Pilocarpine HCl 1.25% for treatment of presbyopia after laser vision correction: pooled analysis of two phase 3 randomized trials (GEMINI 1 and 2).

PURPOSE: To evaluate the efficacy of topical pilocarpine HCl 1.25% (Pilo) in treating presbyopia in individuals with or without a history of laser vision correction (laser-assisted in situ keratomileusis [LASIK] or photorefractive keratectomy [PRK]). SETTING: Multiple clinical sites. DESIGN: Pooled analysis of 2 identically designed prospective, randomized, vehicle-controlled studies (GEMINI 1 and 2). METHODS: Adults aged 40 to 55 years with presbyopia received once-daily Pilo or vehicle bilaterally for 30 days. Responder rates for ≥3-line improvement in mesopic, high-contrast, binocular distance-corrected near visual acuity (DCNVA) were determined on day 30. RESULTS: Among participants with a history of LASIK/PRK (n = 39 in the Pilo group, n = 41 in the vehicle group), responder rates for ≥3-line improvement in DCNVA on day 30 at hours 0.25, 0.5, 1, 3, 6, 8, and 10, respectively, were 16.7%, 38.9%, 41.7%, 37.8%, 16.2%, 13.9%, and 8.3% with Pilo and 0.0%, 2.6%, 10.5%, 5.1%, 7.7%, 2.6%, and 0.0% with vehicle. Responder rates in the LASIK/PRK subgroup were significantly higher with Pilo than vehicle at hours 0.25 ( P = .0087), 0.5 ( P = .0001), 1 ( P = .0022), and 3 ( P = .0005). In contrast, there were no significant differences in responder rates between Pilo-treated participants with and without LASIK/PRK. Among non-LASIK/PRK participants in the Pilo group (n = 336), responder rates for ≥3-line improvement in DCNVA on day 30 at hours 0.25, 0.5, 1, 3, 6, 8, and 10, respectively, were 16.8%, 32.7%, 39.0%, 28.0%, 17.4%, 12.6%, and 10.5%. CONCLUSIONS: Pilo treatment effectively and similarly improved DCNVA in presbyopes with or without a history of laser vision correction.

N-Formyl-Methionyl-Leucyl-Phenylalanine Plays a Neuroprotective and Anticonvulsant Role in Status Epilepticus Model.

Status epilepticus (SE) is described as continuous and self-sustaining seizures, which triggers hippocampal neurodegeneration, inflammation, and gliosis. N-formyl peptide receptor (FPR) has been associated with inflammatory process. N-formyl-methionyl-leucyl-phenylalanine (fMLP) peptide plays an anti-inflammatory role, mediated by the activation of G-protein-coupled FPR. Here, we evaluated the influence of fMLP peptides on the behavior of limbic seizures, memory consolidation, and hippocampal neurodegeneration process. Male Wistar rats (Rattus norvegicus) received microinjections of pilocarpine in hippocampus (H-PILO, 1.2 mg/µL, 1 µL) followed by fMLP (1 mg/mL, 1 µL) or vehicle (VEH, saline 0.9%, 1 µL). During the 90 min of SE, epileptic seizures were analyzed according to the Racine's Scale. After 24 h of SE, memory impairment was assessed by the inhibitory avoidance test and the neurodegeneration process was evaluated in hippocampal areas. There was no change in latency and number of wet dog shake (WDS) after administration of fMLP. However, our results showed that the intrahippocampal infusion of fMLP reduced the severity of seizures, as well as the number of limbic seizures. In addition, fMLP infusion protected memory dysfunction followed by SE. Finally, the intrahippocampal administration of fMLP attenuated the process of neurodegeneration in both hippocampi. Taken together, our data suggest a new insight into the functional role of fMLP peptides, with important implications for their potential use as a therapeutic agent for the treatment of brain disorders, such as epilepsy. Schematic drawing on the neuroprotective and anticonvulsant role of fMLP during status epilepticus. Initially, a cannula was implanted in hippocampus and pilocarpine/saline was administered into the hippocampus followed by fMLP/saline (A-C). fMLP reduced seizure severity and neuronal death in the hippocampus, as well as protecting against memory deficit (D).

