Dose-related Adverse Drug Reactions Research Articles

Folate receptor targeted nanoparticles containing niraparib and doxorubicin as a potential candidate for the treatment of high grade serous ovarian cancer

Combination chemotherapy is an established approach used to manage toxicities while eliciting an enhanced therapeutic response. Delivery of drug combinations at specific molar ratios has been considered a means to achieve synergistic effects resulting in improvements in efficacy while minimizing dose related adverse drug reactions. The benefits of this approach have been realized with the FDA approval of Vyxeos®, the first liposome formulation to deliver a synergistic drug combination leading to improved overall survival against standard of care. In the current study, we demonstrate the synergistic potential of the PARP inhibitor niraparib and doxorubicin for the treatment of ovarian cancer. Through in vitro screening in a panel of ovarian cancer cell lines, we find that niraparib and doxorubicin demonstrate consistent synergy/additivity at the majority of evaluated molar ratio combinations. Further to these findings, we report formulation of a nanoparticle encapsulating our identified synergistic combination. We describe a rational design process to achieve highly stable liposomes that are targeted with folate to folate-receptor-alpha, which is known to be overexpressed on the surface of ovarian cancer cells. With this approach, we aim to achieve targeted delivery of niraparib and doxorubicin at a pre-determined synergistic molar ratio via increased receptor-mediated endocytosis.

Therapeutic effects of atorvastatin on doxorubicin-induced hepatotoxicity in rats via antioxidative damage, anti-inflammatory, and anti-lipotoxicity.

Doxorubicin (DOX), is a high efficiency anthracycline antitumor drug. However, the clinical application of DOX is limited mainly by dose-related adverse drug reactions. Currently, the therapeutic effects of Atorvastatin (ATO) on DOX-induced hepatotoxicity were studied in vivo. The results indicated that DOX impaired hepatic function, as measured by an increased levels of liver weight index and serum concentrations of aspartate transaminase and alanine transaminase, as well as alteration of hepatic histology. In addition, DOX increased the serum levles of triglyceride(TG) and nonestesterified fatty acid. ATO prevented these changes. Mechanical analysis revealed that ATO restored the changes of malondialdehyde, reactive oxygen radical species, glutathione peroxidase and manganese superoxide dismutase. Additionally, ATO inhibited the increased expression levels of nuclear factor-kappa B and interleukin 1β, hence suppressing inflammation. Meanwhile, ATO inhibited cell apoptosis by dramatically decreasing the Bax/Bcl-2 ratio. In addition, ATO mitigated the lipidtoxicity by inhibiting the adipolysis of TG and accelerating hepatic lipid metabolism. Taken together, the results suggest ATO has therapeutic effect on DOX-induced hepatotoxicity via inhibition of oxidative damage, inflammatory and apoptosis. In addition, ATO attenuates DOX-induced hyperlipidemia via modulation of lipid metabolism.

Obtaining and Characterization of a Polydisperse System Used as a Transmembrane Carrier for Isosorbide Derivatives.

Due to their effect of vasodilatation, isosorbide nitrates represent one of the most important and most used solutions for angina pectoris. Unfortunately, these compounds have multiple dose-related adverse drug reactions such as headache, weakness, mild dizziness, and occasionally heart rate changes, nausea, vomiting, and sweating. The main aims of this research were to obtain and to evaluate new polyurethane (PU) structures that can be used as a proper transmembrane carrier with an improved release kinetic. Chitosan-based PU structures were obtained by a polyaddition process between hexamethylene diisocyanate and a mixture of chitosan, butanediol, and polyethylene glycol in the presence of caffeine as a synthesis catalyst. The obtained samples (with and without isosorbide nitrates) were characterized regarding the encapsulation and release rate (UV-Vis spectra), chemical composition (FTIR), thermal stability (thermal analysis), morphology changes (SEM and SANS), and in vivo irritation tests. These methods revealed no significant differences between the two sample structures. Multipopulational structures with sizes between 73 and 310 nm, with an increased tendency to form clusters and a high resistance to heat (up to 280°C), were obtained. This study presents an alternative administration of isosorbide derivatives based on a PU carrier with a high biocompatibility and a prolonged release.

