Search

Docetaxel (DTX) has become widely accepted as a first-line treatment for metastatic breast cancer; however, the frequent development of resistance provides challenges in treating the disease.C60 fullerene introduces a unique molecular form of carbon, exhibiting attractive chemical and physical properties. Our study aimed to develop dicarboxylic acid-derivatized C60 fullerenes as a novel DTX delivery carrier. This study investigated the potential of water-soluble fullerenes to deliver the anti-cancer drug DTX through a hydrophilic linker. The synthesis was carried out using the Prato reaction. The spectroscopic analysis confirmed the successful conjugation of DTX molecules over fullerenes. The particle size of nanoconjugate was reported to be 122.13 ± 1.63 nm with a conjugation efficiency of 76.7 ± 0.14%. The designed conjugate offers pH-dependent release with significantly less plasma pH, ensuring maximum release at the target site. In-vitro cell viability studies demonstrated the enhanced cytotoxic nature of the developed nanoconjugate compared to DTX. These synthesized nanoscaffolds were highly compatible with erythrocytes, indicating the safer intravenous route administration. Pharmacokinetic studies confirmed the higher bioavailability (~ 6 times) and decreased drug clearance from the system vis-à-vis plain drug. The histological studies reveal that nanoconjugate-treated tumour cells exhibit similar morphology to normal cells. Therefore, it was concluded that this developed formulation would be a valuable option for clinical use. [ABSTRACT FROM AUTHOR]

Recently, ortho‐phthalaldehyde (OPA) is experiencing a renascence for the modification of proteins and peptides through OPA‐amine two‐component reactions for bioconjugation and intramolecular OPA‐amine‐thiol three‐component reactions for cyclization. Historically, small thiol molecules were used in large excess to allow for the intermolecular OPA‐amine‐thiol reaction forming 1‐thio‐isoindole derivatives. In this study, we discovered that guanidine could serve as an effective additive to switch the intermolecular OPA‐amine‐thiol three‐component reaction to a stoichiometric process and enable the modular construction of peptide‐peptide, and peptide‐drug conjugate structures. Thus, 12 model peptide‐peptide conjugates have been synthesized from unprotected peptides featuring all proteinogenic residues. Besides, 6 peptide‐drug conjugates have been prepared in one step, with excellent conversions and isolated yields. In addition, a conjugate product has been further functionalized by utilizing a premodified OPA derivative, demonstrating the versatility and flexibility of this reaction. [ABSTRACT FROM AUTHOR]

Objective: The aim of this study was to find the efficient medium to bind an anticancer drug, Doxorubicin (DOX), to a synthesized polymer, methoxy poly(ethylene glycol)-block-polycaprolactone (mPEG-b-PCL) via pH sensitive hydrazone bonds and to determine the amount of conjugated drug. Methods: DOX conjugation was carried out in two different media [dimethyl sulfoxide (DMSO) and methanol-trifluoroacetic acid (MeOH-TFA)]. The amount of conjugated drug was determined with two different methods. One method was applied the dissolution of the conjugate in chloroform: methanol (Ch: MeOH, 1: 1 v/v) solution without considering pH responsiveness, and the other method was after breaking pH sensitive hydrazone bonds in acidic medium [using three different media as 0.1 M hydrochloric acid (HCl), concentrated HCl (12 M HCl) and concentrated sulfuric acid (18.3 M H2SO4)]. Results: The highest conjugation efficiency was obtained when the conjugation was achieved in MeOHTFA solution, and for the polymer-drug conjugates after the treatment with concentrated sulfuric acid. Conclusion: It was concluded that, MeOH-TFA method was a good method for conjugation of DOX to mPEG-b-PCL copolymer, and H2SO4 (18.3 M) method was better than any other present in literature for determination of the amount of DOX linked to the polymer via hydrazone conjugation. [ABSTRACT FROM AUTHOR]

