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Marazziti, Donatella; Avella, Maria Teresa; Basile, Lucia; Mucci, Federico; Dell’Osso, Liliana
doi: 10.1080/17425255.2019.1584611pmid: 30793987
Introduction: Although the treatment of obsessive-compulsive disorder (OCD), a common, chronic, and disabling psychiatric condition, has significantly improved in the last decades, with the demonstration of the specific effectiveness of serotonin reuptake inhibitors (SRIs), a large proportion of patients still show high relapse rates. In addition, pharmacological treatments should be maintained for years, so that the clinicians should take into account the pharmacokinetic changes in the long-term, which may be responsible for dangerous side effects or interactions.Areas covered: The aim of this paper was to review the literature on the pharmacokinetics of SSRIs and clomipramine, and on their pharmacokinetic parameters in OCD patients.Expert opinion: Although the literature on the pharmacokinetics of both clomipramine and SSRIs is consistent, data on pharmacokinetic parameters in OCD patients are very few. Given the impact of OCD, its chronicity requiring long-term treatments, together with the need to increase the clinical response rate, more studies in this field are urgently required.
Garcia-Ropero, Alvaro; Santos-Gallego, Carlos G.; Zafar, M. Urooj; Badimon, Juan J.
doi: 10.1080/17425255.2019.1588886pmid: 30822172
Introduction: Cardiac metabolism represents a complex network of numerous pathways responsible for an adequate supply of ATP to the incessant contractile apparatus. Impairments of such pathways are associated with myocardial dysfunction. The newest antidiabetic drugs, the SGLT2 inhibitors, have been demonstrated to reduce cardiovascular mortality and heart failure hospitalizations. The mechanisms underlying these benefits are still uncertain; however, they may play a decisive role in restoring energy efficiency to the damaged heart.Areas covered: This article reviews normal cardiac metabolism and contribution of different substrates to fuel supply. Specific attention is devoted to alterations of these pathways and their association with myocardial dysfunction. In addition, the impact of the novel SGLT2 inhibitors on cardiac mortality and heart failure hospitalizations is discussed. Various postulated mechanisms responsible for such benefits are also discussed.Expert opinion: Metabolic alterations seem to play a crucial role in etiology and progression of heart failure. The cardiovascular benefits of the novel SGLT2 inhibitors have attracted more attention to this field. With effects beyond lowering glucose levels, these agents have been reported to induce changes in cardiac metabolism and to exert anti-inflammatory properties that may contribute to their large cardiovascular beneficial effects by improving contractile bioenergetics. Therefore, SGLT2 inhibitors may become an alternative drug to treat heart failure patients, regardless of diabetic status.
Peeters, L.E.J.; Kester, M.P.; Feyz, L.; Van Den Bemt, P.M.L.A.; Koch, B.C.P.; Van Gelder, T.; Versmissen, J.
doi: 10.1080/17425255.2019.1588249pmid: 30880496
Introduction: Hypertension is an important risk factor for developing cardiovascular diseases. It is more prevalent in the elderly population. Recently updated American and European guidelines recommend treating every elderly patient with hypertension independent of age, starting with a low dose of antihypertensive drugs. However, little information is available on the optimal dosages of antihypertensive drugs to treat the elderly safely.Areas covered: Comorbidities, co-medication and frailty status can alter the clinical outcome of drug treatment and can cause adverse events in the elderly. Also, due to pharmacokinetic and pharmacodynamic changes the interpatient variability when using antihypertensive drugs is considerable. In this review, an overview is given on the extent to which the previously mentioned parameters are changed in elderly patients and what this means for the exposure to antihypertensive medication. Also, recommendations on the starting dose of the most frequently used antihypertensive drugs are given based on literature data.Expert opinion: We believe that recommendations on starting dosages followed by a stepwise increase of dosages will lead to improved blood pressure control and less adverse drug reactions in the elderly patient. This may improve adherence to antihypertensive therapy.
Hattinger, Claudia Maria; Patrizio, Maria Pia; Luppi, Silvia; Magagnoli, Federica; Picci, Piero; Serra, Massimo
doi: 10.1080/17425255.2019.1588885pmid: 30822170
Introduction: DNA damaging drugs are widely used for the chemotherapeutic treatment of high-grade osteosarcoma (HGOS). In HGOS patients, several germline polymorphisms have been reported to impact on the development of adverse toxic events related to DNA damaging drugs treatment. Some of these polymorphisms, when present in tumor cells, may also influence treatment response and prognosis of HGOS patients.Area covered: In this review, the authors have focused on pharmacogenetic markers (mainly germline polymorphisms) described in patients with HGOS, which have proved or indicated to be related to the susceptibility to adverse toxic reactions and/or to influence response to DNA damaging drugs. The concordant and discordant results reported in different studies have also been discussed.Expert opinion: Response and toxicity predisposition to DNA damaging drugs are influenced by genes encoding proteins involved in their uptake, efflux, activation, inactivation, and in DNA repair, activity of which may vary according to specific gene variations. In HGOS, there is a substantial medical need for biomarkers predictive for individual response and toxicity predisposition to DNA-targeting drugs, which may be used to tailor therapy in order to decrease the occurrence of adverse side effects and increase treatment efficacy and safety.