The association between NAT2 acetylator status and adverse drug reactions of sulfasalazine: a systematic review and meta-analysis

N-acetyltransferase 2 (NAT2) acetylator status can be classified into three groups depending on the number of rapid alleles (e.g., NAT2*4): rapid, intermediate, and slow acetylators. Such acetylator status may influence the occurrence of adverse drug reactions (ADRs) during sulfasalazine treatment. This systematic review and meta-analysis aimed to evaluate the association between NAT2 acetylator status and ADRs of sulfasalazine. We searched for qualified studies in PubMed, Web of Science, Embase, and the Cochrane Library. Odds ratio (OR) and 95% confidence intervals (CIs) were calculated to evaluate the strength of the association between NAT2 acetylator status and ADRs of sulfasalazine. Nine cohort studies involving 1,077 patients were included in the meta-analysis. NAT2 slow acetylators were associated with an increase in overall ADRs (OR 3.37, 95% CI: 1.43 to 7.93; p = 0.005), discontinuation due to overall ADRs (OR 2.89, 95% CI: 1.72 to 4.86; p < 0.0001), and dose-related ADRs (OR 5.20, 95% CI: 2.44 to 11.08; p < 0.0001), compared with rapid and intermediate acetylators. In conclusion, NAT2 slow acetylators are at risk of ADRs during sulfasalazine treatment. Based on our findings, NAT2 genotyping may be useful to predict the occurrence of ADRs during sulfasalazine treatment.

Effects of CYP2C19*2 polymorphisms on the efficacy and safety of phenazepam in patients with anxiety disorder and comorbid alcohol use disorder.

Introduction: Phenazepam therapy can often be ineffective and some patients develop dose-related adverse drug reactions. Aim. The purpose of this research was to study the effect of the CYP2C19*2 (681G>A, rs4244285) in patients with anxiety disorders and alcohol dependence taking phenazepam therapy. Materials & methods: Patients (175 males, average age: 37.16±7.84 years) received phenazepam in tablet form for 5 days. Genotyping was performed by real-time polymerase chain reaction. Results: The statistically significant differences in the UKU Side-Effect Rating Scale scores on the fifth day of therapy: (CYP2C19*1/*1) 2.00 [1.00; 2.00), (CYP2C19*1/*2) 7.00 (7.00; 7.00), (CYP2C19*2/*2) 9.00 (8.00; 9.00), p<0.001. Conclusion: This study demonstrated the different efficacy and safety of phenazepam in patients with different genotypes of CYP2C19*2.

Effects of CYP2C19*17 polymorphisms on the efficacy and safety of bromodigyrochlorophenylbenzodiazepine in patients with anxiety disorder and comorbid alcohol use disorder.

Background Bromodihydrochlorophenylbenzodiazepine (Phenazepam®) is used in the therapy of anxiety disorders in patients with alcohol dependence. However, Phenazepam therapy often turns out to be ineffective, and some patients develop dose-related adverse drug reactions (ADR): severe sedation, dizziness, headache, dyspepsia, falling, etc. That ensures the effectiveness of this category of patients. Despite the popularity of Phenazepam® as an anxiolytic drug, there is currently no accurate data on its biotransformation, as well as the effect of polymorphism of a gene on the efficacy and safety of bromodihydrochlorophenylbenzodiazepine in patients. The aim of our study was to study the effect of the polymorphism of the CYP2C19 gene on the efficacy and safety index of Phenazepam® for patients with anxiety disorders, using algorithms for optimizing the therapy of Phenazepam® to reduce the risk of pharmacological resistance and increase the effectiveness of therapy. Methods The study was conducted on 86 Russian patients suffering from alcohol dependence. Patients with trauma anxiety disorders received bromdihydrochlorphenylbenzodiazepine in tablets at a dose of 4.0 [2.0; 6.0] mg per day for 5 days. Genotyping was carried out by the method of polymer chain reaction in real time with allele-specific hybridization. Efficiency and safety assessment was carried out using psychometric scales and scales of Hospital Anxiety and Depression Scale (HADS) severity scores. Results Based on the results of the study, statistically significant differences in the number of scores on the scale of HADS severity of CYP2C19 CT on the third day of therapy were the following: (CC) 10.00 [9.00; 11.00], (CT) 14.00 [13.00; 16.00], (TT) 18.00 [17.00; 19.00], p=0.00, and also on the fifth day: (CC) 6.00 [5.00; 7.00], (CT) 17.50 [16.25; 19.75], (TT) 22.50 [20.00; 24.00], p=0.00. ADRs in patients with different genotypes for this polymorphic marker did not differ. Conclusions Thus, it has been shown that the polymorphism of the CYP2C19 gene may influence the effectiveness indices of Phenazepam therapy in patients with anxiety disorders comorbid with alcohol dependence. This should be taken into account in the appointment of this drug in this way in order to increase effectiveness of therapy and improve the quality of life.

