Levodopa Formulations Research Articles

A technology evaluation of CVT-301 (Inbrija): an inhalable therapy for treatment of Parkinson’s disease

Introduction The most widely used pharmacological treatment for Parkinson’s disease is levodopa, the precursor for dopamine formation in the brain. With time, the effectiveness of levodopa declines, and patients experience motor fluctuations, or OFF periods. A levodopa formulation administered via a capsule-based oral inhaler provides a new delivery mechanism for levodopa that provides rapid relief of OFF periods. Areas covered CVT-301 is a dry powder formulation designed to supply levodopa to the systemic circulation via pulmonary absorption. The technology, pharmacokinetics, efficacy, and safety data of this formulation are presented. Expert opinion Oral inhalation is a novel method of administration for levodopa that bypasses the gastrointestinal tract, allowing levodopa to enter the systemic circulation rapidly and more reliably than oral medications. Gastrointestinal dysfunction, a common feature of Parkinson’s disease, can lead to impaired absorption of oral medications. Pulmonary delivery rapidly elevates levodopa plasma concentrations to provide relief of OFF periods for patients receiving oral levodopa.

Amantadine Revisited: A Contender for Initial Treatment in Parkinson's Disease?

The best practice for the initiation of symptomatic motor treatment for Parkinson's diseaseis an ongoing topic of debate. Fueled by interpretation of the results of the LEAP and MED Parkinson's diseasestudies, many practitioners opt for early initiation of levodopa formulations, avoiding dopamine agonists to circumvent potentialdeleteriousside effects, namely impulse control disorder. Compared with levodopa,monoamine oxidase inhibitors may lack necessarypotency. Ignored in this academic debate is another therapeutic optionfor patients withParkinson's diseaserequiring treatment initiation: amantadine. Amantadine was first reported effective in the treatment ofParkinson's diseasein1969 and several studies were published in the 1970s supporting its efficacy. Currently, amantadine is mainly utilizedas an add-on therapy to mitigate levodopa-related dyskinesia and, more recently, new long-acting amantadine formulations have been developed,withnewindications to treat motor fluctuations. Amantadine has not been reported to cause dyskinesia and is rarely implicated in impulse control disorder.

Efficacy and safety of foslevodopa/foscarbidopa versus oral carbidopa/levodopa in advanced Parkinson's disease patients: Design of a phase 3, randomized, double-blind, double-dummy, active controlled 12-week trial

We compare efficacy and safety of 12-week continuous subcutaneous infusion (CSCI) of foslevodopa/foscarbidopa, a new soluble formulation of carbidopa (CD) and levodopa (LD) prodrugs formally known as ABBV-951a, versus oral CD/LD for the treatment of motor fluctuations in advanced Parkinson's disease (PD) patients.

Engineering of levodopa inhalable microparticles in combination with leucine and dipalmitoylphosphatidylcholine by spray drying technique

The aim of this work was to study the effect of concomitant use of leucine and dipalmitoylphosphatidylcholine, in different ratios, on aerosolization performance of levodopa. Three-component formulations were selected based on a central composite design using percentages of leucine and dipalmitoylphosphatidylcholine as the independent variables. Particle size, surface roughness index, surface phosphorus and fine particle fraction were considered as dependent variables in the model. The spray dried samples were also characterized to determine their particle shape and solid state nature. levodopa was spray dried with 10–40% w/w of the excipients to prepare two- or three-component formulations. A crystalline nature was determined for levodopa in all samples spray dried from water:ethanol (30:70 v/v). Roughness in surface of the processed particles increased with increasing total concentration of the excipients, specially above 25% w/w. Analysis of phosphorus on the surface demonstrated that three-component formulations prepared with combination of 12.5% w/w leucine had the highest amount of dipalmitoylphosphatidylcholine in the surface, regardless of its percentage used in the initial feed. A combination of 12.43% w/w of leucine and 9.80% w/w of dipalmitoylphosphatidylcholine used in formulation exhibited the highest fine particle fraction (72.63%). It can be concluded that spray drying of levodopa with a suitable combination of both excipients leads to production of a three-component formulation of crystalline levodopa, with an aerosolization performance which is significantly higher than two-component formulations composed of the drug with either leucine or dipalmitoylphosphatidylcholine.

Real-World Experience with Carbidopa-Levodopa Extended-Release Capsules (Rytary®): Results of a Nationwide Dose Conversion Survey.

