‘Mutual Prodrug’ and approach to increase the effectiveness of Non-Steroidal Anti-inflammatory Drugs

2021 ◽  
Vol 1 (1) ◽  
pp. 035-045
Author(s):  
Manish S. Junagade ◽  
Anju Goyal
Keyword(s):  
Pharmacokinetic Parameters ◽  
Formulation Development ◽  
Duration Of Action ◽  
Drug Molecules ◽  
Carrier Molecule ◽  
Inflammatory Drugs ◽  
Development Approach ◽  
Pharmacologically Active ◽  
Mutual Prodrug ◽  
Poor Absorption

A clinically useful drug may have limitations in practice because of undesirable side effects, poor solubility, and poor bioavailability, short duration of action, first-pass effect, poor absorption & adverse effects. There are increased efforts in research to increase the therapeutic efficacy of drugs by eliminating or minimizing the undesirable properties of drug molecules. Some of the problems can be solved using a formulation development approach but in some cases, chemical modification in the molecule is necessary to correct the pharmacokinetic parameters. One of the approaches to convert the existing molecule to a more efficient molecule is prodrug design. Mutual Prodrug is the molecule in which an active drug molecule is attached to a carrier molecule having pharmacological activity. So a mutual prodrug consists of two pharmacologically active molecules connected by a bio labile linkage. Both molecules in this act as a pro moiety of each other. The design of mutual prodrug is very fruitful in the area of research & has given successful results in increasing the clinical & therapeutic effectiveness of the drugs. The present article takes a review of various applications of mutual prodrugs & development in this field in the last few decades.

scholarly journals Formulation and Nanotechnology-Based Approaches for Solubility and Bioavailability Enhancement of Zerumbone

Medicina ◽  
2020 ◽  
Vol 56 (11) ◽  
pp. 557
Author(s):  
Siddharth S. Kesharwani ◽  
G. Jayarama Bhat
Keyword(s):  
Aqueous Solubility ◽  
Clinical Development ◽  
World Population ◽  
Formulation Development ◽  
Volatile Oils ◽  
Bioavailability Enhancement ◽  
Drug Molecules ◽  
Development Pipeline ◽  
Traditional Therapies ◽  
Poor Absorption

About 40–70% of drug molecules in the clinical development pipeline suffer from one of either low aqueous solubility, poor absorption, or extremely low bioavailability. Approximately 75% of the world population relies on traditional therapies and therefore there has been a growing interest in the utilization of natural compounds. Zerumbone is one such natural compound, classified as a sesquiterpenoid that is extracted from the essential volatile oils of rhizomes from Zingiber zerumbet. It possesses strong antitumor, antioxidant, antimicrobial, and anti-inflammatory activity. However, despite promising preclinical studies demonstrating the therapeutic utility of zerumbone, its clinical development has been limited due to its low aqueous solubility, poor absorption, or associated low bioavailability. Multiple reviews demonstrating the pharmacological effects of zerumbone for various diseases have been published. However, to our knowledge, no review demonstrates the various formulation strategies developed to overcome the biopharmaceutical challenges of zerumbone. The purpose of this review is to provide a comprehensive perspective on zerumbone as a molecule for formulation development. A section related to pharmacokinetics, toxicity, and patents of zerumbone is included. This review provides the importance of developing novel formulations of zerumbone to overcome its biopharmaceutical challenges thereby advance its potential in the treatment of various diseases.

Effects of Food on Bioavailability of Analgesics; Resulting Dosage and Administration Recommendations

Pain Medicine ◽  
2020 ◽  
Vol 21 (11) ◽  
pp. 2877-2892
Author(s):  
Suresh Babu Naraharisetti ◽  
Salma Srour ◽  
Yun Xu ◽  
David J Lee ◽  
Sharon H Hertz ◽  
...  
Keyword(s):  
Drug Administration ◽  
Food Effect ◽  
Time Profile ◽  
Pharmacokinetic Parameters ◽  
Onset Of Action ◽  
Duration Of Action ◽  
Concentration Time ◽  
Inflammatory Drugs ◽  
Gastrointestinal Adverse Events ◽  
Extent Of Absorption

