Insulin-Derived Cutaneous Amyloidosis: A Possible Complication of Repeated Insulin Injections.

Primary localized cutaneous amyloidosis (PLCA) is characterized by extracellular deposition of pathological fibril aggregation of proteins in the skin without systemic involvement. Macular amyloidosis, lichen (papular) amyloidosis, and nodular amyloidosis are three different subtypes of PLCA. Although the pathological mechanism of PLCA has not yet been clarified, it is assumed that a nucleus formation of amyloid fibril is formed due to repeated external stimulation, such as subcutaneous injection, which often poses diagnostic challenges. Herein, we present a 54-year-old Korean male patient with cutaneous localized amyloidosis which occurred after repeated local insulin injections, and discuss the relationship between insulin therapy in patients with diabetes mellitus and dermal amyloid deposition.

Efficacy and safety of lanadelumab in Japanese patients with hereditary angioedema: A phase 3 multicenter, open-label study.

The safety and efficacy of lanadelumab for the prevention of hereditary angioedema (HAE) attacks have not been studied in Japanese patients. We report outcomes from a phase 3, multicenter, open-label study (NCT04180163) of lanadelumab in Japanese patients with HAE. Japanese patients with HAE aged ≥12 years with ≥1 investigator-confirmed HAE attack during the 4-week run-in baseline period were enrolled into the study and received lanadelumab 300 mg every 2 weeks subcutaneously for 52 weeks. Dosing could be reduced to 300 mg every 4 weeks during the second 26-week treatment period if patients had well-controlled symptoms (e.g., attack-free) for 6 months. The primary efficacy endpoint was no investigator-confirmed HAE attacks (attack-free status) during days 0-182. Other outcomes included the rate of investigator-confirmed HAE attacks per month (28 days) and lanadelumab safety. Twelve patients (mean ± SD age 41.9 ± 12.4 years) were enrolled. During the first 26 weeks (days 0-182), five (41.7%) patients were attack-free. The mean ± SD HAE attack rate per month decreased by 74.0%, from 3.8 ± 2.4 during baseline to 1.2 ± 2.6 during the overall 52-week treatment period. There were no deaths or discontinuations due to treatment-emergent adverse events (TEAEs), no severe or serious TEAEs related to lanadelumab, and no positive anti-drug antibody results. The most frequent TEAEs were injection-site reactions (37 events in six patients). Most of the injection-site reaction adverse events were mild in severity. Results of this study support the findings from two global phase 3 studies for lanadelumab use as prophylactic therapy in Japanese patients with HAE.

Botulinum Toxin Type a for Treating Rest Pain in Chronic Limb-threatening Ischemia: A Case Report.

Botulinum toxin type A (BoNT/A) is a potent neurotoxin with widely use range, for the good outcomes in the treatment of pain, it was considered as an unique analgesic drugs with the feature of sustained efficacy after a single application, but up to now, treating chronic limb-threatening ischemia (CLTI) with BoNT/A was rarely reported. We present a 91-year-old man with CLTI, the main clinical manifestations were left foot rest pain, intermittent claudication and toe necrosis, the patient refused invasive treatments, and the pain failure to respond to conventional analgesic drugs, the subcutaneous injections of BoNT/A was performed to the patient. The pain score on the visual analog scale (VAS), decreased from 5-6 (before treatment) to 1 within days after infiltration, and keep in 1-2 of VAS during follow-up. Our case report demonstrated that BoNT/A may be an unique minimally invasive solution for treating rest pain in CLTI.

Botulinum toxin type a for great auricular neuralgia.

great auricular neuralgia is a rare disorder with only 18 cases described in the literature. Since it's a rare disorder, there are no evidence-based therapeutic recommendations but only case reports to guide physicians. We report a case of great auricular neuralgia treated with botulinum toxin type A subcutaneous injection with significant remission of pain. Botulinum toxin type A could be an effective and safe treatment in this setting; however, more studies are needed to confirm our results.

Subcutaneous Administration of Medications and Fluids by Nonprofessional Caregivers at Home.