In spite of the successful use of monoclonal antibodies (mAbs) in clinic for tumor treatment, their applications are still hampered in therapeutic development due to limitations, such as tumor penetration and high cost of manufacture. Nanobody, a single domain antibody that holds the strong antigen targeting and binding capacity, has demonstrated various advantages relative to antibody. Nanobody is considered as a next‐generation of antibody‐derived tool in the antigen related recognition and modulation. A number of nanobodies have been developed and evaluated in different stages of clinical trials for cancer treatment. Here we summarized the current progress of nanobody in tumor diagnosis and therapeutics, particularly on the conjugation of nanobody with functional moieties. The nanobody conjugation of diagnostic agents, such as radionuclide and optical tracers, can achieve specific tumor imaging. The nanobody‐drug conjugates can enhance the therapeutic efficacy of anti‐tumor drugs and reduce the adverse effects. The decoration of nanobody on nanodrug delivery systems can further improve the drug targeting to specific tumors. This article is categorized under:Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease [ABSTRACT FROM AUTHOR]

As part of an ongoing study of the response of the Streptococcus pneumoniae population to conjugate vaccination, we applied multi-locus sequence typing (MLST) to 291 isolates sampled from nasopharyngeal carriage in Massachusetts children. We found 94 distinct sequence types (STs), including 19 that had not been previously recorded, and a xpt allele containing a large insertion. Comparison with a similar sample collected in 2007 revealed no significant overall difference in the ST composition (p=0.51) suggesting that the population has reached a new equilibrium following the introduction of 7 valent vaccination in 2000. Within serotypes, a large and statistically significant increase (p=0.014 Fisher's Exact test) was noted in the prevalence of the major multiresistant clone ST 320, which is apparently outcompeting ST 199 among serotype 19A strains. This sample will be used as a baseline to study the future evolution of the pneumococcal population in Massachusetts following introduction of vaccines with higher valency.

• Mesoporous Hyaluronic Acid (HA) particle in a single is reported. • HA particles with tunable porosity and degradation kinetic for controlled release. • Linear & sustainable drug release is obtained via tunable crosslinked HA particles. Porous and degradable hyaluronic acid (HA) microparticles was synthesized in a single step using different ratio of crosslinker, divinylsulfone (DVS) ranging between 2.5 and 100% mole ratio of HA repeating unit. HA particles less than 25% (≤10%) crosslinker ratio were found to be mesoporous and provided the highest surface area, calculated as 21.54±10.31 m2/g for 2.5% crosslinked HA particles via BET analysis. Hydrolytic degradation of 2.5% crosslinked HA microparticles in PBS (pH 7.4) and at 37.5 ºC revealed a linear weight loss up to 20 days and 94.5±4.5% weight loss for 30 days was attained. A wide spectrum antibiotic, Vancomycin as a model drug was loaded to mesoporous HA particles via directly loading from aqueous corresponding solution and by chemical conjugation method to obtain controllable and sustained release profiles from HA particles. Up to 168 h linear vancomycin release (50.5±4.2 mg/g) was accomplished from 2.5% DVS crosslinked HA particles. [ABSTRACT FROM AUTHOR]

In this study, the ketoconazole‐conjugated zinc oxide (ZnO) nanoparticles were prepared in a single‐step approach using dextrose as an intermediate compound. The physical parameters confirmed the drug conjugation with ZnO and their size was around 70–75 nm. The drug loading and in vivo drug release studies indicated that the –CHO group from the dextrose increase the drug loading up to 65% and their release kinetics were also studied. The anti‐fungal studies indicated that the prepared nanoparticles exhibit strong anti‐fungal activity and the minimum concentration needed is 10 mg/ml. The nanoparticles loaded semi‐solid gel was prepared using carbopol, methylparaben, propyl paraben and propylene glycol. The in vitro penetration of the ketoconazole‐conjugated nanoparticles was studied using the skin. The results indicated that the semi‐solid gel preparations influenced the penetration and also favoured the accumulation into the skin membrane. The veterinary clinical studies indicated that the prepared gel is highly suitable for treatment of Malassezia. [ABSTRACT FROM AUTHOR]

