Image-Based Dosimetry in Dogs and Cross-Reactivity with Human Tissues of IGF2R-Targeting Human Antibody.

BACKGROUND: Osteosarcoma (OS) represents the most common primary bone tumor in humans and in companion dogs, being practically phenotypically identical. There is a need for effective treatments to extend the survival of patients with OS. Here, we examine the dosimetry in beagle dogs and cross-reactivity with human tissues of a novel human antibody, IF3, that targets the insulin growth factor receptor type 2 (IGF2R), which is overexpressed on OS cells, making it a candidate for radioimmunotherapy of OS. METHODS: [89Zr]Zr-DFO-IF3 was injected into three healthy beagle dogs. PET/CT was conducted at 4, 24, 48, and 72 h. RAPID analysis was used to determine the dosimetry of [177Lu]Lu-CHXA"-IF3 for a clinical trial in companion dogs with OS. IF3 antibody was biotinylated, and a multitude of human tissues were assessed with immunohistochemistry. RESULTS: PET/CT revealed that only the liver, bone marrow, and adrenal glands had high uptake. Clearance was initially through renal and hepatobiliary excretion in the first 72 h followed by primarily physical decay. RAPID analysis showed bone marrow to be the dose-limiting organ with a therapeutic range for 177Lu calculated to be 0.487-0.583 GBq. Immunohistochemistry demonstrated the absence of IGF2R expression on the surface of healthy human cells, thus suggesting that radioimmunotherapy with [177Lu]Lu-CHXA"-IF3 will be well tolerated. CONCLUSIONS: Image-based dosimetry has defined a safe therapeutic range for canine clinical trials, while immunohistochemistry has suggested that the antibody will not cross-react with healthy human tissues.

Safety Evaluation of an Alpha-Emitter Bismuth-213 Labeled Antibody to (1→3)-ß-Glucan in Healthy Dogs as a Prelude for a Trial in Companion Dogs with Invasive Fungal Infections.

Background: With the limited options available for therapy to treat invasive fungal infections (IFI), radioimmunotherapy (RIT) can potentially offer an effective alternative treatment. Microorganism-specific monoclonal antibodies have shown promising results in the experimental treatment of fungal, bacterial, and viral infections, including our recent and encouraging results from treating mice infected with Blastomyces dermatitidis with 213Bi-labeled antibody 400-2 to (1→3)-ß-glucan. In this work, we performed a safety study of 213Bi-400-2 antibody in healthy dogs as a prelude for a clinical trial in companion dogs with acquired invasive fungal infections and later on in human patients with IFI. Methods: Three female beagle dogs (≈6.1 kg body weight) were treated intravenously with 155.3, 142.5, or 133.2 MBq of 213Bi-400-2 given as three subfractions over an 8 h period. RBC, WBC, platelet, and blood serum biochemistry parameters were measured periodically for 6 months post injection. Results: No significant acute or long-term side effects were observed after RIT injections; only a few parameters were mildly and transiently outside reference change value limits, and a transient atypical morphology was observed in the circulating lymphocyte population of two dogs. Conclusions: These results demonstrate the safety of systemic 213Bi-400-2 administration in dogs and provide encouragement to pursue evaluation of RIT of IFI in companion dogs.

A Proof-of-concept Study Using Quantitative Sensory Threshold Analysis to Compare Two Intraoral Topical Anesthetics.