Background The introduction of carbidopa-levodopa extended-release (CD-LD ER) capsules (Rytary®) did not go as smoothly as expected, largely due to difficulty around dose conversion from available immediate-release (IR) levodopa (LD) formulations. The dose conversion table in the CD-LD ER prescribing information was similar to the table used in the pivotal clinical trial and is considered by many prescribing HCPs to be less than optimal. By the end of the dose conversion period in that trial, dosing in 76% of subjects was adjusted for symptom control; roughly 60% of patients required a higher dose and about half required more frequent administration than the recommended TID dosing. Objective The primary objective of our nationwide (US) survey was to determine the dose conversion strategy most commonly employed by CD-LD ER frequent prescribers. The survey also aimed to explore additional features regarding CD-LD ER use in clinical practice. Methods A survey consisting of 21 multiple-choice questions was developed and administered to experts in the use of CD-LD ER, based on prescription volume. Results Of the 394 HCPs who were invited to participate, 90 (23%) HCPs completed the survey. All respondents were aware of the dose conversion table; the largest group did not find the table to be helpful and did not use it to convert patients to CD-LD ER. The most common strategy in calculating the CD-LD ER dose was based on the total daily LD IR dose, with the majority of that group initiating dose conversion by doubling the total daily LD dose from CD-LD IR and administering CD-LD ER one less time per day. Conclusion Overall, most survey respondents agreed that a good starting point for CD-LD ER conversion could be doubling the daily LD IR dose and administering it one time less frequently. Moreover, rapid patient follow-up after initial dose conversion to allow for further dose adjustments plays a critical role in achieving success. Gaining experience over time is important for satisfactory conversion.

Anti- Parkinsonian Drug Estimation by RP-HPLC

Aim: The main aim of the current study is to give best and simple method for the estimation of antiparkinsonian drugs named Carbidopa, levodopa and entacapone.
 Study Design: Simultaneous estimation of Carbidopa, levodopa and entacapone was performed by using Quadrapumped (SHIMADZU Prominance-i, LC-2030C) RP-HPLC equipped with PDA detector.
 Place and Duration of Study: Chalapathi Drug Testing Laboratory, Chalapathi Institute Of Pharmaceutical Sciences, Lam, Guntur-522034, Andhra Pradesh, India during the period of August 2019 to February 2020.
 Methodology: The assets of the study can determined as the process of qualification and quantification was done on SHIMADZU Prominance-i, LC-2030C system equipped with Phenomenex ODS (150 x 4.6 mm, 5μm) column and mobile phase was optimized using combination of acetonitrile and 0.1% ortho phosphoric acid in the ration of 50:50 v/v at a flow rate 1.0 ml/min. The wavelength was set as 270nm at ambient temperature by injecting 20µl of solution and the run time was fixed for 5 min.
 Results: Calibration plot shown best regression over the concentration range of 5-160 µg/ml of Carbidopa, Levodopa and Entacapone standard solutions. The LOD and LOQ were found to be 0.85 and 2.54 µg/ml for Entacapone, 0.24 and 0.71 µg/ml for Levodopa, 0.14 and 0.43 µg/ml for Carbidopa respectively. The accuracy of the proposed method was determined by performing recovery studies and was found to be between 98-102%. The repeatability testing for both sample and standard solutions was found as %RSD<2.0% which is within the acceptable limits showing that the method is precise as well. The proposed method was successfully applied for the marketed formulations of Carbidopa, Levodopa and Entacapone tablets. In addition the main feature of proposed method is economic and eco-friendly with less retention time around 5.0 min.
 Conclusion: Including all the optimized method parameters and statistical results given it can be concluded as a new, simple, sensitive, precise and accurate economical analytical method was developed and validated by RP-HPLC for the detection and quantification of Carbidopa, Levodopa and Entacapone which can be applied to the marketed formulation where there are no official compendial methods reported for this particular combination. The high sensitivity (LOD), mobile phase utilized and run time (=5) can be determined as an important features for this proposal.

Oral Levodopa Formulation Does Not Affect Progression of Parkinson Disease.

