Comparison of chemical-induced temporomandibular osteoarthritis rat models (monosodium iodoacetate versus collagenase type II) for the study of prolonged drug delivery systems.

OBJECTIVE: To compare two agents that can induce a rat model of temporomandibular joint osteoarthritis (TMJOA) by chemical induction: monosodium iodoacetate (MIA) and collagenase type 2 (Col-2). We wished to ascertain the best agent for assessing drug-delivery systems (DDSs). METHOD: Male Wistar rats underwent intra-articular injection with MIA or Col-2. They were manipulated for 30 days. The head withdrawal threshold (HWT), immunohistological assessment, and positron emission tomography (PET) were used to evaluate the relevance of our models. RESULTS: For both the MIA and Col-2 groups, pain persisted for 30 days after injection. Change in the HWT showed that Col-2 elicited a strong action initially that decreased progressively. MIA had a constant action upon pain behavior. Histology of TMJ tissue from both groups showed progressive degradation of TMJ components. CONCLUSIONS: MIA and Col-2 induced orofacial pain by their local chemical action on TMJs. However, based on a prolonged and greater sustained effect on the pain threshold, persistent histological changes, and imaging results, MIA appeared to be more suitable for creation of a rat model of TMJOA for the study of DDSs.

Patients' perspectives of collagenase injection or needle fasciotomy and rehabilitation for Dupuytren disease, including hand function and occupational performance.

PURPOSE: To describe patients' perspectives of collagenase injection or needle fasciotomy for Dupuytren disease (DD) including hand therapy, and their view of hand function and occupational performance. MATERIALS AND METHODS: Interviews were performed with twelve patients who had undergone non-surgical treatment and rehabilitation for DD. Data was analysed using a problem-driven content analysis using the model of Patient Evaluation Process as a theoretical framework. RESULTS: The participants' previous experiences influenced their expectations of the upcoming treatment and they needed information to be prepared for treatment. Treatment and rehabilitation had a positive impact on daily life and were regarded as effective and simple with quick recovery. However, there could be remaining issues with tenderness or stiffness. The participants expressed their belief in rehabilitation and how their own efforts could contribute to an improved result. Despite concerns about future recurrence participants described increased knowledge and sense of control regarding future needs. CONCLUSION: Undergoing a non-surgical treatment and rehabilitation process for DD was regarded as quick and easy and can meet the need for improved hand function and occupational performance. Taking responsibility for one's own rehabilitation was considered to influence the outcome positively. The theoretical framework optimally supported the exploration of participants' perspective.Implications for rehabilitationTreatment of Dupuytren Disease (DD) with needle/collagenase combined with hand therapy was experienced as giving fast improvement in hand function and occupational performance.An individualized care process which satisfies the need for knowledge about the disease, prognosis, treatment options and rehabilitation can give individuals suffering from DD a sense of security.The need for active participation in the DD care process can vary and it is crucial to listen to individuals' opinions and needs.Individuals can take considerable responsibility for rehabilitation after non-surgical treatment for DD and regard it as important for the outcome.

Farrerol alleviates collagenase-induced tendinopathy by inhibiting ferroptosis in rats.

Tendinopathy is mainly characterized by local pain, functional limitation and decreased athletic ability, which seriously affects the quality of life of patients and the career of athletes. Farrerol (FA), one of the main active compounds extracted from Rhododendron and plants in the Rhododendron family, has a wide range of pharmacological activities, such as immunomodulatory, anti-inflammatory and antiviral effects. However, the effect of FA on tendinopathy is unclear. Here, we investigated the pharmacological effect and mechanism of FA in tendon injury through collagenase-induced tendinopathy in vivo and RSL3-induced tenocytes injury in vitro. The results showed that FA alleviated the infiltration of inflammatory cells, promoted tenogenesis and improved mechanical properties of the Achilles tendon in rats. In addition, ferroptosis inducer RSL3 inhibits the tenogenesis in vitro and in vivo, which accelerates the progression of tendinopathy. Moreover, FA effectively inhibited iron accumulation and alleviated ferroptosis in the Achilles tendon. Using in vitro experiments, we found that FA antagonized ferroptosis by reducing lipid peroxidation and iron accumulation in tenocytes. Finally, we found that glutathione peroxidase 4 silencing could block the protective effect of FA on ferroptosis of tenocytes. Therefore, the results of this study suggest that FA can relieve collagenase-induced tendinopathy by inhibiting ferroptosis, and reveal that FA may be a potentially effective drug for the treatment of tendinopathy in the future.

