Investigation of the inhibition of eight major human cytochrome P450 isozymes by a probe substrate cocktail in vitro with emphasis on CYP2E1

1. A protocol has been developed and validated for the high-throughput screening of eight major human cytochrome P450 (CYP) isozymes inhibition (CYP 1A2, 2C9, 2C19, 2D6, 3A4, 2B6, 2C8 and 2E1) using an in vitro probe cocktail containing eight substrates by overcoming the unfavorable effect of assay conditions on CYP2E1 inhibition data.

2. The cocktail consisting of selective probe substrates like tacrine (CYP1A2), diclofenac (CYP2C9), S-mephenytoin (CYP2C19), dextromethorphan (CYP2D6), midazolam (CYP3A4), bupropion (CYP2B6), paclitaxel (CYP2C8) and chlorzoxazone (CYP2E1) was incubated with human liver microsomes.

3. The method was investigated by incubating well-known CYP inhibitors {alphanaphthoflavone (CYP1A2), sulfaphenazole (CYP2C9), N-3-benzylnirvanol (CYP2C19), quinidine (CYP2D6), ketoconazole (CYP3A4), ticlopidine (CYP2B6), quercetin (CYP2C8) and 4-methylpyrazole (CYP2E1)} with the substrate cocktail. A fast gradient liquid chromatography tandem mass spectrometry (LC-MS/MS) was used for this study.

4. The IC₅₀ values determined for typical CYP inhibitors were reproducible and consistent with those in the literature. DMSO has significant effect and itself inhibits CYP2E1. DMSO should not exceed 0.1% for the determination of reliable CYP2E1 inhibition profile. This cocktail assay offers an efficient and robust method to determine the CYP450 isoforms inhibition profiles of large numbers of compounds in a quick turnaround time.     

Effects of CYP2C11 gene knockout on the pharmacokinetics and pharmacodynamics of warfarin in rats

1. CYP2C11 is the most abundant isoform of cytochrome P450s (CYPs) in male rats and is considered the main enzyme for warfarin metabolism.

2. To further access the in vivo function of CYP2C11 in warfarin metabolism and efficacy, a CYP2C11-null rat model was used to study warfarin metabolism with both in vitro and in vivo approaches. Prothrombin time (PT) of warfarin was also determined.

3. The maximum rate of metabolism (V_max) and intrinsic clearance (CL_int) of liver microsomes from CYP2C11-null males were reduced by 37 and 64%, respectively, compared to those in Sprague Dawley (S-D) rats. The K_m of liver microsomes from CYP2C11-null males was increased by 73% compared to that of S-D rats. The time to reach the maximum plasma concentration (T_max) of warfarin in CYP2C11-null males was significantly delayed compared to that in S-D males, and the CL rate was also reduced. The PT of CYP2C11-null rats was moderately longer than that of S-D rats.

4. In conclusion, the clearance rate of warfarin was mildly decreased and its anticoagulant effect was moderately increased in male rats following CYP2C11 gene knockout. CYP2C11 played a certain role in the clearance and efficacy of warfarin, while it did not seem to be essential.     

Characterization of glutathione conjugates derived from reactive metabolites of seven silymarin isomers

1. Silymarin refers to a class of flavonoid lignans occurring in the fruits and seeds of the Silybum manalttlm (L). Gaertn, and is widely used in dietary supplements.

2. The main active ingredients of silymarin are silychristins A and B, silydianin, silybins A and B, and isosilybins A and B. However, the metabolism of silymarin has never been investigated. The major objectives of the present study were to investigate the metabolic pathways of silymarin isomers and to identify reactive metabolites.

3. Fourteen glutathione (GSH) conjugates were detected in rat/human liver microsomes incubations containing NADPH, GSH and seven individual isomers. Seven GSH conjugates (M1-M7) resulted from demethylated silymarin. M8-M14 originated from hydroxylated silymarin. Moreover, we found that GSH was probably conjugated on either ring A or ring E of silymarin based on the mass spectrometric fragments. In addition, recombinant enzyme incubation experiments demonstrated that CYP3A4 was the predominant P450 responsible for the metabolism of silymarin.

