Subcutaneous Injection Of Apomorphine Research Articles

Optimised endoscopic access for intrajejunal levodopa application in idiopathic Parkinson's syndrome

Pump-guided intrajejunal levodopa administration is one of the indispensable forms of therapy in advanced Parkinson's syndrome, along with deep brain stimulation and subcutaneous apomorphine injection. The standard application of levodopa gel via a JET-PEG, i.e. a percutaneous endoscopic gastrostomy (PEG) with an inserted internal catheter into the jejunum, has not been unproblematic due to the restricted absorption area of the drug in the region of the flexura duodenojejunalis and especially due to the sometimes considerable accumulated complication rates of a JET-PEG. Causes of complications are mainly a non-optimal application technique of PEG and internal catheter as well as the often missing adequate follow-up care. This article presents the details of a—compared to the conventional technique—modified and optimised application technique, which has been clinically proven successfully for years. However, many details derived from anatomical, physiological, surgical and endoscopic aspects must be strictly observed during the application to reduce or avoid minor and major complications. Local infections and buried bumper syndrome cause particular problems. The relatively frequent dislocations of the internal catheter (which can ultimately be avoided by clip-fixing the catheter tip) also prove to be particularly troublesome. Finally, using the Hybrid technique, a new combination of an endoscopically controlled gastropexy with 3 sutures and subsequent central thread pull-through (TPT) of the PEG tube, the complication rate can be dramatically reduced and thus a decisive improvement achieved for patients. The aspects discussed here are highly relevant for all those involved in the therapy of advanced Parkinson's syndrome.

Intermittent Subcutaneous Injections of Apomorphine in Parkinson's Disease.

The intermittent subcutaneous injection of apomorphine is highly effective in the management of motor and non-motor symptoms of Parkinson's disease. Although it has been shown that apomorphine injection can be safely used in selected cases at all stages of the disease, there is no consensus regarding intermittent administration strategies. This review aimed to discuss the indications for intermittent subcutaneous apomorphine use in clinical practice, possible side effects and their management, and contraindicated cases in light of the literature and to present practical recommendations for clinical practice.

A deep eutectic-based, self-emulsifying subcutaneous depot system for apomorphine therapy in Parkinson’s disease

Apomorphine, a dopamine agonist, is a highly effective therapeutic to prevent intermittent off episodes in advanced Parkinson's disease. However, its short systemic half-life necessitates three injections per day. Such a frequent dosing regimen imposes a significant compliance challenge, especially given the nature of the disease. Here, we report a deep eutectic-based formulation that slows the release of apomorphine after subcutaneous injection and extends its pharmacokinetics to convert the current three-injections-a-day therapy into an every-other-day therapy. The formulation comprises a homogeneous mixture of a deep eutectic solvent choline-geranate, a cosolvent n-methyl-pyrrolidone, a stabilizer polyethylene glycol, and water, which spontaneously emulsifies into a microemulsion upon injection in the subcutaneous space, thereby entrapping apomorphine and significantly slowing its release. Ex vivo studies with gels and rat skin demonstrate this self-emulsification process as the mechanism of action for sustained release. In vivo pharmacokinetics studies in rats and pigs further confirmed the extended release and improvement over the clinical comparator Apokyn. In vivo pharmacokinetics, supported by a pharmacokinetic simulation, demonstrate that the deep eutectic formulation reported here allows the maintenance of the therapeutic drug concentration in plasma in humans with a dosing regimen of approximately three injections per week compared to the current clinical practice of three injections per day.