Y-2 reduces oxidative stress and inflammation and improves neurological function of collagenase-induced intracerebral hemorrhage rats.

Intracerebral hemorrhage (ICH) is a devastating disease, and there is currently no specific pharmacological treatment that can improve clinical outcomes. Y-2 sublingual tablets, each containing 30 mg edaravone and 6 mg (+)-borneol, is undergoing a phase III clinical trial for treatment of ischemic stroke in China. The purpose of the present study is to investigate the efficacy and potential mechanism of Y-2 in a rat model of collagenase IV injection induced ICH. Sublingual administration of Y-2 at the dose of 1, 3 and 6 mg/kg improved ICH-induced sensorimotor dysfunction, alleviated cell death and histopathological change, restored the hippocampal long-term potentiation (LTP), reduced brain edema and maintained blood-brain barrier (BBB) integrality in ICH rats. Further study demonstrated that Y-2 could reduce inflammatory response and oxidative stress by decreasing the levels of myeloperoxidase (MPO), ionized calcium-binding adaptor protein-1 (Iba-1), inflammatory cytokines and oxidative products, inhibit transcription factor nuclear factor-κB (NF-κB) activation, cyclooxygenase-2 (COX-2) and matrix metallopeptidase 9 (MMP-9) expression in brain tissue around in the core regions of hematoma. Importantly, the protective efficacy of Y-2 from ICH-induced injury was superior to edaravone. In conclusion, Y-2 sublingual tablets might be a promising therapeutic agent for the treatment of ICH.

Function and Biomarkers of the Blood-Brain Barrier in a Neonatal Germinal Matrix Haemorrhage Model.

Germinal matrix haemorrhage (GMH), caused by rupturing blood vessels in the germinal matrix, is a prevalent driver of preterm brain injuries and death. Our group recently developed a model simulating GMH using intrastriatal injections of collagenase in 5-day-old rats, which corresponds to the brain development of human preterm infants. This study aimed to define changes to the blood-brain barrier (BBB) and to evaluate BBB proteins as biomarkers in this GMH model. Regional BBB functions were investigated using blood to brain 14C-sucrose uptake as well as using biotinylated BBB tracers. Blood plasma and cerebrospinal fluids were collected at various times after GMH and analysed with ELISA for OCLN and CLDN5. The immunoreactivity of BBB proteins was assessed in brain sections. Tracer experiments showed that GMH produced a defined region surrounding the hematoma where many vessels lost their integrity. This region expanded for at least 6 h following GMH, thereafter resolution of both hematoma and re-establishment of BBB function occurred. The sucrose experiment indicated that regions somewhat more distant to the hematoma also exhibited BBB dysfunction; however, BBB function was normalised within 5 days of GMH. This shows that GMH leads to a temporal dysfunction in the BBB that may be important in pathological processes as well as in connection to therapeutic interventions. We detected an increase of tight-junction proteins in both CSF and plasma after GMH making them potential biomarkers for GMH.

Co-encapsulation of collagenase type I and silibinin in chondroitin sulfate coated multilayered nanoparticles for targeted treatment of liver fibrosis.

Components of the extracellular matrix (ECM) are overexpressed in fibrotic liver. Collagen is the main component of the liver fibrosis stroma. Here we demonstrate that chondroitin sulfate coated multilayered 50-nm nanoparticles encapsulating collagenase and silibinin (COL + SLB-MLPs) break down the dense collagen stroma, while silibinin inhibits activated hepatic stellate cells. The nanoparticles were taken up to a much greater extent by hepatic stellate cells than by normal hepatocytes, and they down-regulated production of type I collagen. In addition, chondroitin sulfate protected the collagenase from premature deactivation. COL + SLB-MLPs were delivered to the cirrhotic liver, and the collagenase and silibinin synergistically inhibited fibrosis in mice. Immunofluorescence staining of liver tissues revealed that CD44, mediated by chondroitin sulfate, delivered the nanoparticles to hepatic stellate cells. This strategy holds promise for degrading extracellular stroma and thereby facilitating drug penetration into fibrotic liver and related diseases such as liver cirrhosis and liver cancer.