Background: Patients requiring home-based palliative care have advanced complex illnesses with functional limitations and decline. This retrospective study reviewed caregiver administration of subcutaneous (SQ) medications and fluids when symptom control could not be achieved using the oral route. Methods: Medical records from September 1, 2017 to February 28, 2018 were reviewed for 272 consecutive patients who received SQ administration of medications or fluids at a home-based palliative care program. We analyzed the clinical characteristics of patients and caregivers, medications administered, and catheter outcomes. Results: Patients' median age was 74 years, and 163 (60%) were women. The most common cancer diagnoses were stomach 26 (12%), lung 22 (10%), and colorectal 20 (9%). Dementia 24 (44%), cerebrovascular disease 9 (16%), and congestive heart failure 7 (13%) were the most frequent nonmalignant diseases. Poor symptom control 162 (60%) and impaired oral intake 107 (39%) were the most common indications for an SQ route of administration. Nonprofessional caregivers trained by a nurse administered medications to 218 patients (80%). During interventions, the patients received a mean of 4 medications (±2 standard deviation). A total of 903 catheters were inserted, 15/732 (2%) catheters handled by nonprofessional caregivers caused a local infection, compared with 3/171 (1.8%) of catheters handled by nurses. Hydromorphone was the most common opioid used (57%), followed by morphine (35%). The median length of stay in the program was 24 days (interquartile range: 11-60). Conclusions: SQ administration of medications and fluids by nonprofessional caregivers trained by health care professionals is feasible and promising, but additional testing is needed.

Enxertos compostos de gordura para correção de distrofia facial em caso de esclerodermia localizada / Composite fat grafts for correcting facial dystrophy in a case of localized scleroderma

A esclerodermia localizada (morfeia linear) é uma doença rara que causa distrofia e assimetria faciais em mulheres jovens. É relatado o caso de uma paciente de 20 anos que foi tratada com enxertos compostos de gordura. Após a coleta do lipoaspirado de gordura subcutânea profunda, a microgordura e a nanogordura não filtrada foram processadas separadamente para formar enxertos compostos de gordura. Estes foram meticulosamente transplantados em camadas, para reconstruir o subcutaneo da face da paciente. Após um ano, observou-se boa pega de gordura com correção bem-sucedida da assimetria e restabelecimento do equilíbrio facial.

Localized scleroderma (linear morphea) is a rare disease that causes facial dystrophy and asymmetry in young women. We report the case of a 20-year-old female patient who was treated with novel composite fat grafts. After extracting lipoaspirate from deep subcutaneous fat, the microfat and the unfiltered nanofat were processed separately, and amalgamated, obtaining composite fat grafts. These were meticulously transplanted layer by layer to rebuild the subcutaneous tissue of the patient's face. After one year, a good volume of fat retention was observed with successful correction of asymmetry and restoration of facial balance.

Real-world results with IgPro20 for hypo- or agammaglobulinemia in Japan.

BACKGROUND: Subcutaneous immunoglobulin is one of the standard treatments for hypogammaglobulinemia in primary immunodeficiencies (PID) worldwide. In Japan, IgPro20 (Hizentra® ; l-proline-stabilized 20% human subcutaneous immunoglobulin) is approved for agammaglobulinemia or hypogammaglobulinemia due to PID or secondary immunodeficiency (SID); however, its safety and effectiveness has not previously been assessed in a real-world setting. METHODS: This multicenter, open label post-marketing surveillance study was conducted between January 2014 and March 2019. Patients who received IgPro20 due to PID or SID were included after informed consent. Physicians completed a case report form for each patient. Safety was determined from reported adverse events (AEs), adverse drug reactions, and serious AEs (SAEs); effectiveness was assessed by infection rates after the first IgPro20 dose. RESULTS: Of 85 patients receiving IgPro20 in the safety analysis, 39 developed AEs (45.9%; PID n = 28, SID n = 11). At least one adverse drug reaction was observed in 27 patients (31.8%; PID n = 21, SID n = 6), and the most common were injection site reactions (n = 17, 20.0%). Four patients (PID n = 3, SID n = 1) reported SAEs but two were unrelated to IgPro20 administration. The infection rate decreased from 0.54 per patient during the 6 months before IgPro20 to 0.39 per patient during IgPro20 treatment. Serious bacterial infections occurred in six patients before IgPro20 (7.9%; PID n = 2; SID n = 4) but in only one patient with SID during IgPro20 treatment (1.2%). CONCLUSIONS: In Japan, IgPro20 was considered safe and effective among patients with agammaglobulinemia or hypogammaglobulinemia due to PID or SID.