Prospects of successful treatment of Parkinson's disease using apomorphine

Abstract. Optimising the treatment of idiopathic Parkinson's disease is a complex, multifaceted and continuous process that directly affects quality of life. The main position of this examination is the need for individualised therapy that provides optimal motor function with the least negative consequences. Apomorphine, a dopamine agonist used as rescue therapy for patients with motor fluctuations with a potentially positive effect on non-motor symptoms, is the only antiparkinsonian drug whose ability to control motor symptoms is equivalent to that of levodopa. Subcutaneous injection is the most effective and affordable way to correct dopaminergic insufficiency in Parkinson's disease. The data of multi-centre studies presented in the review confirm the high efficiency, adequate tolerability, and prospects of using apomorphine in the complex pathogenetic therapy of the disease. This review provides historical background and summarises the structure, mechanism of action, pharmacodynamics, indications, contraindications, and side effects of subcutaneous apomorphine injections in the advanced stages of Parkinson's disease. Keywords: Parkinson's disease; apomorphine; pharmacokinetics; mechanism of action; clinical trials; indications: and contraindications

Prospects for successful treatment of Parkinson’s disease with the use of apomorphine

Optimizing the treatment of idiopathic Parkinson’s disease is a complex, multifaceted and continuous process that directly affects quality of life. The main position of this review is the need for individualized therapy that provides optimal motor function with the least negative consequences. Apomorphine, a dopamine agonist used as emergency therapy for patients with motor fluctuations with a potential positive effect on non-motor symptoms, is the only antiparkinsonian drug whose ability to control motor symptoms is equivalent to that of levodopa. Subcutaneous administration as a periodic injection is the most effective and affordable way to correct dopaminergic insufficiency in Parkinson’s disease. The data of multicenter studies presented in the review confirm the high efficiency, adequate tolerability and prospects of apomorphine use in comprehensive pathogenetic therapy of the disease. This review contains the historical reference and generalizes structure, the mechanism of action, pharmacodyna-mics, indications, contraindications and side effects in subcutaneous injections of apomorphine at the advanced stages of a clinical course of Parkinson’s disease.

On-Demand Therapy for OFF Episodes in Parkinson's Disease.

Levodopa is the most effective therapy for Parkinson's disease; however, chronic treatment is associated with the development of OFF episodes, in which there is a return of parkinsonian features following a dose of levodopa and prior to the onset of benefit from the subsequent dose. OFF episodes can be a major source of disability for PD patients and frequently result in depression, apathy and an unwillingness to participate in social activities. Most currently available medical and surgical therapies are designed to reduce total daily OFF time but do not provide a rapid and reliable "on-demand" therapy for individual OFF episodes. Indeed, responses to individual doses of levodopa during an acute OFF episode are unreliable, frequently leading to partial-ON, delayed-ON, or no-ON responses even at different times in the same patient. There are now 3 therapies that are available for the on-demand treatment of OFF episodes; subcutaneous injection of apomorphine, sublingual apomorphine film, and inhaled levodopa. The first has not enjoyed widespread use in the PD community, whereas the latter 2 therapies have only recently been approved. This review will consider the currently available on-demand therapies and their potential advantages and disadvantages. © 2021 International Parkinson and Movement Disorder Society.

Unilateral 6-Hydroxydopamine-Lesioned Rat as Relevant Model to Study the Pain Related to Parkinson’s Disease

The present study was conducted to test the use of the hemiparkinsonian rat, obtained by the unilateral injection of 6-hydroxydopamine (6-OHDA) in the substantia nigra pars compacta (SNc), as a suitable model for the study of pain associated to Parkinson’s disease (PD). For this purpose, 14 days after unilateral injection of saline or 6-OHDA, rats were assessed for behavioral function in the cylinder test, and apomorphine-induced circling test. Thereafter, at 21st day after injection, mechanical nociceptive threshold was compared between 6-OHD-lesioned and sham-operated animals using electronic von Frey test. Our results showed that injection of 6-OHDA in the SNc induced alterations of behavioral motor as ascertained by predominant use of the ipsilateral forepaw in cylinder test and by the expression of contralateral turnings after subcutaneous injection of apomorphine. The mechanical nociceptive threshold was significantly decreased in 6-OHDA-lesioned rats compared to that of sham-operated rats (p <0.05). This response was reversed by apomorphine treatment. In conclusion, hemiparkinsonian rat, obtained by the unilateral injection of the 6-OHDA in the SNc, can be used to investigate pain symptoms and central pain processing mechanisms related to PD.