Safar, Zsolt; Kis, Emese; Erdo, Franciska; Zolnerciks, Joseph K; Krajcsi, Peter
doi: 10.1080/17425255.2019.1591373pmid: 30856014
Introduction: ABCG2 has a broad substrate specificity and is one of the most important efflux proteins modulating pharmacokinetics of drugs, nutrients and toxicokinetics of toxicants. ABCG2 is an important player in transporter-mediated drug–drug interactions (tDDI).Areas covered: The aims of the review are i) to cover transporter interaction profile of substrates and inhibitors that can be utilized to test interaction of drug candidates with ABCG2, ii) to highlight main characteristics of in vitro testing and iii) to describe the structural basis of the broad substrate specificity of the protein. Preclinical data utilizing Abcg2/Bcrp1 knockouts and clinical studies showing effect of ABCG2 c.421C>A polymorphism on pharmacokinetics of drugs have provided evidence for a broad array of drug substrates and support drug – ABCG2 interaction testing. A consensus on using rosuvastatin and sulfasalazine as intestinal substrates for clinical studies is in the formation. Other substrates relevant to the therapeutic area can be considered. Monolayer efflux assays and vesicular transport assays have been extensively utilized in vitro.Expert opinion: Clinical substrates display complex pharmacokinetics due to broad interaction profiles with multiple transporters and metabolic enzymes. Substrate-dependent inhibition has been observed for several inhibitors. Harmonization of in vitro and in vivo testing makes sense. However, rosuvastatin and sulfasalazine are not efficiently transported in either MDCKII or LLC-PK1-based monolayers. Caco-2 monolayer assays and vesicular transport assays are potential alternatives.
Barbosa, Anne Caroline S; Feng, Ye; Yu, Chaohui; Huang, Min; Xie, Wen
doi: 10.1080/17425255.2019.1588884pmid: 30822161
Introduction: Biotransformation is important in the metabolism of endobiotics and xenobiotics. This process comprises the activity of phase I and phase II enzymes. Estrogen sulfotransferase (SULT1E1 or EST) is a phase II conjugating enzyme that belongs to the family of cytosolic sulfotransferases. The expression of SULT1E1 can be detected in many tissues, including the liver. SULT1E1 catalyzes the transfer of a sulfate group from 3ʹ-phosphoadenosine-5ʹ-phosphosulfate (PAPS) to any available hydroxyl group in estrogenic molecules. The substrates of SULT1E1 include the endogenous and synthetic estrogens. Upon SULT1E1-mediated sulfation, the hydrosolubility of estrogens increases, preventing the binding between the sulfated estrogens and the estrogen receptor (ER). This sulfated state of the estrogens is not irreversible, as the steroid sulfatase (STS) can convert sulfoconjugated estrogens to free estrogens. The expression of SULT1E1 is inducible by several diseases that involve tissue inflammation, such as type 2 diabetes, sepsis, and ischemia-reperfusion injury.Areas covered: This systematic literature review aims to summarize the role of SULT1E1 in the metabolism of estrogenic drugs and xenobiotics, and the role of SULT1E1 in the pathogenesis of several diseases, including cancer, metabolic disease, sepsis, liver injury, and cystic fibrosis. Meanwhile, ablation or pharmacological inhibition of SULT1E1 can affect the outcomes of the aforementioned diseases.Expert opinion: In addition to its role in metabolizing estrogenic drugs, SULT1E1 is unexpectedly being unveiled as a mediator for the disease effect on estrogen metabolism and homeostasis. Meanwhile, because the expression and activity of SULT1E1 can affect the outcome of diseases, the same sulfotransferase and the reversing enzymes STS can be potential therapeutic targets to prevent or manage diseases. Accumulating evidence suggest that the physiological and pathophysiological effects of SULT1E1 can be estrogen-independent and it is necessary to elucidate what other possible substrates may be recognized by the enzyme. Moreover, human studies are paramount to confirm the human relevance of the animal studies.
doi: 10.1080/17425255.2019.1585427pmid: 30789066
Introduction: Although premixed fixed ratio NPH insulin products are commonly used in type 2 diabetes patients, the advent of Glargine insulin which cannot be formulated together with a rapid-acting insulin (basal-bolus) has largely eliminated premixed insulin from use in type 1 diabetes. Degludec insulin can be formulated together with Aspart insulin in a 70/30 fixed ratio product. We review the potential use of Degludec-Aspart in type 1 diabetes.Areas covered: A historical search of the development and use of premixed insulin preparations was performed relying on Pubmed, FDA, and European Union records.Expert opinion: Degludec is a once daily insulin. There appears to be little advantage to administration of Degludec-Aspart twice daily, and basal bolus injections have proved superior to premixed insulin in type 1 diabetes. There may still be a role for this premixed fixed ratio formulation in patients who have opted to use Technosphere inhaled insulin prior to and post meals. In such patients, the use of a single injection of Degludec-Aspart prior to the largest meal of the day might provide an anchor to allow patients to then self-administer multiple inhalations around mealtimes.
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