Maximizing response to intratumoral immunotherapy in mice by tuning local retention

Direct injection of therapies into tumors has emerged as an administration route capable of achieving high local drug exposure and strong anti-tumor response. A diverse array of immune agonists ranging in size and target are under development as local immunotherapies. However, due to the relatively recent adoption of intratumoral administration, the pharmacokinetics of locally-injected biologics remains poorly defined, limiting rational design of tumor-localized immunotherapies. Here we define a pharmacokinetic framework for biologics injected intratumorally that can predict tumor exposure and effectiveness. We find empirically and computationally that extending the tumor exposure of locally-injected interleukin-2 by increasing molecular size and/or improving matrix-targeting affinity improves therapeutic efficacy in mice. By tracking the distribution of intratumorally-injected proteins using positron emission tomography, we observe size-dependent enhancement in tumor exposure occurs by slowing the rate of diffusive escape from the tumor and by increasing partitioning to an apparent viscous region of the tumor. In elucidating how molecular weight and matrix binding interplay to determine tumor exposure, our model can aid in the design of intratumoral therapies to exert maximal therapeutic effect.

Nanoparticle sterilization methods for biomedical applications in animals

Objective: To review different nanoparticle sterilization methods for their use in biomedical applications in animals. Approach: Sterilization is used to obtain a microorganism-free product without altering its physicochemical characteristics during its preparation, storage, or administration route. This review explores different sterilization methods and their advantages and disadvantages on the nanoparticle level. Study limitations/implications: Nanoparticles are used in animal production, including their parenteral administration. Therefore, establishing the characteristics of different technologies applied to sterilize nanoparticles is essential to ensure the delivery of sterile products preventing health risks. Conclusions: The use of nanotechnology in livestock production offers several advantages for animal nutrition, reproduction, and health, among other things. When nanoparticles must be sterilized, choosing the most suitable method is essential. This depends on the amount of product and its compound type because each technique has specific requirements that must be taken into account to be ready for potential changes in the structure and availability of the final product.

Pharmacokinetics and central accumulation of delta-9-tetrahydrocannabinol (THC) and its bioactive metabolites are influenced by route of administration and sex in rats

Up to a third of North Americans report using cannabis in the prior month, most commonly through inhalation. Animal models that reflect human consumption are critical to study the impact of cannabis on brain and behaviour. Most animal studies to date utilize injection of delta-9-tetrahydrocannabinol (THC; primary psychoactive component of cannabis). THC injections produce markedly different physiological and behavioural effects than inhalation, likely due to distinctive pharmacokinetics. The current study directly examined if administration route (injection versus inhalation) alters metabolism and central accumulation of THC and metabolites over time. Adult male and female Sprague–Dawley rats received either an intraperitoneal injection or a 15-min session of inhaled exposure to THC. Blood and brains were collected at 15, 30, 60, 90 and 240-min post-exposure for analysis of THC and metabolites. Despite achieving comparable peak blood THC concentrations in both groups, our results indicate higher initial brain THC concentration following inhalation, whereas injection resulted in dramatically higher 11-OH-THC concentration, a potent THC metabolite, in blood and brain that increased over time. Our results provide evidence of different pharmacokinetic profiles following inhalation versus injection. Accordingly, administration route should be considered during data interpretation, and translational animal work should strongly consider using inhalation models.

The role of estrone in feminizing hormone treatment

Context In trans women, hormone treatment induces feminization, however the degree of feminization varies from person to person. A possible contributing factor could be estrone, a weak estrogen that interferes with the estrogen receptor. Objective To assess whether estrone is involved in feminization induced by hormone treatment. Design Prospective cohort study, with one year follow-up. Setting Gender identity clinic. Participants 212 adult trans women, starting hormone treatment between July 2017 and December 2019, median age 25 years. Intervention Gender affirming hormone treatment. Main outcome measures Change in fat percentage and breast development. Results After 12 months of hormone treatment, estrone concentration was 187pmol/L (95%CI 153 – 220) in transdermal and 1516pmol/L (95%CI 1284 – 1748) in oral estradiol users. Fat percentage increased by 1.2% (IQR 0.3 – 4.8) in transdermal and 4.6% (IQR 2.5 – 5.9) in oral estradiol users. This was not associated with estrone concentrations in transdermal(+4.4% (95%CI -4.0 – 13) per 100pmol/L increase in estrone concentration) nor in oral estradiol users (-0.7% (95%CI -1.7 – 0.3)). Breast volume increased by 69ml (IQR 58 – 134) in transdermal and 62ml (IQR 32 – 95) in oral estradiol users. This was not associated with estrone concentrations in transdermal (+ 14% (95%CI -49 – 156) per 100pmol/L increase in estrone concentration) nor oral estradiol users (+ 11% (95%CI -14 – 43)). Conclusions Change in fat percentage and breast development in trans women were not associated with estrone concentrations nor with administration route. Therefore measurement of estrone concentrations does not have a place in the monitoring of feminization in trans women.

