The Medicinal Chemistry of Natural and Semisynthetic Compounds against Parkinson's and Huntington's Diseases.

Among the diseases affecting the central nervous system (CNS), neurodegenerations attract the interest of both the clinician and the medicinal chemist. The increasing average age of population, the growing number of patients, and the lack of long-term effective remedies push ahead the quest for novel tools against this class of pathologies. We present a review on the state of the art of the molecules (or combination of molecules) of natural origin that are currently under study against two well-defined pathologies: Parkinson's disease (PD) and Huntington's disease (HD). Nowadays, very few tools are available for preventing or counteracting the progression of such diseases. Two major parameters were considered for the preparation of this review: particular attention was reserved to these research works presenting well-defined molecular mechanisms for the studied compounds, and where available, papers reporting in vivo data were preferred. A literature search for peer-reviewed articles using PubMed, Scopus, and Reaxys databases was performed, exploiting different keywords and logical operators: 91 papers were considered (preferentially published after 2015). The review presents a brief overview on the etiology of the studied neurodegenerations and the current treatments, followed by a detailed discussion of the natural and semisynthetic compounds dividing them in different paragraphs considering their several mechanisms of action.

Trends and drivers of the aesthetic market during a turbulent economy.

BACKGROUND: Aesthetic procedures are significant sources of revenue for plastic surgeons. With the popularity of nonsurgical aesthetic procedures, many plastic surgeons question how to best tailor their aesthetic practice. METHODS: Revenue generated from surgical and minimally invasive aesthetic procedures performed in the United States between 2000 and 2011 was calculated from the American Society of Plastic Surgeons' annual reports. Regression analysis was performed against six commonly cited economic indicators. RESULTS: In 2011, revenue from minimally invasive procedures increased from $3.0 billion to $5.7 billion (90 percent growth), whereas revenue from surgical procedures decreased from $6.6 billion to $6.0 billion (10 percent decline). Between 2000 and 2011, minimally invasive procedure market share grew from 30 percent to nearly 50 percent. Linear regression analysis revealed significant correlations between surgical procedure revenue and indicators of macroeconomic climate: Dow Jones Industrial Average (R = 0.72; p < 0.01), Standard & Poor's 500 Index (R = 0.64, p < 0.05), and unemployment rate (R = -0.81; p < 0.001). Minimally invasive procedure revenue was significantly correlated with indicators related to microeconomic decision trends: disposable income per capita (R = 0.93; p < 0.001), real gross domestic product per capita (R = 0.88; p < 0.001), and home price index (R = 0.63; p < 0.05). No economic indicator in this study was found to be significantly correlated with both surgical and minimally invasive revenue. CONCLUSION: Despite economic turbulence, minimally invasive procedures are the most rapidly growing source of revenue and are poised to be the dominant source of revenue in the aesthetic market.

A new multiple sclerosis spasticity treatment option: effect in everyday clinical practice and cost-effectiveness in Germany.

Sativex® (GW Pharmaceuticals PLC, Porton Down, UK; Laboratorios Almirall, SA, Barcelona, Spain), a cannabinoid oromucosal spray containing a 1:1 ratio of 9-δ-tetrahydrocannabinol and cannabidiol, has been licensed in Germany since July 2011 as add-on therapy for moderate-to-severe multiple sclerosis (MS) treatment-resistant spasticity symptoms. The 'MOVE 2' study evaluated clinical outcomes, treatment satisfaction, quality of life (QoL) and provision of care in MS patients with spasticity receiving Sativex in everyday clinical practice. Data from 300 patients were collected from 42 specialized MS centers across Germany and were available for this analysis. Assessments, including the MS spasticity 0-10 numerical rating scale, modified Ashworth scale, patients' and physicians' clinical impressions, and QoL scales were rated at baseline and at 1 and 3 months after starting treatment with Sativex. Sativex provided relief of MS-related spasticity in the majority of patients who were previously resistant to treatment. In addition, clear improvements were noted in MS spasticity-associated symptoms (e.g., sleep quality, bladder function and mobility), activities of daily living and QoL. Sativex was generally well tolerated. The majority of patients (84%) reported no adverse events, and there was only a limited risk of serious adverse reactions. Furthermore, based on data from Sativex clinical trials, a Markov model-based analysis has shown that Sativex is a cost-effective treatment option for patients with MS spasticity in Germany.

Botulinum toxin treatment of oesophageal achalasia in the old old and oldest old: a 1-year follow-up study.

