Scalable nanoprecipitation of niclosamide and in vivo demonstration of long-acting delivery after intramuscular injection

<p>The spread of SARS-CoV-2 across the world requires the formation of a range of interventions that include immunomodulatory or antiviral therapeutics and repurposing of existing drug compounds is an important strategy to rapidly identify possible options. Niclosamide is a cheap and generic drug compound with a proven <i>in vitro</i> ability to inhibit viral replication of SARS-CoV-2; this drug also has known poor oral bioavailability due to very low water solubility. Here, we demonstrate the nanoparticle formulation of niclosamide using a new, cheap and scalable process to enable long-acting injectable administration and show extended circulating drug exposure <i>in vivo</i> over 28 days using a rodent model after depot injection.</p>

Scalable nanoprecipitation of niclosamide and in vivo demonstration of long-acting delivery after intramuscular injection

<p>The spread of SARS-CoV-2 across the world requires the formation of a range of interventions that include immunomodulatory or antiviral therapeutics and repurposing of existing drug compounds is an important strategy to rapidly identify possible options. Niclosamide is a cheap and generic drug compound with a proven <i>in vitro</i> ability to inhibit viral replication of SARS-CoV-2; this drug also has known poor oral bioavailability due to very low water solubility. Here, we demonstrate the nanoparticle formulation of niclosamide using a new, cheap and scalable process to enable long-acting injectable administration and show extended circulating drug exposure <i>in vivo</i> over 28 days using a rodent model after depot injection.</p>

Availability of Medications Used for Puberty Induction and Maintenance in Adolescents with Hypogonadism in the Arab Region

PurposeInducing puberty in hypogonadal patients enables achieving normal final adult height, healthy bone mass accrual and improves fertility potential. Reliable availability and access to medicines remain a challenge around the world, particularly in low income countries. We aim to study the availability/access to medications used for inducing and maintaining puberty in centers within the Arab region.Patients and MethodsA cross-sectional survey was conducted using a link to an online questionnaire which was emailed to paediatric endocrinologists in the Arab region. The questionnaire consisted of three questions related to availability of various forms of sex hormones.Results99 physicians from 16 countries participated in the study. The commonest available form of estrogen was conjugated estrogen (29% of centers) followed by ethinylestradiol in 26%. Depot estradiol was available in 11centers while topical estrogen preparations of gel and patches were available in 6 and 10 centers respectively. Medroxy progesterone was available in 26% of the centers followed by noresthisterone (24%). The combined forms of oral and transdermal patches of estrogen/progestorne were available in 35 and 9% of centers. Intramuscular testosterone (Sustanon) was the most commonly available preparation of testosterone followed by the depot injection (Nebido), oral testosterone and testosterone gel and cream.ConclusionsWe report the first availability data of medications used for puberty induction and maintenance in paediatric hypogonadism in the Arab region. Recommended preparations for this purpose are not widely available. Creating essential list of medications used in paediatric endocrinology disorders might improve availability, access and consequently practice.

HERO phase III trial: Results comparing relugolix, an oral GnRH receptor antagonist, versus leuprolide acetate for advanced prostate cancer.

5602 Background: LHRH agonists are the mainstay for medical castration in advanced prostate cancer; however, they cause an initial testosterone (T) surge with a delayed onset of castration and require depot injection. Relugolix is the first oral GnRH receptor antagonist, which was previously shown to rapidly suppress T levels. The HERO trial compared the safety and efficacy of relugolix with leuprolide acetate in advanced prostate cancer patients. Methods: HERO is a 48-week, global, pivotal phase III trial that randomized 934 patients with androgen-sensitive advanced prostate cancer in a 2:1 ratio to receive relugolix 120 mg orally QD after a single l or leuprolide acetate 3-month depot injection. The primary endpoint was to achieve and maintain serum T suppression to castrate levels (< 50 ng/dL) through 48 weeks. Key secondary endpoints included castration rates at Day 4, profound castration (< 20 ng/dL) rates at Days 4 and 15, PSA response rate at Day 15 and FSH levels at Week 25. Testosterone recovery was evaluated in a subset of 184 patients. Results: A total of 96.7% (95% CI: 94.9%, 97.9%) of men on relugolix achieved and maintained castration through 48 weeks compared to 88.8% on leuprolide. The difference of 7.9% (95% CI: 4.1%, 11.8%) demonstrated non-inferiority (margin -10%) and superiority (P < 0.0001) of relugolix to leuprolide. All key secondary efficacy endpoints tested demonstrated superiority over leuprolide (P < 0.0001) (Table). In the testosterone recovery subset, median T levels were 270.76 ng/dL in the relugolix compared to 12.26 ng/dL in the leuprolide group 90 days after discontinuation of therapy. In a prespecified analysis, the incidence of major adverse cardiovascular events (MACE) was lower in the relugolix group than in the leuprolide group (2.9% vs. 6.2%, respectively); otherwise the safety and tolerability profiles were generally similar. Conclusion: Relugolix achieved castration as early as Day 4 and demonstrated superiority over leuprolide in sustained T suppression through 48 weeks, faster T recovery after discontinuation and a 50% reduction in MACE. Relugolix has the potential to become a new standard for T suppression for patients with advanced prostate cancer. Clinical trial information: NCT03085095 . [Table: see text]

Emergency contraception using progestin drugs in domestic cats

Today, in conditions of strict quarantine, when it is not always possible to carry out surgery in cats, some methods of emergency drug contraception can be used. Over the years, many contraceptive medications have been developed for companion animals, but many secondary adverse effects have limited their use. However, in all species, the secondary adverse effects of progesterone-type drugs limit their use and vary depending on when treatment is given in relationship to the stage of the estrous cycle. An ideal non-surgical sterilant would be safe, effective, permanent, administered as a single injection and capable of being manufactured inexpensively. Contraceptives are used for cats, as a method of renewable fertility over time for breeding animals, as a method of suppressing sexual function for animals at risk for surgery, and to prevent over populations in stray cats. The use of non-surgical, safe and effective methods of suppression of sexual function in cats eliminates traumatization, anesthesia and complicated postoperative period in animals, which in some cases are impossible in the state of health, etc. The most common and affordable method of medical contraception is progestins, such as megestrol acetate, medroxyprogesterone acetate, proligestone (used orally or as a depot injection). These drugs are effective in inhibiting sexual function. Contraceptives for felids are available as implants, depot injections, and pills or liquid for oral administration, powder for mixing with food, or as vaccines. Regimens may differ according to the timing of first treatment, whether coinciding with the active reproductive period, preceding this period, or during anestrus. Ideally, the treatment regimen is initiated during anestrus to minimize the dose needed for reproductive suppression and to avert exposure to endogenous steroids that can cause lesions in reproductive organs.