4. Several P450 enzymes were reportedly inactivated by some of bioactive constituents of silymarin to some extent. Our findings facilitate the understanding of mechanisms of the reported inactivation of P450 enzymes induced by silymarin.     

Metabolite profiling and identification of enzymes responsible for the metabolism of mitragynine,the major alkaloid of Mitragyna speciosa (kratom)

1. Mitragynine is the major indole-based alkaloid of Mitragyna speciosa (kratom). Decoctions (teas) of the plant leaves have been used traditionally for cough, diarrhoea, pain, hypertension and for the treatment of opioid addiction. In the West, kratom has become increasingly utilized for mood elevation, pain treatment and as a means of self-treating opioid addiction.

2. Metabolic pathways of mitragynine were identified in human liver microsomes (HLM) and S9 fractions. A total of thirteen metabolites were identified, four oxidative metabolites and a metabolite formed by demethylation at the 9-methoxy group were the major metabolites of mitragynine.

3. The cytochrome P450 enzymes involved in the metabolism of mitragynine were identified using selective chemical inhibitors of HLM and recombinant cytochrome P450. The metabolism of mitragynine was predominantly carried out through the CYP3A4 with minor contributions by CYP2D6 and CYP2C9. The formation of five oxidative metabolites (Met2, Met4, Met6, Met8 and Met11) was catalyzed by the CYP3A4.

4. In summary, mitragynine was extensively metabolized in HLM primarily to O-demethylated and mono-oxidative metabolites. The CYP3A4 enzyme plays a predominant role in the metabolic clearance of mitragynine and also in the formation of 7-hydroxymitragynine (Met2), a known active minor alkaloid identified in the leaf material.     

Gut microbiota metabolizes nabumetone in vitro: Consequences for its bioavailability in vivo in the rodents with altered gut microbiome

1. The underlying microbial metabolic activity toward xenobiotics is among the least explored factors contributing to the inter-individual variability in drug response.

2. Here, we analyzed the effect of microbiota on a non-steroidal anti-inflammatory drug nabumetone.

3. First, we cultivated the drug with the selected gut commensal and probiotic bacteria under both aerobic and anaerobic conditions and analyzed its metabolites by high-performance liquid chromatography (HPLC) with UV detection. To analyze the effect of microbiota on nabumetone pharmacokinetics in vivo, we administered a single oral dose of nabumetone to rodents with intentionally altered gut microbiome - either rats treated for three days with the antibiotic imipenem or to germ-free mice. Plasma levels of its main active metabolite 6 methoxy-2-naphthylacetic acid (6-MNA) were analyzed at pre-specified time intervals using HPLC with UV/fluorescence detection.

4. We found that nabumetone is metabolized by bacteria to its non-active metabolites and that this effect is stronger under anaerobic conditions. Although in vivo, none of the pharmacokinetic parameters of 6-MNA was significantly altered, there was a clear trend towards an increase of the AUC, Cmax and t_1/2 in rats with reduced microbiota and germ-free mice.     

Cytotoxicity of safrole in HepaRG cells: studies on the role of CYP1A2-mediated ortho-quinone metabolic activation

1. Safrole is a natural compound categorized as a group 2B carcinogen extracted from sassafras oil or certain other essential oils. The hepatotoxicity of safrole has always been highly concerned. So, the purpose of this study was to evaluate the role of cytochrome P450 (CYP450)-mediated reactive metabolites (RMs) formation and its induced cytotoxicity in HepaRG cells.

2. Safrole belongs to the methylenedioxyphenyl structure which could be activated to RMs. Two metabolites (M1, M2) and three new glutathione conjugates (M3–M5) of safrole ortho-oquinone RMs were found in HepaRG cells. Using human recombinant CYP450 enzymes and chemical inhibitor method, the metabolism of safrole RMs was predominantly carried out through the CYP1A2 with minor contributions by CYP2E1.