Motor fluctuations develop in most patients treated with carbidopa/levodopa for Parkinson disease. The continuous dopamine stimulation hypothesis suggests that longer-acting forms of levodopa might improve outcomes, but this has been inadequately tested in humans. We undertook to determine if there is any difference in symptom progression rate among patients taking immediate-release carbidopa/levodopa (IR), controlled-release carbidopa/levodopa (CR), or carbidopa/levodopa/entacapone (CLE) using standard outcome measures in a naturalistic study. We evaluated Parkinson disease subjects prospectively followed for up to 48 months in the Parkinson's Disease Biomarker Project. Bayesian linear or generalized linear mixed-effects models were developed to determine if oral levodopa formulation influenced the rate of symptom progression as measured by 8 outcome measures. At baseline, the IR, CR, and CLE groups were similar except that the CR group had milder disease and was represented at only 1 site, and the CLE group had a longer disease duration. In the primary analysis, there was no difference in rate of symptom progression as measured by the Movement Disorder Society-Sponsored Revision of the Unified Parkinson's Disease Rating Scale Part II, Part IV, or total score. In the secondary exploratory analysis, there was no difference in progression rate as measured by change in levodopa equivalent daily dose, Montreal Cognitive Assessment, Parkinson's Disease Questionnaire mobility subscore, Schwab and England Activities of Daily Living Scale, or a global composite outcome. We found no difference in symptom progression rate in patients taking IR, CR, or CLE. This clinical observation supports pharmacokinetic studies demonstrating that none of these oral levodopa formulations achieve continuous dopamine stimulation.

New Therapeutic Options for the Individualised Titration of Levodopa

Levodopa is the most effective medication in the treatment of Parkinson's disease. In the course of the disease the storage facility of dopaminergic neurones deteriorates, so that the duration of the half-life period likewise converges. This results in fluctuations in performance, and also in dyskinesias as a further consequence of the narrowing therapeutic window. Therapeutically, this in turn leads to further fractioning of the levodopa dosage and a reduction of single-dose levels. There is, however, only limited scope for doing this with the conventional levodopa formulations. For this reason, the introduction of water-soluble microtablets à 5 / 1.25 mg levodopa / carbidopa can be regarded as a beneficial extension permitting for fine titration of the dopaminergic stimulation. Here we present this new therapeutic principle, the available data and concepts for clinical use.

Comparative examination of levodopa pharmacokinetics during simultaneous administration with lactoferrin in healthy subjects and the relationship between lipids and COMT inhibitory activity in vitro

ABSTRACT Background: Lactoferrin (bLF) is an iron-binding multifunctional protein that is abundant in milk. In mice, it inhibits catechol-O-methyltransferase (COMT) activity and increases blood levodopa levels. However, the clinical effects are unknown. Objective: The objective of this study was to determine the effect of bLF on the kinetics of levodopa in blood. Design: The effects of the concomitant administration of a combined formulation of levodopa and an aromatic amino acid decarboxylase inhibitor and bLF on the concentration of levodopa in blood and its metabolism were assessed in eight healthy subjects. In addition, we analyzed the association with clinical factors and evaluated whether clinical factors affected the COMT inhibitory activity of bLF in vitro. Results: Although not statistically significant, the peak plasma concentration (C max) of levodopa increased by 18.5%. From the results of the stratified analysis of total cholesterol, a relationship with ΔC max was predicted. Therefore, bLF was reacted with cholesterol in the presence of lecithin and sodium deoxycholate in vitro to evaluate COMT inhibitory activity, and an increase in inhibitory activity was observed. By contrast, the ester compound cholesteryl oleate had no effect. The inhibitory activity of free fatty acids, which are known to interact with bLF, was also enhanced. Conclusion: The COMT inhibitory activity of bLF is not effective in elevating blood levodopa levels. However, in humans with high lipid levels, such as cholesterol, interactions may enhance the inhibitory effect, resulting in the enhanced absorption of levodopa. Trial registration: ID, UMIN000026787, registered 30 March 2017; URL, https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000030749 Trial registration: UMIN Japan identifier: UMIN000026787

High levodopa plasma concentration after oral administration predicts levodopa-induced dyskinesia in Parkinson's disease

