Depot medroxyprogesterone acetate and breast cancer: a systematic review.

PURPOSE: Short-acting progestin-only injectables containing depot medroxyprogesterone acetate (DMPA) are a safe method of contraception. Although DMPA has been available for several decades, there is little data on its influence on the risk of breast cancer. Hence, the aim of this paper was to provide an overview of the existing studies and create clarity regarding a possible association with breast cancer. METHODS: Literature searches were executed in MEDLINE, Embase, the Cochrane Library, ClinicalTrials.gov and ICTRP. Search terms were related to DMPA and breast cancer. After elimination of duplicates, 3'850 studies were identified and assessed according to inclusion and exclusion criteria. Finally, ten studies were selected and included in this review. RESULTS: All the selected papers were case-control-studies, except for one pooled analysis and one study comparing observed and expected number of cancer cases. Most of the included studies found no overall elevated breast cancer incidence in DMPA users, only one study found a slightly increased risk and two studies concluded with a significant increase for the overall breast cancer risk. CONCLUSION: There is little evidence that DMPA may increase the overall risk for breast cancer. However, the incidence of breast cancer is possibly increased in current and more recent users, especially in women younger than 35 years. Long-term use did not result in any risk increase. Nevertheless, further studies will be necessary to confirm these findings and weigh up the individual risks and benefits of this contraceptive method.

Postpartum Extended-Release Buprenorphine Tissue Necrosis.

BACKGROUND: Extended-release buprenorphine (XRB) may improve medication for opioid use disorder continuation among postpartum individuals. However, obstetric clinicians have relatively little experience with XRB. We describe two cases of XRB-related tissue necrosis in postpartum individuals to highlight recommended injection technique and management strategies for this rare complication. CASES: One patient developed tissue necrosis after her initial injection. Her wound was expectantly managed. Another patient on long-term XRB developed tissue necrosis within 1 day of injection. General surgery excised the depot. Both instances were attributed to injection of XRB intradermally rather than subcutaneously. Both patients continued monthly XRB without recurrence, suggesting that this complication is not an allergy. CONCLUSION: Clinicians should be able to prevent, recognize, and manage tissue necrosis, a rare complication of XRB injection.

No pain, no strain: Targin® mitigates pain and constipation following spinal cord injury.

BACKGROUND: Opioids effectively reduce chronic pain, but present significant side effects including opioid-induced constipation. Oxycodone/naloxone decreases pain and constipation in cancer patients, however its effect on spinal cord injury population remains understudied. METHODS: We assessed whether oxycodone/naloxone reduces pain, constipation, and severity of autonomic dysreflexia in an individual with spinal cord injury. A 55-year-old male with C5 lesion presented with chief complaint of chronic pain received 5/2.5 mg and 20/10 mg oxycodone/naloxone for 6 and 2 weeks, respectively. RESULTS: Oxycodone/naloxone improved pain, bowel function, and autonomic dysreflexia severity. INTERPRETATION: Oxycodone/naloxone was effective in managing chronic pain and constipation in the studied case.

Carbol fuchsin stain enhances detection of poly-(d, l-lactide-co-glycolide) microspheres in exenatide extended-release cutaneous injection-site foreign body reaction.

Injection of high-viscosity fluids into subcutaneous tissues may lead to a granulomatous reaction called sclerosing lipogranuloma (SL). Poly-(d,l-lactide-co-glycolide) (PLG or PLGA) microspheres are used as vehicles for extended-release drugs. Here we describe the histopathologic features of a case of SL induced by exenatide extended-release injections, and the staining pattern of PLG microspheres and microsphere remnants with carbol fuchsin.

Construction of a Risk Prediction Model of Extended Release Oxycodone Tablet-Induced Nausea and Clarification of Predictive Factors.