3. Induction of CYP1A2 by omeprazole (OME) enhanced safrole-induced cytotoxicity, compared with treatment with safrole alone, whereas inhibition of CYP1A2 by alpha-naphthoflavone (α-NAP) decreased the cytotoxicity. The cytotoxicity of cell induced by safrole was related to the amount of RMs formation. Besides, pretreatment with L-buthionine sulfoximine (BSO) to deplete intracellular GSH markedly enhanced safrole-induced cytotoxicity. OME induced the safrole-induced GSH exhaustion, and GSH depletion by safrole was not via oxidation of GSH and occurred prior to the increase in ROS. Furthermore, mitochondrial membrane potential (ΔΨ_m) could be aggravated by the inducer of CYP1A2 together with safrole. Collectively, these data suggest that the ortho-quinone RM may mediate safrole hepatotoxicity, and CYP1A2 was the core enzyme in ortho-quinone RMs-mediated safrole hepatotoxicity.     

Pharmacokinetic interaction between shuanghuanglian and azithromycin injection: a nonlinear mixed-effects model analysis in rats

1. This study aimed to evaluate the pharmacokinetic interaction of shuanghuanglian (SHL) and azithromycin in rats, and to provide experimental support for rational drug use in clinics.

2. High-performance liquid chromatography with ultraviolet detection (HPLC-UV) and high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) approaches were respectively developed to detect the forsythiaside (active component of SHL) and azithromycin concentrations. Both non-compartmental and compartmental analyzes were employed to calculate pharmacokinetic parameters. A nonlinear mixed-effects modeling method was applied to fit the drug concentration-time data. The influence of drug coadministration on pharmacokinetic parameters was tested using forward inclusion and backward elimination procedures.

3. After drug co-administration, areas under the drug concentration–time curve (AUC) and half-lives (T_1/2) of both azithromycin and forsythiaside increased significantly, meanwhile, the drug clearance (CL) decreased compared to single drug administration. Both forsythiaside and azithromycin exposures increased after coadministration. Two-compartment models were suitable to describe the in vivo behavior of both azithromycin and forsythiaside. The coadministration of SHL could significantly decrease the central volume of azithromycin (V_CA) and forsythiaside clearance (CL_F) decreased after co-intravenous administration of azithromycin.

4. Co-intravenous administration of forsythiaside and azithromycin could significantly increase drug exposures for both drugs. Lower dose can provide sufficient drug exposure to obtain antibacterial activity. The coadministration may be a potential method to increase therapy efficiency while decrease adverse drug reactions.     

Identification of novel glutathione conjugates of terbinafine in liver microsomes and hepatocytes across species

1. Terbinafine (TBF), a common antifungal agent, has been associated with rare incidences of hepatotoxicity. It is hypothesized that bioactivation of TBF to reactive intermediates and subsequent binding to critical cellular proteins may contribute to this toxicity. In the present study, we have characterized the bioactivation pathways of TBF extensively in human, mouse, monkey, dog and rat liver microsomes and hepatocytes.

2. A total of twenty glutathione conjugates of TBF were identified in hepatocytes; thirteen of these conjugates were also detected in liver microsomes. To the best of our knowledge, only two of these conjugates have been reported previously. The conjugates were categorized into three groups based on their mechanism of formation: (a) alkene/alkyne oxidation followed by glutathione conjugation, with or without N-demethylation, (b) arene oxidation followed by glutathione conjugation, with or without N-demethylation, and (c) N-dealkylation followed by glutathione conjugation of the allylic aldehyde, alcohol and acid intermediates.

3. Differences were observed across species in the contributions of these pathways toward overall metabolic turnover. We conclude that, in addition to the glutathione conjugates known to form by Michael addition to the allylic aldehyde, there are other pathways involving the formation of arene oxides and alkene/alkyne epoxides that may be relevant to the discussion of TBF-mediated idiosyncratic drug reactions.     