Oral and injected tamoxifen alter adult hippocampal neurogenesis in female and male mice

Inducible Cre recombinase facilitates temporal control of genetic recombination in numerous transgenic model systems, a feature which has made it a popular tool for studies of adult neurogenesis. One of the most common forms of inducible Cre, CreERT2, requires activation by the synthetic estrogen tamoxifen (TAM) to initiate recombination of LoxP-flanked sequences. To date, most studies deliver TAM via intraperitoneal injection. But the introduction of TAM-infused commercial chows has recently expanded the possible modes of TAM delivery. Despite the widespread use of TAM-inducible genetic models in adult neurogenesis research, the comparative efficiency and off-target effects of TAM administration protocols is surprisingly infrequently studied. Here we compare a standard, 5 day TAM injection regimen with voluntary consumption of TAM-infused chow. First, we used adult NestinCreERT2;Rosa-LoxP-STOP-LoxP-EYFP reporter mice to show that 2 weeks of TAM chow and 5 days of injections led to LoxP recombination in a similar phenotypic population of neural stem and progenitor cells in the adult dentate gyrus. However, TAM chow resulted in substantially less overall recombination than injections. TAM administration also altered adult neurogenesis, but in different ways depending on administration route: TAM injection disrupted neural progenitor cell proliferation 3 weeks after TAM, whereas TAM chow increased neuronal differentiation of cells generated during the diet period. These findings provide guidance for selection of TAM administration route and appropriate controls in adult neurogenesis studies using TAM-inducible Cre mice. They also highlight the need for better understanding of off-target effects of TAM in other neurological processes and organ systems.

Recombinant adeno-associated viruses as a gene delivery vehicle for the use in molecular medicine

Viral mechanisms for the delivery of genetic material are widely used in molecular medicine. Recombinant adeno-associated viruses (rAAV) represent a promising tool for in vivo gene delivery. The review considers nosological spectrum, molecular mechanisms, the choice of drug administration route depending on target structures, the choice of serotype, and the methods of active ingredient manufacturing for rAAV-mediated gene therapy.

Clinical Re-evaluation on Bioequivalence and Relative Bioavailability of Micronized Progesterone Hard Capsule (Yimaxin) and Micronized Progesterone Soft Capsule (Utrogestan) under Vaginal and Oral Administration Routes

Background and Objective: To clinically re-evaluate relative bioavailability and bioequivalence of micronized progesterone (hard capsule) Yimaxin and micronized progesterone (soft capsule) Utrogestan under vaginal and oral administration routes. Methods: From December 2017 to June 2018, a total of 16 postmenopausal healthy women were recruited and received a total of four rounds of drug treatment with cross-over design, respectively Yimaxin and Utrogestan under vaginal and oral administration routes. Changes in the subjects’ hormone levels after medication were monitored and an endometrial biopsy after a course of treatment was performed in our hospital. Result: The Geomeans of AUC0-t of Yimaxin and Utrogestan under vaginal administration route were 252.15 and 115.46, respectively, with a ratio of 2.19, and under oral administration route were 244.64 and 413.68, respectively, with a ratio of 0.59. The Geomeans of Cmax of Yimaxin and Utrogestan under vaginal administration route were 28.11 and 12.21, respectively, with a ratio of 2.30, and under oral administration route were 53.12 and 129.85, respectively, with a ratio of 0.41. Conclusion: Yimaxin was not bioequivalent to Utrogestan. Yimaxin had higher exposure to the drug in vivo at the same dose when administered vaginally, and Utrogestan had higher exposure to the drug in vivo at the same dose when administered orally. doi: https://doi.org/10.12669/pjms.37.7.3949 How to cite this:Wang H, Liu M, Chen R, Deng C. Clinical Re-evaluation on Bioequivalence and Relative Bioavailability of Micronized Progesterone Hard Capsule (Yimaxin) and Micronized Progesterone Soft Capsule (Utrogestan) under Vaginal and Oral Administration Routes. Pak J Med Sci. 2021;37(7):---------. doi: https://doi.org/10.12669/pjms.37.7.3949 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

On the Development of a Cutaneous Flavonoid Delivery System: Advances and Limitations

Flavonoids are one of the vital classes of natural polyphenolic compounds abundantly found in plants. Due to their wide range of therapeutic properties, which include antioxidant, anti-inflammatory, photoprotective, and depigmentation effects, flavonoids have been demonstrated to be promising agents in the treatment of several skin disorders. However, their lipophilic nature and poor water solubility invariably lead to limited oral bioavailability. In addition, they are rapidly degraded and metabolized in the human body, hindering their potential contribution to the prevention and treatment of many disorders. Thus, to overcome these challenges, several cutaneous delivery systems have been extensively studied. Topical drug delivery besides offering an alternative administration route also ensures a sustained release of the active compound at the desired site of action. Incorporation into lipid or polymer-based nanoparticles appears to be a highly effective approach for cutaneous delivery of flavonoids with good encapsulation potential and reduced toxicity. This review focuses on currently available formulations used to administer either topically or systemically different classes of flavonoids in the skin, highlighting their potential application as therapeutic and preventive agents.

Adequacy of antibiotic prophylaxis and incidence of surgical site infections in neck surgery

Health care-related infections are frequent and among them surgical site infection (SSI) are the most frequent in hospitals. The objective was to evaluate the adequacy of antibiotic prophylaxis in patients undergoing neck surgery and its relationship with the incidence of surgical site infection (SSI). Prospective cohort study. The adequacy of antibiotic prophylaxis in patients undergoing neck surgery was evaluated. Antibiotic prophylaxis was considered adequate when it conformed to all items of the protocol (antibiotic used, time of administration, administration route, dose and duration). The cumulative incidence of SSI was calculated, and the relationship between SSI and antibiotic prophylaxis adequacy was determined using adjusted relative risk (RR). Antibiotic prophylaxis was administered in 63 patients and was adequate in 85.7% (95% CI 75.0–92.3) of them. The cumulative incidence of SSI was 6.4% (95% CI 3.4–11.8). There was no significant relationship between antibiotic prophylaxis inadequacy and the incidence of SSI (RR = 2.4, 95% CI 0.6–10.6). Adequacy of antibiotic prophylaxis was high and it did not affect the incidence of SSIs.