Predictive Factors for Rheumatoid Arthritis Flare After Switching From Intravenous to Subcutaneous Formulation of Tocilizumab in Real-World Practice.

BACKGROUND: To evaluate the incidence and related factors of rheumatoid arthritis (RA) flares after switching from intravenous tocilizumab (TCZ-IV) to subcutaneous tocilizumab (TCZ-SC) injection in stable RA patients. METHODS: We retrospectively evaluated the medical records of stable RA patients who used TCZ-IV for more than 6 months and switched to TCZ-SC between January 2013 and April 2020. RA flare was defined as an increase of more than 1.2 in the RA disease activity as assessed by the disease activity score in 28 joints. The factors associated with RA flare were evaluated by logistic regression analysis. RESULTS: Among 106 patients treated with TCZ-IV for > 6 months, 37 patients were switched to TCZ-SC after the acquisition of remission or low disease activity. RA flares occurred in 11 (29.7%) of patients who switched TCZ-SC. Results from the multivariable logistic analysis revealed that the dose of TCZ-IV per weight at switching (odds ratio [OR], 20.70; 95% confidence interval [CI], 2.22-192.84; P = 0.008) and methotrexate (MTX) non-use (OR, 8.53; 95% CI, 1.21-60.40; P = 0.032) were associated with the risk of RA flares after switching to TCZ-SC. Interestingly, most patients who switched back to TCZ-IV had their RA activity controlled again. CONCLUSION: MTX non-use and high dose of TCZ-IV per weight were associated with a risk of RA flare after switching to TCZ-SC. RA patients with these factors need to be carefully observed for flare after switching from TCZ-IV to TCZ-SC.

Evaluation of In Vitro Tools to Predict the In Vivo Absorption of Biopharmaceuticals Following Subcutaneous Administration.

PURPOSE: For injectable biopharmaceuticals, the subcutaneous route of administration is increasingly preferred over intravenous administration. However, one of the challenges in the development of subcutaneously administered biopharmaceuticals is a reduced bioavailability, which is difficult to predict. Since animal models do not reliably reflect bioavailability in patients, in vitro models could help to develop drug candidates. The purpose of this study was to evaluate a versatile set of in vitro tools for their suitability to predict bioavailability of biopharmaceuticals after subcutaneous administration. METHODS: We examined seven commercially available biopharmaceuticals using three instruments, i.e., the Subcutaneous Injection Site Simulator (Scissor), the Osmomat 050, and a dialysis system using three artificial extracellular matrices, two dissolution apparatuses, i.e., the USP4 and the USP7, and two evaluation tools, i.e., the affinity-capture self-interaction nanoparticle spectroscopy (AC-SINS) and the Developability Index (DI). Results were evaluated for their usefulness to predict the bioavailability and other pharmacokinetic parameters in humans using the Pearson correlation. RESULTS: None of the tested instruments and methods could reliably approximate bioavailability. Only pressure values derived with the Osmomat 050 instrument correlated with Cmax with a Pearson correlation coefficient greater than 0.8. CONCLUSION: No single in vitro method confidently predicted the bioavailability in humans. We only found a correlation to maximum plasma concentration values for one of the tested approaches. However, a more focused evaluation would be necessary to confirm our findings and test combinations of orthogonal methods that may improve the confidence of such a prediction.

Free Silicone-Induced Granulomatosis and Hypercalcemia in a Transgender Female.

