Naldemedine. A new option for OIBD

Opioid-induced bowel dysfunction (OIBD) is a common complication in long-term opioid users and abusers. It is a burdensome condition, which significantly limits quality of life and is associated with increasing health costs. OIBD affects up to 60% of patients with chronic non-cancer pain and over 80% of patients suffering from cancer pain and is one of the conditions of the most common symptoms associated with opioid main-tenance. Given the continued use of opioids for chronic pain management in appropriate patients, OIBD is likely to persist in clinical practice in the coming years. We will herein review its underlying pathophysiological mechanisms and the available treatments. In the last years, pharmaceutical research has focused on the opportunity of targeting peripheral mu-opioid receptors without affecting their analgesic activity in the central nervous system, and several peripherally acting mu-opioid receptors antagonists (PAMORAs) drugs have been approved. We will mainly focus on naldemedine, discussing its pharmacological properties, its clinical efficacy and side effects. Head-to-head comparisons between naldemedine and the other PAMORAs are not available yet, but some considerations will be discussed based on the pharmacological and clinical data. As a whole, the available data suggest that naldeme-dine is a valid treatment option for OIBD, as it is a well-tolerated drug that alleviates constipation without affecting analgesia or causing symptoms of opioid withdrawal

Using opioid therapy for pain in clinically challenging situations. Questions for clinicians

Healthcare professionals and organizations increasingly face the conundrum of treating patients with active substance use disorder, a history of personal or familial substance use disorder, or those at elevated risk for substance abuse. Such patients need compassionate care when facing painful conditions; in fact, denying them pain control makes it likely that they will seek out ways to self-medicate with illicit drugs. Yet it remains unclear how to safely and effectively treat patients in these challenging situations. The authors have formulated ten questions to address in order to provide adequate analgesia for such patients. These questions demand a highly individualized approach to analgesia. These ten questions involve understanding the painful condition (presumed trajectory, duration, type of pain), using validated metrics such as risk assessment tools, guidelines, protocols, and safeguards within the system, selection of the optimal analgesic product(s) or combination therapy, and never starting opioid therapy without clear treatment objectives and a definitive exit plan. It is tempting but inaccurate to label these individuals as “inappropriate patients,” rather they are high-risk individuals in very challenging clinical situations. The challenge is that both options — being in pain or being treated with opioids to control pain — expose the patient to a risk of rekindling an addiction. The question is how do we, as clinicians, adequately respond to these very perplexing clinical challenges

Enamel fluorosis in rat’s incisor: S.E.M. and T.E.M. investigation

Findings on the alterations taking place in the enamel have demonstrated that they are generally caused by a daily use of highly fluoritic drinking waters.According to that, the Authors have carried out an ultrastructural study on lower incisors of albino rats after administering for 60 days water with a fluorine concentration five times the normal one.The samples, studied under the S.E.M., showed a general slowing of both the deposition and the maturation phase as well as the presence of some hypomineralized areas even after eruption.All this suggested the possibility that the damages observed were not due to the direct effect of fluorine on the enamel, but to the interaction between fluorine and ameloblasts.The Authors have then carried out an ultrastructural study on the enamel organ using the S.E.M.The results showed the presence of a well-evident endoplasmic reticulum, the lack in dense granules during the secretion phase, the lack in ruffle ended webs during the modulation phase, and the mitochondrial damage in the ameloblast.All this could justify the slowing of the enamel mineralization caused by fluorine effect on the ameloblasts.Il a été démontré que des altérations de l’émail sont généralement dues à l’absorption quotidienne d’eaux de boissons riches en fluor.Les auteurs ont entrepris une étude ultrastructurale des incisives inférieures du rat ayant reçu pendant 60 jours de l’eau dont la concentration en fluor est 5 fois supérieure à la normale.Les échantillons étudiés en microscopie électronique à balayage ont montré un ralentissement global de la déposition et de la phase de maturation ainsi que la présence de territoires hypominéralisés même après l’éruption.Toutes ces constatations suggèrent la possibilité que les dommages observés ne sont pas dus à l’effet direct du fluor sur l’émail, mais aux interactions entre le fluor et les améloblastes.Les auteurs ont mené une étude ultrastructurale de l’émail en utilisant le microscope électronique à balayage.Les résultats ont montré la présence d’un réticulum endoplasmique bien apparent, l’absence de grains denses au cours de la phase secrétoire, l’absence d’extrémités membranaires rugueuses au cours de la phase de modulation, et des altérations des mitochondries dans les améloblastes.Toutes ces constatations pourraient expliquer le ralentissement de la minéralisation de l’émail causé par les effets du fluor sur les améloblastes

Structural changes of tissue samples exposed to low frequency electromagnetic field: A FT-IR absorbance study

In the present work, we report on a preliminary Fourier Transform Infrared (FT-IR) Absorbance study performed on different kind of rat tissues, such as kidney and heart, exposed to a "non-ionizing" radiation source at low frequency, in the range typical of micro-waves (300 MHz <v< 300 GHz). The data were collected in a wide wavenumber region, from 400 cm−1to 4000 cm−1. The comparison of the absorbance spectra in the case of the normal tissues with the irradiated ones has shown significant differences in the spectral features in accordance with the morphological analysis performed by the optical microscopy

Decrease in drug accumulation and in tumour aggressiveness marker expression in a fenretinide-induced resistant ovarianumour cell line

