Errors associated with co-names of medicines: The nomenclature of combination medicinal products.

In comparison to the efforts required to bring a new drug or formulation to the clinic, bestowing a name on a medicine is relatively simple. However, if the name we choose causes confusion-by making its contents ambiguous or if it is too alike another drug-it can precipitate clinical errors. This prompted the World Health Organization to set up the International Nonproprietary Naming Committee in the 1970s to select unambiguous names for drugs. Unfortunately, multidrug products-which are becoming increasingly popular-do not fall under the remit of conventional International Non-proprietary Nomenclature. We have identified 26 combination formulations that have been historically named with the co-drug format in the United Kingdom. Most of them have also been prescribed in the United Kingdom in the past year, and although several of them are not prescribed very often, 11 were prescribed more than 2000 times. In this paper, we have explored the literature to identify prescribing errors with co-drug products and found several idiosyncrasies that have caused drug errors in the past. We advocate for a standard nomenclature (state the international nonproprietary name [INN] of each component followed by dose information in the x + y format) for these products on the box and in prescribing resources. We hope that this will enhance clarity and safety during prescribing and administration, particularly for high-volume drugs like paracetamol + codeine (co-codamol), amoxicillin + clavulanic acid (co-amoxiclav) and trimethoprim + sulfamethoxazole (co-trimoxazole).

Co-delivery of doxorubicin/sorafenib by DNA-decorated green ZIF-67-based nanocarriers for chemotherapy and hepatocellular carcinoma treatment.

Zeolitic imidazolate framework-67 (ZIF-67) has been decorated with natural biomaterials and DNA to develop a promising strategy and suitable and safe co-delivery platform for doxorubicin and sorafenib (DOX-SOR). FT-IR, XRD, FESEM, and TEM were used to characterize the modified MOFs. Combined Ginkgo biloba leaf extract and E. coli DNA were used as green decorations, and as environmentally-friendly methods to be developed, and DOX and SOR were attached to the porosity and on the surface of the MOFs. TEM and FESEM images demonstrated that the green MOFs were successfully synthesized for biomedical applications and showed their cubic structure. As a result of the nanocarrier-drug interactions, 59.7% and 60.2% of the drug payload were achieved with DOX and SOR, respectively. HEK-293, HT-29, and MCF-7 cells displayed excellent viability by decoration with DNA and Ginkgo biloba leaf extract at low and high concentrations (0.1 and 50 µg/mL), suggesting they could be used in biomedical applications. MTT assays demonstrated that the nanocarriers are highly biocompatible with normal cells and possess anticancer properties when applied to HT-29 and MCF-7 cells. As a result of Ginkgo biloba leaf extract and DNA modification, DOX-SOR release was prolonged and pH-sensitive (highest release at pHs 4.5 and 5.5). The internalization and delivery of the drug were also studied using a 2d fluorescence microscope, demonstrating that the drug was effectively internalized. Cell images showed NPs internalizing in MCF-7 cells, proving their efficacy as drug delivery systems.

The Use of Zidovudine Pharmacophore in Multi-Target-Directed Ligands for AIDS Therapy.

The concept of polypharmacology embraces multiple drugs combined in a therapeutic regimen (drug combination or cocktail), fixed dose combinations (FDCs), and a single drug that binds to different targets (multi-target drug). A polypharmacology approach is widely applied in the treatment of acquired immunodeficiency syndrome (AIDS), providing life-saving therapies for millions of people living with HIV. Despite the success in viral load suppression and patient survival of combined antiretroviral therapy (cART), the development of new drugs has become imperative, owing to the emergence of resistant strains and poor adherence to cART. 3'-azido-2',3'-dideoxythymidine, also known as azidothymidine or zidovudine (AZT), is a widely applied starting scaffold in the search for new compounds, due to its good antiretroviral activity. Through the medicinal chemistry tool of molecular hybridization, AZT has been included in the structure of several compounds allowing for the development of multi-target-directed ligands (MTDLs) as antiretrovirals. This review aims to systematically explore and critically discuss AZT-based compounds as potential MTDLs for the treatment of AIDS. The review findings allowed us to conclude that: (i) AZT hybrids are still worth exploring, as they may provide highly active compounds targeting different steps of the HIV-1 replication cycle; (ii) AZT is a good starting point for the preparation of co-drugs with enhanced cell permeability.