Safety and efficacy of oral pilocarpine in radiation-induced xerostomia in oropharyngeal carcinoma patients.

Context: Patients with head-and-neck cancers can develop salivary gland hypofunction after radiotherapy. Oral pilocarpine has been shown to be effective treatment for radiation-induced xerostomia, although its usefulness is being discussed. Aims: We aimed to evaluate the efficacy and safety profile of oral pilocarpine in radiation-induced xerostomia. Materials and Methods: Sixty patients with oropharyngeal carcinoma were planned for radiotherapy and divided into two arms randomly: Arm A (30 patients) received oral pilocarpine and Arm B (30 patients) received placebo tablets for 12 weeks after 3 months of completion of radiotherapy. Salivary gland scintigraphy and xerostomia questionnaire (XQ) were obtained from each patient at baseline and at 3 and 6 months of completion of radiotherapy. Results: There was a marked decrease in uptake ratio (UR) and excretion fraction (EF) after 3 months of completion of radiotherapy. There was a statistically significant difference between both the arms in relation to UR, but no significant difference was observed between the two arms in relation to EF after 6 months of completion of radiotherapy. A statistically significant difference was found comparing the XQ results in both the arms. The XQ results did not correlate with salivary gland dysfunction observed by means of salivary scintigraphy. Adverse effects due to xerostomia were generally mild and occasionally of moderate severity. Conclusion: The use of oral pilocarpine did not significantly improve salivary gland excretory function, despite better results on salivary uptake at 6 months. However, oral pilocarpine significantly improved symptoms of xerostomia with minor side effects that were predominantly limited to sweating.

Effects of GABAB receptor positive allosteric modulator BHF177 and IRS-1 on apoptosis of hippocampal neurons in rats with refractory epilepsy via the PI3K/Akt pathway.

The present study was conducted to determine the effects of the γ-aminobutyric acid B (GABAB ) receptor positive allosteric modulator BHF177 on refractory epilepsy (RE). An RE rat model was initially established via treatment with lithium-pilocarpine. The RE rats were then treated with BHF177 or the GABAB receptor antagonist CGP46381, followed by recording of their seizure rate and assessment of their spatial learning in the Morris water maze test. Treatment of BHF177 reduced the seizure intensity, whereas this effect was revered upoj treatment with CGP46381. Immunohistochemistry revealed that BHF177 treatment diminished P-glycoprotein (P-gp) expression in the hippocampal tissues of RE rats. Next, we found that BHF177 activated GABAB receptor, resulting in upregulated expression of insulin receptor substrate 1 (IRS-1) and PI3K, as well as antiapoptotic factors (Bcl-2 and mTOR), along with suppression of the apoptosis factors Bax and cleaved caspase-3 in the hippocampal tissues. Further, activation of GABAB receptors by BHF177 alleviated the inflammatory response in hippocampal tissues of RE rats, as evidenced by reduced VCAM-1, ICAM-1, and tumor necrosis factor-α levels. Next, we treated primary cultured rat hippocampal neurons with BHF177 and the IRS-1 selective inhibitor NT157. BHF177 inhibited hippocampal apoptosis in rat hippocampal neurons by regulating the IRS-1/PI3K/Akt axis through crosstalk between GABAB and insulin-like growth factor-1 receptors. Collectively, our findings indicate that the BHF177 inhibited neuron apoptosis, thus protecting against RE through the IRS-1/PI3K/Akt axis, which may present a new therapeutic channel for RE.

Role of pilocarpine use following laser peripheral iridotomy in eyes with refractory acute angle closure glaucoma: A case report and literature review.