Subcutaneous apomorphine in advanced Parkinson’s disease and its use in Indian population

Although subcutaneously administered apomorphine is widely used as an effective adjunct therapy for Parkinson’s disease (PD), it was approved for use in India only in 2019. This review summarizes the history, pharmacology, clinical spectrum, indications, efficacy, and side effects of subcutaneous apomorphine use in patients with PD along with clinical recommendations for its use in Indian context. Intermittent subcutaneous apomorphine injection or continuous subcutaneous apomorphine infusion is effective adjunctive treatments for patients with advanced PD with levodopa-related refractory motor complications and some specific nonmotor symptoms (NMS) as growing evidence shows apomorphine also improves aspects of NMS of PD. Common side effects of subcutaneous apomorphine are skin nodules, nausea, and somnolence with incidence being higher with infusion than that with injection. Impulse control disorders and neuropsychiatric complications common to most dopamine agonists can also occur. As per National Institute for Health and Care Excellence (NICE), United Kingdom, apomorphine, as intermittent injection or continuous subcutaneous infusion, is one of the best medical therapies and may be considered before using deep brain stimulation (DBS) or levodopa/carbidopa intestinal gel (LCIG). Head-to-head open-label comparative multicenter data suggest that apomorphine is at least as effective as DBS or LCIG in relation to nonmotor and motor benefit. More studies are needed to reduce the paucity of apomorphine data in Indian population. We also discuss criteria to select one device therapy over another and newer apomorphine delivery strategies in the pipeline.

Understanding the role of the Parkinson's disease nurse specialist in the delivery of apomorphine therapy

Optimal care of Parkinson's disease (PD) patients should involve a multidisciplinary team (MDT) of which a PD nurse specialist (PDNS) is a key member. The role of a PDNS is particularly prominent in the care of advanced PD patients suitable for apomorphine because, in addition to nursing skills, apomorphine treatment requires liaison, training, interaction and coordination with patients, caregivers and other members of the MDT as well as the interface with primary care physicians. The therapeutic success of apomorphine therapy depends not only upon the pharmacologic drug response, but also on how well the patient understands his/her disease and how to handle the therapy. In this respect, a PDNS is a vital member of the MDT who provides education and training, support, and is available for consultation when problems arise. In this article, we review the literature on the contribution of PDNSs in both continuous subcutaneous apomorphine infusion and intermittent subcutaneous apomorphine injection and highlight the various beneficial aspects of PDNS care, supported by scientific evidence when available. Despite a low level of published evidence, there is strong clinical evidence that the impact of PDNSs on the management of apomorphine therapy is vital and indispensable for the success of this treatment.

A case series of rapid titration of subcutaneous apomorphine in Parkinson's disease

Subcutaneous apomorphine injections provide prompt relief of OFF periods, but are considered an underused therapy. One reason for this might be the perception of difficulty in initiating apomorphine therapy. Over the past 30 years of use, Parkinson’s nurses have built a wealth of experience in how to initiate apomorphine in patients with motor fluctuations. The authors present here a case series of 24 Parkinson’s patients whose apomorphine dose was rapidly titrated according to the practice of the Parkinson’s nurse overseeing the titration. Most patients were successfully and safely titrated within 2 hours, indicating that this rapid schedule may be useful in reducing patient distress and making better use of available resources, compared to the slower schedule than is suggested in the UK apomorphine prescribing information. Patients were successfully initiated in a wide variety of settings, including day hospitals and within their own homes.

