MMP/metalloproteinase

Studies were undertaken to determine the ovicidal efficacy of 5,5'-dimethyl-2,2'-bipyridyl (abametapir) against eggs of both human head and body lice. Head lice eggs of different ages (0-2, 3-5, and 6-8-d-old eggs) were exposed to varying concentrations of abametapir in isopropanol and concentration-dependent response relationships established based on egg hatch. One hundred percent of all abametapir-treated eggs failed to hatch at the 0.74 and 0.55% concentrations, whereas 100% of 6-8-d-old head louse eggs failed to hatch only at the 0.74% concentration. The LC50 value for abametapir varied, depending on the age of the head lice eggs, from ∼0.10% recorded for 0-2-d-old eggs and increasing to ∼0.15% for 6-8-d-old eggs. Abametapir was also evaluated once formulated into a lotion referred to as Xeglyze (0.74% abametapir) and serial dilutions made. Ovicidal efficacies were determined against head lice eggs 0-8-d-old. Results indicated 100% ovicidal activity at the 0.74, 0.55, 0.37, and 0.18% concentrations. Additional studies undertaken using body lice eggs also demonstrated that abametapir was 100% ovicidal against eggs of all ages when evaluated at a concentration of 0.37 and 0.55%. Given that ovicidal activity is a critical component of any effective treatment regime for louse control, the data presented in this study clearly demonstrate the ability of abametapir to inhibit hatching of both head and body louse eggs as assessed in vitro. [2]

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Because abametapib can chelate heavy metal ions including iron, copper, and zinc, it can interact with a variety of insect targets, such as metalloproteinases, which need metal cofactors to operate [2].

Few head lice treatments have demonstrated effectiveness against louse eggs. Abametapir, a metalloproteinase inhibitor, is able to target metalloproteinases critical to egg hatching and louse development. In this double-blind, phase 2 study, 50 subjects aged ≥3 years with active head lice infestation were randomized to receive a single treatment of abametapir lotion, 0.74%, or vehicle (control), applied to scalp and hair for 10 minutes. Ovicidal efficacy was measured by recording the hatch rate of eggs collected from each subject's hair before and after treatment and incubated for 14 days. With abametapir, 100% of treated eggs remained unhatched compared with 64.0% for vehicle. Accounting for pretreatment hatch rates, the absolute reduction in egg hatching was 92.9% for abametapir versus 42.3% for vehicle (P < .0001). The most frequently reported adverse event was rash (16%). Abametapir lotion, 0.74%, demonstrated significant ovicidal activity against head lice eggs with a single application. [1]