Nausea is a typical adverse event associated with opioids. In this study, we performed logistic regression analysis with the aim of clarifying the risk factors for nausea induced by extended-release oxycodone (ER-OXY). Furthermore, we constructed a decision tree (DT) model, a typical data mining method, to estimate the risk of oxycodone-induced nausea by combining multiple factors. A retrospective study was conducted on patients who newly received ER-OXY for cancer pain during hospitalization at Hokkaido University Hospital in Japan from April 2015 to March 2018. In logistic regression and DT analyses, the dependent variable was the presence or absence of nausea. Independent variables were the potential risk factors. First, univariate analyses were performed to screen potential factors associated with oxycodone-induced nausea. Then, multivariate and DT analyses were performed using factors with p-values <0.1 in the univariate analysis. Of 267 cases included in this study, nausea was observed in 30.3% (81/267). In multivariate logistic regression analysis, only female sex was extracted as an independent factor affecting nausea (odds ratio, 1.98). In the DT analysis, we additionally revealed that an age <50 years was a risk factor for nausea in female patients. Thus, our DT model indicated that the risk of ER-OXY-induced nausea was highest in the subgroup comprising females <50 years of age (66.7%) and lowest in male patients (25.1%). The DT model suggested that the factor of young women may be an increased risk of ER-OXY-induced nausea.

Efficacy and safety of Biqi capsule in the treatment of knee osteoarthritis: A protocol of a randomized controlled trial.

BACKGROUND: Knee osteoarthritis (KOA) is a chronic and degenerative bone and joint disease, with KOA, cartilage degeneration, destruction and subchondral bone remodeling as the main pathological features. Its clinical symptoms are knee pain, swelling, limited activity, and long course of disease can cause joint deformities. At present, the early treatment of Western medicine is mainly the use of nonsteroidal drugs for anti-inflammation and removing pain, but because the efficacy of these drugs is unstable, the disease is easy to repeat after treatment, and the clinical effect is not good. Although Biqi capsule has advantages in the treatment of KOA, there is a lack of standard clinical studies to verify it, so the purpose of this randomized controlled study is to evaluate the efficacy and safety of Biqi capsule in the treatment of KOA. METHODS: This is a prospective randomized controlled trial to study the efficacy and safety of Biqi capsule in the treatment of KOA. The patients were randomly divided into a treatment group and a control group according to 1:1. Among them, treatment group: Biqi capsule combined with diclofenac sodium sustained release tablets; Control group: Diclofenac sodium sustained-release tablets alone. Both groups were treated with standard treatment for 2 weeks and were followed up for 30 days to pay attention to the efficacy and safety indexes. Observation indicators included: the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), Hospital for Special Surgery Knee Score (HSS), liver and kidney function, adverse reactions, and so on. SPSS 25.0 software is used for data analysis. DISCUSSION: This study will evaluate the efficacy and safety of Biqi capsule in the treatment of KOA, and the results of this experiment will provide a clinical basis for Biqi capsule in the treatment of KOA. TRIAL REGISTRATION: OSF Registration number: DOI 10.17605/OSF.IO/6HB9D.

A novel sustained-release cysteamine bitartrate formulation for the treatment of cystinosis: Pharmacokinetics and safety in healthy male volunteers.

The strict intake regimen of cysteamine bitartrate formulations, associated with side effects, is a concern for the treatment compliance in cystinosis therapy. Therefore, there is a need for a cysteamine formulation with an improved pharmacokinetic profile. This study investigated the pharmacokinetics, safety and tolerability of a new sustained-release cysteamine dosage form, PO-001, in healthy volunteers. This was a randomized, investigator-blinded, three-way cross-over study to compare single doses (600 mg) of PO-001 with Cystagon® (immediate-release) and Procysbi® (delayed-release). Collected blood samples were analyzed for plasma cysteamine concentrations and pharmacokinetic parameters were estimated by noncompartmental analysis. In addition, plasma cysteamine concentrations were analyzed using a population pharmacokinetic approach using NONMEM® . Pharmacokinetics showed clear sustained-release characteristics of PO-001 over time with a lower Cmax and longer Tmax compared to Cystagon® and Procysbi® . All treatment-emergent adverse events were of mild severity, with the exception of two subjects who reported moderate severity gastrointestinal problems including vomiting and diarrhea, which were related to Cystagon® intake. Population PK simulations showed a favourable PK profile based on Cmax and Ctrough concentrations at steady state. In conclusion, a single dose of 600 mg PO-001 was well tolerated with no findings of clinical concern. This new cysteamine bitartrate formulation showed pharmacokinetics of a sustained-release formulation, which may be beneficial for the treatment of cystinosis patients. This study supports advancing this type of sustained-release formulation into a subsequent study to confirm reduced dosing frequency with efficient control of white blood cells (WBCs) cystine levels. Netherlands Trial Registry (NTR) (NL67638.056.18).