Sex Differences in Reported Adverse Drug Reactions of Selective Serotonin Reuptake Inhibitors.

Several studies have investigated sex as a risk factor for the occurrence of adverse drug reactions (ADRs) and found that women are more likely to experience ADRs than men. The aim of this explorative study was to investigate whether differences exist in reported ADRs of selective serotonin reuptake inhibitors (SSRIs) for men and women in the database of the Netherlands Pharmacovigilance Centre Lareb. A ratio of reports concerning women and men, corrected for the number of users, was calculated for all the ADRs reported on SSRIs. We found that 16 ADRs were statistically significantly more reported in women than men, and four ADRS were reported more in men than women. ADRs more reported in women than men when using SSRIs were usually dose-related ADRs or commonly occurring ADRs. Differences in the pharmacokinetics of SSRIs between men and women may explain why these reports of dose-related ADRs when using SSRIs concern women more than men.

ABCG2 Gene Polymorphisms as Risk Factors for Atorvastatin Adverse Reactions: A Case–Control Study

To explore the association between dose-related adverse drug reactions (ADRs) of atorvastatin and polymorphisms of ABCG2, taking into account the influence of CYP3A4 and SLCO1B1 genes. Sixty patients who experienced atorvastatin dose-related ADRs and 90 matched patients without ADRs were enrolled in the study. Genotyping for ABCG2 421C > A, CYP3A4*22, SLCO1B1 388A > G, SLCO1B1 521T > C variants was performed by real-time PCR. Patients with ABCG2 421CA or AA genotypes had 2.9 times greater odds of developing atorvastatin dose-dependent ADRs (OR: 2.91; 95% CI: 1.22-6.95; p = 0.016) than those with ABCG2 421CC genotype. After adjustments for clinical and genetic risk factors, ABCG2 remained a statistically significant predictor of adverse drug reactions (OR: 2.75; 95% CI: 1.1-6.87; p = 0.03;). Also, carriers of SLCO1B1 521 TC or CC genotypes had 2.3 greater odds (OR: 1.03-4.98; 95% CI: 1.03-4.98; p = 0.043) of experiencing ADRs caused by atorvastatin in comparison with carriers of SLCO1B1 521 TT genotype. Our study demonstrated an association between atorvastatin-induced ADRs and genetic variants in the ABCG2 gene.

Arylamine N-acetyltransferase polymorphisms in Han Chinese patients with ankylosing spondylitis and their correlation to the adverse drug reactions to sulfasalazine.

BackgroundPolymorphisms of Arylamine N-acetyltransferase (NAT) that contribute to diverse susceptibilities of some autoimmune diseases are also linked to the metabolism of several drugs including sulfasalazine (SSZ). The aim of this study was to investigate the distribution of NAT polymorphisms in Han Chinese patients with ankylosing spondylitis (AS) and their correlation to sulfasalazine-induced adverse drug reactions (ADRs).MethodsArylamine N-acetyltransferase 1 (NAT1) and arylamine N-acetyltransferase 2 (NAT2) genotypes were determined in 266 AS patients who received SSZ treatment and 280 healthy controls. The correlation between NAT polymorphisms and SSZ-induced ADRs was analyzed.ResultsThe co-occurrence frequency of NAT2 fast acetylator genotype and NAT1*10/NAT1*10 genotype was lower in AS patients than in controls. No positive correlations were detected between NAT polymorphisms and AS clinical features. The prevalence of SSZ-induced ADRs and drug withdrawal was 9.4% and 7.1%, respectively. The frequencies of overall ADRs, dose-related ADRs, and termination of drug treatment because of intolerance were higher in the NAT2 slow acetylator genotype carriers than in the fast-type carriers and in those with co-existence of NAT1 and NAT2 slow acetylator genotypes. Furthermore, the ADRs emerged earlier in the AS cases carrying both NAT1 and NAT2 slow acetylator genotypes.ConclusionsThe prevalence of co-occurring NAT2 fast acetylator genotype and NAT1*10/NAT1*10 genotype was lower in AS patients than in controls. The NAT2 slow acetylator genotype and co-existing NAT1 and NAT2 slow acetylator genotypes appear to be associated with higher risks of SSZ-induced ADRs.