Peyronie's disease: pharmacological treatments and limitations.

Introduction: Peyronie's disease (PD) is a disorder of the tunica albuginea from disordered and excessive deposition of collagen resulting in a palpable scar, pain, erect penile deformity and erectile dysfunction that significantly impacts patients both physically and emotionally.Areas Covered: Several treatment options have been described for PD, including shockwave therapy, traction therapy, both oral and intralesional pharmacological options, and surgery. This review seeks to examine the data for different types of non-surgical treatments for PD. We review how various treatment modalities impact several relevant clinical endpoints for Peyronie's disease, including effects on pain, penile curvature, plaque formation, and erectile function. We performed a literature search using PubMed and SCOPUS while referencing AUA, EAU, and CUA guidelines for management of Peyronie's Disease for studies published 1980-2020.Expert opinion: Intralesional collagenase injections have the strongest evidence and are the only FDA approved intralesional treatment for PD. Penile traction therapy (PTT) is low risk and may be beneficial in patients willing to invest significant time using the devices. Furthermore, oral combination therapy with other modalities may provide some benefit. Further investigation is required to better understand pathophysiology of PD and clarify the therapeutic utility of existing treatments, potentially with a multimodal strategy.

Intraperitoneal collagenase as a novel therapeutic approach in an experimental model of colorectal peritoneal carcinomatosis.

The usefulness of local collagenase in therapeutic approaches to solid tumors has been tested recently. In this study, we evaluate the safety and efficacy of intraperitoneal collagenase associated or not to mitomycin for treatment of colorectal peritoneal metastases in an experimental rat model. Using a fixed-dose procedure, we found that a dose of collagenase of 37 IU/mL administered for 15 min with a hyperthermia pump at 37.5 °C, both in isolation or associated to sequential treatment with intraperitoneal mitomycin, led to a macroscopic decrease in tumor volume as evaluated by the modified peritoneal cancer index (mPCI). Concerning the safety of the procedure, the animals showed no physiological or behavioral disorders during 8 weeks of follow-up. Local treatment for peritoneal metastases of colorectal origin with intraperitoneal collagenase has proved safe and effective in an experimental murine model. Therefore, the stroma-first approach by enzymatic breakdown of collagen from the tumor's extracellular matrix provides a new therapeutic target for colorectal peritoneal metastases.

The burden of productivity loss of U.S. commercially insured patients diagnosed with Dupuytren's disease undergoing collagenase versus fasciectomy treatment.

Background: We conducted a comparative assessment of the productivity loss associated with the two different treatment options for Dupuytren's disease: collagenase and fasciectomy. Methods: The retrospective claims analysis was performed using the data from IBM MarketScan® Commercial (CD) and Health and Productivity Management (HPM) Databases over five years (2012-2016). We identified two cohorts of patients who underwent either collagenase or fasciectomy in the CD. Propensity-score matched patients were linked to their productivity loss claims in the HPM database. Productivity loss measures were assessed over a 12-month follow-up period. Results: Out of 702 collagenase and 999 fasciectomy propensity score-matched patients in the CD, there were 147 collagenase and 273 fasciectomy patients in the HPM database. Over the follow-up period, collagenase-treated patients were significantly less likely to use short-term disability (STD) leave (9.7% vs. 20.2%; P = 0.009), reflecting in the lower average number of absent STD days (mean, 2.8 vs. 8.1; P = 0.002) in comparison to fasciectomy-treated. The mean indirect STD cost was considerably lower in the collagenase vs. fasciectomy group ($375 vs. $1,108; P = 0.002). Conclusion: This study indicates that collagenase vs. fasciectomy treatment may be related to a lower rate of workplace absence and lower indirect cost in a year following the treatment.

Intra-articular collagenase in the spinal facet joint induces pain, DRG neuron dysregulation and increased MMP-1 absent evidence of joint destruction.