Introduction: Vitamin D derangements are a rare but important cause of hypercalcemia. Granulomatous disease is a primary cause of vitamin D derangements and is frequently associated with sarcoidosis, tuberculosis, and in the present case, foreign body granulomatosis. Liquid or injectable silicone is used as a filler for cosmetic body contouring. Transgender patients may seek silicone injections as part of gender affirmation surgeries. Granuloma formation is a rare but well-described complication of injectable silicone. Case Description: A 40-year-old, assigned male at birth (AMAB) transgender female patient, with a history of HIV and chronic kidney disease (CKD) stage 3b, was admitted to the emergency department for evaluation of hypercalcemia. One year prior, the hypercalcemia was attributed to CKD secondary to HIV or HIV medications. The patient presented after two weeks of polyuria and polydipsia. Her vital signs were stable, and the physical exam, EKG, and chest x-ray were unremarkable. Labs were notable for calcium (14.1 mg/dL, assay normal range 8.5-10.5 mg/dL) and acute-on-chronic kidney disease. Follow-up labs were consistent with a vitamin D aberration causing hypercalcemia, raising suspicion for granulomatous disease. CT chest/abdomen/pelvis without contrast demonstrated diffuse skin thickening of the bilateral breasts and buttocks with associated ill-defined soft tissue density and scattered punctate calcifications. No hilar adenopathy or lung abnormalities were observed, decreasing the suspicion of sarcoidosis or an infectious etiology. The patient disclosed having received free silicone injections to which the hypercalcemia was attributed. After single doses of calcitonin (100U SC/IM) and zoledronic acid (4 mg IV), her hypercalcemia resolved. Kidney function gradually returned to baseline with IV fluids. Conclusion: This case illustrates the importance of readily recognizing the imaging characteristics of free silicone granulomatosis, which showed subcutaneous fat infiltrated with soft tissue nodules and calcifications. The distribution of findings in the bilateral breast and buttocks and history of free silicone injections were most useful in arriving at a diagnosis and treatment plan.

Providing End-of-Life Care in the Community: What Are the Challenges in Malaysia?

A 72-year-old woman with metastatic lung cancer to bone and brain and with left external iliac vein thrombosis was under the care of a community palliative care provider. She experienced an acute pain crisis due to acute limb ischemia of the left lower limb. Goals-of-care discussions were held with the patient and her family; she prioritized symptom control and end-of-life care at home. The family and patient were aware of her short prognosis. Her complex pain was managed by the community palliative team, and her family was empowered to give subcutaneous injections. We illustrate a case showing the importance of community health services with palliative care support in providing symptom management and support to patient and family caregivers throughout the course of a life-limiting illness. It also highlights family caregivers' potential psychological distress in delivering subcutaneous injections in terminal care for a patient at home.

The effect of topically administered lavender aromatherapy on the pain of insulin injection in diabetic patients: a double-blind randomized controlled clinical trial.

BACKGROUND: Needle phobia occurs in more than half of diabetic patients due to the pain caused by frequent insulin injections. Therefore, this study evaluated the effect of topically administered lavender aromatherapy on the pain of insulin injections in diabetic patients. METHODS: In this double-blind randomized controlled and experimental study, patients who met the study criteria were divided into three groups; topical lavender oil (n = 60), placebo (n = 60), and control (n = 60) groups. The data were collected using the "Patient Information Form", the "Follow-up Form", the "Verbal Category Scale (VCS)", and the "Visual Analogue Scale (VAS)". RESULTS: The results revealed no significant difference between the patients in the topical lavender oil group before and during the insulin injection in terms of VAS and VCS pain scores (p > 0.05). In the placebo and control groups, the mean VAS and VCS pain scores during insulin injection were found to be significantly higher than before insulin injection (p < 0.05). Besides, the mean VAS and VCS scores during insulin injection were significantly higher in the placebo and control groups than the topical lavender oil group (p < 0.05). DISCUSSION: : The study showed that patients who were administered topical lavender oil felt less pain after insulin injection than those in the placebo and control groups. Therefore, topically applied lavender aromatherapy can be easily used for pain control in insulindependent diabetic patients (clinical trial number NCT04767737).

Subacute AMD3100 Treatment Is Not Efficient in Neonatal Hypoxic-Ischemic Rats.