PURPOSE: CTY-5339A is an investigational topical anesthetic spray containing 14% benzocaine/2% tetracaine in a metered canister. Each spray delivers ∼0.2 mL of solution. This double-blind, randomized, crossover study compared the local anesthetic effect of CTY-5339A versus 14% benzocaine alone by using 2 quantitative sensory threshold experimental pain paradigms on the maxillary gingiva: pin prick test pain intensity (PPT PI) and heat pain threshold (HPT). METHODS: American Society of Anesthesiology Class 1 and 2 subjects (N = 50) were enrolled in this study. To qualify for the study, subjects were tested on the anterior maxillary gingiva with both PPT and HPT. Subjects had to report a PPT PI of ≥3 on a 0 to 10 numeric pain intensity scale on 1 of 2 consecutive pin pricks separated by 10 s, with at least one score ≥4. After PPT, mean HPT following 2 ramps in the same location had to be ≤ 46.5 °C, with each ramp beginning at 35 °C and an automatic cutoff of 50.6 °C. For treatment visits, subjects were randomly administered either 1 spray of CTY-5339A or 14% benzocaine to the anterior maxillary gingiva within 3 weeks of screening and then the alternative treatment 5 days to 2 weeks later. PPT PI and HPT were recorded immediately before drug application. After drug administration, PPT PI was recorded every minute through 5 min. Commencing at 5 min, PPT PI and HPT were recorded every 5 min through 60 min. For assessment of methemoglobin concentrations, venous blood (5 mL) was drawn from the antecubital fossa both before and 60 min after drug application. Oxygen saturation was recorded via pulse oximetry at baseline and every 10 min. FINDINGS: The AUCs for pain intensity difference from 0-30 and 0-60 min after PPT and HPT differences were significantly greater (P < 0.0001) for CTY-5339A compared with 14% benzocaine. Multiple time points on the time-action curves for PPT PI difference and HPT difference statistically (P < 0.05) favored CTY-5399A. Methemoglobin and oxygen saturation levels did not change compared with baseline after dosing with either treatment. IMPLICATIONS: Recommended doses of CTY-5339A provided significantly more profound and sustained local anesthesia than 14% benzocaine when applied to the maxillary gingiva. Significant changes in methemoglobin or oxygen saturation concentrations did not occur for either drug. ClinicalTrials.gov identifier: NCT03233737.

Lack of Methemoglobin Elevations After Topical Applications of Benzocaine Alone or Benzocaine Plus Tetracaine to the Oral Mucosa.

PURPOSE: This study evaluated changes in methemoglobin and oxygen saturation concentrations after the administration of recommended doses of 14% benzocaine alone or 14% benzocaine combined with 2% tetracaine. METHODS: American Society of Anesthesiology class 1 and 2 subjects (n = 40) were enrolled in this modified crossover study. Subjects were administered 0.2 mL of 14% benzocaine alone, 0.2 mL of 14% benzocaine plus 2% tetracaine, or 0.4 mL of 14% benzocaine plus 0.2% benzocaine to their cheek mucosa. Venous blood (5 mL) was drawn from the antecubital fossa before and 60 minutes after drug application for methemoglobin analyses. Oxygen saturation was also recorded via pulse oximetry at baseline and every 10 minutes through 60 minutes after drug application. FINDINGS: Methemoglobin and oxygen saturation levels did not change from baseline after the administration of benzocaine alone or when combined with tetracaine. IMPLICATIONS: Recommended doses of benzocaine or benzocaine combined with tetracaine when applied to the cheek mucosa do not induce even clinically insignificant elevations in methemoglobin levels. Metered dosing, such as that used in this study, can help avoid this overdose phenomena with these drugs. ClinicalTrials.gov identifier: NCT02908620.

Phase Four, Randomized, Double-Blinded, Controlled Trial of Phentolamine Mesylate in Two- to Five-year-old Dental Patients.

PURPOSE: The purpose of this study was to evaluate, using a randomized, double-blind methodology: (1) the safety of phentolamine mesylate (Oraverse) in accelerating the recovery of soft tissue anesthesia following the injection of two percent lidocaine plus 1:100,000 epinephrine in two- to five-year-olds; and (2) efficacy in four- to five-year-olds only. METHODS: One hundred fifty pediatric dental patients underwent routine dental restorative procedures with two percent lidocaine plus 1:100,000 epinephrine with doses based on body weight. Phentolamine mesylate or a sham injection (two to one ratio) was then administered. Subjects were monitored for safety and, in four- to five-year-olds, for efficacy during the two-hour evaluation period. RESULTS: There were no significant differences in adverse events between the phentolamine and sham injections. Compared to sham, phentolamine was not associated with nerve injury, increased analgesic use, or abnormalities of the oral cavity. Phentolamine was associated with transient decreased blood pressure in some children. In four- and five-year-olds, phentolamine induced more rapid recovery of lip anesthesia by 48 minutes (P<0.0001). CONCLUSIONS: Phentolamine was well tolerated and safe in three- to five-year-olds; in four- to five-year-olds, a statistically significant more rapid recovery of lip sensation compared to sham injections was determined.

