Assessment of prolonged proteasome inhibition through ixazomib-based oral regimen on newly diagnosed and first-relapsed multiple myeloma: A real-world Chinese cohort study.

OBJECTIVE: To evaluate the effectiveness, safety, and convenience of in-class transition (iCT) from intravenous bortezomib-based induction to ixazomib-based oral regimens. METHODS: This retrospective real-world study was conducted in 16 Chinese hospitals between October 2017 and April 2023 and analyzed newly diagnosed (NDMM) and first-line relapsed multiple myeloma (FRMM) patients who attained at least a partial response from bortezomib-based induction therapy, followed by an ixazomib-based oral regimen for 2 year or until disease progression or intolerable toxicity. RESULTS: The study enrolled 199 patients, median age: 63 years old, male 55.4%, 53% as high risk (HR), and 47% as standard risk. Cytogenetic risk stratification by metaphase fluorescence in situ hybridization (M-FISH), based on the Mayo Clinic risk stratification system. The median duration of total PI therapy was 11 months, with ixazomib-based treatment spanning 6 months. At the 20-month median follow-up, 53% of patients remained on therapy. The 24-month PFS rate was 84.3% from the initiation of bortezomib-based induction and 83.4% from the start of ixazomib-based treatment. Overall response rate (ORR) was 100% post-bortezomib induction and 90% following 6 cycles of the ixazomib-based regimen. Based on the Sankey diagrams, 89.51% of patients maintained or improved their disease response after 2 cycles of iCT, 6 cycles (90.14%), and 12 cycles (80%). The HR level of Mayo was found to be a significant independent factor in a worse remission (hazard ratio (HR) 2.55; p = 0.033). Ixazomib's safety profile aligned with previous clinical trial data, with 49% of patients experiencing at least one AE of any grade. The most common AEs included peripheral neuropathy, nausea and vomiting, diarrhea, thrombocytopenia, and granulocytopenia. CONCLUSION: In the real-world Chinese MM population, NDMM and FRMM patients responded favorably to PI-based continuous therapy, demonstrating substantial response rates. The ixazomib-based iCT allows for sustained PI-based treatment, offering promising efficacy and tolerable AEs.

Medication use evaluation of the financial and clinical implications of ixazomib compared to bortezomib in the outpatient setting.

In the past decade, several new therapies have been approved for use in multiple myeloma, including the novel oral agent, ixazomib. Ixazomib, like bortezomib and carfilzomib, is a proteasome inhibitor, a class of agents that are a mainstay of treating multiple myeloma in both the frontline and relapsed settings. Ixazomib is administered orally and offers many potential advantages over the subcutaneous or intravenous administration of bortezomib. In this single-center, retrospective medication use evaluation, adult patients with multiple myeloma receiving either ixazomib or bortezomib in the outpatient setting were assessed to evaluate financial implications and tolerability. A total of 28 patients were included. The total wholesale acquisition cost for one cycle of ixazomib was $9942, and $6412 for bortezomib. Average reimbursement per cycle was $9205 for ixazomib and $5664 for bortezomib. Secondarily, the incidence of interruption in therapy was evaluated. Ixazomib was associated with a slightly higher incidence of interruption compared to bortezomib, 42.9% and 35.7%, respectively. It is notable that ixazomib has similar drug reimbursement rates to bortezomib, but slightly higher rates of interruption in therapy. In conclusion, if tolerable for the patient, ixazomib may offer a financially acceptable alternative for the treatment of multiple myeloma.

Cost-effectiveness analysis on binary/triple therapy on the basis of ixazomib or bortezomib for refractory or relapsed multiple myeloma.

This study analyzed the cost utility on the use of ixazomib/lenalidomide/dexamethasone (IRD), lenalidomide/dexamethasone (RD), bortezomib/thalidomide/dexamethasone (VTD), or bortezomib/dexamethasone (VD) for patients with refractory or relapsed multiple myeloma (rrMM). Patients' lifelong direct medical costs and quality-adjusted life years (QALYs) are simulated by using the Markov model on the basis of the China's healthcare system. VTD, RD, and IRD are 0.12, 0.32, and 0.42 QALYs higher than VD, and $9401, $16,868, and $39,671 higher than those of VD in terms of lifelong cost. The incremental cost-effectiveness ratios are 78,342, 52,713, and 94,455, respectively. IRD can extend the life years of patients with rrMM, improve the quality of life, and increase the cost of medical treatment. The use of VD has a comparative advantage of cost utility. For patients who cannot tolerate bortezomib or were drug-fast with first-line bortezomib, RD plan is another economical and effective strategy.

