic as well as pharmacodynamic characteristics of commonly used drugs and new drugs.This mini review focuses on the design, synthesis and pharmacological effects of several prodrugs and codrugs of the non-steroidal anti-inflammatory (NSAIDs), mefenamic acid. Exploitation of the prodrug approach has the potential to achieve a reduction of mefenamic acid GI (gastrointestinal) intolerance, enhance its bioavailability, mask its unpleasant sensation and prolong its duration of action. In addition, utilizing the prodrug concept migh enhance the bioavailability of the counter partner drug of mefenamic acid codrug by increasing its lipophilicity

Mefenamic acid Prodrugs and Codrugs- Two Decades of Development

prodrugs are bioreversible derivatives of drug molecules that undergo intermolecular or intramolecular reactions by enzymatic or chemical biotransformation in the human body to give the corresponding active parent drugs and a non-toxic promoiety. Prodrugs have been extensively and successfully used as a chemical tool for modification of the physicochemical, pharmacokinetic as well as pharmacodynamic characteristics of commonly used drugs and new drugs.This mini review focuses on the design, synthesis and pharmacological effects of several prodrugs and codrugs of the non-steroidal anti-inflammatory (NSAIDs), mefenamic acid. Exploitation of the prodrug approach has the potential to achieve a reduction of mefenamic acid GI (gastrointestinal) intolerance, enhance its bioavailability, mask its unpleasant sensation and prolong its duration of action. In addition, utilizing the prodrug concept migh enhance the bioavailability of the counter partner drug of mefenamic acid codrug by increasing its lipophilicity

Anti-cancer Prodrugs-Three Decades of Design

The conventional old treatment method for cancer therapy is associated with severe side effects along with several limitations. Therefore, searching and developing new methods for cancer became crucial. This mini review was devoted on the design and synthesis of prodrugs for cancer treatment. The methods discussed include targeted prodrugs which are depending on the presence of unique cellular conditions at the desired target, especially the availability of certain enzymes and transporters at these target sites, antibody directed enzyme prodrug therapy (ADEPT), gene-directed enzyme prodrug therapy (GDEPT) which is considered one of the important strategies for the treatment of cancer and prodrugs based on enzyme models that have been advocated to understand enzyme catalysis. In this approach, a design of prodrugs is accomplished using computational calculations based on molecular orbital and molecular mechanics methods. Correlations between experimental and calculated rate values for some intramolecular processes provided a tool to predict thermodynamic and kinetic parameters for intramolecular processes that can be utilized as prodrugs linkers. This approach does not require any enzyme to catalyze the prodrug interconversion. The interconversion rate is solely dependent on the factors govern the limiting step of the intramolecular process

Antibacterial Predrugs-from 1899 till 2015

The predrug (prodrug) term involves chemically modified inert compound which upon an administration releases the active parent drug to elicit its pharmacological response within the body. For many years, the predrug strategy has been extensively developed to solve many unwanted drug properties. This approach has several advantages over conventional drug administration and it has the potential to be quite effective method for the treatment of diseases in the future. In this mini-review we describe a number of antibacterial agents‘ predrugs, and the ways by which predrug strategy was exploited to overcome many pharmaceutical and pharmacokinetic problems that the parent active antibacterial drugs suffer from such as, low bioavailability by increasing or decreasing lipophilicity, site selectivity for higher absorption and less toxicity, short duration of action to increase patient compliance, rapid metabolism to increase oral bioavailability and masking bitter sensation which is crucial for geriatric and pediatric patient compliance

Removal of Two NSAIDs: Naproxen and Diclofenac and a Heavy Metal Cr (VI) by Advanced Membranes Technology.

ODTMA-micelle-clay complex as an efficient adsorbent was prepared from a cationic surfactant, octadecyltrimethylammonium (ODTMA) and a negatively charged clay (montmorillonite). It is characterized with a positive charge and large hydrophobic sites. The micelle- clay complex was investigated towards removal of the ant-inflammatory drugs (NSAIDs), Diclofenac and Naproxen and a heavy metal Cr (VI) as part of comprehensive evaluation study to utilize this adsorbent in advanced wastewater treatment technology. Stability studies demonstrated that while Diclofenac potassium was completely stable in fresh water and in sludge Naproxen underwent biodegradation in sludge to provide O-desmethyl naproxen (DMN) as its single metabolite. Al-Quds Wastewater Treatment Plant (WWTP) which includes ultrafiltration (UF) (hollow fiber HF and spiral wound SW) membranes, activated carbon (AC) and reverse osmosis (RO) has demonstrated high removal efficiency toward these two NSAIDs and Naproxen metabolite (DMN). Furthermore, the filtration results by Al-Quds WWTP revealed that the UF-HF membrane was not efficient in removing the three studied pollutants from wastewater. In contrast, the RO and AC membranes were found to be quite efficient in removing (100%) all studied pharmaceuticals. The column filtration experiments with a mixture of sand and ODTMA-micelle-clay complex as adsorbent indicated 100% removal of the adsorbates, Diclofenac and Naproxen and Naproxen metabolite (SMN). Similarly, ODTMA-micelle-clay complex was found to completely remove the heavy metal Cr (VI) from its aqueous solutions at ambient pH and temperature