Characterization and treatment of postsurgical dental implant pain employing intranasal ketorolac.

The intensity and duration of pain following surgical placement of dental implants has not been well studied. Thus, the aim of this open-label study was to characterize the nature of postsurgical pain following the placement of one to three implants. The secondary goal was to explore the analgesic efficacy and tolerability of intranasal ketorolac in this patient population. Following implant surgery, postoperative pain was rated moderate or severe in 25/28 patients (89 percent), requiring prn analgesic dosing for up to 3 days in 14/25 individuals (56 percent). Intranasal ketorolac displayed an analgesic onset within 20 minutes, a duration of at least 6 hours, and was well tolerated by the cohort with brief stinging of the nasal mucosa reported by 9/25 individuals (36 percent).

The cardiovascular effects and pharmacokinetics of intranasal tetracaine plus oxymetazoline: preliminary findings.

BACKGROUND: The authors evaluated the cardiovascular effects and pharmacokinetics of an intranasal 3 percent tetracaine/0.05 percent oxymetazoline spray developed to provide needle-free anesthesia of maxillary teeth. METHODS: The authors administered to 12 participants a proposed maximum recommended dose (MRD) (18 milligrams tetracaine/0.3 mg oxymetazoline) as three bilateral pairs of 0.1-milliliter nasal sprays. They administered two times this dose (36 mg tetracaine/0.6 mg oxymetazoline) as six bilateral pairs one to three weeks later. The authors recorded the patients' heart rate, blood pressure and oxygen saturation. They drew blood samples at baseline and 15 times during the two hours after drug administration. RESULTS: Physiological measures remained fairly stable throughout the two-hour period, with small but significant decreases (P < .05) in heart rate at 40 and 50 minutes for the two-times MRD (6.1 beats/minute) and MRD (7.5 beats/minute) administrations, respectively, and a significant increase in diastolic blood pressure (5.9 millimeters of mercury) for the two-times-MRD administration at 90 minutes. Mean oxygen saturation remained above 99 percent. Tetracaine plasma levels were undetectable in most participants, whereas concentrations of its major metabolite parabutylaminobenzoic acid from the two-times-MRD administration were approximately twice that from the MRD administration. Oxymetazoline concentrations from the two-times-MRD administration were approximately 50 percent greater than those from the MRD administration, with a half-life of 1.72 to 2.32 hours. CONCLUSIONS: Intranasal tetracaine/oxymetazoline mist generally was well tolerated in study participants. CLINICAL IMPLICATIONS: The safety profile and pharmacokinetics of this intranasal formulation indicate that it appears to be generally well tolerated in patients for achieving anesthesia of the maxilla. Additional safety and efficacy data are required, particularly in patients with cardiovascular disease and other comorbidities.

Hemostatic and anesthetic efficacy of 4% articaine HCl with 1:200,000 epinephrine and 4% articaine HCl with 1:100,000 epinephrine when administered intraorally for periodontal surgery.

BACKGROUND: The objective of this double-masked, randomized, multicenter crossover study was to compare the efficacy of 4% articaine HCl with 1:100,000 epinephrine (A100) to 4% articaine HCl with 1:200,000 epinephrine (A200) for providing effective local anesthesia and hemostasis for periodontal surgery. METHODS: Anesthetic efficacy was based on patient self-report and lack of need for reinjection during the surgical procedures. Hemostatic properties of the formulations were compared using ratings of the surgeons' ability to visualize the surgical field and expectation for bleeding. The volume of blood collected during each surgical session also was measured and compared. RESULTS: Forty-two adult subjects (26 males and 16 females, mean age 46.3 +/- 9.7 years) diagnosed with moderate to severe periodontal disease requiring local anesthesia for matched bilateral periodontal surgery were enrolled and completed the study. Subjects reported satisfactory surgical anesthesia following the A100 and A200 formulations; no supplemental local anesthesia was administered. Significant differences between the A100 and A200 treatments were found for the surgeons' ability to visualize the surgical field (rated as clear 83.3% of the time with A100 and 59.5% of the time with A200; P = 0.008), bleeding expectation (rated as equal to or better than expected 85.7% of the time with A100 and 71.4% of the time with A200; P = 0.034), and volume of blood loss (54.9 +/- 36.0 ml for A100 and 70.2 +/- 53.0 ml for A200; P = 0.018). Sixteen patients experienced 27 mild or moderate adverse events; the most common were postoperative pain (nine patients) and swelling (eight patients). Six adverse events may have been related to treatment. The frequency of adverse events did not vary between formulations. CONCLUSIONS: For patients undergoing periodontal surgery, 4% articaine anesthetic formulations containing epinephrine (1:100,000 or 1:200,000) provided excellent surgical pain control. For patients who can tolerate higher amounts of epinephrine, the 4% articaine 1:100,000 epinephrine formulation had the additional therapeutic advantage of providing better visualization of the surgical field and less bleeding.