Hyperbranched polymers (HPs) have widely been used for drug delivery owing to their highly branched topology, which endows the HPs with a large amount of intramolecular cavities for drug encapsulation and terminal groups for drug conjugation. Additionally, one‐pot, large‐scale preparations enable the easy fabrication of HPs for biomedical applications. This review provides an overview of the synthesis of HPs and their application for drug delivery. First, we introduce a diversity of methods for the synthesis of HPs with controllable topologies. Subsequently, we discuss drug encapsulation and drug conjugation by using HPs. Finally, we highlight the use of HPs with controllable topologies for promising drug delivery. Hyper active: Hyperbranched polymers with controllable topologies are promising nanocarriers for biomedical applications. These polymers have a large amount of intramolecular cavities for drug loading and terminal groups for drug conjugation. The synthesis of hyperbranched polymers and strategies to control their topologies are discussed. The use of hyperbranched polymers for drug delivery is highlighted. [ABSTRACT FROM AUTHOR]

Nanoparticles are normally classified as “hard”, mainly consisting of metal or metal oxide cores, or “soft”, including polymer-based, liposomes and biomimetic nanoparticles. Soft nanoparticles have been studied in depth for drug formulation and therapeutic delivery applications, albeit hard nanoparticles may offer easier synthesis, smaller size and more effective tumor penetration. Among them, silica nanoparticles maintain excellent biocompatibility and biodegradability and can be finely adjusted in size and shape, easily produced in a large scale and functionalized or loaded with active molecules. To help filling the gap of a poor clinical translation of hard nanoparticles, we have designed and developed three different nonporous silica nanocarriers loading the chemotherapeutic doxorubicin within the core matrix, on the surface or both inside and outside, respectively. A comparative study was performed on drug loading and drug release, silica matrix degradation and nanodrug cytotoxic activity, highlighting unexpected correlation between the strategy adopted for drug incorporation and nanoparticle behavior in a physiological environment. This study offers a new insight on the impact of the choice of the prodrug nanoparticles on the kinetics and efficacy of drug delivery, which may encourage the scientific community in developing a new generation of drug delivery systems based on hard nanocarriers. [ABSTRACT FROM AUTHOR]

Short interfering RNA (siRNA) is one of the members of the family of RNA interference (RNAi). Coupled with the RNA-induced silencing complex (RISC), siRNA is able to trigger the cleavage of target RNAs which serve as a defensive system against pathogens. Meanwhile, siRNA in gene silencing opens a new avenue for the treatment of various diseases. SiRNA can effectively inhibit viral infection and replication and suppress tumorigenesis and various inflammation-associated diseases and cardiovascular diseases by inactivation of viral genes and downregulation of oncogene expression. Recently, endogenous siRNAs (endo-siRNAs) were discovered in the reproductive cells of animals which may be associated with regulation of cell division. Structural modification of siRNA enhances the delivery, specificity and efficacy and bioavailability to the target cells. There are at least five categories of siRNA delivery systems including viral vectors, lipid-based nanoparticles, peptide-based nanoparticles, polymer-based nanoparticles and inorganic small molecules like metal ions, silica and carbon. Sufficient preclinical and clinical studies supported that siRNA may be a potential medicine for targeted therapy of various diseases in the near future. [ABSTRACT FROM AUTHOR]

The resistance of cancer cells to chemotherapeutic agents, whether through intrinsic mechanisms or developed resistance, motivates the search for new chemotherapeutic strategies. In the present report, we demonstrate a facile synthetic strategy towards the discovery of new anti-cancer substances. This strategy is based on simple covalent coupling between known anti-cancer drugs, which results in novel 'chimeric' small molecules. One of these novel compounds, CM358, is the product of an amide bond formation between the known Topoisomerase II (Topo II) inhibitor amonafide (AM) and the known DNA mustard alkylator chlorambucil (CLB). It demonstrates significant enhanced cytotoxicity over an equimolar mixture of AM and CLB in various cancer cell lines and in a xenograft model of human metastatic melanoma. Topo II inhibition as well as in silico docking studies suggest that CM358 is a stronger Topo II binder than AM. This may be attributed, at least partially, to the placement of the CLB moiety in a favorable orientation with respect to DNA cross-linking with nearby guanines. In a human metastatic melanoma (WM 266-4) xenograft model, this compound was profoundly superior to a mixture of AM and CLB in reduction of tumor growth, maintenance of body weight and extension of overall survival. [ABSTRACT FROM AUTHOR]