Ixazomib - the first oral proteasome inhibitor.

Ixazomib, as a proteasome inhibitor, inhibits the chymotrypsin-like activity of the ß5 subunit of the 20S proteasome. Based on the TOURMALINE-MM1 study, ixazomib was proved by the FDA as the orphan drug in November 2015. With a promising effect in prolonging the progression-free survival compared with placebo treatment (median: 20.6 versus 14.7 months), it was the first oral compound combined with lenalidomide and dexamethasone for the treatment of patients with relapsed/refractory multiple myeloma (RRMM) who have received at least one prior therapy. The main adverse events include low-grade hematological, digestive, or cutaneous events, which were manageable with care. Overall, ixazomib demonstrated favorable safety profile. Ongoing trials are conducted to define its place in first-line, maintenance, and relapse therapies. In this review, we summarized the clinical pharmacology, efficacy, tolerability, safety, and cost-effectiveness of ixazomib.

An assessment of the acute dietary exposure to glyphosate using deterministic and probabilistic methods.

Use of glyphosate in crop production can lead to residues of the active substance and related metabolites in food. Glyphosate has never been considered acutely toxic; however, in 2015 the European Food Safety Authority (EFSA) proposed an acute reference dose (ARfD). This differs from the Joint FAO/WHO Meeting on Pesticide Residues (JMPR) who in 2016, in line with their existing position, concluded that an ARfD was not necessary for glyphosate. This paper makes a comprehensive assessment of short-term dietary exposure to glyphosate from potentially treated crops grown in the EU and imported third-country food sources. European Union and global deterministic models were used to make estimates of short-term dietary exposure (generally defined as up to 24 h). Estimates were refined using food-processing information, residues monitoring data, national dietary exposure models, and basic probabilistic approaches to estimating dietary exposure. Calculated exposures levels were compared to the ARfD, considered to be the amount of a substance that can be consumed in a single meal, or 24-h period, without appreciable health risk. Acute dietary intakes were <100% of the ARfD for all foodstuffs, except wild fungi, when calculated using the EFSA model. The model assumptions differ from those of the source model (German national model), resulting in the use of a higher variability factor. Intakes estimated with the German model represented only 18% of the ARfD. The impact of differing assumptions regarding variability and other input parameters is discussed. Probabilistic exposure estimates showed that the acute intake on no person-days exceeded 10% of the ARfD, even for the pessimistic scenario.

The health consequences of aerial spraying illicit crops: The case of Colombia.

This paper exploits variations in aerial spraying across time and space in Colombia and employs a panel of individual health records in order to study the causal effects of the aerial spraying of herbicides (glyphosate) on short-term health-related outcomes. Our results show that exposure to the herbicide used in aerial spraying campaigns increases the number of medical consultations related to dermatological and respiratory illnesses, as well as the number of miscarriages. These findings are robust to the inclusion of individual fixed effects, which compare the prevalence of these medical conditions for the same person under different levels of exposure to the herbicide used in the aerial spraying program over a period of 5 years. Also, our results are robust to controlling for the extent of illicit coca cultivation in the municipality of residence.

Measures of Total Energy Expenditure and Its Components Using the Doubly Labeled Water Method in Rehabilitating Burn Children.

BACKGROUND: A persistent hypermetabolic state delays anabolism and growth in burned children. However, our own clinical experience has been that resting energy expenditure (REE) is not increased during the rehabilitative phase, suggesting other contributing factors. We measured total energy expenditure (TEE) and its components in rehabilitating pediatric burn patients to identify the basis for accelerated energy metabolism in this population. MATERIALS AND METHODS: Children admitted with initial burns of 20% of their total body surface area (TBSA) or greater were enrolled into this prospective, descriptive study. TEE was measured using the doubly labeled water method over a 7-day period. During that period, REE was measured on 2 days by indirect calorimetry. Activity energy expenditure (AEE) was assessed using a physical activity monitoring device for a 24-hour period. TEE and REE were compared with sex-specific, age-matched, and weight-matched norms using the Dietary Reference Intakes (DRI) standards. RESULTS: Ten children with an average burn size of 53.7% ± 20% (range, 27%-82%) of TBSA completed this study. Their mean age and weight were 10.4 ± 5.5 years and 35.8 ± 16.4 kg, respectively. Daily TEE averaged 66 kcal/kg and was 1.08% of reference DRI. REE was 92% ± 25% of predicted basal metabolic rate, not exceeding 120% as a maximum value in any child. CONCLUSIONS: TEE and REE in rehabilitating burn children are comparable to reference standards. Increased REE was not typical in our population, but measures of AEE were commonly high.