D-mannose functionalized MgAl-LDH/Fe-MOF nanocomposite as a new intelligent nanoplatform for MTX and DOX co-drug delivery.

Commonly the directly administered chemotherapy drugs lack targeting in tumor treatment. Thus, trying to improve cancer treatment efficiency led us to design a new intelligent system for cancer treatment. Considering these, in the current work, at first, the 2-aminoterephthalic acid (NH2-BDC) intercalated layered double hydroxides (MgAl-(NH2-BDC) LDH) were synthesized simply. Afterward, the in situ growth of the iron-based metal-organic frameworks in the presence of MgAl-(NH2-BDC) LDH occurred (MgAl-LDH/Fe-MOF). In the end, the reaction of MgAl-LDH/Fe-MOF with D-mannose (D-Man) achieved the MgAl-LDH/Fe-MOF/D-Man ternary hybrid nanostructure. Scanning electron microscopy (SEM) and energy dispersive X-ray (EDX) analysis confirmed the formation of the monodisperse Fe-MOF with nanosize in the presence of MgAl-LDH. Importantly, methotrexate (MTX) and doxorubicin (DOX) entrapment efficiency reached respectively about 28 wt% and 21% for MgAl-LDH/Fe-MOF/D-Man. The in vitro drug release experiments revealed a higher drug release at pH 5.0 in comparison with pH 7.4 which revealed its promising potential for anticancer drug delivery applications. Bioassay results revealed that the co-drug-loaded MgAl-LDH/Fe-MOF/D-Man has higher cytotoxicity on MDA-MB 231 cells. At last, fluorescence microscopy and flow cytometric analysis confirmed the successful uptake of MgAl-LDH/Fe-MOF/D-Man into MDA-MB 231 cell lines, as well as its bioimaging potential. A survey in the published literature approved that this work is the first report on the evaluation of the MgAl-LDH/Fe-MOF/D-Man for targeted co-delivery of both MTX and DOX. Finally, results collectively demonstrate the importance of the biocompatible MgAl-LDH/Fe-MOF/D-Man as a hopeful candidate for biomedicinal applications from the targeted co-drug delivery and bioimaging potential viewpoints.

Co-drug of isoniazid and sulfur containing antioxidant for attenuation of hepatotoxicity and treatment of tuberculosis.

The prolonged use of isoniazid (INH) - a highly effective drug in the treatment of tuberculosis - causes fatal liver injury. In order to overcome this adverse effect, a unique amide codrug was designed by covalently linking INH with sulfur-containing antioxidant- alpha-lipoic acid for possible hepatoprotective and antimycobacterial effect. Co-drug LI was prepared by Schotten Baumann reaction and was characterized by spectroscopic analysis. To check the bioreversibility of LI, in vitro release tests were conducted in buffers of specific pH, stomach, and intestinal homogenates of rat employing HPLC. Male Wistar rats were used for the evaluation of the hepatoprotective activity. Liver function markers, oxidative stress markers, and biochemical parameters were estimated. The antimycobacterial efficacy of LI was examined in terms of its ability to decrease the lung bacillary load in Balb/c mice infected intravenously with Mycobacterium tuberculosis. LI resisted hydrolysis in buffers of pH 1.2 (acidic), pH 7.4 (basic), and stomach homogenate of the rat while displayed significant hydrolysis (88.19%) in intestinal homogenates over a period of 6 h. The effect of LI on liver function, antioxidant and biochemical paradigms was remarkable as it reestablished the enzyme levels and restored hepatic cytoarchitecture representing its abrogating effect. The findings of antimycobacterial activity assessment evidently demonstrated that LI was as potent as INH in lowering the mycobacterial load in mice. The outcome of this exploration confirmed that the described co-drug can offer desirable safety and therapeutic benefit in the management of tuberculosis.

Preparation and Evaluation of Colon-Targeted Prodrugs of the Microbial Metabolite 3-Indolepropionic Acid as an Anticolitic Agent.