The palladium(II)-catalyzed C(sp3)−H alkynylation of oligopeptides was developed with tetrabutylammonium acetate as a key additive. Through molecular design, the acetylene motif served as a linchpin to introduce a broad range of carbonyl-containing pharmacophores onto oligopeptides, thus providing a chemical tool for the synthesis and modification of novel oligopeptide-pharmacophore conjugates by C−H functionalization. Dipeptide conjugates with coprostanol and estradiol were synthesized by this method for potential application in targeted drug delivery to tumor cells with overexpressed nuclear hormone receptors. [ABSTRACT FROM AUTHOR]

Drug conjugation, improving drug stability, solubility and body permanence, allows achieving impressive results in tumor control. Here, we show that conjugation may provide a straightforward method to administer drugs by the emerging anticancer metronomic approach, presently consisting of low, repeated doses of cytotoxic drugs used in traditional chemotherapy, thus reducing toxicity without reducing efficiency; however, low dose maintenance in tumor sites is difficult. We show that conjugating the antitumor drug etoposide to dextran via pH-sensitive bond produces slow releasing, apoptosis-proficient conjugates rapidly internalized into acidic lysosomes; importantly, release of active etoposide requires cell internalization and acidic pH. Conjugation, without impairing etoposide-induced complete elimination of tumor cells, shifted the mode of apoptosis from cytotoxicity- to differentiation-related; interestingly, high conjugate doses acted as low doses of free etoposide, thus mimicking the effect of metronomic therapy. This indicates slow release as a promising novel strategy for stabilizing low drug levels in metronomic regimens. [ABSTRACT FROM AUTHOR]

Challenges remain to load and deliver two or multiple drugs of complementary effects for synergistic cancer therapies. In the current study, multiarmed amphiphilic copolymers of 4-arm poly(ethylene glycol) (PEG) and polyaspartate (PAsp) are created for conjugation of camptothecin (CPT) and condensation with tumor necrosis factor-α (TNF) plasmids. Diethylenetriamine (DET) is grafted on PAsp, and CPT is conjugated onto PAsp(DET) by disulfide linkages to form hydrophobic cores of micelles, followed by condensation with TNF plasmids to form micelleplexes. The cis -aconitic linkers are introduced between PEG and PAsp(DET) to remove PEG shells in response to acidic pH, resulting in destabilized micelleplexes and prompted endosomal escape into the cytosol. The micelleplex disintegration in response to reductive stimuli in the cytosol leads to an efficient CPT release and pDNA disassociation. The co-delivery of CPT with TNF plasmids enhances the gene transfection of micelleplexes at low N/P ratios, and shows synergetic cytotoxicities to tumor cells with 2.5 and 8 folds lower IC 50 s compared with those after treatment with CPT or TNF alone, respectively. The micelleplex treatment on 4T1 tumor models dramatically extends the animal survival and suppresses the tumor growth with 2.3 and 3 folds lower in volume compared with CPT or TNF treatment alone, respectively. Histological and biochemical analyses display TNF expressions in tumor tissues after micelleplex treatment, resulting in significantly larger necrotic regions in tumors, higher cell apoptosis rates, and no obvious sign of tumor metastasis in lungs compared with other treatment. Therefore, the multifunctional micelleplexes based on multiarmed PEG-PAsp(DET) copolymers offer the targeted drug/gene delivery, dually responsive drug/gene release and synergistic antitumor efficacy, holding great promises for combination therapies. Statement of Significance Micelleplexes are constructed from multiarmed amphiphilic copolymers with conjugation of captothecin (CPT) and condensation of tumor necrosis factor-α (TNF) plasmid. The pH/redox stimuli realize co-delivery of CPT and pDNA in a sequential manner of folate-mediated endocytosis, endosomal escape induced by PEG cleavage, reduction-sensitive release of CPT in cytosol, and pDNA release from disintegrated polyplexes after CPT release. Compared with CPT or TNF treatment alone, the micelleplexes achieve 2.5 and 8 folds higher cytotoxicities to tumor cells, and suppress the tumor growth with 2.3 and 3 folds lower in volume, respectively. It demonstrates a feasible strategy to develop multifunctional micelleplexes with simultaneous drug conjugation and pDNA condensation, dually responsive drug/gene release and synergistic antitumor efficacy, holding great promise for combinational therapies. [ABSTRACT FROM AUTHOR]