Louse eggs from the DDT- and permethrin-resistant SF-HL strain of human head louse (Pediculus humanus capitis, De Geer, Anoplura: Pediculidae) were oviposited on tufts of human hair (Lee et al. 2000, Yoon et al. 2003, Yoon et al. 2006). The eggs were topically treated with either abametapir alone in isopropanol or in the formulation referred to as Xeglyze containing 0.74% abametapir. Serial dilutions for 0.74% abametapir were prepared in isopropanol in the following concentrations: 0.55, 0.37, 0.18, 0.09, 0.009, and 0.0009%. Serial dilutions were also prepared from Xeglyze, resulting in the following concentrations: 0.55, 0.37, 0.18, and 0.09%. The Xeglyze formulation without abametapir (termed vehicle: an oil-in-water emulsion containing the following inactive ingredients: water, light mineral oil, polysorbate 20, carbomer 980, trolamine, butylated hydroxytoluene, and benzyl alcohol) was also evaluated, as was the commercially available pediculicide treatment Nix (1% permethrin; INSIGHT Pharmaceuticals, LLC., Trevose, PA). For assessing the efficacy of abametapir alone, a solvent-only control (isopropanol) was included in addition to a distilled, deionized water control (ddH2O). [2]
The procedure for setting up the ovicidal assay involved using eggs that were laid on hair tufts (∼300 strands, ∼4 cm in length) over a 48-h period and collected from rearing units of the in vitro rearing system containing male and female adult lice (∼30 of each sex; Yoon et al. 2006, Strycharz et al. 2011, Strycharz et al. 2012). The day that adults were placed into feeding cups of the rearing system was designated Day 0 and development stages were determined from this day onward. After 48 h, adults were removed and the hair tufts with ∼150–180 eggs/rearing unit divided in three equal groups (∼50–60 eggs per group) and were designated as Group 1 (0–2-d-old eggs), Group 2 (3–5-d-old eggs), or Group 3 (6–8-d-old eggs). Group 1 eggs were treated on Day 2, Group 2 on Day 5, and Group 3 on Day 8, post-infestation of the tufts by adults. In each group, 349–530 eggs/biological replicates were used for ovicidal bioassay with abametapir. Also, 273–363 eggs/biological replicates were used for ovicidal bioassays with Xeglyze formulation in each age group. Tufts with attached eggs were immersed into 0.5 ml of the various treatments for 30 s with swirling to ensure saturation of the tuft with treatment and complete egg coverage and then placed onto a glass petri dish for 10 min at 31°C and 70–80% relative humidity (RH). To ensure saturation and complete egg coverage, the tufts were visually inspected under a stereomicroscope. At the end of the exposure period, treated tufts with attached eggs were sequentially washed in three separate ddH2O baths (100 mL ddH2O each bath) with gentle swirling for 30 s per wash, placed on filter paper for blotting, and air-dried for 5 min at room temperature. Dried tufts with treated eggs were then placed into covered sterile glass petri dishes and moved to an incubator at 31°C and 70–80% RH and incubated for 14 d. Egg viability was recorded daily by examining individual eggs for proper size, shape, and color to determine survivorship of eggs throughout their development before and after treatment. The number of lice that hatched from the eggs was recorded and used to determine the percent egg hatch. Undeveloped eggs and stillborn lice were recorded as dead. [2]
Human body louse eggs were from the S.C. Barker isolate that was originally adapted from the Orlando strain of body louse, P. h. humanus, at the University of Queensland. The Barker isolate was founded with lice from the isolate of Dr. K. Mumcuoglu from the Hebrew University, Jerusalem. The Orlando strain was originally founded from body lice from a small, but unspecified, number of people in Washington DC and Orlando, Florida, USA, around 1942. The ovicidal assay was conducted using body louse eggs based on the ASTM “Standard test method for effectiveness of liquid gel, cream or shampoo against human louse ova,” designation E-1517-99 (reapproved 2006). Louse eggs were obtained from gravid female P. h. humanus by incubating adult lice on cotton cloth at 32 °C and 50% RH for 12–16 h. After this period, the lice were removed and eggs still attached to the cloth were collected, counted, and placed in a 12-well tissue culture plate (Falcon; ∼20 eggs per well). In each age group, 68–137 eggs/experimental replications were used in ovicidal bioassays with the experimental abametapir formulations. Eggs of different ages were then treated with either an experimental formulation containing 0.55% abametapir or serial dilutions (0.37, 0.18, 0.09, and 0.02%). In addition, the experimental formulation without abametapir (vehicle) and a water control were also evaluated. Treatment involved immersing the eggs into the various formulations for 10 min, followed by removing the treatment and rinsing the cloth containing the eggs for 1 min in 100 mL of distilled water. The treated and rinsed eggs were then placed on a paper towel and blotted dry before each piece of cloth was placed into a clean well of a 12-well tissue culture plate and incubated at 32°C and 50% RH for ∼12 d to enable all eggs time to hatch. Undeveloped eggs and stillborn lice were recorded as dead. The number of lice that hatched from the eggs was recorded and used to determine the percent egg hatch.[1]

Study Design [1]
This phase 2 study was a double-blind, randomized, vehicle-controlled, parallel-group study in subjects aged 3 years and older with an active head lice infestation. The study was designed to assess the ovicidal efficacy of a single application of abametapir lotion compared with a vehicle control, when applied to the scalp and hair for 10 minutes at the study site. Fifty subjects were randomized 1:1 to receive either abametapir lotion or vehicle lotion. [1]
All subjects completed a screening visit (days −7 to 0) in which trained evaluators systematically examined the scalps of the subjects for up to 15 minutes to detect any live lice and eggs. Subjects were randomized to either abametapir lotion or vehicle lotion. On day 0, before application of the investigational product, at least 5 undamaged eggs located on hair shafts <1 cm from the scalp were randomly selected as untreated controls and removed from each subject’s head by hair clipping. Study drug (abametapir lotion or vehicle lotion) was applied to the dry scalp and hair, left for 10 minutes, and then rinsed with warm water and towel dried. Immediately after treatment, the random egg collection process was repeated. Hair shafts collected at the site both before and after treatment were microscopically examined to assess egg viability; nonviable eggs (non-ellipsoid, squashed, flattened, or crushed) were discarded. Viable eggs were incubated at 30°C (±1°C) and ~60% relative humidity for 14 days. All eggs were then examined by an independent assessor to determine whether eggs were hatched, partially hatched, or unhatched. The assessor was blinded to the treatment assignments and the time of collection of the egg samples. The proportion of pretreatment versus posttreatment hatched eggs was compared across treatment groups following incubation. Subjects returned to the site on day 1 (+1) and day 7 (+2) to assess for the presence of live lice.