Metabolism and excretion of (S)-6-(3-cyclopentyl-2-(4-trifluoromethyl)-1H-imidazol-1-yl)propanamido)nicotinic acid (PF-04991532), a hepatoselective glucokinase activator,in humans: confirmation of the MIST potential noted in first-in-Human metabolite scouting studies

1. The absorption, metabolism, and excretion of a single oral 450-mg dose of [¹⁴C]-(S)-6-(3-cyclopentyl-2-(4-trifluoromethyl)-1H-imidazol-1-yl)propanamido)nicotinic acid (PF-04991532), a hepatoselective glucokinase activator, was investigated in humans. Mass balance was achieved with ～94.6% of the administered dose recovered in urine and feces. The total administered radioactivity excreted in feces and urine was 70.6% and 24.1%, respectively. Unchanged PF-04991532 collectively accounted for ～47.2% of the dose excreted in feces and urine, suggestive of moderate metabolic elimination in humans.

2. The biotransformation pathways involved acyl glucuronidation (M1), amide bond hydrolysis (M3), and CYP3A4-mediated oxidative metabolism on the cyclopentyl ring in PF-04991532 yielding monohydroxylated isomers (M2a–d). Unchanged PF-04991532 was the major circulating component (64.4% of total radioactivity) whereas M2a–d collectively represented 28.9% of the total plasma radioactivity.

3. Metabolites M2a–d were not detected systemically in rats and dogs, the preclinical species for the toxicological evaluation of PF-04991532. In contrast, cynomologus monkeys dosed orally with unlabeled PF-04991532 revealed M2a–d in circulation, whose UV abundance was comparable to the profile in humans. This observation suggested that monkeys could potentially serve as a non-rodent alternative for studying the toxicity of PF-04991532 and its metabolites M2a–d.

4. The present results are in excellent agreement with our previously generated metabolite scouting data, which provided preliminary evidence for the disproportionate metabolism of PF-04991532 in humans.     

Comparison of the hepatic metabolism of triazolam in wild-type andCyp3a-knockout mice for understanding CYP3A-mediated metabolism inCYP3A-humanised mice in vivo

1. To investigate cytochrome P450 3A (CYP3A)-mediated metabolism in vivo, plasma concentrations of triazolam (TRZ) are often monitored as a CYP3A marker in CYP3A-humanised mice. However, it has not been determined whether plasma concentrations of TRZ after intravenous administration can reflect hepatic CYP3A activity in CYP3A-humanised mice.

2. Firstly, we investigated the pharmacokinetics of TRZ in wild-type and Cyp3a-knockout (Cyp3a-KO) mice. Plasma concentration profiles of TRZ and α-hydroxy (OH) TRZ were very similar in wild-type and Cyp3a-KO mice. On the other hand, AUC of 4-OH TRZ in Cyp3a-KO mice was significantly lower than that in wild-type mice. Pregnenolone 16α-carbonitrile (PCN) decreased the areas under the plasma concentration-time curves (AUCs) of TRZ and α-OH TRZ in both groups. There was no significant effect of PCN on AUC of 4-OH TRZ in Cyp3a-KO mice.

3. Next, we verified that AUC of 4-OH TRZ in CYP3A-humanised mice was higher than that in Cyp3a-KO mice, although the difference was not significant.

4. In conclusion, plasma concentrations of 4-OH TRZ, but not those of TRZ and α-OH TRZ, might reflect hepatic CYP3A activity in mice in vivo. These results provide important insights for in vivo studies using a CYP3A-humanised model.     

Evaluation of the inhibition of human carboxylesterases (CESs) by the active ingredients from Schisandra chinensis

1. Schisandra chinensis, also called wuweizi in Chinese, is the fruit of Schisandra chinensis (Turcz.) Baill., and has been officially utilized as an astringent tonic for more than two thousand years in China. This study aims to evaluate the inhibition of carboxylesterases (CESs) by the major ingredients isolated from Schisandra chinensis, including Anwuligan, Schisandrol B, Schisanhenol, deoxyschizandrin, and Schisandrin B.

2. In vitro human liver microsomes (HLMs)-catalyzed hydrolysis of 2-(2-Benzoyl-3-methoxyphenyl) benzothiazole (BMBT) and fluorescein diacetate (FD) was employed as the probe reaction for CES1 and CES2, respectively. Initial screening, inhibition kinetics determination (inhibition type and parameters (K_i)), and in silico docking method were carried out.