RATIONALE: Angle closure glaucoma (ACG) is one of the most emergent types of glaucoma in clinical practice. Laser peripheral iridotomy (LPI) could minimize pupillary block and prevent ACG from an acute attack. However, recurrent increase in intraocular pressure (IOP) may still occur despite successful LPI. The aim of this study is to highlight the importance of postLPI pilocarpine use and larger LPI size as well as to share some experiences of cataract surgery in patients with ACG. PATIENT CONCERNS: A 63-year-old female was referred to our hospital for headache, and poor control of IOP in the right eye for 3 hours. DIAGNOSES: The patient was diagnosed ACG in the right eye. Recurrence of ACG in the right eye and new-onset and recurrent ACG in the left eye were noted during follow-up, despite successful LPI. The diagnosis was confirmed through slit lamp and gonioscope examination. INTERVENTIONS: The LPI size was enlarged and pilocarpine use was maintained at 2% (1 drop 4 times a day) in both the eyes. Finally, cataract surgery was performed in both the eyes. OUTCOMES: No recurrence of ACG was noted during postLPI pilocarpine use in both the eyes. The postoperative IOP was stable for >6 months after cataract surgery without any surgical intervention or antiglaucoma medication use. No discomfort or major complication was observed. CONCLUSION: This report highlights the importance of postLPI pilocarpine use and larger LPI size in patients with refractory ACG.

Topical Xerostomia Treatment with Hyaluronate Sheets Containing Pilocarpine.

Sjogren's syndrome and radiation therapy for head and neck cancers are often accompanied by xerostomia. Oral pilocarpine (PCP) to treat xerostomia produces systemic side effects, such as runny nose and lacrimation. To improve the therapeutic efficacy of PCP and reduce the aforementioned side effects, we developed a topical delivery system for PCP using freeze-dried sheets of hyaluronic acid (HA). The advantages of HA sheets over conventional oral formulations were examined through in vivo pharmacokinetic and pharmacodynamic studies after their application to oral tissues and salivary glands. The concentration of PCP in the submucosal tissue of the oral cavity was determined using the microdialysis (MD) method after buccal application of HA sheets containing PCP to hamsters. The concentration of PCP in the MD outflow was quite low after gastric administration, whereas the PCP concentration in plasma was high. In contrast, after buccal application of HA sheets containing PCP, the concentration of the drug in the MD outflow increased, despite the negligible concentration in plasma. These findings indicated that both enhancement of saliva secretion and the avoidance of systemic side effects could be achieved through buccal administration of PCP-loaded HA sheets. In addition, the pharmacodynamic study showed that when compared with intravenous and gastric administration, salivary application of HA sheets containing PCP resulted in similar volumes of saliva secretion and reduced lacrimal secretions. In conclusion, freeze-dried HA sheets allow for the development of a novel buccal delivery system with enhanced therapeutic efficacy and safety to treat xerostomia.

Histopathological and Biochemical Assessment of Neuroprotective Effects of Sodium Valproate and Lutein on the Pilocarpine Albino Rat Model of Epilepsy.

Epilepsy is one of the most frequent neurological disorders characterized by an enduring predisposition to generate epileptic seizures. Oxidative stress is believed to directly participate in the pathways of neurodegenerations leading to epilepsy. Approximately, one-third of the epileptic patients who suffer from seizures do not receive effective medical treatment. Sodium valproate (SVP) is a commonly used antiepileptic drug (AED); however, it has toxic effects. Lutein (L), a carotenoid, has potent antioxidant and anti-inflammatory properties. The aim of this study was to determine the neuroprotective effect of sodium valproate (SVP) and lutein (L) in a rat model of pilocarpine- (PLC-) induced epilepsy. To achieve this aim, fifty rats were randomly divided into five groups. Group I: control, group II: received PLC (400 mg/kg intraperitoneally), group III: received PLC + SVP (500 mg/kg orally), group IV: received PLC + SVP + L (100 mg/kg orally), and group V: received (PLC + L). Racine Scale (RC) and latency period to onset seizure were calculated. After eight weeks, the hippocampus rotarod performance and histological investigations were performed. Oxidative stress was investigated in hippocampal homogenates. Results revealed that SVP and L, given alone or in combination, reduced the RC significantly, a significant delay in latency to PLC-kindling onset, and improved rotarod performance of rats compared with the PLC group. Moreover, L was associated with a reduction of oxidative stress in hippocampal homogenate, a significant decrease in serum tumor necrosis factor-alpha (TNF-α) level, and inhibition of cerebral injury and displayed antiepileptic properties in the PLC-induced epileptic rat model. Data obtained from the current research elucidated the prominent neuroprotective, antioxidant, and anti-inflammatory activities of lutein in this model. In conclusion, lutein cotreatment with AEDs is likely to be a promising strategy to improve treatment efficacy in patients suffering from epilepsy.

