Chloroquine and Hydroxychloroquine: how about switching?

Early studies suggesting that chloroquine (CQ) and hydroxychloroquine (HCQ) could benefit coronavirus patients brought these old medicines back to the spotlight. This led to an increase in demand and price, turning their counterfeiting a pharmacovigilance issue worldwide. Meanwhile, lack of evidence on effectiveness and safety concerns have reduced their clinical trials in severe COVID-19 cases. Despite the knowledge that CQ and HCQ toxic effects are stereo specific rather than their therapeutic effects, these drugs are available only as racemates. In this context, this work brings a discussion about chiral switching to their eutomers so that CQ and HCQ distomers would become impurities, what may be a viable alternative to test new dose-response curves. Even if it is proven that the use of pure CQ and HCQ enantiomers are useless against COVID-19, chiral switching would certainly improve safety and efficacy in the treatment of many autoimmune inflammatory diseases, benefiting chronic users of these drugs.

Is Response to Genotoxic Stress Similar in Populations of African and European Ancestry? A Study of Dose-Response After in vitro Irradiation

Background: Exposure to genotoxic stress such as radiation is an important public health issue affecting a large population. The necessity of analyzing cytogenetic effects of such exposure is related to the need to estimate the associated risk. Cytogenetic biological dosimetry is based on the relationship between the absorbed dose and the frequency of scored chromosomal aberrations. The influence of confounding factors on radiation response is a topical issue. The role of ethnicity is unclear. Here, we compared the dose-response curves obtained after irradiation of circulating lymphocytes from healthy donors of African and European ancestry.Materials and Methods: Blood samples from six Africans living in Africa, five Africans living in Europe, and five Caucasians living in Europe were exposed to various doses (0–4 Gy) of X-rays at a dose-rate of 0.1 Gy/min using an X-RAD320 irradiator. A validated cohort composed of 14 healthy Africans living in three African countries was included and blood samples were irradiated using the same protocols. Blood lymphocytes were cultured for 48 h and chromosomal aberrations scored during the first mitosis by telomere and centromere staining. The distribution of dicentric chromosomes was determined and the Kruskal-Wallis test was used to compare the dose-response curves of the two populations.Results: No spontaneous dicentric chromosomes were detected in African donors, thus establishing a very low background of unstable chromosomal aberrations relative to the European population. There was a significant difference in the dose response curves between native African and European donors. At 4 Gy, African donors showed a significantly lower frequency of dicentric chromosomes (p = 8.65 10–17), centric rings (p = 4.0310–14), and resulting double-strand-breaks (DSB) (p = 1.32 10–18) than European donors. In addition, a significant difference was found between African donors living in Europe and Africans living in Africa.Conclusion: This is the first study to demonstrate the important role of ethnic and environmental factors that may epigenetically influence the response to irradiation. It will be necessary to establish country-of-origen-specific dose response curves to practice precise and adequate biological dosimetry. This work opens new perspective for the comparison of treatments based on genotoxic agents, such as irradiation.

A Universal Delayed Difference Model Fitting Dose-response Curves

Purpose Dose-response curves, which fit a multitude of experimental data derived from toxicology, are widely used in physics, chemistry, biology, and other fields. Although there are many dose-response models for fitting dose-response curves, the application of these models is limited by many restrictions and lacks universality, so there is a need for a novel, universal dynamical model that can improve fits to various types of dose-response curves. Methods We expand the hormetic Ricker model, taking the delay inherent in the dose-response into account, and develop a novel and dynamic delayed Ricker difference model (DRDM) to fit various types of dose-response curves. Furthermore, we compare the DRDM with other dose-response models to confirm that it can mimic different types of dose-response curves. Data analysis By fitting various types of dose-response data sets derived from drug applications, disease treatment, pest control, and plant management, and comparing the imitative effect of the DRDM with other models, we find that the DRDM fits monotonic dose-response data well and, in most circumstances, the DRDM has a better imitative effect to non-monotonic dose-response data with hormesis than other models do. Results The MSE of fits of the DRDM to S-shaped dose-response data (DS2-G) is not lower than those for four other models, but the MSE of fits to U-shaped (DS7) and inverted U-shaped dose-response data (DS10) were lower than for two other models. This means that the imitative effect of the DRDM is comparable to other models of monotonic dose-response data, but is a significant improvement compared to traditional models of non-monotonic dose-response data with hormesis. Conclusion We propose a novel dynamic model (DRDM) for fitting to various types of dose-response curves, which can reflect the dynamic trend of the population growth compared with traditional static dose-response models. By analyzing data, we have confirmed that the DRDM provides an ideal description of various dose-response observations and it can be used to fit a wide range of dose-response data sets, especially for hormetic data sets. Therefore, we conclude that the DRDM has a good universality for dose-response curve fitting.

Antipsychotics for negative and positive symptoms of schizophrenia: dose-response meta-analysis of randomized controlled acute phase trials

Determining the optimal antipsychotic target dose in acute phase treatment is of high clinical relevance. The effect of antipsychotics on negative symptoms should be taken into account because patients will often continue on the treatment received in the acute phase. Therefore, we conducted a formal dose-response meta-analysis of negative symptoms and positive symptoms based on a systematic review of fixed-dose randomized controlled trials (RCTs) that examined the effectiveness of antipsychotics for the acute exacerbation of schizophrenia. Forty RCTs included a total of 15,689 patients. The 95% effective doses per day for the 13 antipsychotics included and 3 long acting were mostly different for negative and positive symptoms: amisulpride (481 mg, 690.6 mg); aripiprazole (11.9 mg, 11 mg); asenapine (7.61 mg, 5.66 mg); brexpiprazole (2.1 mg, 4 mg); cariprazine (4 mg, 6.51 mg); haloperidol (6.34 mg, 7.36 mg); lurasidone (58.2 mg, 86.3 mg); olanzapine (15.5 mg, 9.52 mg); olanzapine long-acting injection (15.7 mg, 13.5 mg); paliperidone (7.2 mg, 7 mg); paliperidone long-acting injection (7.5 mg, 5.9 mg); quetiapine instant-release (264.2 mg, 316.5 mg); quetiapine extended-release (774 mg, 707.2 mg); risperidone (7.5 mg, 7.7 mg); risperidone long-acting injection (5.13 mg, 6.7 mg); sertindole (13.5 mg, 16.3 mg); and ziprasidone (71.6 mg, 152.6 mg). The shape of the dose-response curves varied across different drugs with most drugs showing a plateau at higher doses. Most dose-response curves suggested that the near-maximum effective doses could be in the lower-to-medium range of the licensed dose. Additional RCTs are necessary to establish the optimal dose.