3. Schisandrin B showed strong inhibition on the activity of CES1, and the activity of CES2 was strongly inhibited by Anwuligan and Schisandrin B. Schisandrin B exhibited noncompetitive inhibition towards CES1 and CES2. Anwuligan showed competitive inhibition towards CES2. The inhibition kinetic parameters (K_i) were calculated to be 29.8, 0.6, and 8.1 uM for the inhibition of Schisandrin B on CES1, Anwuligan on CES2, and Schisandrin B on CES2. In silico docking showed that hydrogen bonds and hydrophobic interactions contributed to the inhibition of Schisandrin B on CES1, Anwuligan on CES2, and Schisandrin B on CES2. All these information will be helpful for understanding the adverse effects of Schisandra chinensis due to the inhibition of CESs-catalyzed metabolism.     

LC-MS/MS detection of citrus unshiu peel-derived flavonoids in the plasma and brain after oral administration of yokukansankachimpihange in rats

1. Yokukansankachimpihange (YKSCH), a Kampo formulation combining Citrus unshiu peel (CUP) and Pinellia tuber (PT) with yokukansan (YKS), has been recently used to treat the behavioral and psychological symptoms of dementia. Several flavonoids derived from CUP and PT reportedly exhibit psychopharmacological activity, but it remains unclear whether these flavonoids reach the brain after oral administration of YKSCH.

2. In this study, we first measured eight target flavonoids in the plasma and brain in rats orally administered YKSCH. Among these flavonoids, hesperidin, narirutin, nobiletin, and heptamethoxyflavone (HMF) were detected in the plasma, and nobiletin and HMF were detected in the brain.

3. Next, to clarify whether CUP and PT affect the pharmacokinetics of YKS ingredients in YKSCH, the plasma pharmacokinetics of geissoschizine methyl ether (GM) as a representative active ingredient in YKS was examined in rats orally administered YKSCH or YKS. There was no significant difference between the two groups, inferring that the pharmacokinetics of GM may not be affected by the two additional crude drugs.

4. Taken together, this study suggests that the CUP-derived flavonoids nobiletin and HMF may be responsible for the psychopharmacological effects of YKSCH in addition to YKS ingredients.     

Prediction of human pharmacokinetics of long half-life compounds using chimeric mice with humanised liver

1. The prediction of human pharmacokinetic (PK) parameters is an important theme to select drug candidates from preclinical studies. It is essential to improve the prediction accuracy of compound half-life (t_1/2) in humans. In this study, the predictability of t_1/2 in humans using PXB mice®, chimeric mice with humanised liver, was assessed using 14 compounds showing long t_1/2 in humans.

2. After intravenous administration of the compounds to PXB mice, the plasma concentration–time profiles were fitted using one- or two-compartment models and the human clearance (CL_t) and distribution volume (Vd_ss) were predicted from single-species scaling. Using the obtained parameters, the t_1/2 in humans was predicted. Using PXB mice, the predicted t_1/2 values of 71.4% of the compounds were within two-fold of the actual values. Meanwhile, based on predictions using SCID mice, the host strain of the PXB mice, only 7.1% of tested compounds were within two-fold.

3. In conclusion, we demonstrated the novel utility of PXB mice for human PK predictions of compounds having long t_1/2 in humans.     

Effects of phillyrin and forsythoside A on rat cytochrome P450 activities in vivo and in vitro

1. Phillyrin and forsythoside A are two important active ingredients in Forsythia suspensa. However, the effects of phillyrin and forsythoside A on the activities of cytochrome P450 (CYP450) remain unclear.

2. This study aimed to investigate the effects of phillyrin and forsythoside A on the activities of CYP1A2, CYP2C11, CYP2D1 and CYP3A1/2 by cocktail probe drugs in rats both in vivo and in vitro.