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Endpoints [1]
The primary efficacy endpoint was the proportion of hatched eggs following a 14-day incubation period, comparing those collected before treatment with those collected after treatment with abametapir lotion or vehicle. [1]
The primary safety endpoints were defined as changes in the irritation scores of scalp and eye assessments and the proportion of subjects reporting treatment-emergent adverse events (TEAEs) at day 1. Scalp and eye examinations were performed at screening, baseline, and day 1. Scalp irritation was graded on 4-point scales for erythema and edema, pruritus, and excoriation and pyoderma (0 = none, 1 = mild, 2 = moderate, and 3 = severe).

Absorption, Distribution and Excretion
In a pharmacokinetic study involving adult and pediatric patients, the Cmax and AUC0-8h were 41 ng/mL and 121 ng·h/mL in the adult group, respectively, and 73 ng/mL and 264 ng·h/mL in the pediatric group, respectively. Overall, systemic exposure to abemetidine appeared to decrease with age. The median Tmax for abemetidine was 0.57–1.54 hours. Following topical administration, benzyl alcohol was detected in the serum of 7 out of 39 pediatric patients. The Cmax of benzyl alcohol in these subjects ranged from 0.52–3.57 μg/mL. The major circulating metabolite of abametaspirine (abedemataspirine carboxylate) is slowly cleared from circulation, resulting in higher serum concentrations than the parent drug—based on data collected 72 hours after administration, the serum Cmax and AUC0-72h ratios of abametaspirine and abametaspirine carboxylate were approximately 30 and 250, respectively. Clearance and excretion of abametaspirine have not been studied in patients. Data on the volume of distribution of abametaspirine are currently unavailable. Clearance and excretion of abametaspirine have not been studied in patients. Metabolism/Metabolites Abedemataspirine undergoes extensive biotransformation, primarily mediated by CYP1A2. Abedemataspirine is first metabolized to hydroxyabedemataspirine, and then further metabolized to carboxyabedemataspirine—the latter is slowly cleared from plasma, resulting in higher systemic concentrations than the parent drug. In vitro studies have shown that carboxyabametapyr may inhibit CYP3A4, CYP2B6, and CYP1A2, particularly at the relatively high and prolonged concentrations observed after topical application of abametapyr.

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Biological Half-Life
The elimination half-life of abametapyr and its metabolites has not been fully characterized, but it is estimated that the half-life of carboxyabametapyr in adults is 71 ± 40 hours (or longer).

Protein Binding
Both abamatetape and its carboxylated derivative exhibit high protein binding rates in plasma, but the specific proteins they bind to are not yet fully understood. Following local administration, the protein binding rate of abamatetape is 91.3-92.3%, while that of its carboxylated derivative is 96.0-97.5%.

[1]. Effect of a New Head Lice Treatment, Abametapir Lotion, 0.74%, on Louse Eggs: A Randomized, Double-Blind Study. Glob Pediatr Health. 2019; 6: 2333794X19831295.

[2]. Ovicidal Efficacy of Abametapir Against Eggs of Human Head and Body Lice (Anoplura: Pediculidae). J Med Entomol. 2017 Jan; 54(1): 167-172.