Degeneration is a hallmark of painful joint disease and is mediated by many proteases that degrade joint tissues, including collagenases. We hypothesized that purified bacterial collagenase would initiate nociceptive cascades in the joint by degrading the capsular ligament's matrix and activating innervating pain fibers. Intra-articular collagenase in the rat facet joint was investigated for its effects on behavioral sensitivity, joint degeneration, and nociceptive pathways in the peripheral and central nervous systems. In parallel, a co-culture collagen gel model of the ligament was used to evaluate effects of collagenase on microscale changes to the collagen fibers and embedded neurons. Collagenase induced sensitivity within one day, lasting for 3 weeks (p < 0.001) but did not alter ligament structure, cartilage health, or chondrocyte homeostasis. Yet, nociceptive mediators were increased in the periphery (substance P, pERK, and MMP-1; p ≤ 0.039) and spinal cord (substance P and MMP-1; p ≤ 0.041). The collagen loss (p = 0.008) induced by exposing co-cultures to collagenase was accompanied by altered neuronal activity (p = 0.002) and elevated neuronal MMP-1 (p < 0.001), suggesting microscale collagen degradation mediates sensitivity in vivo. The induction of sustained sensitivity and nociception without joint damage may explain the clinical disconnect in which symptomatic joint pain patients present without radiographic evidence of joint destruction.

Characterization of a novel model of global forebrain ischaemia-reperfusion injury in mice and comparison with focal ischaemic and haemorrhagic stroke.

Stroke is caused by obstructed blood flow (ischaemia) or unrestricted bleeding in the brain (haemorrhage). Global brain ischaemia occurs after restricted cerebral blood flow e.g. during cardiac arrest. Following ischaemic injury, restoration of blood flow causes ischaemia-reperfusion (I/R) injury which worsens outcome. Secondary injury mechanisms after any stroke are similar, and encompass inflammation, endothelial dysfunction, blood-brain barrier (BBB) damage and apoptosis. We developed a new model of transient global forebrain I/R injury (dual carotid artery ligation; DCAL) and compared the manifestations of this injury with those in a conventional I/R injury model (middle-cerebral artery occlusion; MCAo) and with intracerebral haemorrhage (ICH; collagenase model). MRI revealed that DCAL produced smaller bilateral lesions predominantly localised to the striatum, whereas MCAo produced larger focal corticostriatal lesions. After global forebrain ischaemia mice had worse overall neurological scores, although quantitative locomotor assessment showed MCAo and ICH had significantly worsened mobility. BBB breakdown was highest in the DCAL model while apoptotic activity was highest after ICH. VCAM-1 upregulation was specific to ischaemic models only. Differential transcriptional upregulation of pro-inflammatory chemokines and cytokines and TLRs was seen in the three models. Our findings offer a unique insight into the similarities and differences in how biological processes are regulated after different types of stroke. They also establish a platform for analysis of therapies such as endothelial protective and anti-inflammatory agents that can be applied to all types of stroke.

Clostridium histolyticum (AA4500) for the Treatment of Adhesive Capsulitis of the Shoulder: A Randomised Double-Blind, Placebo-Controlled Study for the Safety and Efficacy of Collagenase - Single Site Report.

BACKGROUND/HYPOTHESIS: Adhesive capsulitis of the shoulder results in pain and restricted movement of the glenohumeral joint. Hypothesis: There would be a difference in active range of movement in the affected shoulder of patients with adhesive capsulitis after receiving a series of injections of collagenase Clostridium histolyticum (CCH) compared to placebo. METHODS: This study reports the results from a single site that was part of a 321-participant, multicenter, double-blind, prospective parallel-group, randomized controlled clinical trial. Inclusion criteria: over 18 years of age, unilateral idiopathic adhesive capsulitis for >3 months, but <12 months. Exclusion criteria: recent physical therapy, injections, subacromial impingement, calcific tendonitis or glenohumeral joint arthritis in the affected shoulder. Subjects were randomized 3:1 to receive CCH 0.58 mg or placebo under ultrasound guidance. Injections were on days 1, 22, and 43. The primary outcome measure was a functional assessment of active range of movement. RESULTS: Overall, 37 patients were screened, 26 subjects were excluded, and 11 subjects were randomly assigned to the treatment group (n=9) or the control group (n=2). Both control and treatment groups showed improvement in ROM between baseline and day 95. In the treatment group, AROM improved from the baseline of 272.89° (SD 86.25) to 462.11° (SD 96.89) and the control group from 246.00° (SD 5.66) to 451.50° (SD 50.20) at day 95 with no statistical difference between groups p=0.78. Site data were in line with the whole study findings. Treatment-related adverse events at the injection site, including haematoma (bruising) and localised pain and swelling, were common. CONCLUSION: Although the participants showed improvement in function, statistical significance was neither reached in the site nor the overall study cohort. Given the adverse events and the potential risks of the procedure, we would not recommend this drug for the treatment of adhesive capsulitis of the shoulder. LEVEL OF EVIDENCE: 2, cohort from one site of RCT.