BACKGROUND AND PURPOSE: Despite the advances in treating neonatal hypoxic-ischemic encephalopathy (HIE) with induced hypothermia, the rates of severe disability are still high among survivors. Preclinical studies have indicated that cell therapies with hematopoietic stem/progenitor cells could improve neurological outcomes in HIE. In this study, we investigated whether the administration of AMD3100, a CXCR4 antagonist that mobilizes hematopoietic stem/progenitor cells into the circulation, has therapeutic effects in HIE. METHODS: P10 Wistar rats of both sexes were subjected to right common carotid artery occlusion or sham procedure, and then were exposed to hypoxia for 120 minutes. Two subcutaneous injections of AMD3100 or vehicle were given on the third and fourth day after HIE. We first assessed the interindividual variability in brain atrophy after experimental HIE and vehicle treatment in a small cohort of rats. Based on this exploratory analysis, we designed and conducted an experiment to test the efficacy of AMD3100. Brain atrophy on day 21 after HIE was defined as the primary end point. Secondary efficacy end points were cognitive (T-water maze) and motor function (rotarod) on days 17 and 18 after HIE, respectively. RESULTS: AMD3100 did not decrease the brain atrophy in animals of either sex. Cognitive impairments were not observed in the T-water maze, but male hypoxic-ischemic animals exhibited motor coordination deficits on the rotarod, which were not improved by AMD3100. A separate analysis combining data from animals of both sexes also revealed no evidence of the effectiveness of AMD3100 treatment. CONCLUSIONS: These results indicate that the subacute treatment with AMD3100 does not improve structural and functional outcomes in a rat HIE model.

Subcutaneous progesterone versus vaginal progesterone for luteal phase support in in vitro fertilization: A retrospective analysis from daily clinical practice.

OBJECTIVE: Progesterone application for luteal phase support is a well-established concept in in vitro fertilization (IVF) treatment. Water-soluble subcutaneous progesterone injections have shown pregnancy rates equivalent to those observed in patients receiving vaginal administration in randomized controlled trials. Our study aimed to investigate whether the results from those pivotal trials could be reproduced in daily clinical practice in an unselected patient population. METHODS: In this retrospective cohort study in non-standardized daily clinical practice, we compared 273 IVF cycles from 195 women undergoing IVF at our center for luteal phase support with vaginal administration of 200 mg of micronized progesterone three times daily or subcutaneous injection of 25 mg of progesterone per day. RESULTS: Various patient characteristics including age, weight, height, number of oocytes, and body mass index were similar between both groups. We observed no significant differences in the clinical pregnancy rate (CPR) per treatment cycle between the subcutaneous (39.9%) and vaginal group (36.5%) (p=0.630). Covariate analysis showed significant correlations of the number of transferred embryos and the total dosage of stimulation medication with the CPR. However, after adjustment of the CPR for these covariates using a regression model, no significant difference was observed between the two groups (odds ratio, 0.956; 95% confidence interval, 0.152-1.786; p=0.888). CONCLUSION: In agreement with randomized controlled trials in study populations with strict selection criteria, our study determined that subcutaneous progesterone was equally effective as vaginally applied progesterone in daily clinical practice in an unselected patient population.

Factors That Affect Symptoms of Injection Site Infection among Japanese Patients Who Self-Inject Insulin for Diabetes.

In Japan, skin disinfection is typically considered necessary before an insulin injection to prevent infection at the injection site. This cross-sectional study evaluated factors that influenced symptoms of injection site infection among 238 Japanese patients who self-injected insulin for diabetes between October 2015 and January 2016. A structured questionnaire was used to collect data regarding skin disinfection practices, infection symptoms at the injection site, frequency of injections, environment at the time of injection, and hygiene habits. The majority of patients (83.2%) performed skin disinfection before the self-injection. Logistic regression analysis revealed that infection at the injection site was positively associated with skin disinfection before injection, age, and performing injections outside home. It was speculated that omitting skin disinfection before administering subcutaneous insulin injection was not the factor that affected the symptoms of injection site infection. The greatest contributor to infection symptoms was injections performed outside the home. Future studies focusing on the environment, in which patients administer insulin injections, to assess its influence on symptoms of injection site infections are warranted.

Tumescent Injections in Subcutaneous Pig Tissue Disperse Fluids Volumetrically and Maintain Elevated Local Concentrations of Additives for Several Hours, Suggesting a Treatment for Drug Resistant Wounds.