The pharmacokinetics and cardiovascular effects of high-dose articaine with 1:100,000 and 1:200,000 epinephrine.

OBJECTIVES: The authors conducted a randomized, double-blind, two-way crossover clinical trial to compare the pharmacokinetics and cardiovascular effects of 11.9 milliliters of 4 percent articaine hydrochloride (HCl) plus 1:100,000 epinephrine (A100) with those of 11.9 mL of 4 percent articaine HCl plus 1:200,000 epinephrine (A200). METHODS: During two testing sessions, the authors administered injections of A100 and A200 over a seven-minute period (in one-cartridge doses unless otherwise noted): maxillary right first molar infiltration, maxillary left first molar infiltration, maxillary right first premolar infiltration, maxillary left first premolar infiltration, right inferior alveolar injection, left inferior alveolar injection, right long buccal infiltration (one-half cartridge) and left long buccal infiltration (one-half cartridge). They analyzed venous blood samples for articaine levels. They used noninvasive acoustic tonometry to measure a variety of cardiovascular parameters over a two-hour period. RESULTS: Plasma concentration curves of articaine over time were similar for both solutions, with peak concentrations and times to maximum concentration being 2,037 nanograms per milliliter and 22 minutes for A100 and 2,145 ng/mL and 22 minutes for A200. At the 10-minute point, the mean systolic blood pressure and heart rate were significantly elevated (P < .05) with A100 versus A200. CONCLUSIONS: Maximum dose recommendations for the A100 solution also can be applied to the A200 solution. A200 produces less cardiovascular stimulation than does A100. CLINICAL IMPLICATIONS: A200 is as safe as A100, and may be preferable to A100 in patients with cardiovascular disease and in those taking drugs that reportedly enhance the systemic effects of epinephrine.

The anesthetic efficacy of 4 percent articaine 1:200,000 epinephrine: two controlled clinical trials.

OBJECTIVE: The authors conducted two double-blinded, randomized, multicenter clinical trials to determine the efficacy and clinical anesthetic characteristics of 4 percent articaine hydrochloride (HCl) with 1:200,000 epinephrine (A200) as compared with those of 4 percent articaine HCl with 1:100,000 epinephrine (A100) and 4 percent articaine HCl without epinephrine (Aw/o). METHODS: During separate testing sessions, members of the authors' research team used three articaine study formulations to induce either inferior alveolar nerve block anesthesia (Trial 1) or maxillary infiltration anesthesia (Trial 2). In each trial, subjects received, in a randomized sequence, each of the three formulations to determine efficacy (success rate) and anesthetic characteristics (onset time and duration). The authors evaluated pulpal anesthesia via subjects' response to electric pulp testing (EPT). RESULTS: A total of 126 subjects were enrolled in the two studies (63 subjects in each trial). In both mandibular and maxillary trials, the success rates for inducing profound anesthesia (EPT score > 80), the mean onset times and the mean durations of anesthesia were similar for both epinephrine-containing formulations (A200 and A100). In subjects who received the formulation containing no epinephrine (Aw/o), the success rate for profound anesthesia was significantly less. CONCLUSION: These studies demonstrated that the inclusion of epinephrine in 4 percent articaine anesthetic formulations is essential for achieving profound anesthesia. The authors found that the A200 formulation provided a level of pulpal anesthesia comparable with that of the A100 formulation.