Safety evaluation of collagenase from Streptomyces violaceoruber.

A safety assessment was conducted for microbial collagenase (COL) enzyme expressed in Streptomyces violaceoruber. The acute oral toxicity of COL was examined in Sprague-Dawley rats and the LD50 of COL via single oral administration to rats was higher than 2000 mg/kg body weight. A 13-week oral gavage study of COL showed no adverse effects due to the enzyme up to a dose of 234.9 mg total organic solids (TOS)/kg body weight per day (NOAEL). A bacterial reverse mutation test showed no mutagenic activity at the highest dose (4698 µg TOS per plate). In the mouse lymphoma TK assay, a positive result was observed at the highest dose of 4698 µg TOS/mL although it had low reproducibility. To confirm the chromosome aberration potential, an in vivo micronucleus test was conducted that demonstrated the lack of mutagenic potential on the bone marrow of rats at doses up to 1879 mg TOS/kg body weight per day. The results of the genotoxicity studies and acute and subchronic rat studies support the safe use in food production of collagenase produced from S. violaceoruber.

Efficacy of Collagenase Clostridium histolyticum (Xiapex®) in Patients with the Acute Phase of Peyronie's Disease.

BACKGROUND AND OBJECTIVE: Plaque formation ordinarily takes place in the acute phase of Peyronie's disease. There is no unanimous consent regarding the management of the acute phase of Peyronie's disease. The objective of this study was to evaluate the advantages of using a single intralesional injection of collagenase Clostridium histolyticum in patients with the active phase of Peyronie's disease and to assess its effect on disease progression by reducing penile curvature and ameliorating pain during sexual intercourse. METHODS: Sexually active men aged older than 18 years with the acute phase of Peyronie's disease were enrolled. All patients received treatment with a single intralesional injection of collagenase Clostridium histolyticum. The primary outcome of the study was the change in penile curvature after treatment while secondary outcomes were the change in sexual function (International Index of Erectile Function [IIEF-5]) and in the Peyronie Disease Questionnaire (PDQ) and its sub-scores, PDQ-PS (psychological symptoms), PDQ-PP (penile pain) and PDQ-BD (bother disease). RESULTS: Overall, 74 patients were enrolled. Mean penile curvature at baseline was 41.1° ± 12.2°. The mean changes before and at the 3-month evaluation in terms of penile curvature, Visual Analog Scale score at rest, and Visual Analog Scale score during intercourse were - 19.3 ± 8.4 (p < 0.0001), - 0.8 ± 1.1 (p < 0.0001) and - 3.8 ± 0.9 (p < 0.0001) with the benefit persisting also after 6 months. Moreover, improvements of mean IIEF-5 score (1.1 ± 0.9, p = 0.03; 0.9 ± 0.5, p = 0.02), PDQ-PS (- 2.7 ± 2.2; - 2.5 ± 2.0, p = 0.01), PDQ-PP (- 1.2 ± 1.6; - 1.1 ± 1.2, p = 0.02) and PDQ-BD (- 3.8 ± 3.4; - 3.5 ± 3.1, p = 0.001) were observed 3 and 6 months after the end of treatment, respectively. At the multivariable regression analysis, the time since disease onset (modelled with non-linear terms) and baseline curvature were independently associated with the degree of curvature improvement (coefficient: 0.30; 95% confidence interval 0.16-0.44) after a single intralesional injection (all p < 0.03). CONCLUSIONS: Although intralesional therapy with collagenase Clostridium histolyticum is not yet indicated for the acute phase of Peyronie's disease, these preliminary results suggest the effectiveness of this minimally invasive option by improving penile curvature and IIEF-5 and PDQ scores.