Microbial metabolites play a critical role in mucosal homeostasis by mediating physiological communication between the host and colonic microbes, whose perturbation may lead to gut inflammation. The microbial metabolite 3-indolepropionic acid (3-IPA) is one such communication mediator with potent antioxidative and anti-inflammatory activity. To apply the metabolite for the treatment of colitis, 3-IPA was coupled with acidic amino acids to yield colon-targeted 3-IPA, 3-IPA-aspartic acid (IPA-AA) and 3-IPA-glutamic acid (IPA-GA). Both conjugates were activated to 3-IPA in the cecal contents, which occurred faster for IPA-AA. Oral gavage of IPA-AA (oral IPA-AA) delivered a millimolar concentration of IPA-AA to the cecum, liberating 3-IPA. In a 2,4-dinitrobenzene sulfonic acid (DNBS)-induced rat colitis model, oral IPA-AA ameliorated rat colitis and was less effective than sulfasalazine (SSZ), a current anti-inflammatory bowel disease drug. To enhance the anticolitic activity of 3-IPA, it was azo-linked with the GPR109 agonist 5-aminonicotinic acid (5-ANA) to yield IPA-azo-ANA, expecting a mutual anticolitic action. IPA-azo-ANA (activated to 5-ANA and 2-amino-3-IPA) exhibited colon specificity in in vitro and in vivo experiments. Oral IPA-azo-ANA mitigated colonic damage and inflammation and was more effective than SSZ. These results suggest that colon-targeted 3-IPA ameliorated rat colitis and its anticolitic activity could be enhanced by codelivery of the GPR109A agonist 5-ANA.

Design, synthesis and antihypertensive evaluation of novel codrugs with combined angiotensin type 1 receptor antagonism and neprilysin inhibition.

The multifactorial etiology of hypertension has promoted the research of blood pressure-lowering agents with multitarget actions to achieve better clinical outcomes. We describe here the discovery of novel dual-acting antihypertensive codrugs combining pharmacophores with angiotensin type 1 (AT1) receptor antagonism and neprilysin (NEP) inhibition. Specifically, the codrugs combine the AT1 antagonists losartan or its carboxylic acid active metabolite (E-3174) with selected monocarboxylic acid NEP inhibitors through a cleavable linker. The resulting codrugs exhibited high rates of in vitro conversion into the active molecules upon incubation with human/rat liver S9 fractions and in vivo conversion after oral administration in rodents. Moreover, the acute effects of one of the designed codrugs (3b) was confirmed at the doses of 10, 30 and 60 mg/kg p.o. in the spontaneous hypertensive rat (SHR) model, showing better antihypertensive response over 24 hours than the administration of an equivalent fixed-dose combination of 15 mg/kg of losartan and 14 mg/kg of the same NEP inhibitor used in 3b. The results demonstrate that the codrug approach is a plausible strategy to develop a single molecular entity with combined AT1 and NEP activities, aiming at achieving improved pharmacokinetics, efficacy and dosage convenience, as well as reduced drug-drug interaction for hypertension patients. In addition, the developability of the codrug should be comparable to the one of marketed AT1 antagonists, most of them prodrugs, but bearing only the AT1 pharmacophore.

Potential Anticancer Effect of Carvacrol Codrugs on Human Glioblastoma Cells.

BACKGROUND: Essential oils are considered as promising sources of novel anticancer compounds. Carvacrol (CVC), the major constituent of many aromatic plants including oregano and thymus, is endowed with curative properties on different cancers, including liver, colon, and lung. Little information is available regarding the potential of CVC for the treatment of brain cancers, notably Glioblastoma Multiforme (GBM). OBJECTIVE: In this work, we investigated the in vitro effect of CVC codrugs (CVC1-8), synthesized by direct-coupled co-drug strategies, on human glioblastoma cell line (U87-MG) for the first time. METHODS: Cell viability was detected by MTT and LDH assays while expression levels of important genes (such as EGFR, NFKB1A, AKT1, AKT2, and others) associated with GBM and inflammatory pathways were detected by PCR array. RESULTS: Results showed that CVC1-8 codrugs induced cytotoxicity and positive alterations in molecular responses on U87MG cells. Particularly, important pathways (such as PI3K/PTEN/AKT) involved in the onset and progression of GBM resulted in modulation by CVC3 and CVC8. CONCLUSION: Our results suggest that CVC3 and CVC8 could be suitable candidates for further investigation to develop new strategies for the prevention and/or treatment of GBM.