Chemotherapy is one of the major therapeutic options for cancer treatment. Chemotherapy is often associated with a low therapeutic window due to its poor specificity towards tumor cells/tissues. Antibody-drug conjugate (ADC) technology may provide a potentially new therapeutic solution for cancer treatment. ADC technology uses an antibody-mediated delivery of cytotoxic drugs to the tumors in a targeted manner, while sparing normal cells. Such a targeted approach can improve the tumor-to-normal tissue selectivity and specificity in chemotherapy. Considering its importance in cancer treatment, we aim to review recent efforts for the design and development of ADCs. ADCs are mainly composed of an antibody, a cytotoxic payload, and a linker, which can offer selectivity against tumors, anti-cancer activity, and stability in systemic circulation. Therefore, we have reviewed recent updates and principal considerations behind ADC designs, which are not only based on the identification of target antigen, cytotoxic drug, and linker, but also on the drug-linker chemistry and conjugation site at the antibody. Our review focuses on site-specific conjugation methods for producing homogenous ADCs with constant drug-antibody ratio (DAR) in order to tackle several drawbacks that exists in conventional conjugation methods.

We show for the first time how polymeric nanotubes (NTs) based on self-assembled conjugates of polymers and cyclic peptides can be used as an efficient drug carrier. RAPTA-C, a ruthenium-based anticancer drug, was conjugated to a statistical co-polymer based on poly(2-hydroxyethyl acrylate) (pHEA) and poly(2-chloroethyl methacrylate) (pCEMA), which formed the shell of the NTs. Self-assembly into nanotubes (length 200-500 nm) led to structures exhibiting high activity against cancer cells. [ABSTRACT FROM AUTHOR]

We developed a new pH-sensitive drug delivery carrier based on β-cyclodextrin (β-CD) and 1-methyl-2-(2′-carboxyethyl) maleic anhydrides (MCM). The primary hydroxyl groups of β-CD were successfully attached to MCM residues to produce a medusa-like β-CD-MCM. The MCM residue was conjugated with cephradine (CP) with high efficiency ( > 90%). More importantly, β-CD-MCM-CP responded to the small pH drop from 7.4 to 5.5 and released greater than 80% of the drugs within 0.5 h at pH 5.5. In addition, the inclusion complex between β-CD-MCM-CP and the adamantane derivative was formed by simple mixing to show the possibility of introducing multi-functionality. Based on these results, β-CD-MCM can target weakly acidic tissues or organelles, such as tumours, inflammatory tissues, abscesses or endosomes, and be easily modified with various functional moieties, such as ligands for cell binding or penetration, enabling more efficient and specific drug delivery. [ABSTRACT FROM AUTHOR]