A case of extended-release Quetiapine causing recurrent low-grade fevers.

This case highlights recurrent low-grade fevers caused by extended-release Quetiapine (Quetiapine XR), a previously unreported side effect, in a patient with Schizophreniform Disorder. While there have been case reports of Quetiapine causing neuroleptic malignant syndrome, there is paucity of data specifically describing recurrent low-grade fevers, with no other accompanying symptoms, caused by Quetiapine XR.

Efficacy and safety of prolonged release budesonide granules in mesalazine-refractory ulcerative colitis: A multi-centre Phase IIa study (TOPICAL-1).

BACKGROUND: In patients with mesalazine-refractory ulcerative colitis, systemic corticosteroids are the treatment of choice. OBJECTIVE: To evaluate the efficacy and safety of prolonged release budesonide granules for the induction of remission in patients with mesalazine-refractory ulcerative colitis. METHODS: Patients with mesalazine-refractory ulcerative colitis discontinued mesalazine at baseline and received 9 mg prolonged release budesonide granules daily for 8 weeks in this open-label, phase IIa study, followed by a 2-week follow-up phase wherein patients continued treatment on alternate days (EudraCT number 2014-005635-14; ClinicalTrials.gov identifier NCT02550418). The primary endpoint was clinical remission (Clinical Activity Index ≤4; stool frequency <18 per week; absence of rectal bleeding) at Week 8. Secondary endpoints included clinical, endoscopic and histological measures of disease at Week 8. A post hoc analysis assessed histo-endoscopic mucosal healing. Treatment-emergent adverse events and morning cortisol levels were assessed throughout the treatment and follow-up phases. RESULTS: A total of 61 patients were included in the intention-to-treat population; 50 were included in the follow-up analysis set. Clinical remission was achieved in 29 patients (47.5%; 95% confidence interval: 34.6-60.7%) by Week 8. Mean stool and bloody stool frequency decreased significantly from 32.5 to 22.9 per week (p<0.0001) and from 17.6 to 8.1 per week (p<0.0001), respectively. Rates of mucosal healing, endoscopic remission and histological remission were 58.0%, 54.0% and 36.0%, respectively. Histo-endoscopic mucosal healing was achieved by 34.0% of patients. Twenty-four patients (39.3%) experienced treatment-emergent adverse events, of which gastrointestinal disorders (16.4%) were the most common. Mean morning cortisol levels were not significantly suppressed by Week 8. CONCLUSIONS: Treatment with prolonged release budesonide granules for 8 weeks was associated with clinical, endoscopic and histological remission and demonstrated a favourable safety profile in patients with mesalazine-refractory ulcerative colitis. These results warrant further investigation into the potential of prolonged release budesonide granules as an alternative treatment for this patient population.

Phase 3 Trial of a Small-volume Subcutaneous 6-Month Duration Leuprolide Acetate Treatment for Central Precocious Puberty.