Effect of acute lithium administration on penile erection: involvement of nitric oxide system

Lithium has been the treatment of choice for bipolar disorder (BD) for many years. Although erectile dysfunction is a known adverse effect of this drug, the mechanism of action by which lithium affects erectile function is still unknown. The aim was to investigate the possible involvement of nitric oxide (NO) in modulatory effect of lithium on penile erection (PE). We further evaluated the possible role of Sildenafil in treatment of lithium-induced erectile dysfunction. Erectile function was determined using rat model of apomorphine-induced erections. For evaluating the effect of lithium on penile erection, rats received intraperitoneal injection of graded doses of lithium chloride 30 mins before subcutaneous injection of apomorphine. To determine the possible role of NO pathway, sub-effective dose of N (G)-nitro-L-arginine methyl ester (L-NAME), a nitric oxide synthase (NOS) inhibitor, was administered 15 min before administration of sub-effective dose of lithium chloride. In other separate experimental groups, sub- effective dose of the nitric oxide precursor, L-arginine, or Sildenafil was injected into the animals 15 min before administration of a potent dose of lithium. 30 min after administration of lithium chloride, animals were assessed in apomorphine test. Serum lithium levels were measured 30 min after administration of effective dose of lithium. Lithium at 50 and 100 mg/kg significantly decreased number of PE (p<0.001), whereas at lower doses (5, 10 and 30 mg/kg) had no effect on apomorphine induced PE. The serum Li+ level of rats receiving 50 mg/kg lithium was 1±0.15 mmol/L which is in therapeutic range of lithium. The inhibitory effect of Lithium was blocked by administration of sub-effective dose of nitric oxide precursor L-arginine (100 mg/kg) (p<0.001) and sildenafil (3.5 mg/kg) (p<0.001) whereas pretreatment with a low and sub-effective dose of L-NAME (10mg/kg) potentiated sub-effective dose of lithium, (p<0.001). These results suggest acute treatments with lithium cause erectile dysfunction in an in-vivo rat model. Furthermore it seems that the NO pathway might play role in erectile dysfunction associated with lithium treatment. Findings also suggest that Sildenafil may be effective in treatment of lithium-associated erectile dysfunction.

Effects of autologous adipose-derived stromal vascular fraction on erectile dysfunction of hypertensive rats

To study the effect of autologous adipose stromal vascular fraction (SVF) injection into corpora cavernosa on the hypertension-associated erectile dysfunction (ED) in rats and its possible mechanism. Healthy male spontaneously hypertensive rats (SHR) at 30-week (n=40) and homologous rats with normal blood pressure (WKY) (n=20) were selected. Noninvasive blood pressure meter was used to measure the systolic blood pressure (SBP) at the tail. Cervical subcutaneous injection of apomorphine was applied to test penile erectile function. The rats with ED were divided into hypertension-associated ED rats treated with autologous SVF injection into corpora cavernosa (ED-SHR-SVF group) (n=8) and hypertension-associated ED rats treated with phosphate buffered saline (PBS) injection into corpora cavernosa (ED-SHR-PBS group) (n=8). The intracavernosal pressure (ICP) was measured in each group. Western blot and RT-PCR were conducted to test protein and mRNA expressions of endothelial nitric oxide synthase (eNOS) in corpora cavernosa. The tail SBP in SHR rats was significantly higher than that in WKY rats ((197.47±6.82) mmHg vs (125.23±4.65) mmHg, P<0.05). The erectile rate in SHR rats was 60% (24/40), and that in WKY rats was 100% (20/20). After 5 V electrical stimulation, the ICP in the ED-SHR-SVF group was significantly higher than in the ED-SHR-PBS group ((83.42±3.21) mmHg vs (52.37±3.11) mmHg, P<0.05). The protein and mRNA expressions of eNOS in the ED-SHR-SVF group were significantly higher than in the ED-SHR-PBS group (0.43±0.03 vs 0.18±0.05, 0.92±0.05 vs 0.41±0.06, both P<0.05). High blood pressure can cause ED in rats, which could be mitigated by autologous SVF injection. The mechanism may be related to up-regulation of eNOS expression in corpus cavernosa.

