Minimizing chemotherapy-induced peripheral neuropathy: preclinical and clinical development of new perspectives

Introduction: Chemotherapy-induced peripheral neuropathies (CIPN) are a dose-limiting adverse effect of certain anticancer drugs (platinum salts, vinca alkaloids, taxanes, bortezomib, thalidomide, epothilones, eribulin). CIPN are mainly responsible for sensory disturbances and are associated with a decrease in quality of life. After the end of chemotherapy, CIPN can last for several months and even years. Unfortunately, recent meta-analyses of clinical trials have demonstrated that there is no univocal gold standard for the prevention and treatment of CIPN.

Areas covered: Using animal models of CIPN, several new strategies to prevent or treat CIPN are under development. These new strategies involve several pathways, including ion channels, neuroprotectants, glutamatergic neurotransmission, oxidative stress, cannabinoid system, inflammation, and mitochondrial functions.

Expert opinion: To date, based on meta-analyses of clinical trials, no drug can be proposed as a gold standard to prevent or treat CIPN. Consequently, there is a strong discrepancy between the optimistic results of animal studies and the poor outcomes of clinical trials. Pain assessment in preclinical and clinical studies is probably not the best outcome measurement tool and all these studies should include composite outcomes including the full complexity of CIPN symptoms, such as positive symptoms (pain, paresthesia, and dysesthesia) and negative ones (numbness).     

Benzoate treatment and the glycine index in nonketotic hyperglycinaemia

Summary High-dose benzoate treatment aimed at reducing plasma glycine levels to normal reduces seizures and increases wakefulness in patients with nonketotic hyperglycinaemia (NKH). Since benzoate metabolism is dependent on the available glycine pool, and since the glycine pool is variably affected by the deficiency in the glycine cleavage enzyme system, we examined the importance of interpatient variability in benzoate requirement. To correct for the dietary glycine contribution, the glycine index was introduced as the molar requirement of benzoate dose necessary to normalize plasma glycine levels and subtracting from that the dietary glycine intake, both corrected for weight. The glycine index varied between 3.62 and 4.87 mmol/kg per day in five patients with a poor neurodevelopmental outcome and between 0.92 and 1.90 mmol/kg per day in four patients with a better neurodevelopmental outcome, and was 2.54 mmol/kg per day in a single patient with an intermediate outcome. The glycine index was stable over time within each patient. Exceeding the balance by either increasing food glycine intake or decreasing the benzoate dose resulted in increased glycine levels. Exceeding the glycine tolerance by increasing benzoate resulted in elevated and toxic levels of benzoate. The glycine index is a stable, individually specific parameter in patients with NKH. It has clinical consequences for the dose of benzoate required and the role of dietary management. Through its correlation with neurodevelopmental outcome, the glycine index points to potential genetic factors that could contribute to the psychomotor retardation in NKH.     

Benign Pneumatosis Intestinalis with Subcutaneous Emphysema in a Liver Transplant Recipient

Pneumatosis intestinalis (PI) occurred in a pediatric liver transplant recipient experiencing chronic rejection. Signs and symptoms included abdominal distention, subcutaneous emphysema, fever, and malaise. Antibiotic treatment and nasogastric decompression resulted in prompt relief of symptoms, and surgery was not necessary. The etiology, pathophysiology, and therapy of this rare condition are discussed.     

The role of the spleen in regulating the plasma levels of factor VIII-- von Willebrand's factor after DDAVP

Organ transplantation and perfusion studied indicate that the spleen plays an important role in the regulation of plasma levels of factor VIII-von Willebrand's factor (FVIII-vWF). To better understand the mechanisms that regulate the FVIII-vWF increases after infusion of 1- deamino-8-D-arginine vasopressin (DDAVP), we have measured factor VIII coagulant activity (FVIII:C) and antigen (FVIII:CAg) and von Willebrand's factor antigen (vWF:Ag) and ristocetin cofactor (vWF:RCof) in 9 asplenic subjects with normal baseline concentrations, in 7 asplenic subjects with high concentrations, and in 14 normal controls with intact spleens. In "normal" aasplenics, all the FVIII-vWF-related measurements increased significantly over baseline values, indicating that responsiveness to DDAVP is not abolished by splenectomy. The maximal vWF:Ag and vWF:RCof responses were no different from those of normal controls, suggesting that DDAVP releases vWF from storage sites other than the spleen. The FVIII:C response was significantly lower than in normal controls, but FVIII:CAg did not differ, making FVIII:CAg higher than FVIII:CAg in "normal" asplenics. These findings suggest that the spleen, rather than being a storage site for FVIII, is the organ in which a partially inactive form of FVIII acquires full coagulant activity. In "high" asplenics, all the FVIII-vWF-related measurements increased less than in "normal" splenics, indicating that long-term elevations of plasma concentrations of FVIII-vWF are accompanied by decreased release from those storage pool(s) mobilized by DDAVP.     

Pre‐exposure prophylaxis: awareness,acceptability and risk compensation behaviour among men who have sex with men and the transgender population

Objectives

This exploratory study examined the facilitators of and barriers to acceptance of pre‐exposure prophylaxis (PrEP) and potential risk compensation behaviour emerging from its use among men who have sex with men (MSM) and transgender individuals (TGs) in India.

Methods

A questionnaire was administered to 400 individuals registered with a targeted intervention programme. Logistic regression models were used to identify facilitators of and barriers to PrEP acceptance.

Results

The respondents consisted of 68% MSM and 32% TGs. Risk behaviour categorization identified 40% as low risk, 41% as medium risk and, 19% as high risk for HIV infection. About 93% of the respondents were unaware of PrEP, but once informed about it, 99% were willing to use PrEP. The facilitators of PrEP acceptance were some schooling [odds ratio (OR) 2.16; P = 0.51], being married or in a live‐in relationship (OR 2.08; P = 0.46), having a high calculated risk (OR 3.12; P = 0.33), and having a high self‐perceived risk (OR 1.8; P = 0.35). Increasing age (OR 2.12; P = 0.04) was a significant barrier. TGs had higher odds of acceptance of PrEP under conditions of additional cost (OR 2.12; P = 0.02) and once‐daily pill (OR 2.85; P = 0.04). Individuals identified as low risk for HIV infection showed lower odds of potential risk compensation, defined as more sexual partners (OR 0.8; P = 0.35), unsafe sex with new partners (OR 0.71; P = 0.16), and decreased condom use with regular partners (OR 0.95; P = 0.84), as compared with medium‐risk individuals. The associations, although not statistically significant, are nevertheless important for public health action given the limited scientific evidence on PrEP use among MSM and TGs in India.

Conclusions

With high acceptability and a low likelihood of risk compensation behaviour, PrEP can be considered as an effective prevention strategy for HIV infection among MSM and TGs in India.