Abstract Objectives To evaluate currently approved analgesics, that is, opioids, nonsteroidal anti-inflammatory drugs (NSAIDs), anticonvulsants, and serotonin and norepinephrine reuptake inhibitors (SNRIs) used as analgesics, for 1) differences in pharmacokinetic parameters under fed vs fasting conditions and 2) factors involved in dosage recommendations in relation to food. Design Systematic review. Results Food effect on the rate, extent of absorption, or shape of concentration–time profile can alter the onset of action, duration of action, or tolerability of a medication. Based on 79 analgesic products reviewed, food effect dosage recommendations depend on whether an analgesic will be dosed on a regular interval around-the-clock vs on an as-needed basis, the shape of concentration–time profile, steady-state concentrations, the type of meals used in the pharmacokinetic study, and drug administration with regard to food in clinical trials. Overall, most opioids do not have food restriction and are taken without regard to food, with the exception of OPANA products and XTAMPZA ER. For many NSAIDs, food does not affect absorption characteristics, with the exception of ZORVOLEX and CELEBREX. Although NSAIDs are commonly to be taken without regard to food, prescribers recommend administering them with food to reduce their propensity for gastrointestinal adverse events. A larger percentage of anticonvulsants and SNRIs used as analgesics are taken with food to improve their tolerability. Of all analgesic products, seven NSAIDs and six opioids lack food effect information, maybe due to their approval before Food and Drug Administration food effect guidance. Conclusions Overall, because food effects could alter the onset and/or duration of pain relief, analgesic medication should be used as per labeled recommendations for proper pain management.

Medicinal Chemistry of Alternative Therapeutics: Novelty and Hopes with Genus Ammannia

2019 ◽  
Vol 19 (10) ◽  
pp. 784-794 ◽  
Author(s):  
Harish C. Upadhyay
Keyword(s):  
Traditional Medicine ◽  
Biological Activities ◽  
World Health ◽  
Biologically Relevant ◽  
Traditional Medicines ◽  
Drug Molecules ◽  
Health Organization ◽  
Tract Infections ◽  
Pharmacologically Active ◽  
Herbal Formulations

The plants have formed the basis of folklore remedy since the beginning of human civilization. The cumulative human endeavor and experience over a period of thousands of years developed into well to organize traditional medicine systems viz. Ayurvedic, Unani, Chinese amongst others. Across the world, traditional medicine is either the mainstay of health care or serves as a complement to modern drugs. In view of worldwide use of traditional medicines, World Health Organization launched ‘WHO-Traditional Medicine Strategy 2014-2023’ for the development of strong policies regarding knowledge-base, safety, quality-control and effectiveness of traditional/alternative therapeutics for national health systems. Besides their use in traditional medicine, plants have always been a good source of modern drug/pharmacologically active molecules. More than half of the modern pharmaceuticals are either plant isolates or their derivatives. The plant-based drugs are not only effective, but have better compatibility with human biological systems because of more biologically relevant chemistry, hence lesser side effects. Some of the species of genus Ammannia (Lythraceae) have been reported for their magical medicinal values. Many herbal formulations containing Ammannia spp. have been patented for treatment of serious diseases/disorders like cancer, spinal disease, human female infertility, chronic tonsillitis, pelvic inflammatory disease, treatment of bladder stones, urinary tract infections, dermatitis etc. The uses of Ammannia spp. in traditional medicine have been further verified by the biological activities of their extracts as well as isolation of bioactive phytomolecules. The current review provides details about Ammannia spp.; its use in folklore remedy, herbal formulations, biological activities of extracts, isolation of bioactive phytomolecules and SAR study of semi-synthetic derivatives to analyze the possibility of new drug molecules of plant origin.

Concentration–Effect Relation of Succinylcholine Chloride during Propofol Anesthesia

2002 ◽  
Vol 97 (5) ◽  
pp. 1082-1092 ◽  
Author(s):  
Julie J. Roy ◽  
François Donati ◽  
Daniel Boismenu ◽  
France Varin
Keyword(s):  
Rate Constant ◽  
Plasma Concentrations ◽  
Elimination Rate ◽  
Quantitative Model ◽  
Concentration Effect ◽  
Pharmacokinetic Parameters ◽  
Effect Compartment ◽  
Duration Of Action ◽  
Arterial Blood ◽  
Effect Relation

