The safety and tolerability of levodopa eye drops for the treatment of ocular disorders: A randomized first‐in‐human study

Myopia is the leading cause of low vision worldwide and can lead to significant pathological complications. Therefore, to improve patient outcomes, the field continues to develop novel interventions for this visual disorder. Accordingly, this first‐in‐human study reports on the safety profile of a novel dopamine‐based ophthalmic treatment for myopia, levodopa/carbidopa eye drops. This phase I, first‐in‐human, monocenter, placebo‐controlled, double‐blind, paired‐eye, multidose, randomized clinical trial was undertaken in healthy adult males aged 18–30 years (mean age 24.9 ± 2.7) at the University of Canberra Eye Clinic, Australia. Participants were randomly assigned to receive either a low (1.4 levodopa:0.34 carbidopa [μmoles/day], n = 14) or standard dose (2.7 levodopa:0.68 carbidopa [μmoles/day], n = 15) of levodopa/carbidopa eye drops in one eye and placebo in the fellow eye once daily for 4 weeks (28 days). Over this 4‐week trial, and after a 4‐month follow‐up visit, levodopa/carbidopa treatment had no significant effect on ocular tolerability and anterior surface integrity, visual function, ocular health, refraction/ocular biometry, and did not induce any non‐ocular adverse events. These results indicate that topical levodopa/carbidopa is safe and tolerable to the eye, paving the way for future studies on the efficacy of this novel ophthalmic formulation in the treatment of human myopia. The findings of this study have implications not only for the treatment of myopia, but in a number of other visual disorders (i.e., amblyopia, diabetic retinopathy, and age‐related macular degeneration) in which levodopa has been identified as a potential clinical intervention.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Preclinical data indicate that levodopa/carbidopa eye drops can safely inhibit the development of experimental myopia in animal models.

• WHAT QUESTION DID THIS STUDY ADDRESS?

This study investigated whether levodopa/carbidopa eye drops are safe and tolerable to the human eye.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

In this phase I, first‐in‐human, monocenter, randomized, double‐blind, placebo‐controlled, multidose trial, levodopa/carbidopa eye drops were found to be safe and well tolerated in healthy adult males over a 4‐week period. Furthermore, no non‐ocular adverse events were reported.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

As topical administration of levodopa/carbidopa eye drops is well tolerated in humans, the efficacy of this novel ophthalmic treatment at inhibiting the development of myopia in patient populations can now be assessed. If found to be effective, this will provide a powerful new method for inhibiting the onset and development of the leading cause of low vision worldwide. This topical formulation may also provide a valuable tool in the treatment of other visual disorders shown to be responsive to levodopa therapy (i.e., amblyopia, diabetic retinopathy, and age‐related macular degeneration).     

Multimodal study of pelvic splenosis: a rare cause of abdominal pain

We present a rare case of pelvic splenosis, in a 46-year-old man, with a previous history of partial splenectomy, complaining of nonspecific pain in the lower abdominal quadrants. Splenosis is a benign acquired condition, defined as a heterotopic autotransplantation of splenic tissue in other compartments of the body, caused by rupture of the splenic capsule following trauma or splenectomy. Splenosis is often asymptomatic and incidentally found and does not require treatment. Surgery is indicated only in patients presenting with symptoms or complications. In our case, the multimodal imaging study (ultrasound, MRI, CT, and scintigraphy) allowed a correct differential diagnosis without resorting to invasive procedures, susceptible to complications     

Effects of quercetin on the gastrointestinal tract in rats and mice

Intraperitoneal administration of quercetin (6.25–50 mg/kg) significantly (p<0.5-0.01) reduced intestinal transit in mice and this effect was antagonized by yohimbine and phentolamine but not by atropine or naloxone. Quercetin (12.5–50 mg/kg) reduced also (p<0.05-0.01) intraluminal accumulation of fluid and diarrhoea induced by castor oil and these effects were antagonized by yohimbine. Finally quercetin (12.5–50 mg/kg) reduced the area of gastric ulcer but not the number. It is suggested that α2-adrenergic receptors mediate the effect of quercetin on intestinal motility and secretion.     