BACKGROUND: Intrasphincteric injection of botulinum toxin (BTX) has become one of the most frequent therapeutic approaches for the treatment of oesophageal achalasia. This treatment seems particularly effective in elderly patients who are not candidates for more invasive procedures. AIMS: There are few or no data on BTX treatment of achalasia in the old old and oldest old. Therefore, we evaluated BTX treatment in a group of patients with achalasia in the extreme age range who were too ill or frail to undergo surgery or pneumatic dilatation. PATIENTS AND METHODS: Twelve elderly achalasic patients (age range 81-94 years, average age 86 years) with American Society of Anesthesiologists (ASA) class III-IV status were recruited for the study. After baseline clinical and instrumental evaluations, BTX 100U was injected at time 0 and 1 month later. Clinical follow-up was carried out after 3, 6 and 12 months. RESULTS: A significant improvement in symptom score was documented at each follow-up step. On the basis of improvements in scores, approximately 70% of patients were considered responders at the end of follow-up. CONCLUSIONS: BTX treatment is an effective treatment in a substantial proportion of achalasic patients >80 years of age, in whom benefits are still detectable after 12 months. BTX is a therapeutic option in patients unsuitable for surgery or pneumatic dilatation.

[Spasticity and botulinum toxin in 2003. An update]. / spasticité et toxine botulique. Le point en 2003.

After the spastic foot in cerebral palsy, there are now wider indications for botulinum toxin injections in spasticity. Post stroke upper limb spasticity has been usefully treated by botulinum toxin in several studies, including double blind placebo-controlled studies. Two serotypes and one serotype B are marketed, with various properties. Botulinum toxin has been studied in multiple etiologies of spasticity. In multiple sclerosis, few studies revealed an efficacy in angulations and comfort. In spinal cord injuries, gait and sphincter disorders can be improved. In post stroke spasticity, lower limb angulations are improved, but gait remained difficult to evaluate. In upper limb spasticity, angulation, function and quality of life were improved in double blind, placebo controlled studies. Comparisons of costs and efficacy are made between botulinum toxin and the other antispastic methods.

Treatment of achalasia: botulinum toxin injection vs. pneumatic balloon dilation. A prospective study with long-term follow-Up.

BACKGROUND AND STUDY AIMS: In patients with achalasia, intrasphincteric injection of botulinum toxin (BTX) has been suggested as an alternative regimen to balloon dilation and has been shown to be superior to placebo injection. The aim of the present study was to test the effectiveness, the long-term outcome and the cumulative costs of BTX injection in consecutive patients with symptomatic achalasia in comparison with pneumatic balloon dilation. PATIENTS AND METHODS: 37 patients, who presented with symptomatic achalasia between January 1994 and December 1996 were treated with either BTX injection (n = 23) or pneumatic dilation (n = 14). Patients with short-term or long-term symptomatic failures of the initial procedure were treated again, either with the same or with the alternative method, depending on the initial response and on the patient's wish. Symptoms were assessed using a global symptom score (0 - 10) which was evaluated before treatment and 1 week, 1 month and then every 6 months after the treatment. In addition, body weight and recurrence of symptoms were noted and manometry was carried out before and after treatment. The patients were regularly contacted for the long-term follow-up. RESULTS: There were significant improvements in the global symptom scores of all patients treated, in both the BTX injection group (before 8.2 +/- 1.3, after 3.0 +/- 1.6) and the dilation group (before 8.3 +/- 1.1, after 2.3 +/- 1.9). There was also a significant decrease of lower esophageal sphincter pressure after treatment in the BTX group and the dilation group. There were no significant differences with regard to overall treatment failure and long-term outcome between patients who had or had not received previous treatment. No major complications were encountered in either group. An actuarial analysis over 48 months comparing patients receiving BTX injection or balloon dilation demonstrated that after 12 months neither therapy was significantly superior. After 24 months a single pneumatic dilation was superior to a single BTX injection, and after 48 months all patients treated by BTX injection had experienced a symptomatic relapse. In contrast, 35 % of all patients treated by dilation and 45 % of patients treated successfully by dilation were still symptom-free in an intention-to-treat analysis after 48 months. When the overall costs of treatment and further treatment after recurrence were compared, dilation and BTX injection showed a similar cost-effectiveness (costs per symptom-free day) after 48 months. CONCLUSIONS: BTX injection, which can be performed in an outpatient setting, is as safe and cost-effective as balloon dilation in symptomatic achalasia. Taking into account the lower long-term efficacy of BTX injection therapy, however, it is an alternative only in a minority of older or high-risk patients.

Botulinum toxin for people with dystonia treated by an outreach nurse practitioner: a comparative study between a home and a clinic treatment service.