Abstract: Despite palliative treatments, tumor-induced bone disease (TIBD) remains highly debilitating for many cancer patients and progression typically results in death within two years. Therefore, more effective therapies with enhanced anti-resorptive and cytotoxic characteristics are needed. We developed bisphosphonate-chemotherapeutic conjugates designed to bind bone and hydrolyze, releasing both compounds, thereby targeting both osteoclasts and tumor cells. This study examined the effects of our lead compound, MBC-11 (the anhydride formed between arabinocytidine (AraC)-5′-phosphate and etidronate), on bone tumor burden, bone volume, femur bone mineral density (BMD), and overall survival using two distinct mouse models of TIBD, the 4T1/luc breast cancer and the KAS-6/1-MIP1α multiple myeloma models. In mice orthotopically inoculated with 4T1/luc mouse mammary cells, MBC-11 (0.04μg/day; s.c.) reduced the incidence of bone metastases to 40% (4/10), compared to 90% (9/10; p =0.057) and 100% (5/5; p =0.04) of PBS- or similarly-dosed, zoledronate-treated mice, respectively. MBC-11 also significantly decreased bone tumor burden compared to PBS- or zoledronate-treated mice (p =0.021, p =0.017, respectively). MBC-11 and zoledronate (0.04μg/day) significantly increased bone volume by two- and four-fold, respectively, compared to PBS-treated mice (p =0.005, p <0.001, respectively). In mice systemically injected with human multiple myeloma KAS-6/1-MIP1α cells, 0.04 and 4.0μg/day MBC-11 improved femur BMD by 13% and 16%, respectively, compared to PBS (p =0.025, p =0.017, respectively) at 10weeks post-tumor cell injection and increased mean survival to 95days compared to 77days in mice treated with PBS (p =0.047). Similar doses of zoledronate also improved femur BMD (p ≤0.01 vs PBS) and increased mean survival to 86days, but this was not significantly different than in PBS-treated mice (p =0.53). These results demonstrate that MBC-11 decreases bone tumor burden, maintains bone structure, and may increase overall survival, warranting further investigation as a treatment for TIBD. [Copyright &y& Elsevier]

• Efficient NTD control can be achieved when different public health approaches are put in place, including the supply and distribution of more effective drugs. • There is a serious lack of R&D funding for new agents to combat NTDs. • FDCs can be presented as viable alternatives for combating NTDs. • FDCs can promote simplification of the therapeutic regimen, circumvent parasitic resistance and problems related to toxicity. • Despite efforts to increase the therapeutic arsenal, pharmacokinetic studies to confirm the efficacy and maintenance of the quality of therapy are still insufficient. The present paper aims to establish different treatments for neglected tropical disease by a survey on drug conjugations and possible fixed-dose combinations (FDC) used to obtain alternative, safer and more effective treatments. The source databases used were Science Direct and PubMed/Medline, in the intervals between 2015 and 2021 with the drugs key-words or diseases, like "schistosomiasis", "praziquantel", "malaria", "artesunate", "Chagas' disease", "benznidazole", "filariasis", diethylcarbamazine", "ivermectin", " albendazole". 118 works were the object of intense analysis, other articles and documents were used to increase the quality of the studies, such as consensuses for harmonizing therapeutics and historical articles. As a result, an effective NTD control can be achieved when different public health approaches are combined with interventions guided by the epidemiology of each location and the availability of appropriate measures to detect, prevent and control disease. It was also possible to verify that the FDCs promote a simplification of the therapeutic regimen, which promotes better patient compliance and enables a reduction in the development of parasitic resistance, requiring further studies aimed at resistant strains, since the combined APIs usually act by different mechanisms or at different target sites. In addition to eliminating the process of developing a new drug based on the identification and validation of active compounds, which is a complex, long process and requires a strong long-term investment, other advantages that FDCs have are related to productive gain and gain from the industrial plant, which can favor and encourage the R&D of new FDCs not only for NTDs but also for other diseases that require the use of more than one drug. [ABSTRACT FROM AUTHOR]

Abstract: Cyanocobalamin (vitamin B12) is an essential nutrient as well as a very useful carrier in drug delivery. Conjugates of vitamin B12 are investigated due to their wide range of therapeutic applications. We report the synthesis of six vitamin B12 conjugates, and the effect of conjugation on their solubilities and stabilities in various media. We reveal here that vitamin B12 can be released readily if a 2′-hydroxyl group is conjugated rather than the 5′-hydroxyl group, and the solubility (thus the equivalents of vitamin B12) could be enhanced as much as 19-fold, by simple conjugates such as glycolates. Findings disclosed here provide insights into the reactivities of vitamin B12 conjugates, the design of future prodrugs and similar conjugated moieties using vitamin B12. [Copyright &y& Elsevier]