CONTEXT: Gonadotropin-releasing hormone agonists (GnRHas) are standard of care for central precocious puberty (CPP). A 6-month subcutaneous injection has recently been approved by the Food and Drug Administration. OBJECTIVE: Determine efficacy, pharmacokinetics, and safety of 6-month 45-mg subcutaneous leuprolide acetate for CPP. DESIGN: Phase 3 multicenter, open-label, single-arm study. SETTING: 25 sites in 6 countries. SUBJECTS: 64 GnRHa-naïve children with CPP (age: 7.5 ± 0.1 years) received study drug: 59 completed the study. INTERVENTION(S): 2 doses of 45-mg subcutaneous leuprolide acetate (0.375 mL) at 0 and 24 weeks; children were followed for 48 weeks. MAIN OUTCOME MEASURE(S): Percentage of children with serum luteinizing hormone (LH) <4 IU/L 30 minutes following GnRHa stimulation at week 24. RESULTS: 54/62 (87%) children achieved poststimulation LH <4 IU/L at week 24; 49/56 (88%) girls and 1/2 boys maintained peak LH <4 IU/L at week 48. Mean growth velocity decreased from 8.9 cm/year at week 4 to 6.0 cm/year at week 48. Mean bone age was advanced 3.0 years beyond chronological age at screening and 2.7 years at week 48. Breast pubertal stage regressed or was stable in 97% of girls and external genitalia development regressed in both boys. Adverse events were mild and did not cause treatment discontinuation. CONCLUSIONS: A small volume of 45-mg subcutaneous leuprolide acetate administered at a 6-month interval effectively suppressed pubertal hormones and stopped or caused regression of pubertal progression. This long-acting GnRHa preparation of leuprolide acetate is a new, effective, and well-tolerated therapy for children with CPP.

Benefits of prolonged-release pirfenidone plus standard of care treatment in patients with advanced liver fibrosis: PROMETEO study.

BACKGROUND AND AIMS: Pirfenidone (PFD), an oral antifibrotic drug, has been authorized by the EMA and FDA for treatment of idiopathic pulmonary fibrosis. Few studies have addressed its use in advanced liver fibrosis (ALF). We evaluated a prolonged-release formulation (PR-PFD) plus standard of care on disease progression in ALF. METHODS: 281 ALF patients from 12 centers receiving PR-PFD (600 mg bid) were screened; 122 completed 1 year of treatment. Additionally, 74 patients received only standard of care regimen. Average age was 64 ± 12 years, 58% female. 43.5% had fatty liver disease (NAFLD), 22.5% viral hepatitis C (VHC), 17% autoimmune hepatitis (AIH), and 17% alcoholic liver disease (ALD). Baseline fibrosis was F4 in 74% and F3 in 26%. Antifibrotic effects were assessed by transient elastography (Fibroscan®) and Fibro Test® (FT); Cytokines and PFD plasma levels were tracked and quality of life evaluated. RESULTS: We found a significant reduction in fibrosis in 35% of PR-PFD patients and only in 4.1% in non PR-PFD patients. Child-Pugh score improved in 29.7%. Biochemical values remained stable; 40.6% and 43.3% decreased ALT or AST, respectively. TGFß1 (pg/mL) levels were lower in PFD-treated patients. PFD serum concentration (µg/mL) was higher (8.2 ± 1.7) in fibrosis regression profile (FRP) patients compared to fibrosis progression profile (FPP) patients (4.7 ± 0.3 µg/mL, p < 0.01). 12% reported transient burning or nausea and 7% photosensitivity. Quality of life (Euro-Qol scale) improved from 62 ± 5 to 84 ± 3 (p < 0.001) and from 32 ± 3 to 42 ± 2 (p < 0.008) (FACIT scale). CONCLUSIONS: PR-PFD is efficacious and safe in ALF and associated with promising antifibrotic effects. TRIAL REGISTRATION: Clinical trial number: NCT04099407.

Trend survey on adverse event profiles of antipsychotic long-acting injections and oral agents using the Japanese adverse drug event report database.