Hormonal and biochemical changes in female Proechimys guyannensis, an animal model of resistance to pilocarpine-induced status epilepticus.

The Amazon rodent Proechimys guyannensis is widely studied for hosting various pathogens, though rarely getting sick. Previous studies on male Proechimys have revealed an endogenous resistance to epilepsy. Here, we assess in female Proechimys, whether sex hormones and biochemical aspects can interfere with the induction of status epilepticus (SE). The lithium-pilocarpine ramp-up protocol was used to induce SE, and blood sera were collected at 30 and 90 min after SE, alongside brains, for biochemical, western blot and immunohistochemical analyses. Results from non-ovariectomised (NOVX) Proechimys were compared to ovariectomised (OVX) animals. Data from female Wistars were used as a positive control of SE inductions. SE latency was similar in NOVX, OVX, and female Wistars groups. However, the pilocarpine dose required to induce SE in Proechimys was higher (25- to 50-folds more). Despite a higher dose, Proechimys did not show strong SE like Wistars; they only reached stage 2 of the Racine scale. These data suggest that female Proechimys are resistant to SE induction. Glucose and progesterone levels increased at 30 min and returned to normal at 90 min after SE. A relevant fact because in humans and rodents, SE leads to hypoglycaemia after 30 min of SE and does not return to normal levels in a short time, a typical adverse effect of SE. In OVX animals, a decrease in GABAergic receptors within 90 min of SE may suggest that ovariectomy produces changes in the hippocampus, including a certain vulnerability to seizures. We speculate that progesterone and glucose increases form part of the compensatory mechanisms that provide resistance in Proechimys against SE induction.

Sjögren's Syndrome as an Immune-related Adverse Event of Nivolumab Treatment for Gastric Cancer.

Immune checkpoint inhibitors can affect any organ, including the salivary glands. A case of Sjögren's syndrome (SjS) induced by nivolumab for the treatment of gastric cancer is herein presented. Nivolumab treatment caused marked tumor shrinkage, but xerostomia developed after two cycles. It took 3 months after symptom onset to confirm the diagnosis of SjS. Prednisolone and pilocarpine hydrochloride did not relieve the symptoms. SjS is a relatively rare immune-related adverse event that might sometimes be overlooked. Since SjS can severely impair a patient's quality of life, oncologists should not miss any signs of salivary gland hypofunction and cooperate with specialists for SjS.

Low-dose Pilocarpine Spray to Treat Xerostomia.

Although pilocarpine hydrochloride tablets are currently indicated for the treatment of xerostomia, their adverse effects are frequently reported. The development of a new, low-dose pilocarpine solution for topical oral-cavity use is needed. This article discusses a few clinical trials to formulate a topical low-dose solution of pilocarpine hydrochloride for the treatment of xerostomia and presents two low dose, stable formulations of pilocarpine topical spray that can improve the patient's quality of life with minimal adverse effects.

Effect of adenovirus-mediated overexpression of PTEN on brain oxidative damage and neuroinflammation in a rat kindling model of epilepsy.