Distant muscular (gluteus maximus muscle) metastasis from laryngeal squamous cell carcinoma

Clinical evidence of non-lymphatic distant metastasis has been reported in approximately 10% of cases of head and neck squamous cell carcinoma (HNSCC). The lungs are the commonest site of distant metastasis of HNSCC, followed by the bones, liver and skin. A 65-year-old male underwent supraglottic laryngectomy and left modified neck dissection for a carcinoma of the laryngeal surface of the epiglottis extending to both false cords. Eight months later the patient underwent right radical modified neck dissection for hypodermal metastatic disease involving the underlying (sternocleidomastoid) muscle. Thirty-two months later, surgical excision of a lesion in the right gluteus maximus muscle was performed. Histological study diagnosed a muscular metastasis with the same morphological aspect as the laryngeal carcinoma. The patient showed no evidence of cervical or distant recurrence at follow-up after 13 months. Although skeletal muscles represent approximately 50% of total body mass and receive a large proportion of total cardiac output, haematogenous metastases to skeletal muscle are extremely uncommon. Most skeletal muscle metastases are of pulmonary origin. Distant skeletal muscle metastasis from HNSCC is an extremely rare occurrence. Treatment options, depending upon the clinical setting, include observation, radiotherapy, chemotherapy and excision; these approaches rarely alter the patient outcome. The prognosis associated with skeletal muscle metastasis is thought to be poor, consistent with the fact that it generally occurs as a feature of systemic spread.     

Probiotics Administration in Cystic Fibrosis: What Is the Evidence?

In the last 20 years, gut microbiota in patients with cystic fibrosis (CF) has become an object of interest. It was shown that these patients had gut dysbiosis and this could explain not only the intestinal manifestations of the disease but also part of those involving the respiratory tract. The acquisition of previously unknown information about the importance of some bacteria, i.e., those partially or totally disappeared in the gut of CF patients, in the regulation of the activity and function of the gut and the lung was the base to suggest the use of probiotics in CF patients. The main aim of this paper is to discuss the biological basis for probiotic administration to CF patients and which results could be expected. Literature analysis showed that CF intestinal dysbiosis depends on the same genetic mutations that condition the clinical picture of the diseases and is aggravated by a series of therapeutic interventions, such as dietary modifications, the use of antibiotics, and the administration of antacids. All this translates into a significant worsening of the structure and function of organs, including the lung and intestine, already deeply penalized by the genetic alterations of CF. Probiotics can intervene on dysbiosis, reducing the negative effects derived from it. However, the available data cannot be considered sufficient to indicate that these bacteria are essential elements of CF therapy. Further studies that take into account the still unsolved aspects on how to use probiotics are absolutely necessary.     

Impact of Dynamic Soil-Structure Interaction on Performance of a Single Span Footbridge with Overhangs Subjected to Mining-Induced Shocks

The impact of the dynamic soil-structure interaction (DSSI) on the response of a single-span footbridge to mining-induced shocks was assessed. Firstly, the eigen values, modes and damping of the footbridge were evaluated based on in-operation field tests. Then, natural frequencies were determined numerically by a model usually used in static calculations, i.e., a simple supported beam with overhangs. The numerical natural frequencies turned out to be inconsistent with the experimentally determined values. In turn, the model, assuming the overhangs’ ends translationally restrained, gave natural frequency values closer to the experimental ones. However, for the third mode, that is lateral, the frequency error (~26%) can be considered greater than usually accepted values. Hence, the three-dimensional numerical model of the footbridge was tuned by considering the DSSI between the overhangs and the ground, and implementing springs (in three directions) at the overhangs’ ends. To estimate the impact of DSSI on the dynamic performance of the footbridge, time history analyses were carried out for the model with fixed overhang ends and for the model with additional springs. Two different types of mining-induced tremors were used as excitations. Those two tremors (narrow and wide band) induced different dynamic responses in the models with and without the springs. Hence, the impact of the DSSI on the dynamic footbridge performance needs to be considered to predict the effect of mining-induced shocks.     