Twenty Years of Apomorphine Therapy – How Does it Compare with Levodopa?

Apomorphine administered subcutaneously has provided clinicians with an effective option for the rapid resolution of the symptoms of Parkinson’s disease (PD) for over a quarter of a century. It is available for use either as an intermittent injection or a continuous infusion, depending on the severity of the patient’s symptoms. This satellite symposium, held during the 18th International Congress of Parkinson’s Disease and Movement Disorders in Stockholm, Sweden, from 8–12 June 2014, and chaired by Professor Andrew Lees, set out to review the extensive clinical experience of subcutaneous apomorphine in the management of PD accumulated over the past 25 years. It also aimed to explore why it continues to play such a valuable therapeutic role in this setting. The presenters highlighted key clinical data demonstrating why apomorphine is an effective choice for the management of both motor and non-motor symptoms in PD. Results from the limited number of comparative studies of apomorphine continuous infusion with other therapies for complex PD suggest that it has a robust motor effect, resulting in a reduction of OFF periods comparable to that achieved with more invasive options such as intrajejunal levodopa infusion or deep brain stimulation. In a large European study, apomorphine infusion has been shown to provide similar improvements in health-related quality of life to intrajejunal levodopa infusion but with a superior side-effect profile. In addition, apomorphine infusion has demonstrated beneficial non-motor effects in PD patients and reports suggest it is associated with low rates of impulse control disorders (ICDs). The motor fluctuations that occur over time in PD patients treated with oral levodopa present a management challenge as the disease progresses. Many PD patients experience these OFF periods despite optimised oral therapy and the use of multiple medications. They are due to both end-of-dose wearing OFF and delayed time to ON (TTO). A prolonged TTO is common in PD patients who have gastroparesis (delayed gastric emptying) whereby the levodopa dose is delayed exiting the stomach and is slow in reaching its site of absorption in the small intestine. Alternative non-oral formulations that avoid the gastrointestinal route, such as subcutaneous apomorphine intermittent injection, have therefore been investigated for the relief of motor fluctuations in this setting. Interim results from the ongoing Apokyn for Motor IMProvement of Morning AKinesia Trial (AM IMPAKT) study have shown that subcutaneous apomorphine injection is a valuable treatment option in PD patients with morning akinesia. This is due to a delayed onset of levodopa dose as it produces a rapid and reliable TTO, with 95 % of patients achieving at least a 20-minute reduction in TTO and an average reduction of 40 minutes. Patients also experienced improvements in Unified Parkinson’s Disease Rating Scale (UPDRS) motor score and Hoehn and Yahr stage, as well as measures of quality of life and global impression of severity.

アポモルヒネ皮下注射製剤（販売名：アポカイン&lt;sup&gt;&amp;reg;&lt;/sup&gt;皮下注30 mg）―レボドパ治療に伴う運動症状の日内変動に対するレスキュー療法―