BACKGROUND: Epilepsy is a chronic and severe neurological disorder. Phosphatase and tensin homolog deleted on chromosome ten (PTEN)-deficient mice exhibit learning and memory deficits and spontaneous epilepsy. The aim of this study was to investigate the role of PTEN in brain oxidative damage and neuroinflammation in a rat model of epilepsy. METHODS: An adenovirus (Ad)-PTEN vector was constructed, and status epilepticus (SE) was induced in 41 model rats using lithium chloride-pilocarpine. Thirty-six SE rats were then allocated into the Ad-PTEN, Ad-LacZ, and SE groups, those were administered intracerebroventricular injections of Ad-PTEN, Ad-enhanced green fluorescent protein, and phosphate buffer saline, respectively. The normal group was comprised of healthy Sprague-Dawley rats. Nissl staining was conducted to evaluate neuronal damage, and immunohistochemistry was conducted to observe the morphology of cells in the hippocampal CA1 region and the distribution of ionized calcium-binding adaptor molecule 1 (Iba1) and ED1 (rat homologue of human CD68). Levels of apoptosis-related proteins, inflammatory-related factors, and oxidative stress-related markers (reactive oxygen species [ROS], glutathione [GSH], superoxide dismutase [SOD], and malondialdehyde [MDA]) were measured. Comparisons between multiple groups were conducted using one-way analysis of variance (ANOVA), and pairwise comparisons after ANOVA were conducted using the Tukey multiple comparisons test. RESULTS: After SE induction, PTEN expression in the rat brain exhibited a four-fold decrease (P = 0.000) and the expression of both Iba1 and ED1 increased. Furthermore, significant neuronal loss, oxidative damage, and neuroinflammation were observed in the SE rat brain. After intracerebroventricular injection of Ad-PTEN, PTEN expression exhibited a three-fold increase (P = 0.003), and the expression of both Iba1 and ED1 decreased. Additionally, neurons were restored and neuronal apoptosis was inhibited. Furthermore, ROS and MDA levels decreased, GSH level and SOD activity increased, and neuroinflammation was reduced. CONCLUSION: Our study demonstrated that brain oxidative damage and neuroinflammation in SE rats were ameliorated by intracerebroventricular injection of Ad-PTEN.

Risk of Parkinson disease in Sjögren syndrome administered ineffective immunosuppressant therapies: A nationwide population-based study.

To determine the incidence and risk of Parkinson disease (PD) in patients with Sjögren syndrome (SS) according to a nationwide population-based database.In total, 12,640 patients in the SS cohort and 50,560 in the non-SS cohort were enrolled from Taiwan's National Health Insurance Research Database from 2000 to 2010. We used the Cox multivariable proportional hazards model to determine the risk factors for PD in the SS cohort.We observed an increased incidence of PD in patients with SS, with a crude hazard ratio (HR) of 1.40 and an adjusted HR (aHR) of 1.23. The cumulative incidence of PD was 1.95% higher in the SS cohort than in the non-SS cohort. The SS cohort had an elevated HR under medication use, namely cevimeline and pilocarpine (crude HR, 1.28), hydroxychloroquine (crude HR, 1.43; aHR, 1.46), and methylprednisolone (crude HR, 2.21; aHR, 1.49). Patients receiving other non-hydroxychloroquine immunosuppressant therapies had a lower risk (aHR, 0.86) of PD. Furthermore, patients with SS aged 20 to 49 years had a 1.93-fold higher risk of PD than did those without SS (aHR, 1.93). The risk of PD was higher (aHR, 2.20) in patients with SS without comorbidities than in those with comorbidities. The aHR of PD significantly increased when the follow-up period exceeded 9 years (aHR, 1.93).We determined an increased risk of PD in patients with SS. Further investigation is warranted to determine the possible underlying mechanisms and the potential role of non-hydroxychloroquine immunosuppressants in ameliorating PD.

Changes in Iridocorneal Angle and Anterior Chamber Structure in Eyes With Anatomically Narrow Angles: Laser Iridotomy Versus Pilocarpine.

PURPOSE: To compare the effects of laser iridotomy (LI) and pilocarpine on iridocorneal angle and anterior chamber structure in anatomically narrow angles (ANAs). MATERIALS AND METHODS: Temporal LI was performed 90 minutes after 2% pilocarpine administration in patients with occludable ANA. Swept-source optical coherence tomography B-scans of the anterior segment were obtained at baseline, 60 minutes after 2% pilocarpine administration, and 1 week after LI. Angle-opening distance (AOD), trabecular-iris surface area (TISA), and angle recess area (ARA) were measured at the temporal, superior, nasal, and inferior quadrants. Anterior chamber depth (ACD) and lens vault (LV) were also measured. AOD, TISA, ARA, ACD, and LV were compared among 3 time points: at baseline, 60 minutes after 2% pilocarpine administration, and 1 week after LI. RESULTS: Twenty-four eyes (24 patients; mean age, 55 y) were included. In all 4 quadrants and globally, AOD, TISA, and ARA increased from baseline after pilocarpine and after LI (all P<0.010). The increase in AOD, TISA, and ARA was greater after LI than after pilocarpine globally and in the temporal and superior quadrants (all P<0.040). ACD decreased and LV increased from baseline after pilocarpine (both P<0.001). Postpilocarpine anterior chambers were shallower with higher LV than post-LI (both P<0.016). CONCLUSION: LI is more effective than pilocarpine in widening the iridocorneal angle without significant shallowing the anterior chamber in eyes with ANA.