An economic method to build a puffing instrument for drug application in vitro.

BACKGROUND: In in vitro electrophysiological studies, a quick application of picoliters of drug within milliseconds is required to avoid the desensitization of membrane receptors. However, conventional gravity-fed drug delivery devices sometime fail to achieve this. Moreover, the high financial cost of the advanced drug delivery system often limits the application of commercial instruments in academic research. NEW METHOD: Taking advantage of the availability of data acquisition system and software in almost every electrophysiology laboratory, a simple puffing device was designed and assembled using low-cost commercially off-the-shelf components to inject picoliter amounts of drugs. RESULTS: An optimal drug delivery with precise timing and volume was achieved using the custom made puffing device. The glutamate-evoked currents of cortical neurons recorded with patch-clamp technique were maintained for a prolonged period of time. Similarly, puffed inhibitory transmitters including GABA and glycine also produced satisfactory currents. COMPARISON WITH EXISTING METHOD(S): Our custom-made puffing system holds the advantage over conventional gravity-fed systems in operating within milliseconds of time. The channel number of the new device can easily be increased by simply adding more identical modules in parallel, and thus offering more flexibility than commercial puffing devices. CONCLUSIONS: This custom-made puffing device can be characterized as reliable, modular and inexpensive system for modern drug delivery research and application.

Activation of amygdalar metabotropic glutamate receptors modulates anxiety, and risk assessment behaviors in ovariectomized estradiol-treated female rats.

Anxiety disorders are more prevalent in females than males. The underlying reasons for this gender difference are unknown. Metabotropic glutamate receptors (mGluRs) have been linked to anxiety and it has been shown that interaction between estrogen receptors and mGluRs modulate sexual receptivity in rats. We investigated the role of mGluRs in anxiety-related behaviors in ovariectomized female rats with (OVX+EB) or without (OVX) estradiol implants. We centrally infused (s)-3,5-dihydroxyphenylglycine (DHPG), a group I mGluR agonist, into the basolateral amygdala (BLA) of OVX+EB and OVX rats at 0.1 and 1.0 µM. Male rats that normally have low estradiol levels were used to compare with OVX rats. Generalized anxiety, explorative activity and detection and analysis of threat were analyzed in the elevated plus maze (EPM) and risk assessment behaviors (RABs). DHPG (1.0 µM) increased the percentage of time spent in- and entries into- the open arms in OVX+EB, but not in OVX or male rats. Flat-back approaches and stretch-attend postures, two RABs, were significantly reduced by DHPG (0.1 and 1.0 µM) in OVX+EB rats only. DHPG did not modulate rearing and freezing, behaviors related to exploration and fear-like behavior, respectively. However, DHPG (1.0 µM) increased head dipping and decreased grooming behaviors in OVX rats, suggesting a weak explorative modulation. The effects of DHPG observed in OVX+EB, were blocked by 50 µM of (RS)-1-aminoindan-1,5-dicarboxylic acid (AIDA), a mGluR1 antagonist. AIDA and/or estradiol did not modulate anxiety and or RABs. Our results show that intra-BLA infusion of DHPG exerts an anxiolytic-like effect in OVX+EB, but not in OVX or male rats. This effect seems to depend upon mGluR1 subtype activation. Our findings led us to suggest that the effects observed in OVX+EB rats might be due to an interaction at the membrane level of estrogen receptors with mGlu1 within the BLA.

Clinical and instrumental assessment of the effects of a new product based on hydroxypropyl chitosan and potassium azeloyl diglycinate in the management of rosacea.