パーキンソン病（PD）はアルツハイマー病に次いで患者数が多い慢性進行性の神経変性疾患である．レボドパ製剤はPDの運動機能障害に対して最も強力な改善効果を示すが，長期間の使用により運動症状の日内変動が大きくなり，薬効持続時間の短縮や突発的かつ予測困難な薬効減弱等のオフ症状が増加する．オフ症状の発現は患者のQOLを著しく低下させることから適切な対処が必要であるが，進行期のPD患者では，他のPD治療薬の追加・併用やレボドパの用量・用法の最適化の後もオフ症状が残存することがある．この残存したオフ症状に対しては，症状が発現した時に即効的に症状を改善するレスキュー療法が有用と考えられる．アポモルヒネはドパミンD1およびD2受容体サブファミリーに対して幅広く作動活性を有しており，PD患者の線条体においてドパミン受容体を介して間接経路出力および直接経路出力の両方を調節することにより，抗PD作用を示すと考えられる．霊長類の病態モデル動物および進行期のPD患者において，皮下投与したアポモルヒネはレボドパと遜色ない強い薬効を示す．またアポモルヒネ製剤は，顕著な薬効，即効性および作用時間が比較的短いこと等から，既存のPD治療薬によりコントロールできないオフ症状に対するレスキュー治療薬として，欧米各国で長い臨床使用の実績がある．アポモルヒネの薬理作用として嘔吐中枢の刺激による悪心・嘔吐等の発現が知られているが，これらの副作用は制吐剤の適切な使用等により制御可能である．レスキュー用途には，患者が必要と感じた時に患者自らが決められた薬物量を安全かつ確実に投与できることが重要となる．そのため，本邦においては，アポモルヒネの皮下投与のための専用の電動式インジェクターが開発された．本剤は内服薬に反応しない重篤なオフ症状に対するアンメットニーズを充たす新しいタイプのPD治療薬であり，本邦においては2012年3月に「パーキンソン病におけるオフ症状の改善（レボドパ含有製剤の頻回投与及び他の抗パーキンソン病薬の増量等を行っても十分に効果が得られない場合）」を効能・効果として承認された．海外と同様に本邦においても，本剤が患者とその家族および介護者のQOLに貢献することが期待される．

Morning Akinesia and the Potential Role of Gastroparesis – Managing Delayed Onset of First Daily Dose of Oral Levodopa in Patients with Parkinson’s Disease

In patients with Parkinson’s disease (PD), motor and non-motor symptoms are frequent during OFF periods, especially when the next levodopa dose has a delayed onset of action (delayed ON). Delayed ON of the first daily dose of levodopa is known as morning akinesia, which can significantly affect quality of life and impair daily activities. Morning akinesia can occur due to a delay in gastric emptying, impaired intestinal absorption, pharmacodynamic effects or other mechanisms. Gastroparesis is common in patients with PD and can cause gastrointestinal symptoms, delayed ON and morning akinesia. Alternative delivery of dopaminergic therapy by a non-oral route may be useful in patients with PD and gastroparesis. Subcutaneous apomorphine injection is used by patients with PD in the OFF state to decrease time-to-ON. An ongoing study is investigating its use for morning akinesia, as well as the frequency of delayed gastric emptying in these patients.

Characterization of corpus cavernosum smooth muscle cell phenotype in diabetic rats with erectile dysfunction

Phenotypic modulation from a contractile to a proliferative state within vascular smooth muscle cells has a critical role in the pathogenesis of a variety of cardiovascular diseases. To investigate the characterization of corpus cavernosum smooth muscle cell phenotype in diabetic rats with erectile dysfunction, a group of Sprague-Dawley rats (n=30) were induced by intraperitoneal injection of streptozotocin (60 mg kg(-1)) and screened by subcutaneous injection of apomorphine (100 μg kg(-1)) for the measurement and comparison of the penile erections, and then three different groups were defined. Primary corpus cavernosum smooth muscle cells were cultured and passaged. The cavernous tissue segments were subjected to quantitative real-time polymerase chain reaction to determine the expressions of smooth muscle α-actin (SMA), SM myosin heavy chain (SMMHC), smoothelin, calponin and myocardin. Cell contractility in vitro and western blot analysis of SMA and SMMHC in the cavernous tissues and cells were determined. Compared with the control group (n=8) and the diabetes mellitus group (n=5), the expressions of SMA, calponin, SMMHC, smoothelin and myocardin mRNA were decreased in the cavernous tissues in rats of the diabetic erectile dysfunction group (n=15; P=0.001 and 0.02, P=0.014 and 0.012, both P<0.001, P=0.005 and <0.001, P=0.003 and 0.035, respectively). The levels of SMA and SMMHC proteins showed a significant decrease in cavernous tissues and cultured cells in rats of the diabetic erectile dysfunction group. Cells of the diabetic erectile dysfunction group exhibited significantly less contractility compared with those of other groups (P<0.001). Corpus cavernosum SM cell possesses the ability to modulate the phenotype under hyperglycemic conditions, which could have a key role in the pathogenesis of diabetic erectile dysfunction.