Background The pharmacokinetics and pharmacodynamics of succinylcholine were studied simultaneously in anesthetized patients to understand why the drug has a rapid onset and short duration of action. A quantitative model describing the concentration-effect relation of succinylcholine was proposed. The correlation between hydrolysis in plasma and elimination was also examined. Methods Before induction of anesthesia, blood was drawn for analysis in seven adults. Anesthesia was induced with propofol and remifentanil. Single twitch stimulation was applied at the ulnar nerve every 10 s, and the force of contraction of the adductor pollicis was measured. Arterial blood was drawn frequently after succinylcholine injection to characterize the front-end kinetics. Plasma concentrations were measured by mass spectrometry, and pharmacokinetic parameters were derived using compartmental and noncompartmental approaches. Pharmacokinetic-pharmacodynamic relations were estimated. Results The mean degradation rate constant in plasma (1.07 +/- 0.49 min(-1)) was not different from the elimination rate constant (0.97 +/- 0.30 min(-1)), and an excellent correlation (r2 = 0.94) was observed. Total body clearance derived using noncompartmental (37 +/- 7 ml x min(-1) x kg(-1)) and compartmental (37 +/- 9 ml x min(-1) x kg(-1)) approaches were similar. The plasma-effect compartment equilibration rate constant (k(eo)) was 0.058 +/- 0.026 min(-1), and the effect compartment concentration at 50% block was 734 +/- 211 ng/ml. Conclusion Succinylcholine is a low-potency drug with a very fast clearance that equilibrates relatively slowly with the effect compartment. Its disappearance is greatly accountable by a rapid hydrolysis in plasma.

scholarly journals Prodrugs of NSAIDs: A Review

2017 ◽  
Vol 11 (1) ◽  
pp. 146-195 ◽  
Author(s):  
Kamal Shah ◽  
Jeetendra K. Gupta ◽  
Nagendra S. Chauhan ◽  
Neeraj Upmanyu ◽  
Sushant K. Shrivastava ◽  
...  
Keyword(s):  
Active Drug ◽  
Pharmacological Action ◽  
Patient Acceptance ◽  
Synergistic Activity ◽  
Bioavailability Enhancement ◽  
Drug Molecules ◽  
Presystemic Metabolism ◽  
Pass Through ◽  
Reduced Toxicity ◽  
Mutual Prodrug

Intoroduction:Prodrug approach deals with chemical biotransformation or enzymatic conversion or involves inactive or less active bio-reversible derivatives of active drug molecules. They have to pass through enzymatic or chemical biotransformation before eliciting their pharmacological action.Methods & Materials:The two different pharmacophores combine to give synergistic activity or may help in targeting the active drug to its target. Prodrug super seeds the problems of prodrug designing, for example solubility enhancement, bioavailability enhancement, chemical stability improvement, presystemic metabolism, site specific delivery, toxicity masking, improving patient acceptance, or eradicating undesirable adverse effects.Results:As an outcome the search for a prodrug or mutual prodrug with reduced toxicity has continued during recent years. This present review emphasizes the common help to revamp physiochemical, pharmaceutical and therapeutic effectiveness of drugs.Conclusion:This gives the researcher a common platform where they can find prodrugs of commonly used NSAIDs to overcome the gastrointestinal toxicity (irritation, ulcergenocity and bleeding).

scholarly journals Population Pharmacokinetics of Clozapine and Norclozapine and Switchability Assessment between Brands in Uruguayan Patients with Schizophrenia

2019 ◽  
Vol 2019 ◽  
pp. 1-10 ◽  
Author(s):  
Ismael Olmos ◽  
Manuel Ibarra ◽  
Marta Vázquez ◽  
Cecilia Maldonado ◽  
Pietro Fagiolino ◽  
...  
Keyword(s):  
Active Metabolite ◽  
Smoking Status ◽  
Antipsychotic Agent ◽  
Comparable Efficacy ◽  
Pharmacokinetic Parameters ◽  
Therapeutic Drug ◽  
Uv Detector ◽  
Caffeine Consumption ◽  
Apparent Clearance ◽  
Pharmacologically Active

Clozapine (CZP) is an atypical antipsychotic agent commonly used in the treatment of schizophrenia. It is metabolized primarily by CYP1A2 enzyme, yielding a pharmacologically active metabolite, norclozapine (NCZP). Significant intra- and interindividual pharmacokinetic (PK) variability for CZP and NCZP has been observed in routine therapeutic drug monitoring. So the goal of this study was to evaluate the magnitude and variability of concentration exposure to CZP and its active metabolite NCZP on pharmacokinetic parameters in Uruguayan patients with schizophrenia with a focus on covariates such as cigarette smoking, age, sex, caffeine consumption, brands available of CZP, and comedication using population PK (PPK) modeling methodologies. Patients with a diagnosis of schizophrenia treated with brand-name CZP (Leponex®) for more than a year were included in the study. Then these patients were switched to the similar brand of CZP (Luverina®). Morning predose blood samples for determination of CZP and NCZP using a HPLC system equipped with a UV detector were withdrawn on both occasions at steady state and under the same comedication. Ninety-eight patients, 22 women and 76 men, took part in the study. Mean ± standard deviation for CZP and NCZP concentration was 421 ± 262 ng/mL and 275 ± 180 ng/mL, respectively. After covariate evaluation, only smoking status remained significant in CZP apparent clearance, inducing a mean increment of 32% but with no clinical impact. The results obtained with the two brands of CZP should ensure comparable efficacy and tolerability with the clinical use of either product. Smoking was significantly associated with a lower exposure to CZP due to higher clearance. The results obtained with the two brands commercialized in our country hint a bioequivalence scenario in the clinical setting.