Prognostic implications of microRNA-21 overexpression in pancreatic ductal adenocarcinoma: an international multicenter study of 686 patients

Despite progress in genomic characterization, no single prognostic marker that can be evaluated using an easy-to-perform and relatively inexpensive method is available for pancreatic ductal adenocarcinoma (PDAC). MicroRNAs, which are stable, tumor- and tissue-specific molecules, are potentially ideal biomarkers, and we established an inter-laboratory validated method to investigate miR-21 as a prognostic biomarker in PDAC. The study samples of PDAC patients were recruited from a test cohort of Glasgow (n = 189) and three validation cohorts of Pisa (n = 69), Sydney (n = 249), and International Cancer Genome Consortium (ICGC) (n = 249). Tissue microarrays were used for miR-21 staining by chromogenic in situ hybridization (CISH). The patients were subdivided into no/low and high miR-21 staining groups using a specific histoscore. Furthermore, miR-21 staining was evaluated against clinicopathological variables and follow-up data by Fisher/log-rank test and Cox proportional models. The prognostic variables found to be significant in univariate analysis (P value < 0.10) were included in multivariate analysis in a backward-stepwise fashion. MiR-21 expression was cytoplasmic, with more consistent staining in the malignant ductal epithelium than in the stroma. The expression of miR-21 was significantly associated with tumor size and lymph node metastasis, whereas no association was observed with other clinicopathological variables. High miR-21 staining (histoscore ≥ 45 [median score]) was an independent predictor of survival in the Glasgow test cohort (HR 2.37, 95% CI: 1.42-3.96, P < 0.0001) and three validation cohorts (Pisa, HR 2.03, 95% CI: 1.21-3.39, P = 0.007; Sydney, HR 2.58, 95% CI (1.21-3.39), P < 0.0001; and ICGC, HR 3.34, 95% CI: 2.07-5.84, P = 0.002) when adjusted for clinical variables in a multivariate model. In comparison to the patients with low miR-21, the patients with high miR-21 expression had significant increase in OS as they benefit from gemcitabine-based adjuvant chemotherapy (Glasgow 16.5 months [with chemotherapy] vs 10.5 months [without chemotherapy]); Sydney 25.0 vs 10.6; ICGC 25.2 vs 11.9. These results indicated that miR-21 is a predictor of survival, prompting prospective trials. Evaluation of miR-21 offers new opportunities for the stratification of patients with PDAC and might facilitate the implementation of clinical management and therapeutic interventions for this devastating disease.     

Clinical usefulness of transcutaneous laryngeal ultrasonography in otolaryngology practice during COVID-19 pandemic: a literature review

As a consequence of the outbreak of SARS-CoV-2, the clinical practice of otolaryngologists underwent profound transformations. Non-aerosol-generating procedures have been researched and implemented. Transcutaneous laryngeal ultrasonography (TLUSG) provides a rapid and noninvasive method to assess laryngeal function and can support the management of laryngeal disorders. With the aim of investigating the clinical usefulness of TLUSG in otolaryngology practice, a review of the literature published on PubMed, Cochrane Library and Ovid/ Medline databases was performed up to March 2022. 38 studies were eligible to be included in the review. The selected papers were divided into six topics of interest: evaluation of vocal cords function, diagnosis of laryngeal disorders in infants and children, evaluation of swallowing disorders, assessment of laryngeal cancer and other laryngeal lesions, ultrasound-guided cricothyroidotomy, ultrasound-guided laryngeal electromyography. The results of this review demonstrated that TLUSG, applied to ENT practice, can be a valid method for dynamic laryngeal assessment and airway management, since it is time-efficient, non invasive, well tolerated and easily performed.