Neuroprotection by trans-resveratrol against collagenase-induced neurological and neurobehavioural deficits in rats involves adenosine A1 receptors.

Objective: Trans-resveratrol has been shown to have neuroprotective effects and could be a promising therapeutic agent in the treatment of intracerebral haemorrhage (ICH). This study aimed to investigate the involvement of the adenosine A1 receptor (A1R) in trans-resveratrol-induced neuroprotection in rats with collagenase-induced ICH.Methods: Sixty male Sprague-Dawley rats weighing 330-380 g were randomly divided into five groups (n = 12): (i) control, (ii) sham-operated rats, (iii) ICH rats pretreated with vehicle (0.1% DMSO saline, i.c.v.), (iv) ICH rats pretreated with trans-resveratrol (0.9 µg, i.c.v.) and (v) ICH rats pretreated with trans-resveratrol (0.9 µg) and the A1R antagonist, DPCPX (2.5 µg, i.c.v.). Thirty minutes after pretreatment, ICH was induced by intrastriatal injection of collagenase (0.04 U). Forty-eight hours after ICH, the rats were assessed using a variety of neurobehavioural tests. Subsequently, rats were sacrificed and brains were subjected to gross morphological examination of the haematoma area and histological examination of the damaged area.Results: Severe neurobehavioural deficits and haematoma with diffuse oedema were observed after intrastriatal collagenase injection. Pretreatment with trans-resveratrol partially restored general locomotor activity, muscle strength and coordination, which was accompanied with reduction of haematoma volume by 73.22% (P < 0.05) and damaged area by 60.77% (P < 0.05) in comparison to the vehicle-pretreated ICH group. The trans-resveratrol-induced improvement in neurobehavioural outcomes and morphological features of brain tissues was inhibited by DPCPX pretreatment.Conclusion: This study demonstrates that the A1R activation is possibly the mechanism underlying the trans-resveratrol-induced neurological and neurobehavioural protection in rats with ICH.

Collagenase loaded chitosan nanoparticles for digestion of the collagenous scar in liver fibrosis: The effect of chitosan intrinsic collagen binding on the success of targeting.

A variety of hepatic insults result in the accumulation of collagen-rich new extracellular matrix in the liver, ultimately culminating in liver fibrosis and cirrhosis. For such reasons, approaches looking into digestion of the collagen-rich extracellular matrix present an interesting therapeutic approach for cases of chronic liver disease, where the fibrotic scar is well established. Portal collagenase administration has recently led to the successful reversion of cirrhosis in an experimental rabbit model. Notwithstanding, the question of how such a sensitive therapeutic macromolecule could be administered in a less invasive manner, and in a way that preserves its functionality and avoids digestion of other non-hepatic vital collagen presents itself. Chitosan is a biodegradable polymer that has been reported to interact and bind to collagen. Chitosan nanoparticles (CS NPs) have also been reported to encapsulate therapeutic proteins, maintaining their functional form and protecting them from in-vivo degradation. For such reasons, CS NPs were loaded with collagenase and evaluated in-vitro and in-vivo for their ability to target and digest collagen. CS NPs were able to encapsulate collagenase (≈ 60% encapsulation efficiency) and release its content in active form. To determine whether chitosan's collagen interaction would enable NP collagen binding or whether the modification with collagen binding peptides (CBPs) is necessary, CS NPs were modified with the CBP; CCQDSETRTFY. Since the density of targeting ligand and the length of tether play a significant role in the success of active targeting, the surface of NPs was modified with different densities of the CBP either directly or using a polyethylene glycol (PEG) spacer. PEGylated NPs showed higher levels of CBP tagging; high, intermediate and low density of CBPs corresponded to 585.8 ± 33, 252.9 ± 25.3 and 56.5 ± 8.8 µg/mL for PEGylated NPs and 425.56 ± 12.67, 107.91 ± 10.3 and 49.86 ± 3.2 µg/mL for unPEGylated NPs, respectively. In-vitro collagen binding experiments showed that unmodified CS NPs were able to bind collagen and that modification with CBPs either directly or via PEG did not enhance collagen binding. In-vivo experiments demonstrated that unmodified CS NPs were able to reverse fibrosis with a survival rate of 100% at the end of the study, indicating the ability of CS NPs to deliver functional collagenase to the fibrotic liver and making the use of CBPs unnecessary.