BACKGROUND: Rosacea is a chronic inflammatory skin disease affecting mostly facial skin. Its origin is multifactorial. Important steps in its treatment are avoidance of any triggering factor and control of skin inflammation. AIM: To assess the benefit of topical applications of a new product (P-3075). PATIENTS/METHODS: A randomized, multicenter, double-blind, placebo-controlled, parallel-group, pilot study was carried out to evaluate the efficacy and tolerability of a cream (P-3075) based on 5% potassium azeloyl diglycinate (PAD, Azeloglicina(®)) and 1% hydroxypropyl chitosan (HPCH). Forty-two patients (rosacea stages I and II) were enrolled and randomized, 28 in the P-3075 group and 14 in the placebo group. They were asked to apply the cream twice daily for 4 weeks. The main assessments were the objective quantification of erythema and skin hydration using the Mexameter(®) and Corneometer(®) devices, respectively. Clinical signs and symptoms were evaluated on a four-point scale. RESULTS: The P-3075 cream applied for 28 days was effective in skin protection by reducing erythema, evaluated both instrumentally and clinically. In addition, the clinical assessments of other symptoms such as flushing, stinging, and burning supported the beneficial effect of the P-3075 cream. CONCLUSIONS: The anti-inflammatory and moisturizing effects of potassium azeloyl diglycinate combined with the protective properties of HPCH allow the new product to be a good candidate for controlling signs and symptoms of rosacea.

Assessment of whole body protein metabolism in critically ill children: can we use the [15N]glycine single oral dose method?

BACKGROUND & AIMS: Most stable-isotope methods to evaluate whole body protein metabolism in patients are invasive and difficult to use in children. In this study protein metabolism was evaluated with the non-invasive [15N]glycine single oral dose method in critically ill children and the value of the method is discussed. METHODS: [15N]glycine (100mg) was given orally to children (mean age 5.5 years; range 0.6-15.5 years) with meningococcal septic shock (MSS, n = 8), pneumonia (n = 5), and to healthy, fed and post-absorptive children (n = 10). Urine was collected during 9h, total amount of NH(3), labelled NH(3) and nitrogen were measured, and protein turnover, synthesis and breakdown were calculated using urinary NH(3) as end-product. RESULTS: Mean protein turnover in children with MSS, pneumonia and fed and post-absorptive healthy children was 0.63+/-0.13, 0.38+/-0.10, 0.28+/-0.03 and 0.28+/-0.02g N/kg/9h, respectively. Mean protein synthesis was 0.55+/-0.12, 0.29+/-0.09, 0.18+/-0.02, 0.20+/-0.02g N/kg/9h, respectively. Mean protein breakdown was 0.56+/-0.14, 0.28+/-0.12, 0.08+/-0.03, 0.28+/-0.02g N/kg/9h, respectively. Protein turnover, synthesis and breakdown were significantly increased in MSS patients compared to fed healthy children (P <0.01) and post-absorptive children (P <0.05). Protein turnover, protein synthesis, protein breakdown were significantly correlated with disease severity and body temperature (P <0.05). CONCLUSION: Results of whole body protein metabolism measured with the [15N]glycine single oral dose method in children with MSS and in healthy children were in line with expectations based on results obtained in earlier reports and with different methods.

Glycine, glycyl-glycine and maltodextrin based oral rehydration solution. Assessment of efficacy and safety in comparison to standard ORS.

We evaluated the efficacy and safety of an oral rehydration solution containing glycyl-glycine, glycine, and maltodextrin (GGG-ORS), in comparison to the glucose based ORS (standard ORS). The osmolality of the GGG-ORS (305 mOsm/l) and standard ORS (311 mOsm/l) was similar. Ninety-two children presenting with acute gastroenteritis and moderate dehydration, aged 3 months to 3 years, were randomly assigned to receive standard ORS or GGG-ORS. All the patients were successfully rehydrated orally. The two groups were comparable for baseline characteristics including the microbial etiology. Rotavirus (49%, 36%), ETEC (11%, 18%) or a combination of rotavirus and ETEC (15%, 9%) were the main stool pathogens isolated. There was no significant difference in the mean stool output or duration of diarrhoea between the two groups. Patients in the GGG-ORS group had higher urine output (p less than 0.01) and weight gain (p less than 0.05) in the initial 6 hours when feeding was withheld, but no such differences were observed beyond this period. Hypernatremia did not develop in any patient during the study. We conclude that glycine and glycyl-glycine supplemented oral rehydration solution does not have any therapeutic advantage in the treatment of acute gastroenteritis with moderate dehydration caused predominantly by rotavirus.