OBJECTIVE: To study whether a trained outreach nurse practitioner could provide a service that is as good as, or better than, that provided at a hospital outpatient clinic for people who had been diagnosed with dystonia and required treatment with botulinum toxin. DESIGN: Randomized trial. SETTING: An outpatient department of a regional neurorehabilitation center and patients' homes in northern England. PATIENTS: Eighty-nine patients with a clinical diagnosis of spasmodic torticollis, blepharospasm, or hemifacial spasm who had ongoing treatment of dystonia with botulinum injections. INTERVENTIONS: Individuals were randomly allocated either to receive ongoing botulinum injections at home by the nurse practitioner or to continue attending the hospital outpatient clinic and be injected by medical staff. MAIN OUTCOME MEASURES: The following measures were recorded at each visit: demographic descriptors, dosage of botulinum toxin, treatment interval, side-effect profile, external referrals, and a questionnaire to determine qualitative opinion. RESULTS: Efficacy and duration of the botulinum was similar in both groups. Botulinum dosage and side-effect profiles were similar in both groups except for significantly less dysphagia (p < .018) in the home group (7 vs 24 occasions). Subjective opinion by the patients indicated statistically significant preference for home injections. Economic analysis indicated that the overall cost of the treatment was less in the home injection group (total cost per visit $36.90 [ pound 23.36] vs $79.00 [ pound 50.01]), but this difference was not statistically significant. CONCLUSION: A trained outreach nurse practitioner provided a service that was as good as, and in certain aspects better than, that provided by a hospital outpatient clinic. The nurse practitioner provided a more flexible, much appreciated, safe, and cost-effective service for this client group. Wider use of outreach nurse practitioners for dystonia should be encouraged.

Pharmacotherapy with botulinum toxin: harnessing nature's most potent neurotoxin.

Botulinum toxin (BTX), a potent biologic neurotoxin, commonly is associated with lethal outbreaks of food poisoning; however, it also plays a role as a therapeutic agent. Since the 1970s physicians have investigated BTX therapy in patients with neurologic disorders. The number of applications greatly expanded over the years to include certain focal dystonias (blepharospasm, torticollis, laryngeal dystonias, writer's cramp), strabismus, and a wide variety of other indications (gastrointestinal disorders, cosmetic wrinkle correction, spasticity, hyperhidrosis). BTX's safety and efficacy are reviewed.

The current use of botulinum toxin.

Botulinum toxin is the most potent neurotoxin known, and has been in clinical use since the late 1970s. The toxin inhibits the release of acetylcholine from nerve terminals by inhibiting transport of the synaptic vesicles, thus causing functional denervation lasting up to 6 months. Our understanding of the mechanism of action of the toxin and the spectrum of diseases treatable with this agent continues to increase. Efficacy has been demonstrated in hemifacial spasm, dystonia, spasticity, hyperhidrosis and other conditions. Alternative serotypes are used in some centres, generally after the development of immunoresistance to the standard toxin (serotype A), and are likely to be in routine use in the near future. This paper reviews the history, pharmacology and current uses of botulinum toxin.

The long-term use of botulinum toxin for adult strabismus.

PURPOSE: To characterize patients choosing repeated botulinum toxin injection as a treatment for their strabismus, and assess their demand for it over time (up to 8 years). METHOD: Patients who had undergone at least eight injections were identified and their clinical records analyzed for diagnosis, demographic details, and demand for toxin injections with time. To establish any predictive variables, the details for these cases were compared with those of matched controls who had undergone fewer injections. Lastly, a questionnaire was mailed to research patients' views as to the indications and preferences for regular toxin injection as a method of treatment. RESULTS: Ninety-five patients were identified (34 men, 61 women; median age 37 years), of whom 35 had consecutive exotropia and 16 had secondary exotropia. Other diagnoses represented were residual and primary deviations, restrictive exotropias, and oscillopsias. A trend of fewer injections over the attendance period was seen, and the only complication observed was upper lid ptosis in 1% of injections. Cases exhibited similar demographic composition to matched controls, but were more likely to have consecutive exotropia or secondary esotropia as a diagnosis. Univariate analysis showed evidence (p < 0.001) of an association between the number of previous operations and the odds of being a case. No evidence was found that cases and controls lived at differing distances from our hospital. The questionnaire found that 71% of patients stated appearance as the prime reason for seeking treatment, and 37% stated simplicity of toxin therapy as their reason for reattendance. Twenty-six percent of the patients were disillusioned with the results of previous surgery and preferred toxin therapy as a means of controlling their symptoms. CONCLUSION: Botulinum toxin injection is an appropriate long-term treatment for some strabismus patients who choose not to undergo further surgery. A trend toward fewer injections with time was observed, and no adverse effects were associated with long-term treatment.