3. Many pharmacokinetic parameters of caffeine and metoprolol in phillyrin pretreatment group, caffeine and tolbutamide in forsythoside A pretreatment group were affected significantly. In rat liver microsomal incubation system, the concentrations of acetaminophen and dextrophan in the phillyrin pretreatment group are higher than blank control group by 207.69% and 125.00%, however, the concentrations of 4-hydroxytolbutamide and 6β-hydroxytestosterone were not significantly altered. The concentrations of acetaminophen and 4-hydroxytolbutamide in the forsythoside A pretreatment group are higher than blank control group by 223.07% and 154.16%, whereas the concentrations of dextrophan and 6β-hydroxytestosterone were not significantly altered.

4. These results indicated that Phillyrin had potential inductive effects on rat CYP1A2 and CYP2D1 activities, without affecting CYP2C11 and CYP3A1/2 activities. Moreover, forsythoside A had inductive effects on the activities of CYP1A2 and CYP2C11, without affecting CYP2D1 and CYP3A1/2 activities.     

Association with polymorphic marmoset cytochrome P450 2C19 of in vivo hepatic clearances of chirally separated R-omeprazole and S-warfarin using individual marmoset physiologically based pharmacokinetic models

1. Simulated clearances of R-warfarin and efavirenz were recently reported for individual cynomolgus monkeys genotyped for cytochrome P450 2C19 and 2C9, respectively. To expand and verify this modeling procedure, simulations of R/S-omeprazole and R/S-warfarin clearances after oral administrations in individual marmosets were performed using individual simplified physiologically based pharmacokinetic (PBPK) modeling consisting of gut, liver and central compartments.

2. Pharmacokinetics of R/S-omeprazole were chirally determined using the previously reported plasma microsamples in this study. The areas under the plasma concentration/time curves (AUC) of R-omeprazole and S-warfarin, but not S-omeprazole and R-warfarin, after oral administrations in the P450 2C19 homozygous mutant group were significantly higher than those in the wild-type group. These modeled hepatic intrinsic clearances were also significantly associated with the marmoset P450 2C19 genotypes. Other parameter values, e.g. absorption rate constants or systemic circulation volumes, were not likely determining factors.

3. The reported individual AUC values measured in 4–6 marmosets after oral R-omeprazole and S-warfarin administrations were significantly correlated with the AUC values predicted using the PBPK models after virtual administrations.

4. This study indicates that clearances of R-omeprazole, S-warfarin and related medicines associated with polymorphic P450 2C19 in individual marmosets can be simulated using simplified individual PBPK models.     

Factors that facilitate reporting of adverse drug reactions by pharmacists in Saudi Arabia

Objectives: Adverse drug reactions (ADRs) are a pervasive global problem, and its management is integral to patient safety and healthcare quality. Pharmacists play a pivotal role in monitoring and reporting ADRs, which has a direct impact on patient care. The aim of this study was to identify potential factors that facilitate pharmacists in community and hospital settings to report ADRs.

Methods: A cross-sectional, online survey using a validated questionnaire was administered to pharmacists working in community and hospital pharmacies in Saudi Arabia.

Results: 1,717 community and 153 hospital pharmacists participated in this study. Only 10.2% and 26.8% of community and hospital pharmacists, respectively, admitted ever reporting an ADR. The most reported factors that may facilitate ADRs reporting have included ongoing improvements in therapeutic knowledge about ADRs, attending educational programs with continuous medical education credits, the seriousness of the experienced ADRs and accessibility to patients’ medical profile. The impact of peers by seeing colleagues reporting ADRs and ADRs due to herbal or traditional medicine were the least important factors reported by pharmacists.

Conclusion: The study identified factors that can effectively address the under-reporting of ADRs by pharmacists. A multi-stakeholder, multi-pronged approach of ADR reporting is needed to develop greater awareness of this issue among pharmacists.     

Systemic thromboembolic adverse events in patients treated with intravitreal anti-VEGF drugs for neovascular age-related macular degeneration: an update

Introduction: Intravitreal anti-VEGF is the most effective therapy for wet AMD, although systemic effects on the endothelium cannot be excluded.