Self-assembled peptide nanoparticles with endosome escaping permits for co-drug delivery.

The diagnosis and treatment of major diseases, especially tumors, was the key to improving the cure rate and survival rate of patients. Therefore, one of the main goals of modern medicine was to develop effective, non-toxic treatments. This paper successfully established dipeptide nanoparticles/clofarabine/aptamer AS1411/influenza hemagglutinin peptide/siRNA/doxorubicin (DNPs/Clolar/AS1411/HA/RNA/DOX) multi-functional nanoparticles for specific delivery, cancer treatment and bioimaging. It was an ideal choice for multi-drug synergy treatment. First, non-toxic DNPs formed by self-assembly of dipeptides with safe and biocompatible effect. Second, from the perspective of the multi-functional nanoparticles for nano-drug tumors imaging monitoring, AS1411 and HA were used as cell permits for enhancing the specificity of cell drug delivery ability and improving the endosomal escape, respectively. Third, the multi-functional nanoparticles with Clolar, siRNA and DOX, three drug synergistic treatments were used to improve the therapeutic effect of tumors. Both cell experiments and vivo experiments demonstrated that the synergistic treatment of the multi-drugs was superior to the effect of single-drug therapy. Thus, the proposed multi-functional nanoparticles have initiated new ideas for these hybrid anticancer drugs based on peptide self-assembled nanocarriers and its widely applications in biomedicine.

5-Aminosalicylic Acid Azo-Coupled with a GPR109A Agonist Is a Colon-Targeted Anticolitic Codrug with a Reduced Risk of Skin Toxicity.

To develop a 5-aminosalicylic acid (5-ASA)-based anticolitic drug with enhanced therapeutic activity, a colon-targeted codrug constituting 5-ASA and a GPR109A agonist was designed. 5-ASA azo-coupled with nicotinic acid (ASA-azo-NA) was synthesized, and the colon specificity and anticolitic effects were evaluated. Approximately 89% of ASA-azo-NA was converted to 5-aminonicotinic acid (5-ANA) and 5-ASA after 24 h of incubation in the cecal contents. 5-ANA was identified as a GPR109A agonist (concentration that gives half-maximal response (EC50): 18 µM) in a cell-based assay. Upon oral gavage of ASA-azo-NA (oral ASA-azo-NA) and sulfasalazine (oral SSZ), a colon-targeted 5-ASA prodrug, cecal accumulation of 5-ASA was comparable, and 5-ANA was barely detectable in the blood, while it was detected up to 62.7 µM with oral 5-ANA. In parallel, oral ASA-azo-NA did not elicit an adverse skin response. In murine macrophage and human colon carcinoma cells, activation of GPR109A by 5-ANA elevated the level of the anti-inflammatory cytokine IL-10, suppressed NF-κB activation, and potentiated the inhibitory activity of 5-ASA on NF-κB. Oral ASA-azo-NA ameliorated rat colitis and was more effective than oral SSZ, which were substantially blunted following cotreatment with the GPR109A antagonist, mepenzolate. In conclusion, ASA-azo-NA is a colon-targeted anticolitic codrug with a reduced risk of skin toxicity induced by the GPR109A agonist, therapeutically surpassing a current 5-ASA-based anti-inflammatory bowel disease drug in a rat colitis model.

Design, Synthesis, and in Vitro Biological Evaluation of 14-Hydroxytylophorine-dichloroacetate Co-drugs as Antiproliferative Agents.

Co-drug, or mutual-prodrug, is a drug design approach consisting of covalently linking two active drugs so as to improve the pharmacokinetics and/or pharmacodynamics properties of one or both drugs. Co-drug strategy has proven good success in overcoming undesirable properties such as absorption, poor bioavailability, nonspecificity, and gastrointestine tract (GIT) side effects. In this work, we successfully developed a co-drug of 14-hydroxytylophorine, a phenanthroindolizidine derivative with remarkable antiproliferative activity, and dichloroacetate, a known inhibitor of pyruvate dehydrogenase kinase. Dichloroacetate steers tumour cell metabolism from glycolysis back to glucose oxidation, which in turn reverses the Warburg effect and renders tumour cells with a proliferative disadvantage. The obtained co-drugs retained the cytotoxicity of 14-hydroxytylophorine. However, they showed similar unselectivity towards normal cells.