Abametapillin belongs to the bipyridine class of compounds. Abametapillin is a novel lice-killing metalloproteinase inhibitor used to treat head lice infestations. The life cycle of head lice (Pediculus capitis) is approximately 30 days, with 7 to 12 days spent laying eggs on the hair shaft near the scalp. Topical liceicides often lack sufficient ovicidal activity, including standard treatments such as permethrin, and many require a second dose 7–10 days after the initial application to kill newly hatched lice resistant to the first treatment. The necessity of follow-up treatment can lead to patient compliance issues, and resistance to permethrin and pyrethroids/synergists may be more severe in some regions. Research into novel ovicidal treatments has shown that several metalloproteinases are crucial for the hatching and survival of head lice eggs, thus identifying these enzymes as potential therapeutic targets. Abametapillin is a metalloproteinase inhibitor and the first topical liceicide to utilize this novel target. Compared to many other topical medications, abametaprine exhibits higher ovicidal activity (90-100% ovicidal rate in vitro) and requires only a single dose. Furthermore, its novel and relatively non-specific mechanism of action may help inhibit the development of resistance. Abametaprine was first approved for marketing in the United States on July 27, 2020, under the brand name Xeglyze.
See also: Liceicides (subclass).

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Drug Indications
Abametaprine is indicated for the topical treatment of head lice infestations in patients 6 months and older, as part of a comprehensive lice management program.

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Mechanism of Action
Multiple metalloproteinases (enzymes that require metal cofactors to function) are involved in lice egg hatching and survival. In vitro studies have shown that metal chelators can inhibit the activity of these proteins and therefore may have lice-killing effects. Abametaprine is a metalloproteinase inhibitor that targets metalloproteinases crucial for lice development and hatching. Pharmacodynamics Studies have shown that abametapillin inhibits various stages of head and body lice embryonic development by interfering with enzymes crucial for lice embryonic development. Abametapillin is unique compared to other lice treatments, requiring only a single dose, while many existing therapies, due to their superior efficacy and unique mechanism of action, typically require two doses. Its main metabolite, the abametapillin carboxyl group, has a long residence time in the body, with an estimated half-life of 71 ± 40 hours or longer in adults. Because this metabolite has been shown to inhibit cytochrome P450 enzymes in vitro, substrates of CYP3A4, CYP2B6, or CYP1A2 should be avoided for two weeks after abametapillin administration. The abametapillin emulsion formulation contains benzyl alcohol, which has been associated with significant toxicity following accidental systemic exposure, particularly in newborns and low birth weight infants. Preparations containing benzyl alcohol should not be given to infants under 6 months of age, and caution should be exercised when administering it to pediatric patients under direct adult supervision to minimize the risk of accidental oral ingestion.

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0.74% abametapillin emulsion is a single 10-minute topical treatment for head lice. Two large phase 3 clinical trials have confirmed its efficacy in treating head lice infestations in subjects 6 months and older. This study demonstrates that abametapillin emulsion is effective in killing lice eggs. [1]

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Current in vitro results fully confirm the ovicidal activity of abametapillin. The novel chemical structure and unique predictive mechanism of action of abametapillin represent a new treatment approach that incorporates ovicidal efficacy as a key component of effective treatment throughout the entire life cycle of head lice. Further studies will evaluate the safety and efficacy of this new approach in the practical application of treating head lice infestations. [2]

C12H12N2

184.242

184.1

C, 78.23; H, 6.57; N, 15.21

1762-34-1

1762-34-1

15664

White to off-white solidw powder

1.1±0.1 g/cm3

315.7±37.0 °C at 760 mmHg

114-117 °C(lit.)

119.3±18.1 °C

0.0±0.6 mmHg at 25°C

1.566

2.2

0

2

1

14

161

0

N1C([H])=C(C([H])([H])[H])C([H])=C([H])C=1C1C([H])=C([H])C(C([H])([H])[H])=C([H])N=1

PTRATZCAGVBFIQ-UHFFFAOYSA-N

InChI=1S/C12H12N2/c1-9-3-5-11(13-7-9)12-6-4-10(2)8-14-12/h3-8H,1-2H3

5,5'-dimethyl-2,2'-bipyridinyl

Xeglyze 6,6'-Bi-3-picoline HA-44 BRN-0123183HA44 BRN 0123183HA 44 BRN0123183 Abametapir

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: (1). This product requires protection from light (avoid light exposure) during transportation and storage.  (2). Please store this product in a sealed and protected environment (e.g. under nitrogen), avoid exposure to moisture.

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ~25 mg/mL (~135.69 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (13.57 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (13.57 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (13.57 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)