Areas covered: The purpose of this review was to evaluate risk of thromboembolic events associated with intravitreal anti-VEGF.

Expert opinion: Current data are insufficient to confirm the safety of these compounds, due to the paucity of specific studies. Thus, pharmacovigilance for all anti-VEGF should be improved to verify the true role of anti-VEGF in the occurrence of systemic adverse events.     

Oral antineoplastic agents: assessment of safety and dose adjustments in clinical practice

Objectives: Although the safety profile of oral antineoplastic agents (OAAs) is better than that of classic chemotherapy, the rate of severe adverse events (AEs) is high. The objective was to assess the reasons for adjustments to treatment with OAAs during the first 100 days of treatment.

Methods: The authors performed a prospective observational study of cancer outpatients who initiated OAAs between November 2015 and October 2017. Dose reductions and treatment interruptions were closely followed-up during the first 100 days after the beginning of treatment with an OAA. The authors described the different safety profile of different OAA classes.

Results: The authors included 443 patients (31 different OAA assessed), of whom 53.0% required their OAA to be adjusted during the first 100 days of treatment. A total of 151 patients required dose reductions and/or interruptions of OAAs owing to AEs. The authors identified 203 AEs in these patients. Treatment with sorafenib, lower ECOG performance status, and first-line treatment were associated with a higher proportion of treatment adjustments due to AEs.

Conclusion: These results in clinical practice could be a first approach to help healthcare professionals to design patient monitoring programs by identifying priority patients and drugs, and remarks the importance of pharmacovigilance in OAAs.     

An update on the safety and efficacy of oral antidiabetic drugs: DPP-4 inhibitors and SGLT-2 inhibitors

Introduction: Oral antidiabetic medications are important in many type 2 diabetes care plans

Areas covered: The article summarizes the cardiovascular and renal safety data for DPP-4 inhibitors and SGLT-2 inhibitors and specific safety data particular to each class.

Expert opinion: DPP-4 and SGLT-2 inhibitors provide unique anti-hyperglycemic mechanisms. The cardiovascular safety profiles of DPP-4 inhibitors are promising, but do not show the strong CV risk reduction of empagliflozin and canagliflozin. The heart failure signal associated with DPP-4 inhibitor use is unclear with differing agents, demonstrating increased risk or maybe even protective effects. The risk reduction in cardiovascular disease associated with SGLT-2 inhibitors has translated to recommendations to consider these therapies early in the treatment pathway. Both classes have potential safety concerns that necessitate appropriate patient selection and thorough education on potential side-effects. DPP-4 inhibitors are considered to have neutral or in some studies beneficial renoprotective effects. SGLT-2 inhibitor safety effects on the kidney are more complex. There are reports of acute kidney injury occurring soon after initiating SGLT-2 inhibitor therapy. However, there are large recent studies that have demonstrated the beneficial effect of SGLT-2 inhibitors in slowing the progression of established chronic kidney disease.     

The safety of treatment options for acute bacterial skin and skin structure infections

Introduction: Acute bacterial skin and skin-structure infections (ABSSSI) may develop in both in-patients and out-patients, possibly with a severe clinical presentation. Since most phase 3 randomized clinical trials have shown non-inferiority in efficacy across different agents, considerations regarding their different safety profiles inevitably play a crucial role in the everyday choice about which of them should be employed for the treatment of ABSSSI.

Areas covered: In this review, the authors discuss the safety profile of different treatment options for ABSSSI.

Expert opinion: The spread of methicillin-resistant Staphylococcus aureus (MRSA) in the last decades has inevitably influenced the therapeutic approach to ABSSSI. Adequate knowledge of the peculiar toxicity profile of each drug active against MRSA is essential for guiding, monitoring and managing adverse events, in turn reducing any unfavorable impact of toxicity on patients’ outcomes. In the next five years, potential toxicity will play a critical role in establishing the best available therapy for each specific patient, together with consideration regarding the possibility of avoiding hospitalization or allowing a switch from intravenous to oral therapy and early discharge.