This study aims to assess the differences in adverse event profiles of long-acting injectable antipsychotics (LAIs) and oral antipsychotics (OAPs) using real-world data in the Japanese Adverse Drug Event Report database. Reporting odds ratios were determined using disproportionality analysis to estimate the risk of adverse events for LAIs and OAPs. Differences in adverse event profiles between formulations were determined after propensity score matching. Time-to-onset of adverse events was compared between LAIs and OAPs using the Weibull shape parameter. Signals were detected for approximately 50% of the adverse events (12 of 22) with LAIs and for the majority of adverse events (19 of 22) with OAPs. LAIs was associated with significantly lower reporting rate than OAPs for extrapyramidal symptom, neuroleptic malignant syndrome, and dystonia. For QT prolongation, convulsions, and hyperglycemia associated with LAIs, the 95% Confidence Interval of ß included 1 in time-to-onset analysis. Real-world data suggest that LAIs tend to reduce the occurrence of extrapyramidal symptom and neuroleptic malignant syndrome, but a number of other adverse events have potential risks as well as OAPs. In addition, onset of adverse events with LAIs have been shown to be slightly delayed, requiring more careful long-term monitoring.

Case Series: Rapid Induction Onto Long Acting Buprenorphine Injection for High Potency Synthetic Opioid Users.

BACKGROUND AND OBJECTIVES: Highly potent synthetic opioids (HPSO) are increasingly responsible for opioid overdose deaths in the United States. METHODS: In an open-label, uncontrolled trial to test the feasibility of extended-release buprenorphine (BXR) injection treatment of heroin-using individuals with opioid use disorder testing positive for HPSO, participants were enrolled and began an induction with sublingual BXR (n = 5). During the induction, ancillary medications (clonidine, clonazepam, zolpidem, and prochlorperazine) were provided for breakthrough opioid withdrawal symptoms. RESULTS: Two participants received the BXR injection on the second day of the induction and three participants on the third day. DISCUSSION AND CONCLUSION: All five participants were retained at least 1-month postinduction. SCIENTIFIC SIGNIFICANCE: It may be feasible to provide BXR treatment to HPSO-positive heroin users rapidly to achieve clinical stabilization. (Am J Addict 2020;00:00-00).

"Fucoidan, a natural biopolymer in cancer combating: From edible algae to nanocarrier tailoring".

Fucoidan is an edible algae that has long been used as part of east Asians' diet. Recently, various pharmacological activities of the polymer have been discovered including its ability to act as antimicrobial, anti-thrombotic, antiviral, anti-inflammatory and anti-cancer. This review is the first to focus on the anti-cancer ability of this biopolymer and factors affecting it. The review discusses the mechanism by which fucoidan can kill cancer cells efficiently without having chemotherapeutic side effects and the ability of fucoidan to act as an adjuvant to classic therapy. Furthermore, multifaceted nanotechnological applications of fucoidan in cancer treatment were reviewed. Fucoidan nanoparticles with efficient drug loading and release had been developed. The polymer had also been used as coating material for different organic and inorganic nanoparticles imparting biocompatibility characters to these systems. Most recently, there has been a focus on the role of fucoidan as active targeting ligand for cancer cells. The polymer could target P-selectin receptors over-expressed on cancer cells in nanomolar concentrations. Combining all these activities, fucoidan could be considered as one of the most important biopolymers combating cancer during tailoring of cancer nanomedicine. Finally, we discussed safety of fucoidan, challenges facing its application on industrial scale and future projections.

A Preliminary, Open-Label Study of Naltrexone and Bupropion Combination Therapy for Treating Binge Drinking in Human Subjects.

AIMS: The combination of bupropion and naltrexone has shown efficacy in reducing binge drinking in animal models. This study assessed the tolerability and potential utility of combined naltrexone and bupropion in reducing binge drinking in human subjects. METHODS: This preliminary study employed an open-label, single-arm, 12-week, prospective design. Twelve men and women who exhibited a minimum of five (men) or three (women) binge drinking episodes per month over the past 3 months were recruited. All subjects received both bupropion-extended release 300 mg/day and naltrexone 50 mg/day and were monitored throughout the 3-month treatment period. Binge drinking was assessed using the timeline follow-back method. RESULTS: Treatment with combined naltrexone and bupropion reduced the average number of drinks per binge drinking day from 7.8 drinks to 6.4 drinks and reduced the average percentage of binge drinking days per month from 19% (5.7 days/month) to 5% (1.5 days/month). Naltrexone and bupropion were generally well tolerated, with insomnia, headache and nausea/diarrhea being the most common side effects. Six subjects elected to stay on medication after the trial. CONCLUSIONS: This study suggests that combined naltrexone and bupropion therapy should be further investigated for tolerability and efficacy in reducing binge drinking in humans.