Collagenase Clostridium Histolyticum: A Review in Peyronie's Disease.

Collagenase Clostridium Histolyticum (hereafter referred to as CCH) [Xiaflex®; Xiapex®] is a mixture of two Clostridium histolyticum collagenases [AUX-I (a Class I clostridial collagenase) and AUX-II (a Class II clostridial collagenase)]. Administered by intralesional injection, it is available in various countries for the treatment of adult men with Peyronie's disease (PD). In two double-blind, multinational, phase III studies, CCH improved the physical (penile curvature) and psychological (patient-reported bother) aspects of PD in adult men. Such beneficial effects were also seen in two open-label, multinational, phase III studies, with potential benefits for patients' partners and maintained efficacy over up to 5 years additionally reported. Moreover, large real-world studies generally supported the therapeutic efficacy of CCH. CCH was generally well tolerated in these patient populations, with most treatment-related adverse events [TRAEs; most commonly penile haematoma (or 'bruising'), pain and swelling] being mild or moderate in severity, not serious and resolving without intervention. Moreover, the use of CCH was not associated with penile length shortening. Current evidence indicates that CCH is an effective, generally well tolerated and, compared with surgery, minimally invasive option for the treatment of adult men with PD.

The collagenase model of intracerebral hemorrhage in awake, freely moving animals: The effects of isoflurane.

Intracerebral hemorrhage (ICH) is a devastating stroke often modelled in rats. Isoflurane anesthetic, commonly used in preclinical research, affects general physiology (e.g., blood pressure) and electrophysiology (e.g., burst suppression) in many ways. These physiological changes may detract from the clinical relevance of the model. Here, we revised the standard collagenase model to produce an ICH in rats without anesthetic. Guide cannulas were implanted stereotaxically under anesthetic. After 3 days of recovery, collagenase was infused through an internal cannula into the striatum of animals randomly assigned to the non-anesthetized or isoflurane group. We assessed whether isoflurane affected hematoma volume, core temperature, movement activity, pain, blood pressure, and seizure activity. With a small ICH, there was a hematoma volume increased from 8.6 (±3.3, 95% confidence interval) µL in anesthetized rats to 13.2 (±3.1) µL in non-anesthetized rats (P = 0.008), but with a larger ICH, hematoma volumes were similar. Isoflurane decreased temperature by 1.3 °C (±0.16 °C, P < 0.001) for 2 h and caused a 35.1 (±1.7) mmHg group difference in blood pressure (P < 0.007) for 12 m. Blood glucose increased twofold after isoflurane procedures (P < 0.001). Pain, as assessed with the rat grimace scale, did not differ between groups. Seizure incidence rate (62.5%) in non-anesthetized ICH rats was similar to historic amounts (61.3%). In conclusion, isoflurane appears to have some significant and injury size-dependent effects on the collagenase model. Thus, when anesthetic effects are a known concern, the use of the standardized cannula infusion approach is scientifically and ethically acceptable.

Therapy for patients with burns - an integrating review.

OBJECTIVE: to identify, through an integrative review, national studies published over the last ten years highlighting products and therapies used in burns. METHODS: integrative research with studies published in the last ten years. Including clinical studies describing the use of the already established or innovative therapies in burns and the results obtained, published in national journals in the last ten years. Excluding articles published before 2007 and those that did not present results regarding the use of products in burns. RESULTS: ten articles that met the inclusion criteria were selected. Collagenase, 1% silver sulfadiazine, and porous cellulose membrane were some of the therapies cited. CONCLUSION: the casuistry was low; however, the good results obtained with porous cellulose membrane and silver nanocrystalline dressing are highlighted, since they were used in a larger number of patients in the studies evaluated.