Understanding adverse drug reactions: An overview

Some adverse drug reactions (ADRs) are so dramatic that once seen they are never forgotten. However, many ADRs are more subtle and difficult to ascribe to a particular drug. Moreover, patients often do not bring ADRs to a health professional's attention. Therefore, nurse prescribers need to remain vigilant for, and report, ADRs. ‘Classic’ dose-related ADRs, such as respiratory depression with opioids, account for about 95% of ADRs that result in hospital admissions in the UK. Approximately 60–70% of serious ADRs are preventable. Hypersensitivity reactions (HSRs) account for about 20% of ADRs and include anaphylaxis with penicillin. However, while all drug allergies are HSRs, not all HSRs are allergies. Clinical studies may not always paint a full picture of a drug's tolerability, due to reporting bias, inclusion and exclusion criteria that result in an unrepresentative population, and enrolling too few patients to detect less common ADRs. As a result, nurses should report adverse events using the Yellow Card system, which offers a rich source of data about drugs and means that every nurse, in every practice, at every consultation helps ensure patients derive the maximum benefit from their medicines, while prescribers do the least harm possible. This review briefly introduces the classification of ADRs and underscores why it is so important that nurse prescribers report adverse events.

Women encounter ADRs more often than do men

Several publications indicate that the female gender experiences a higher incidence of adverse drug reactions (ADRs) than does the male gender. The reasons, however, remain unclear. Gender-specific differences in the pharmacokinetic and pharmacodynamic behaviour of drugs could not be identified as an explanation. The aim of this study was to analyse ADR risk with respect to gender, age and number of prescribed drugs. A prospective multicenter study based on intensive pharmacovigilance was conducted. Information on patient characteristics and evaluated ADRs was stored in a pharmacovigilance database--KLASSE. In 2,371 patients (1,012 female subjects), 25,532 drugs were prescribed. In 782 patients, at least one ADR was found. A multivariate regression analysis adjusting for age, body mass index (BMI) and number of prescribed drugs showed a significant influence of female gender on the risk of encountering ADRs [odds ratio (OR) 1.596, confidence interval (CI) 1.31-1.94; p < 0.0001). Dose-related ADRs (51.8%) were the dominant type in female subjects. Comparing system organ classes of the World Health Organisation (SOC-WHO), cardiovascular (CV) ADRs were particularly frequent in female subjects (OR 1.92, CI 1.15-3.19; p = 0.012). Our data confirm the higher risk of ADRs among female subjects compared with a male cohort. Several explanations were investigated. No single risk factor could be identified.

Dose optimisation—the effect of age

Although the absolute and relative size of the pensionable population is not currently rising, that population is ageing. As a result, prescriptions for elderly patients continue to increase. People over the age of 60 represent around 22% of the many western European populations, yet receive nearly 54% of the medication prescribed. Over the age of 75, the proportion of the population is around 14%, yet 33% of prescriptions are written for this group. Depending on the age group, between 20% and 30% are taking at least three drugs. A number of problems complicate the process of prescribing for elderly patients. Pharmacokinetic changes consequent upon the physiological changes associated with ageing result in a fall in the renal clearance of drugs. Similarly, the reduced proportion of body water seen in old age results in an increased volume of distribution, and hence elimination half-life of lipid-soluble drugs. Liver volume falls with increasing age, although in vitro studies demonstrate enzyme activity is normal. As a result of this, the clearance of hepatically metabolised drugs tends to fall with age. Over and above the effects of ageing, changes associated with frailty are also seen. These result additionally in a reduction in plasma albumin protein binding—clinically relevant only for acidic drugs very extensively bound—leading to a reduction in volume of distribution. In addition, reduced hepatic enzyme activity further reduces the hepatic clearance of drugs which undergo hepatic metabolism. In addition to age-related pharmacokinetic changes, changes in pharmacodynamics also occur. A change in pharmacodynamics implies a change in drug effect per unit concentration or change in sensitivity. The characterisation of such effects often requires formal concentration effect analysis to separate kinetic from dynamic effects. Increased sensitivity to benzodiazepines, warfarin, hypertensives, anaesthetics, neuroleptics are well described, as is the reduced sensitivity to the hypotensive effect of β-blockers and dystonic effects of neuroleptics. The higher prevalence of dose-related adverse drug reactions seen in elderly patients relates not only to age-associated pharmacokinetic and pharmacodynamic changes, but also to the increased prevalence of disease states and use of concomitant drug therapy. Indeed, numbers of drugs prescribed is probably the most important factor. Although age is only one determinant, these changes are clearly important determinants of the optimal dosage for older patients.