Impairment of human antipyrine metabolism by piroxicam

1990 ◽  
Vol 68 (6) ◽  
pp. 711-717 ◽  
Author(s):  
Luis José Battellino ◽  
Susana Tereza Dorronsoro de Cattoni ◽  
Carmen Ragagnin
Keyword(s):  
Half Life ◽  
Oxidative Degradation ◽  
Pharmacokinetic Parameters ◽  
Metabolic Clearance ◽  
Metabolic Clearance Rate ◽  
Metabolizing Enzymes ◽  
Inflammatory Drugs ◽  
Antipyrine Disposition ◽  
Cytochrome P 450

The pharmacokinetics of a single oral dose of antipyrine was determined in healthy young volunteers (18–28 years), both 3 days before piroxicam, ketoprofen, or naproxen administration and on the following day of their discontinuation. In all subjects treated with piroxicam (10, 20, and 40 mg daily) for 5 consecutive days, the rate of salivary antipyrine elimination slowed. Antipyrine half-life was prolonged and metabolic clearance was reduced significantly (p < 0.01) proportional to the dose administered. After piroxicam was discontinued, both pharmacokinetic parameters of antipyrine returned toward normal. No significant modification in antipyrine half-life or metabolic clearance rate was demonstrated after pretreatment with ketoprofen (50, 100, and 200 mg daily) or naproxen (250 and 500 mg daily). The impairment on antipyrine disposition produced by piroxicam has been interpreted as a consequence of a reduction in the activity of hepatic microsomal drug-metabolizing enzymes, particularly the cytochrome P-450 system. These results suggest the possibility of drug accumulation and toxicity when certain other therapeutic agents are administered simultaneously with piroxicam. For the same reason, it is recommended to bear in mind the potential danger of long-term piroxicam therapy on the oxidative degradation of steroid hormones and other endogenous compounds that are metabolized by the mixed-function oxidase system.Key words: antipyrine, piroxicam, ketoprofen, naproxen, nonsteroidal anti-inflammatory drugs, drug metabolism.

A Formulation Development Approach to Identify and Select Stable Ultra–High-Concentration Monoclonal Antibody Formulations With Reduced Viscosities

2017 ◽  
Vol 106 (11) ◽  
pp. 3230-3241 ◽  
Author(s):  
Neal Whitaker ◽  
Jian Xiong ◽  
Samantha E. Pace ◽  
Vineet Kumar ◽  
C. Russell Middaugh ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Formulation Development ◽  
High Concentration ◽  
Development Approach

scholarly journals Broad-Spectrum, Patient-Adaptable Inhaled Niclosamide-Lysozyme Particles are Efficacious Against Coronaviruses in Lethal Murine Infection Models

2020 ◽  
Author(s):  
Ashlee D. Brunaugh ◽  
Hyojong Seo ◽  
Zachary Warnken ◽  
Li Ding ◽  
Sang Heui Seo ◽  
...  
Keyword(s):  
Methicillin Resistance ◽  
Low Cost ◽  
Dry Powder Inhaler ◽  
Oral Formulation ◽  
Lung Damage ◽  
Carrier Molecule ◽  
Development Approach ◽  
Staphylococcus Aureus Pneumonia

ABSTRACTNiclosamide (NIC) has demonstrated promising in vitro antiviral efficacy against SARS-CoV-2, the causative agent of the COVID-19 pandemic. Though NIC is already FDA-approved, the oral formulation produces systemic drug levels that are too low to inhibit SARS-CoV-2. As an alternative, direct delivery of NIC to the respiratory tract as an aerosol could target the primary site of for SARS-CoV-2 acquisition and spread. We have developed a niclosamide powder suitable for delivery via dry powder inhaler, nebulizer, and nasal spray through the incorporation of human lysozyme (hLYS) as a carrier molecule. This novel formulation exhibits potent in vitro and in vivo activity against MERS-CoV and SARS-CoV-2 and may protect against methicillin-resistance staphylococcus aureus pneumonia and inflammatory lung damage occurring secondary to CoV infections. The suitability of the formulation for all stages of the disease and low-cost development approach will ensure wide-spread utilization

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