We investigated whether the efficacy of fenretinide (HPR) against ovarian tumours may be limited by induction of resistance. The human ovarian carcinoma cell line A2780, which is sensitive to a pharmacologically achievable HPR concentration (IC 50= 1 μM), became 10-fold more resistant after exposure to increasing HPR concentrations. The cells (A2780/HPR) did not show cross-resistance to the synthetic retinoid 6-[3-adamantyl-4-hydroxyphenyl]-2-naphthalene carboxylic acid (CD437) and were not sensitive, similarly to the parent line, to all- trans -retinoic acid, 13- cis -retinoic acid or N-(4-methoxyphenyl)retinamide. A2780/HPR cells showed, compared to parental cells, a 3-fold reduction in colony-forming ability in agar. The development of HPR resistance was associated with a marked increase in retinoic acid receptor β (RARβ) mRNA and protein levels, which decreased, together with drug resistance, after drug removal. The expression of cell surface molecules associated with tumour progression including HER-2, laminin receptor and β1 integrin was markedly reduced. The increase in the levels of reactive oxygen species is not involved in HPR-resistance because it was similar in parental and resistant cells. Conversely differences in pharmacokinetics may account for resistance because, in A2780/HPR cells, intracellular peak drug levels were 2 times lower than in A2780 cells and an as yet unidentified polar metabolite was present. These data suggest that acquired resistance to HPR is associated with changes in marker expression, suggestive of a more differentiated status and may be explained, at least in part, by reduced drug accumulation and increased metabolism. © 2001 Cancer Research Campaign http://www.bjcancer.co

A Novel Radiotherapeutic Approach to Treat Bulky Metastases Even From Cutaneous Squamous Cell Carcinoma: Its Rationale and a Look at the Reliability of the Linear-Quadratic Model to Explain Its Radiobiological Effects

Introduction: Metastatic cutaneous squamous cell carcinoma (cSCC) is a very rare condition. The lack of definition of an oligometastatic subgroup means that there is no consensus for its treatment, unlike the mucosal head and neck counterpart. Like the latter, the cutaneous form is able to develop bulky tumor masses. When this happens, the classic care approach is just for palliative intent due to a likely unfavorable benefit–risk balance typical of aggressive treatments. Here we proposed a novel radiotherapy (RT) technique to treat bulky metastases from cSCC in the context of an overall limited tumor burden and tried to explain its clinical outcome by the currently available mathematical radiobiological and ad hoc developed models. Methods: We treated a case of facial cSCC with three metastases: two of them by classic stereotactic RT and the other by lattice RT supported by metabolic imaging (18F-FDG PET) due to its excessively large dimensions. For the latter lesion, we compared four treatment plans with different RT techniques in order to define the best approach in terms of normal tissue complication probability (NTCP) and tumor control probability (TCP). Moreover, we developed an ad hoc mathematical radiobiological model that could fit better with the characteristics of heterogeneity of this bulky metastasis for which, indeed, a segmentation of normoxic, hypoxic, and necrotic subvolumes might have been&nbsp;assumed. Results: We observed a clinical complete response in all three disease sites; the bulky metastasis actually regressed more rapidly than the other two treated by stereotactic RT. For the large lesion, NTCP predictions were good for all four different plans but even significantly better for the lattice RT plan. Neither the classic TCP nor the ad hoc developed radiobiological models could be totally adequate to explain the reported outcome. This finding might support a key role of the host immune system. Conclusions: PET-guided lattice RT might be safe and effective for the treatment of bulky lesions from cSCC. There might be some need for complex mathematical radiobiological models that are able to take into account any immune system’s role in order to explain the possible mechanisms of the tumor response to radiation and the relevant key points to enhance it

Image-guided multisession radiosurgery of skull base meningiomas

Background: The efficacy of single-session stereotactic radiosurgery (sSRS) for the treatment of intracranial meningioma is widely recognized. However, sSRS is not always feasible in cases of large tumors and those lying close to critically radiation-sensitive structures. When surgery is not recommended, multi-session stereotactic radiosurgery (mSRS) can be applied. Even so, the efficacy and best treatment schedule of mSRS are not yet established. The aim of this study is to validate the role of mSRS in the treatment of skull base meningiomas. Methods: A retrospective analysis of patients with skull base meningiomas treated with mSRS (two to five fractions) at the University of Messina, Italy, from 2008 to 2018, was conducted. Results: 156 patients met the inclusion criteria. The median follow-up period was 36.2 \ub1 29.3 months. Progression-free survival at 2-, 5-, and 10-years was 95%, 90%, and 80.8%, respectively. There were no new visual or motor deficits, nor cranial nerves impairments, excluding trigeminal neuralgia, which was reported by 5.7% of patients. One patient reported carotid occlusion and one developed brain edema. Conclusion: Multisession radiosurgery is an effective approach for skull base meningiomas. The long-term control is comparable to that obtained with conventionally-fractionated radiotherapy, while the toxicity rate is very limited

Spectroscopy 16 (2002) 245-250 245 IOS Press Recent results on biomedical problems: A Fourier transform infrared (FT-IR) study

Abstract. In the present work, we report on a vibrational study performed on rat encephalon samples and on human tissue affected by cancer, using Fourier Transform Infrared absorbance spectroscopy. As the brain rat tissue is concerned, the FT-IR measurements, performed in the CH-OH vibrational stretching region (2400-3800 cm −1 ), permitted us to reveal the presence of a very diffuse commercial benzodiazepine: VALIUM R . The comparison between the spectral features of normal brain and the ones of samples with administrated substance has unambiguously showed that the CH stretching region seems not to be affected by any change for the pharmacological treatment, instead the OH band is strongly modified probably due to the presence of a new spectral contribution characteristic of diazepam molecule. In the case of skin tissue the investigation was addressed to characterize the presence of two different pathologies, namely epithelioma and basalioma, and to show clear different spectral features passing from the normal tissue to the malignant one in particular in the region (1500-2000 cm −1 ) which is typical of the lipids vibrational bands