Nanoscale Hybrid Coating Enables Multifunctional Tissue Scaffold for Potential Multimodal Therapeutic Applications.

Through a nature-inspired layer-by-layer assembly process, we developed a unique multifunctional tissue scaffold that consists of porous polyurethane substrate and nanoscale chitosan/graphene oxide hybrid coating. Alternative layers of drug-laden chitosan and graphene oxide nanosheets were held together through strong electrostatic interaction, giving rise to a robust multilayer architecture with control over structural element orientation and chemical composition at nanoscale. Combined pH-controlled co-delivery of multiple therapeutic agents and photothermal therapy has been achieved by our scaffold system. The new platform technology can be generalized to produce other tissue scaffold systems and may enable potential multimodal therapeutic applications such as bone cancer managements.

Novel ketoprofen-antioxidants mutual codrugs as safer nonsteroidal anti-inflammatory drugs: Synthesis, kinetic and pharmacological evaluation.

Ketoprofen belongs to one of the most common nonsteroidal anti-inflammatory drugs (NSAIDs) but its clinical usefulness has been restricted due to the high incidence of gastrointestinal complications. The release of reactive oxygen species (ROS) in NSAIDs therapy plays a major role in causing gastric complications. Antioxidants not only prevent gastric ulceration and lipid peroxidation but also preserve glutathione-type peroxidase (GPO) activity. Therefore, the present study investigates the utility of combining anti-inflammatory and antioxidant properties of two different compounds in a single molecule to form a series of 16 ketoprofen-antioxidant mutual codrugs. The free carboxylic group, which is believed to be one of the reasons for gastric toxicity of ketoprofen, was masked temporarily by simple and double esterification with alcoholic/phenolic-OH of natural antioxidants. In simple esterification, ketoprofen is directly linked to natural antioxidants (IIa-h) in the hope to obtain drugs free of gastric side effects. In an attempt to improve the in vivo lability, as well as gastric side effects, the double ester codrugs, that is, ketoprofen-antioxidant through the glycolic acid spacer (-CH2 COO; IIIa-h), have also been designed and synthesized. The synthesized codrugs were characterized by IR, 1 H NMR, 13 C NMR, mass spectroscopy and elemental analysis. The in vitro hydrolysis studies showed the lowest hydrolysis (highest stability) in acidic pH 1.2, whereas moderate hydrolysis was seen at pH 7.4 and significant hydrolysis in 80% human blood plasma, as indicated by their t1/2 . The pharmacological evaluation results indicate that these ketoprofen-antioxidant mutual codrugs showed the retention of anti-inflammatory and analgesic activity with a significant reduction in the ulcer index.

Boosting GSH Using the Co-Drug Approach: I-152, a Conjugate of N-acetyl-cysteine and ß-mercaptoethylamine.

Glutathione (GSH) has poor pharmacokinetic properties; thus, several derivatives and biosynthetic precursors have been proposed as GSH-boosting drugs. I-152 is a conjugate of N-acetyl-cysteine (NAC) and S-acetyl-ß-mercaptoethylamine (SMEA) designed to release the parent drugs (i.e., NAC and ß-mercaptoethylamine or cysteamine, MEA). NAC is a precursor of L-cysteine, while MEA is an aminothiol able to increase GSH content; thus, I-152 represents the very first attempt to combine two pro-GSH molecules. In this review, the in-vitro and in-vivo metabolism, pro-GSH activity and antiviral and immunomodulatory properties of I-152 are discussed. Under physiological GSH conditions, low I-152 doses increase cellular GSH content; by contrast, high doses cause GSH depletion but yield a high content of NAC, MEA and I-152, which can be used to resynthesize GSH. Preliminary in-vivo studies suggest that the molecule reaches mouse organs, including the brain, where its metabolites, NAC and MEA, are detected. In cell cultures, I-152 replenishes experimentally depleted GSH levels. Moreover, administration of I-152 to C57BL/6 mice infected with the retroviral complex LP-BM5 is effective in contrasting virus-induced GSH depletion, exerting at the same time antiviral and immunomodulatory functions. I-152 acts as a pro-GSH agent; however, GSH derivatives and NAC cannot completely replicate its effects. The co-delivery of different thiol species may lead to unpredictable outcomes, which warrant further investigation.