In continuation of studies in these laboratories aiming at the bioevaluation of macromolecular anticancer drug models, in vitro cytotoxicity screens are performed on several series of water-soluble polymer-methotrexate conjugates. The methotrexate drug in these conjugates is bound through amide or ester linkages to water-soluble polyamide- or polyamidoamine-type carriers by previously developed anchoring techniques. Tests were conducted against the HeLa human cervical carcinoma cell line generally considered to be drug-sensitive, and against two variants of the rather refractory Colo 320 DM, a human colon adenocarcinoma line. [ABSTRACT FROM AUTHOR]

Systematic toxicity and drug resistance significantly limited FDA-approved platinum drugs for further clinical applications. In order to reverse the resistance (MDR) and enhance their anticancer efficiency, four Pt(IV) complexes (12 – 15) conjugating with P-glycoprotein (P-gp) inhibitors were designed and synthesized. Among them, complex 14 (IC 50 = 3.37 μM) efficiently reversed cisplatin resistance in SGC-7901/CDDP cell line and increased selectivity index (6.9) against normal HL-7702 cell line. Detailed mechanisms in SGC-7901/CDDP cells assays revealed that complex 14 efficiently induced apoptosis via down-regulating expression of P-gp for enhanced intracellular uptake of platinum, arrested cells at G2/M phase, induced DNA damage and initiated mitochondrial apoptosis pathway. Further in vivo studies demonstrated that the enhanced accumulation of complex 14 contributed to tumor inhibition of 75.6% in SGC-7901/CDDP xenografts, which was much higher than cisplatin (25.9%) and oxaliplatin (43%). Moreover, the low systematic toxicity made 14 a potential novel P-gp-mediated MDR modulator. [Display omitted] • Four novel Pt(IV) complexes based on P-gp inhibitors were prepared. • 14 strongly reversed P-gp mediated efflux and enhanced intracellular uptake of platinum. • 14 exserted apoptosis-promoting activity via mitochondrial apoptosis pathway. • 14 efficiently inhibited tumor growth in SGC-7901/CDDP xenografts. [ABSTRACT FROM AUTHOR]

Factors which might affect paracetamol disposition have been studied in a heterogenous group of patients in need of mild analgesia in an intensive care unit. Following oral administration of 1 g of paracetamol, plasma and urinary concentrations of the parent compound and metabolites were assessed by HPLC. The renal clearance of paracetamol was significantly correlated with urine flow ( r=0.84) and creatinine clearance ( r=0.77), but not with urine pH. Metabolite output was diminished in patients with reduced renal function. Despite the heterogeneity of patients and the diversity of drug treatment, the urine to plasma paracetamol concentration ratio appeared remarkably constant in patients with normal renal function (9.8±2.7). It is concluded that the metabolite to paracetamol ratio may only be regarded as a measure of the drug metabolizing capacity in subjects with normal renal function, if factors influencing urine volume and paracetamol absorption are standardized. [ABSTRACT FROM AUTHOR]

The metabolism of indocyanine green, bromsulphophthalein and bilirubin was studied before and after a treatment for 2 weeks with cimetidine 1.0 g/day in 12 subjects with Gilbert's syndrome. There was no effect on the plasma clearance of indocyanine green and bromsulphophthalein, on the maximal biliary excretion capacity of bromsulphophthalein, on serum bilirubin concentrations or on the biliary metabolites of bromsulphophthalein and bilirubin. It is concluded that in Gilbert's syndrome two weeks of treatment with cimetidine had no effect on liver blood flow or on conjugation mechanisms which were independent of cytochrome P. [ABSTRACT FROM AUTHOR]