Lesions of the entopeduncular nucleus in rats prevent apomorphine-induced deficient sensorimotor gating

Dopamine-induced hyperactivity and deficient sensorimotor gating, measured as prepulse inhibition (PPI) of the acoustic startle response (ASR), are used as animal models for neuropsychiatric disorders such as schizophrenia and Tourette's syndrome. We here investigated whether excitotoxic lesions of the rat entopeduncular nucleus (EPN), the equivalent to the human globus pallidus internus (GPi), would improve apomorphine-induced PPI-deficits and hyperactivity. Additionally, we investigated the effect of EPN lesions on cognition, motivation and motor skills. In male Sprague Dawley rats bilateral EPN lesions were induced by stereotactic injection of ibotenate (4 μg in 0.4 μl phosphate buffered saline, PBS) or sham-lesions by injection of vehicle PBS. After one week, rats were tested for learning and memory (continuous and delayed alternation, T-maze), for motivation (progressive ratio test with breakpoint of 3 min inactivity, Skinner box), and for motor skills (rotating rod). Thereafter, rats were tested for PPI of ASR (startle response system) after subcutaneous injection of apomorphine (1.0 mg/kg and vehicle) and for locomotor activity (0.5 mg/kg and vehicle). Ibotenate-induced EPN lesions did not affect learning and memory, motivation or motor skills. Basal locomotor activity and PPI was also not affected, but EPN lesions ameliorated apomorphine-induced hyperlocomotion and deficient PPI. This work indicates an important role of the EPN for the modulation of dopamine agonist-induced deficient sensorimotor gating and hyperlocomotion, without affecting normal behavioral function.

Apomorphine treatment in Alzheimer mice promoting amyloid‐β degradation

Intracellular amyloid β-protein (Aβ) contributes to neurodegeneration in Alzheimer disease (AD). Apomorphine (APO) is a dopamine receptor agonist for Parkinson disease and also protects against oxidative stress. Efficacy of APO for an AD mouse model and effects of APO on cell cultures are studied. The triple transgenic AD mouse model (3xTg-AD) has 2 familial AD-related gene mutations (APP(KM670/671NL) /PS1(M146V)) and a tau gene mutation (Tau(P301L)). Six-month-old 3xTg-AD mice were treated with subcutaneous injections of APO once a week for 1 month. Memory function was evaluated by Morris water maze before and after the treatment. Brain tissues were examined by immunohistochemical staining and Western blotting. Effects of APO on intracellular Aβ degradation, activity of Aβ-degrading enzymes, and protection against oxidative stress were studied in cultured SH-SY5Y cells. After APO treatment, short-term memory function was dramatically improved. Significant decreases in the levels of intraneuronal Aβ, hyper-phosphorylated tau (p-tau), p53, and heme oxygenase-1 proteins were observed. Moreover, APO promoted degradation of intracellular Aβ, increased activity of proteasome and insulin-degrading enzyme, protected against H(2) O(2) toxicity, and decreased p53 protein levels in the cultured cells. 3xTg-AD mice show intraneuronal Aβ accumulation and memory disturbances before extracellular Aβ deposition. Our data demonstrating improvement of memory function of 3xTg-AD mice with decreases in intraneuronal Aβ and p-tau levels by APO treatment strongly suggest that intraneuronal Aβ is an important therapeutic target and APO will be a novel drug for AD.