Mce3R Stress-Resistance Pathway Is Vulnerable to Small-Molecule Targeting That Improves Tuberculosis Drug Activities.

One-third of the world's population carries Mycobacterium tuberculosis (Mtb), the infectious agent that causes tuberculosis (TB), and every 17 s someone dies of TB. After infection, Mtb can live dormant for decades in a granuloma structure arising from the host immune response, and cholesterol is important for this persistence of Mtb. Current treatments require long-duration drug regimens with many associated toxicities, which are compounded by the high doses required. We phenotypically screened 35 6-azasteroid analogues against Mtb and found that, at low micromolar concentrations, a subset of the analogues sensitized Mtb to multiple TB drugs. Two analogues were selected for further study to characterize the bactericidal activity of bedaquiline and isoniazid under normoxic and low-oxygen conditions. These two 6-azasteroids showed strong synergy with bedaquiline (fractional inhibitory concentration index = 0.21, bedaquiline minimal inhibitory concentration = 16 nM at 1 µM 6-azasteroid). The rate at which spontaneous resistance to one of the 6-azasteroids arose in the presence of bedaquiline was approximately 10-9, and the 6-azasteroid-resistant mutants retained their isoniazid and bedaquiline sensitivity. Genes in the cholesterol-regulated Mce3R regulon were required for 6-azasteroid activity, whereas genes in the cholesterol catabolism pathway were not. Expression of a subset of Mce3R genes was down-regulated upon 6-azasteroid treatment. The Mce3R regulon is implicated in stress resistance and is absent in saprophytic mycobacteria. This regulon encodes a cholesterol-regulated stress-resistance pathway that we conclude is important for pathogenesis and contributes to drug tolerance, and this pathway is vulnerable to small-molecule targeting in live mycobacteria.

A co-drug conjugate of naringenin and lipoic acid mediates neuroprotection in a rat model of oxidative stress.

Using our in vitro and in vivo models of oxidative stress, the current study was designed to determine the neuroprotective potential of naringenin, alone or in combination with lipoic acid. In our mixed neuronal culture exposed to hypoxia and subsequent reoxygenation, naringenin was shown to provide significant neuroprotection against cell death at a concentration of 2.5 µmol/L. Lipoic acid (LA) did not produce neuroprotection at any concentration tested (0.25-100 µmol/L). In contrast, when naringenin was covalently combined with LA, producing a novel compound named "VANL-100", significant neuroprotection was observed at a concentration as low as 2×10-2  µmol/L (100-fold more potent). An ELISA for antioxidant capacity demonstrated that naringenin and VANL-100 likely resulted in neuroprotection by increasing the free radical scavenging capacity of the neuronal cells. Pretreatment of rats with the above compounds prior to middle cerebral artery occlusion (MCAO) followed by reperfusion, showed similar results. Naringenin significantly reduced infarct volume at a dose of 10 mg/kg while VANL-100 produced significant neuroprotection at a dose as low as 1×10-4  mg/kg (10 000-fold more potent). This VANL-100-induced neuroprotection persisted even when administered 1 and 3 hours into the reperfusion time course. Taken together, these results suggest that our novel compound, VANL-100 is neuroprotective, likely via a mechanism that involves increasing the antioxidant capacity of neuronal cells. Our results also show that VANL-100 is 100-10 000-fold more potent than the parent compounds, which adds to the growing evidence in support of combination therapy targeting oxidative stress in neurodegenerative diseases.

Anti-melasma codrug of retinoic acid assists cutaneous absorption with attenuated skin irritation.