PURPOSE: Bolus injection of fluid into subcutaneous tissue results in accumulation of fluid at the injection site. The fluid does not form a pool. Rather, the injection pressure forces the interstitial matrix to expand to accommodate the excess fluid in its volume, and the fluid becomes bound similar to that in a hydrogel. We seek to understand the properties and dynamics of externally tumesced (swollen) subcutaneous tissue as a first step in assessing whether tumescent antibiotic injections into wounds may provide a novel method of treatment. METHODS: Subcutaneous injections of saline are performed in live and dead pigs and the physical properties (volume, expansion ratio, residence time, apparent diffusion constant) of the resulting fluid deposits are observed with diffusion-weighted magnetic resonance imaging, computed tomography, and 3D scanning. RESULTS: Subcutaneous tissue can expand to a few times its initial volume to accommodate the injected fluid, which is dispersed thoroughly throughout the tumescent volume. The fluid spreads to peripheral unexpanded regions over the course of a few minutes, after which it remains in place for several hours. Eventually the circulation absorbs the excess fluid and the tissue returns to its original state. CONCLUSIONS: Given the evidence for dense fluid dispersal and several-hour residence time, a procedure is proposed whereby tumescent antibiotic injections are used to treat drug-resistant skin infections and chronic wounds that extend into the subcutaneous tissue. The procedure has the potential to effectively treat otherwise untreatable wounds by keeping drug concentrations above minimum inhibitory levels for extended lengths of time.

[Infiltration anesthesia]. / Infiltrationsanästhesie.

OBJECTIVE: Complete anesthesia of any skin and soft tissue area by intradermal, subcutaneous, or intramuscular injections. INDICATIONS: Small injuries or incisions in limbs or trunk, minor surgery on the face/jaw (e.g., on the teeth), or postoperative analgesia (local infiltration anesthesia, LIA). CONTRAINDICATIONS: Local infections at the injection site. SURGICAL TECHNIQUE: By means of intradermal, subcutaneous or intramuscular administration, a grandeur arises, here the local anesthetic blocks nerve transmission. If anesthetized distal to end arteries, vasoconstrictors (e.g., epinephrine) should be avoided. Proximal to end arteries, localized ischemia may facilitate operative care. POSTOPERATIVE MANAGEMENT: The effect of local anesthesia is self-limiting. RESULTS: By means of infiltration anesthesia or "field block", larger areas of skin are easily accessible for surgical treatment. The amount to be applied has to be adapted to the extent of the operation and the maximal dose. Postoperatively, after knee or hip arthroplasty, analgesia consumption can be reduced, and early mobilization promoted using LIA.

Insulin-derived amyloidosis without a palpable mass at the insulin injection site: A report of two cases.

To date, almost all case reports of insulin-derived amyloidosis described the presence of a subcutaneous mass that was observable on physical examination. This report presents two cases of insulin-derived amyloidosis without palpable masses at insulin injection sites. In both cases, blood glucose concentrations improved, and the insulin dose could be reduced by an average of 45% after changing the insulin injection sites. The insulin absorption at the site was reduced to at most 40% of that at a normal site in one case. Magnetic resonance imaging and ultrasonography were useful to screen and differentiate insulin-derived amyloidosis without a palpable mass. This report showed that insulin-derived amyloidosis without a palpable mass can be present at the insulin injection site, and has similar clinical effects to insulin-derived amyloidosis with palpable masses.

Investigation of factors that cause insulin precipitation and/or amyloid formation in insulin formulations.