ANTIBACTERIAL PREDRUGS-FROM 1899 TILL 2015

The classical approach for delivery of drugs into the central nervous system (CNS) is associated with adverse effects and it has many limitations. Therefore, extensive efforts have been done in searching and developing novel methods for achieving such delivery. This minireview discusses the design and synthesis of selected targeting prodrugs for the treatment of conditions related to impairment in the CNS such as Parkinson‘s and Alzheimer‘s diseases. Such approaches include targeting prodrugs which are designed to interact with unique cellular conditions at the target site, especially the availability of certain enzymes and transporters at these sites. In addition, part of this mini-review is devoted to prodrugs design based on enzyme models that have been invoked to understand how enzymes catalyzebiotransformation. In this approach, the prodrugs design isdone using quantum molecular orbital and molecular mechanics methods. The equations obtained from correlations of experimental and calculated rate values for some intramolecular processes are used to predict parameters for other intramolecular processes that can be utilized as prodrugs linkers. In this approach, there is no need for enzymes to catalyze the conversion of the prodrug to its active parent drug and the conversion rate of the prodrug is dependent only on those factors playing dominant role in the rate-limiting step of the process

Diclofenac Codrugs and Prodrugs-Three Decades of Design

Prodrugs or predrugs are inactive molecules which become active after in vivo conversion to release the active parent drug. The prodrug’s cleavage can be catalyzed by metabolic enzymes or can occur by chemical means without the involvement of enzymes. Prodrugs are designed to improve undesirable physicochemical and pharmacokinetic properties of their parent drugs. Non-steroidal anti-inflammatory (NSAIDs) drugs are among the most commonly used drugs for treatment of pain, inflammation and fever. Despite their frequent use, these agents suffer from gastrointestinal side effects that limit their use for those patients with gastrointestinal conditions. This mini review discusses the design, synthesis and pharmacological effects of prodrugs and codrugs of the non-steroidal anti-inflammatory (NSAIDs) Diclofenac sodium or potassium. It argues that the prodrug approach has the potential to eliminate Diclofenac associated gastrointestinal complications, increases its bioavailability and masks its bitter taste

Efficiency of membrane technology, activated charcoal, and a micelle-clay complex for removal of the acidic pharmaceutical mefenamic acid

The efficiency of sequential advanced membrane technology wastewater treatment plant towards removal of a widely used non-steroid anti-inflammatory drug (NSAID) mefenamic acid was investigated. The sequential system included activated sludge, ultrafiltration by hollow fibre membranes with 100 kDa cutoff, and spiral wound membranes with 20 kDa cutoff, activated carbon and a reverse osmosis (RO) unit. The performance of the integrated plant showed complete removal of mefenamic acid from spiked wastewater samples. The activated carbon column was the most effective component in removing mefenamic acid with a removal efficiency of 97.2%. Stability study of mefenamic acid in pure water and Al-Quds activated sludge revealed that the anti-inflammatory drug was resistant to degradation in both environments. Batch adsorption of mefenamic acid by activated charcoal and a composite micelle (otadecyltrimethylammonium (ODTMA)–clay (montmorillonite) was determined at 25.0◦C. Langmuir isotherm was found to fit the data with Qmax of 90.9 mg g−1 and 100.0 mg g−1 for activated carbon and micelle-clay complex, respectively. Filtration experiment bymicelle-clay columnsmixed with sand in themg L−1 range revealed complete removal of the drug with much larger capacity than activated carbon column. The combined results demonstrated that an integration of a micelle-clay column in the plant system has a good potential to improve the removal efficiency of the plant towards NSAID drugs such as mefenamic acid.Bir-zeit Pharmaceutical Co. is thanked for the supply of mefenamic acid. This work was supported by the European Commission in the framework of the Project ‘Diffusion of nanotechnology based devices for water treatment and recycling - NANOWAT’ (ENPI CBC MED I-B/2.1/049, Grant No. 7/1997)

Design, synthesis and in vitro kinetic study of tranexamic acid prodrugs for the treatment of bleeding conditions

Based on density functional theory (DFT) calculations for the acid-catalyzed hydrolysis of several maleamic acid amide derivatives four tranexamic acid prodrugs were designed. The DFT results on the acid catalyzed hydrolysis revealed that the reaction rate-limiting step is determined on the nature of the amine leaving group. When the amine leaving group was a primary amine or tranexamic acid moiety, the tetrahedral intermediate collapse was the rate-limiting step, whereas in the cases by which the amine leaving group was aciclovir or cefuroxime the rate-limiting step was the tetrahedral intermediate formation. The linear correlation between the calculated DFT and experimental rates for N-methylmaleamic acids 1-7 provided a credible basis for designing tranexamic acid prodrugs that have the potential to release the parent drug in a sustained release fashion. For example, based on the calculated B3LYP/6-31G(d,p) rates the predicted t(1/2) (a time needed for 50 % of the prodrug to be converted into drug) values for tranexamic acid prodrugs ProD 1-ProD 4 at pH 2 were 556 h [50.5 h as calculated by B3LYP/311+G(d,p)] and 6.2 h as calculated by GGA: MPW1K), 253 h, 70 s and 1.7 h, respectively. Kinetic study on the interconversion of the newly synthesized tranexamic acid prodrug ProD 1 revealed that the t(1/2) for its conversion to the parent drug was largely affected by the pH of the medium. The experimental t(1/2) values in 1 N HCl, buffer pH 2 and buffer pH 5 were 54 min, 23.9 and 270 h, respectively