Melasma treatment with combined retinoic acid (RA) and hydroquinone (HQ) usually causes unsatisfactory outcomes and safety concerns. This study attempted to evaluate the cutaneous absorption and skin tolerance of the codrug conjugated with RA and HQ via ester linkage. The codrug's permeation of the pig skin was estimated using Franz diffusion cell. The codrug and parent drugs were comparatively examined for anti-inflammatory activity and tyrosinase inhibition. In vivo cutaneous irritation was assessed on nude mouse skin. Chemical conjugation of RA with HQ increased the lipophilicity and thus the skin absorption. The codrug absorption produced a 5.5- and a 60.8-fold increment compared to RA skin deposition at an equimolar (1.2mM) and saturated solubility dose, respectively. The cumulative amount of HQ derived from the codrug in the receptor was comparable to or less than that of topically applied HQ. The RA-HQ codrug was partly hydrolyzed on penetrating the skin. The hydrolysis rate in intact skin was significantly lower than that in esterase medium and skin homogenates. The codrug showed an interleukin (IL)-6 inhibition activity comparable to RA. A therapeutic index 6-fold greater than RA was obtained with the topical codrug. The tyrosinase inhibition percentage of the codrug and HQ was 13% and 21%, respectively. The skin tolerance test determined by transepidermal water loss (TEWL), redness, and histopathology had exhibited minor skin irritation caused by the codrug compared to the physical mixture of RA and HQ at an equivalent dose. Topical codrug delivery not only promoted RA absorption, but also diminished the adverse effects of the parent agents.

UPEI-400, a conjugate of lipoic acid and scopoletin, mediates neuroprotection in a rat model of ischemia/reperfusion.

Previously, our laboratory provided evidence that lipoic acid (LA) covalently bonded to various antioxidants, resulted in enhanced neuroprotection compared to LA on its own. The naturally occurring compound scopoletin, a coumarin derivative, has been shown in various in vitro studies to have both antioxidant and anti-inflammatory mechanism of actions. The present investigation was designed to determine if scopoletin on its own, or a co-drug consisting of LA and scopoletin covalently bonded together, named UPEI-400, would be capable of demonstrating a similar neuroprotective efficacy. Using a rat stroke model, male rats were anesthetized (Inactin®; 100 mg/kg, iv), the middle cerebral artery was permanently occluded for 6 h (pMCAO), or in separate animals, occluded for 30 min followed by 5.5 h of reperfusion (ischemia/reperfusion; I/R). Pre-administration of either scopoletin or UPEI-400 significantly decreased infarct volume in the I/R model (p < 0.05), but not in the pMCAO model of stroke. UPEI-400 was ∼1000 times more potent compared to scopoletin alone. Since UPEI-400 was only effective in a model of I/R, it is possible that it may act to enhance neuronal antioxidant capacity and/or upregulate anti-inflammatory pathways to prevent the neuronal cell death.

Synthesis of (125) I-lamivudine and (125) I-lamivudine-ursodeoxycholic acid codrug.

The preparation of (125) I-lamivudine ((125) I-3TC) and (125) I-lamivudine-ursodeoxycholic acid codrug ((125) I-3TC-UDCA), suitable for comparative biodistribution studies, is described. The synthesis of the unlabeled precursor 3TC-UDCA proceeds in an 11.6% yield, and the radiolabelling yields for (125) I-3TC and (125) I-3TC-UDCA were 89 and 92%, respectively. The final products are radiochemically pure (greater than 98%).

The codrug approach for facilitating drug delivery and bioactivity.

INTRODUCTION: Codrug or mutual prodrug is a drug design approach to chemically bind two or more drugs to improve therapeutic efficiency or decrease adverse effects. The codrug can be cleaved in the body to generate parent actives. The codrug itself can be inactive, less active, or more active than the parent agents. It has been demonstrated that codrugs possess some benefits over conventional drugs, including enhanced solubility, increased permeation for passing across biomembranes, prolonged half-life for extending the therapeutic period, and reduced toxicity. AREAS COVERED: This review article describes the history, design strategy, and potential applications of codrugs. Codrugs are predominantly used to treat some conditions such as neurodegenerative, cardiovascular, cancerous, infectious, and inflammatory disorders. Many codrugs are developed to increase lipophilicity for better transport into/across biomembranes, especially the skin and cornea. A targeted delivery of codrugs to specific tissues or organs thus can be achieved to promote bioavailability. The chemical and enzymatic hydrolysis, bioactivity, and pharmacokinetics of codrugs are systematically introduced in this review. EXPERT OPINION: Additional profiles pertaining to clinical trials will support further applicability of codrug therapy. Caution should be used in optimizing the benefits of codrugs to ensure a balance between damage or toxicity and the effectiveness of delivery enhancement.