BACKGROUND: Multiple daily subcutaneous injections (MDSIs) are mainly used for formulating an insulin therapy for diabetic patients; however, they also cause insulin-derived amyloidosis (IDA) and lead to poor glycemic control. In addition, for the continuous subcutaneous insulin infusion system (CSII), precipitation frequently causes catheter occlusion and, if the precipitate in the formulations is amyloid, the injection of the insoluble amyloid into the subcutaneous tissue leads to IDA. The aim of this study was to conduct in vitro experiments and present a situation where insulin formulations cause precipitation and amyloid formation. METHODS: Humulin®R and NovoRapid® were used as model formulations for MDSIs and CSII, respectively. The generation of the precipitation was evaluated by measuring turbidity, and amyloid formation was evaluated by using Thioflavin T. Humulin®R was mixed with saline buffer solutions and glucose solutions to evaluate the effect of dilution. In addition, we created an experimental system to consider the effect of the time course of condition changes, and investigated the effects of insulin concentration, m-cresol existence, and pH change on the generation of the precipitate and amyloid in the formulation. RESULTS: In both the original and diluted formulations, physical stimulation resulted in the formation of a precipitate, which in most cases was an amyloid. The amyloid was likely to be formed at a near neutral pH. On the contrary, although a precipitate formed when the pH was decreased to near the isoelectric point, this precipitate was not an amyloid. Further decreases in pH resulted in the formation of amyloids, suggesting that both the positive and negative charged states of insulin tended to form amyloids. The formulation additive m-cresol suppressed amyloid formation. When additives were removed from the formulation, the amyloid-containing gel was formed in the field of substance exchange. CONCLUSIONS: To consider changes in conditions that may occur for insulin formulations, the relationship between the formation of precipitates and amyloids was demonstrated in vitro by using insulin formulations. From the in vitro study, m-cresol was shown to have an inhibitory effect on amyloid formation.

Safety of a New Subcutaneous Testosterone Enanthate Auto-Injector: Results of a 26-Week Study.

INTRODUCTION: Patients with testosterone deficiency (TD) can be treated with exogenous testosterone (T) to achieve and maintain physiologic T levels and prevent negative clinical symptoms; with many testosterone replacement therapies currently available, this registration safety study was conducted to further characterize the clinical profile of chronically administered, concentration-guided subcutaneous testosterone enanthate (TE) dosing. AIM: The purpose of this study was to confirm the safety and characterize the pharmacokinetic (PK) profile of the subcutaneous TE auto-injector (SCTE-AI) in adult men with TD. METHODS: In this phase III, 26-week study, 133 men 18-75 years of age with symptomatic TD self-administered SCTE-AI 75 mg once weekly for 6 weeks from July 2015 to June 2016. Dosing was adjusted when indicated to 50 mg or 100 mg to maintain T trough levels between 350 and 650 ng/dL (12.1-22.5 nmol/L). PK data were collected from a subgroup of patients receiving 75 mg SCTE-AI through week 12. Safety, including ambulatory blood pressure monitoring (ABPM), lipid levels, and adverse drug reactions, and PK were assessed. MAIN OUTCOME MEASURES: The main outcomes were the documentation of the reproducibility of trough concentration-guided exposure to SCTE, 6-month safety profile, and PK data for the 75 mg dose SCTE. RESULTS: In total, 34 patients (25.6%) experienced adverse drug reactions; the most frequently reported were increased hematocrit (≥52%) in 10 patients (7.5%), injection-site hemorrhage in 6 patients (4.5%), injection-site bruising in 4 patients (3.0%), and increased prostate-specific antigen in 4 patients (3.0%). By week 26, mean systolic and diastolic blood pressure (BP) measured in the clinic increased by 3.4 mmHg (125.6-129.0 mmHg) and 1.8 mmHg (78.2-80.0 mmHg), respectively, from baseline. At week 12, ABPM showed 24-hour mean systolic and diastolic BP increases of 3.7 mmHg and 1.3 mmHg, respectively. All measured lipid fractions were below baseline levels at week 26. T, TE, dihydrotestosterone, and estradiol increased from weeks 1-12. T trough levels ranged from 300-650 ng/dL (10.4-22.5 nmol/L) in 82.4% and 83.2% of patients at weeks 12 and 26, respectively. Of the 965 assessed injections, mild pain was reported by 1 patient. CLINICAL IMPLICATIONS: Dosing with SCTE is well-tolerated overall, yet associated with a numerically small mean systolic BP increase. STRENGTHS & IMPLICATIONS: This study used a standardized ABPM protocol, confirming a numerically small systolic BP increase may be associated with reintroducing therapeutic T exposure in hypogonadal men. It is unknown at this time whether this applies with all routes of T supplementation. CONCLUSION: SCTE-AI has a favorable safety profile and is well-tolerated, with a stable PK profile. Gittelman M, Jaffe JS, Kaminetsky JC. Safety of a New Subcutaneous Testosterone Enanthate Auto-Injector: Results of a 26-Week Study. J Sex Med 2019;16:1741-1748. Clinicaltrials.gov Identifier: NCT02504541.