Athetoid Movements as Initial Manifestation of Primary Sjögren Syndrome.

Background: Primary Sjögren syndrome (pSS) is an autoimmune disorder characterized by exocrine gland and extraglandular symptoms. We present a case report of pSS with an initial presentation of athetoid movements. Case Report: A 74-year-old female presented with a 2-month history of slow undulating movements in her trunk and thighs that eventually spread to her neck and lower extremities. She also reported dry eyes, dry mouth, as well as pain in her shoulders and thighs. Her proinflammatory markers and rheumatologic profile were positive. Her salivary gland biopsy revealed a Focus score > 2. Brain magnetic resonance imaging was normal. A diagnosis of pSS was made. The patient's symptoms improved with hydroxychloroquine, pilocarpine, gabapentin, and clonazepam. Discussion: Clinicians should consider and screen for primary autoimmune disorders as a cause of subacute athetoid movements in elderly patients. Although aggressive treatment has been recommended, treatment should be tailored to each patient's specific needs.

Primary Sjogren syndrome diagnosed simultaneously with localized amyloidosis of the lacrimal gland: A case report.

INTRODUCTION: Amyloidosis accompanied by Sjögren's syndrome (SS) has been reported to occur primarily in the skin, lungs, tongue, and mammary gland. However, SS in association with secondary amyloidosis is rarely reported, and knowledge of its relevance is inadequate. Here we report a case of primary SS diagnosed simultaneously with localized amyloidosis of the lacrimal gland. CASE PRESENTATION: A 45-year-old woman complaining of a left eyelid mass was referred to the hospital and was diagnosed with localized amyloidosis after excisional biopsy. She was then referred to the rheumatology department for additional evaluation for amyloidosis. Subsequently, her diagnosis was primary SS based on the presented symptoms and results of the Schirmer test, serologic testing, and minor salivary gland biopsy. Pilocarpine (10 mg/d) and hydroxychloroquine (200 mg/d) were initiated for the treatment of SS. Six months after the initial diagnosis, the dry eyes and mouth did not worsen and no masses suggestive of localized amyloidosis were reported. CONCLUSION: This is a rare case of amyloidosis, localized to the lacrimal gland, with SS. Therefore, despite its rarity, physicians should be aware of the potential coexistence of secondary amyloidosis, even in the localized form, in patients with SS.

Murine Salivary Functional Assessment via Pilocarpine Stimulation Following Fractionated Radiation.

Hyposalivation is commonly observed in the autoimmune reaction of Sjögren's syndrome or following radiation injury to the major salivary glands. In these cases, questions remain regarding disease pathogenesis and effective interventions. An optimized technique that allows functional assessment of the salivary glands is invaluable for investigating exocrine gland biology, dysfunction, and therapeutics. Here, we present a step by step approach to performing pilocarpine stimulated saliva secretion, including tracheostomy and the dissection of the three major murine salivary glands. We also detail the appropriate murine head and neck anatomy accessed during these techniques. This approach is scalable, allowing for multiple mice to be processed simultaneously, thus improving the efficiency of the work flow. We aim to improve the reproducibility of these methods, each of which has further applications within the field. In addition to saliva collection, we discuss metrics for quantifying and normalizing functional capacity of these tissues. Representative data are included from submandibular glands with depressed salivary gland function 2 weeks following fractionated radiation (4 doses of 6.85 Gy).