Chronic Administration of Sildenafil Modified the Impaired VEGF System and Improved the Erectile Function in Rats with Diabetic Erectile Dysfunction

Men frequently develop diabetic erectile dysfunction (DMED), as a result of endothelial dysfunction. DMED patients often have reduced efficacy with phosphodiesterase type 5 inhibitors therapy. To determine whether chronic sildenafil administration can modify the impaired vascular endothelial growth factor (VEGF) system and improve the erectile function in rats with diabetic erectile dysfunction. A group of Sprague Dawley rats (n = 30) with DMED were induced by intraperitoneal injection of streptozotocin (40 mg/kg) and screened by subcutaneous injection of Apomorphine (100 mg/kg). They were then exposed to either vehicle or sildenafil (prescribed in our hospital, 5 mg/kg and 10 mg/kg, respectively) for 10 weeks. An additional nondiabetic and age-matched control group (n = 10) was also allocated and given the routine diet for the same period. Assessments were performed to both groups at 36 hours after the last dose of sildenafil. Penile intracavernous pressure (ICP), mean arterial pressure (MAP), penile tissue morphology, immunohistologic analysis, and Western blot analysis of VEGF, VEGFR1, and eNOS were determined. Functional, morphological, and proteomical changes on penile structures by the chronic Sildenafil (5 mg/kg and 10 mg/kg, respectively) administration were determined. A significant increase of ICP, ICP/MAP ratio, and area under the curve were observed in the both groups treated by sildenafil (5 mg/kg and 10 mg/kg, respectively), compared with the DMED rats without receiving Sildenafil. Immunohistochemical staining of their penile tissue showed a decrease in VEGF, VEGFR1, and eNOS staining in the controlled group compared with an improvement in the chronic sildenafil administration group. Western blot analysis demonstrated exactly the same results. We demonstrated that daily sildenafil administration can restore the impaired VEGF system in the penis of DMED rats and progressively improve both erectile function and endothelial function, suggesting a potential general mechanism of improved signaling through the VEGF/eNOS signaling cascade.

Nécroses cutanées localisées aux points d’injection d’apomorphine

Apomorphine is a specific dopaminergic agonist used in the treatment of severe fluctuations of Parkinson's disease, particularly in patients on L-dopa. The drug is usually given subcutaneously, either as several daily injections or via a continuous subcutaneous delivery system. We describe two cases of localized cutaneous necrosis at the points of subcutaneous apomorphine injection. Two male patients presenting Parkinson's disease were treated by subcutaneous injection of apomorphine. One month later, asymptomatic necrotic lesions measuring from 2 to 5 mm appeared at the injection sites. Complete blood count, standard and advanced coagulation studies and screening tests were normal. One patient had taken acetylsalicylic acid. A skin biopsy showed normal epidermis, oedema of the papillary dermis with perivascular lymphocytic infiltrates, reticular dermal infiltrate with neutrophils, and necrosis of the reticular dermis and hypodermis in one patient, and in the other, necrosis in the epidermis, dermis, hypodermis and skin appendages, with dermal leucocytoclastic vasculitis and cytosteatonecrosis. Due to the severity of necrosis, apomorphine was stopped, resulting in improvement of skin lesions in one patient. In the second, due to the localized nature of the lesions and the improvement in the patient's quality of life since the introduction of apomorphine, the drug was continued, resulting in the appearance of new lesions, which continued to be limited to the injection sites. To our knowledge, this is the first description of biopsy-proven apomorphine-induced localized skin necrosis. Reported cutaneous side effects of the drug include pruritic subcutaneous nodules corresponding to panniculitis with large numbers of eosinophils, allergic contact dermatitis, pigmented nodules resulting from oxidation of apomorphine, and nonspecific rashes. Cutaneous necrosis at injection sites could arise through various mechanisms: localized vasoconstriction ("dopamine necrosis"), direct toxicity of the injected drug, local manifestations of pre-existent coagulation disorders, immunological mechanisms or poor administration technique involving intravascular injection. The specific pharmacodynamic properties of apomorphine rule out vasomotor phenomena in the aetiology of such necrosis. Screening tests for thrombophilia were negative in the first patient. Although the underlying mechanism of this form of necrosis remains unknown, an immunological mechanism of the immune complex type could be considered aetiologically relevant on histological grounds due to the presence of vasculitis in one of the two patients.