Safety of Combination Laser or Intense Pulsed Light Therapies and Doxycycline for the Treatment of Rosacea.

BACKGROUND: Current treatment options for rosacea include topical agents, oral therapies, phototherapy using lasers, or intense pulsed light (IPL). Combination therapy for rosacea often yields better results than monotherapy. The safety of laser/light treatments in combination with systemic doxycycline has been questioned because of the theoretical risk of photosensitivity. OBJECTIVE: The purpose of this study was to assess the incidence of phototoxicity or photosensitivity in rosacea patients receiving concomitant laser or light treatments and systemic doxycycline. METHODS: Treatment records of 36 patients receiving laser/light treatments while also being treated with standard dose or anti-inflammatory dose of doxycycline were retrospectively reviewed. RESULTS: No adverse reactions related to doxycycline combined with laser/light therapy were reported. Specifically, no photosensitivity or sensitivity to wavelengths in the pulsed dye laser (PDL), or IPL range was observed in this cohort. All patients achieved some degree of clearance. CONCLUSION: The results of this retrospective study demonstrate that doxycycline used in conjunction with laser or nonlaser light therapy is a valid combination therapy for improving signs and symptoms of rosacea. No photosensitivity reactions were observed to commonly used IPL or PDL devices.

Bupropion Hydrochloride Sustained Release and Diurnal Enuresis: A Previously Unreported Adverse Effect.

Bupropion hydrochloride (HCl) is an antidepressant that has many different biological targets, acting as both a norepinephrine-dopamine reuptake inhibitor as well as a nicotinic antagonist. This second-generation antidepressant is available in 3 bioequivalent formulations: immediate release, sustained release, and extended release, allowing providers to customize a patient's regimen for maximum tolerability and compliance. Although bupropion HCl's safety and tolerability have been demonstrated through several clinical trials, there are still a number of adverse effects that have been reported in the literature. These include headache, agitation, tremor, and insomnia. There is also an increased risk of developing seizures during bupropion treatment. Although urinary symptoms were noted during the clinical trials, these are relatively rare adverse effects. Here we report the case of a 61-year-old man who developed diurnal enuresis during treatment with bupropion HCl sustained release. We will review the adverse effect burden associated with the use of bupropion and discuss the neuropharmacology of urinary symptoms associated with antidepressant treatment.

Cardio-metabolic risk in individuals prescribed long-acting injectable antipsychotic medication.

People living with severe mental illness (SMI) experience significant physical health co-morbidity. Few studies have focused on physical health outcomes for those prescribed long-acting injectable (LAI) antipsychotics. This observational cross-sectional study aimed to assess the prevalence of metabolic syndrome (MetS) and other cardio-metabolic risk factors in a large cohort prescribed LAI and managed by community mental health services. For participants with elevated cardio-metabolic risk factors, the proportion receiving appropriate management was assessed. Of the 301 eligible participants, many met the full criteria for MetS (44%) and its components. Cardio-metabolic risk factors were largely under- or un-treated. Smoking rates were very high (62%) along with reported high rates of physical inactivity and poor dietary intake. The vast majority (89%) reported seeing their general practitioner in the preceding twelve months. Individuals prescribed LAI have a very high prevalence of MetS and potentially modifiable risk factors for cardiovascular disease. Routine monitoring accompanied by evidence-based treatment of cardiometabolic abnormalities which contribute to significant morbidity, disability and premature death should be prioritised. Better collaboration between mental health services and primary care providers should be pursued to optimise the delivery of effective physical health care to individuals living with SMI.