Terapia farmacológica y avances terapéuticos en xerostomía e hiposalivación / Pharmacological therapy and therapeutic advancesin xerostomy and hyposalivation

La saliva juega un rol determinante en el mantenimiento y función de los tejidos orales, donde un decremento en los niveles del flujo salival conllevan a una hiposalivación o hiposialia, trayendo consigo una serie de características que propician un ambiente ideal para la instalaciónde microorganismos oportunistas y condiciones nocivas para la saludoral y sistémica de los pacientes. Hoy en día existen múltiples causas que conllevan a una hiposialia, entre ellas el síndrome de Sjõgren, la radioterapia de haz externo, entre otras, los cuales se han puesto a prueba mediante sialogogos farmacológicos como pilocarpina, cevimelina, betanecoly carbacolina, además de alternativas terapéuticas para revertir los signos obtenidos por la hiposalivación y mitigar los síntomas de xerostomía. El objetivo del presente es realizar una revisión de literatura sobre el tratamiento farmacológico en hiposalivación y xerostomía ensíndrome de Sjõgren y radioterapia de haz externo.

Saliva plays a determinant role in the maintenance and function of oral tissues, where a decrease in salivary flow levels leads to hyposalivation or hyposialia, bringing with it a series of characteristics that provide anideal environment for the installation of opportunistic microorganisms and conditions harmful to the oral and systemic health of patients.Today there are many causes that lead to hyposialia, including Sjögren’ssyndrome, external beam radiotherapy, among others, which have beentested by pharmacological sialogogs such as pilocarpine, cevimelin, betanecol and carbacoline, in addition to therapeutic alternativesto reverse the signs obtained by hyposalivation and to mitigate the symptoms of xerostomia. The objective of the present is to make a reviewof the literature on the pharmacological treatment in hyposalivation and xerostomia in Sjögren’s syndrome and external beam radiotherapy.

Pharmacological interventions for preventing dry mouth and salivary gland dysfunction following radiotherapy.

BACKGROUND: Salivary gland dysfunction is an 'umbrella' term for the presence of either xerostomia (subjective sensation of dryness), or salivary gland hypofunction (reduction in saliva production). It is a predictable side effect of radiotherapy to the head and neck region, and is associated with a significant impairment of quality of life. A wide range of pharmacological interventions, with varying mechanisms of action, have been used for the prevention of radiation-induced salivary gland dysfunction. OBJECTIVES: To assess the effects of pharmacological interventions for the prevention of radiation-induced salivary gland dysfunction. SEARCH METHODS: Cochrane Oral Health's Information Specialist searched the following databases: Cochrane Oral Health's Trials Register (to 14 September 2016); the Cochrane Central Register of Controlled Trials (CENTRAL; 2016, Issue 8) in the Cochrane Library (searched 14 September 2016); MEDLINE Ovid (1946 to 14 September 2016); Embase Ovid (1980 to 14 September 2016); CINAHL EBSCO (Cumulative Index to Nursing and Allied Health Literature; 1937 to 14 September 2016); LILACS BIREME Virtual Health Library (Latin American and Caribbean Health Science Information database; 1982 to 14 September 2016); Zetoc Conference Proceedings (1993 to 14 September 2016); and OpenGrey (1997 to 14 September 2016). We searched the US National Institutes of Health Ongoing Trials Register (ClinicalTrials.gov) and the World Health Organization International Clinical Trials Registry Platform for ongoing trials. No restrictions were placed on the language or date of publication when searching the electronic databases. SELECTION CRITERIA: We included randomised controlled trials, irrespective of their language of publication or publication status. Trials included participants of all ages, ethnic origin and gender, scheduled to receive radiotherapy on its own or in addition to chemotherapy to the head and neck region. Participants could be outpatients or inpatients. We included trials comparing any pharmacological agent regimen, prescribed prophylactically for salivary gland dysfunction prior to or during radiotherapy, with placebo, no intervention or an alternative pharmacological intervention. Comparisons of radiation techniques were excluded. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. MAIN RESULTS: We included 39 studies that randomised 3520 participants; the number of participants analysed varied by outcome and time point. The studies were ordered into 14 separate comparisons with meta-analysis only being possible in three of those.We found low-quality evidence to show that amifostine, when compared to a placebo or no treatment control, might reduce the risk of moderate to severe xerostomia (grade 2 or higher on a 0 to 4 scale) at the end of radiotherapy (risk ratio (RR) 0.35, 95% confidence interval (CI) 0.19 to 0.67; P = 0.001, 3 studies, 119 participants), and up to three months after radiotherapy (RR 0.66, 95% CI 0.48 to 0.92; P = 0.01, 5 studies, 687 participants), but there is insufficient evidence that the effect is sustained up to 12 months after radiotherapy (RR 0.70, 95% CI 0.40 to 1.23; P = 0.21, 7 studies, 682 participants). We found very low-quality evidence that amifostine increased unstimulated salivary flow rate up to 12 months after radiotherapy, both in terms of mg of saliva per 5 minutes (mean difference (MD) 0.32, 95% CI 0.09 to 0.55; P = 0.006, 1 study, 27 participants), and incidence of producing greater than 0.1 g of saliva over 5 minutes (RR 1.45, 95% CI 1.13 to 1.86; P = 0.004, 1 study, 175 participants). However, there was insufficient evidence to show a difference when looking at stimulated salivary flow rates. There was insufficient (very low-quality) evidence to show that amifostine compromised the effects of cancer treatment when looking at survival measures. There was some very low-quality evidence of a small benefit for amifostine in terms of quality of life (10-point scale) at 12 months after radiotherapy (MD 0.70, 95% CI 0.20 to 1.20; P = 0.006, 1 study, 180 participants), but insufficient evidence at the end of and up to three months postradiotherapy. A further study showed no evidence of a difference at 6, 12, 18 and 24 months postradiotherapy. There was low-quality evidence that amifostine is associated with increases in: vomiting (RR 4.90, 95% CI 2.87 to 8.38; P < 0.00001, 5 studies, 601 participants); hypotension (RR 9.20, 95% CI 2.84 to 29.83; P = 0.0002, 3 studies, 376 participants); nausea (RR 2.60, 95% CI 1.81 to 3.74; P < 0.00001, 4 studies, 556 participants); and allergic response (RR 7.51, 95% CI 1.40 to 40.39; P = 0.02, 3 studies, 524 participants).We found insufficient evidence (that was of very low quality) to determine whether or not pilocarpine performed better or worse than a placebo or no treatment control for the outcomes: xerostomia, salivary flow rate, survival, and quality of life. There was some low-quality evidence that pilocarpine was associated with an increase in sweating (RR 2.98, 95% CI 1.43 to 6.22; P = 0.004, 5 studies, 389 participants).We found insufficient evidence to determine whether or not palifermin performed better or worse than placebo for: xerostomia (low quality); survival (moderate quality); and any adverse effects.There was also insufficient evidence to determine the effects of the following interventions: biperiden plus pilocarpine, Chinese medicines, bethanechol, artificial saliva, selenium, antiseptic mouthrinse, antimicrobial lozenge, polaprezinc, azulene rinse, and Venalot Depot (coumarin plus troxerutin). AUTHORS' CONCLUSIONS: There is some low-quality evidence to suggest that amifostine prevents the feeling of dry mouth in people receiving radiotherapy to the head and neck (with or without chemotherapy) in the short- (end of radiotherapy) to medium-term (three months postradiotherapy). However, it is less clear whether or not this effect is sustained to 12 months postradiotherapy. The benefits of amifostine should be weighed against its high cost and side effects. There was insufficient evidence to show that any other intervention is beneficial.

Sjogren's syndrome from the perspective of ophthalmology.

Sjogren's syndrome (SS) is an autoimmune disease affecting the lacrimal glands resulting in dry eye disease (DED). Ophthalmologists may be the first line of detection of Sjogren's syndrome given the frequency of DED in SS and that dry eye is often the presenting symptom. Numerous symptom questionnaires and tests have been developed to help diagnose DED, but as of yet, there is no "gold standard." Minimally invasive objective metrics are needed for a reliable diagnosis of DED. Currently there is no single test to diagnose SS-associated DED. Although there are several approaches to treatment, none are specific for DED in SS, and, generally, several methods need to be tried to find what works best for a specific patient. Treatment for DED continues to be an unmet medical need, especially given that DED in SS is typically on the severe end of the spectrum.