IntroductionIn patients with Parkinson's disease (PD), pulsatile dopaminergic stimulation may be a primary cause of levodopa-induced dyskinesia (LID). We aimed to investigate the correlation between levodopa pharmacokinetics (PK) and LID in PD. MethodsWe retrospectively reviewed the consecutive series of 255 PD patients without LID who underwent PK assessments with 100 mg levodopa. The type of peripheral decarboxylase inhibitor used in the PK assessments was determined by the usual prescription of the formulations of levodopa (10 mg carbidopa [n = 185] and 25 mg benserazide [n = 70]). ResultsDuring a median follow-up of 32 months (IQR, 16–49 months), 73 patients (29%) developed LID. Compared with patients who did not develop LID (PD–LID−), those who developed LID (PD–LID+) were younger (p = 0.003) and had significantly higher maximum levodopa concentration (Cmax) (p = 0.002) and area under the curve (p < 0.001), LEDD (p < 0.001), and improvement of motor symptoms (p = 0.009). In the multivariate Cox proportional hazards models, Cmax and AUC were associated with incident LID (Hazard Ratio [HR] 1.11, 95% confidence interval [CI] 1.03–1.19 and HR 1.13, 95% CI 1.03–1.24, respectively). In addition, younger age, benserazide use, LEDD, and MAOBI use were associated with incident LID. ConclusionHigh levodopa plasma concentration after oral administration was associated with incident LID in patients with PD.

Therapeutic Strategies to Treat or Prevent Off Episodes in Adults with Parkinson's Disease.

Parkinson's disease is a chronic, neurodegenerative disease, which manifests with a mixture of motor, cognitive and behavioural symptoms. Levodopa is the most effective antiparkinsonian treatment to date, although chronic use engenders a mixture of complications in a substantial proportion of patients. Amongst these is the occurrence of episodes of worsening symptoms-'off' phenomena. These episodes can manifest with either motor or non-motor symptoms or a combination of these features and have been found to have profound impacts on patients' quality of life. Although preventative measures are poorly evidenced, avoiding excessive total daily levodopa intake in selected populations that are deemed to be of a higher risk for developing these episodes warrants further exploration. Methods to improve levodopa bioavailability and delivery to the brain are currently available and are of value in addressing these episodes once they have become established. These include modifications to levodopa formulations as well as the use of complimentary agents that improve levodopa bioavailability. The deployment of device-assisted approaches is a further dimension that can be considered in addressing these debilitating episodes. This review summarises the clinical manifestations of 'off' phenomena and the current approaches to treat them. Although we briefly discuss clinical advances on the horizon, the predominant focus is on existing, established treatments.

Initiation of pharmacological therapy in Parkinson's disease: when, why, and how.

Debate is ongoing regarding when, why, and how to initiate pharmacotherapy for Parkinson's disease. Early initiation of dopaminergic therapies does not convey disease-modifying effects but does reduce disability. Concerns about the development of motor complications arising from the early initiation of levodopa, which led to misconceived levodopa-sparing strategies, have been largely mitigated by the outcomes of the PD MED and Levodopa in Early Parkinson's Disease (LEAP) studies. The LEAP study also showed the potential for early improvement in quality of life, even when disability is negligible. Until more effective methods of providing stable dopamine concentrations are developed, current evidence supports the use of levodopa as initial symptomatic treatment in most patients with Parkinson's disease, starting with low doses and titrating to therapeutic threshold. Monoamine oxidase-B inhibitors and dopamine agonists can be reserved as potential adjunct treatments later in the disease course. Future research will need to establish effective disease-modifying treatments, address whether patients' quality of life is substantially improved with early initiation of treatment rather than a wait and watch strategy, and establish whether new levodopa formulations will delay onset of dyskinesia.

Inhaled levodopa for intermittent treatment of OFF episodes in patients with Parkinson’s disease

ABSTRACTIntroduction: Many patients with advanced Parkinson’s disease (PD) have inadequate control of motor symptoms despite optimized treatment. Predictable and unpredictable OFF periods severely interfere with the quality of life. A drug that easily and rapidly reverts the OFF state is still needed. Subcutaneous apomorphine, the only approved drug for this indication, although efficacious, is not widely used probably due to its potential side effects and complicated administration.Levodopa is the most efficacious drug for the treatment of PD motor symptoms. However, issues related to the oral route and intestinal absorption in later disease stages render this route lengthy and inefficacious.Areas covered: Literature on the development of an inhaled formulation of levodopa has been reviewed. Significant advances in the field of pulmonary delivery systems and in dry powders have enabled the development of a new formulation of levodopa that can be inhaled and adequate blood levels rapidly achieved, bypassing intestinal absorption. Several clinical trials have reported efficacy, safety, and tolerability data. Some pulmonary-related adverse events have been reported but are mostly mild.Expert opinion: This new way of administering levodopa is likely to be very welcome and may fill a gap for OFF rescue treatments, at least for some patients.

Chitosan-Coated Hydroxypropylmethyl Cellulose Microparticles of Levodopa (and Carbidopa): In Vitro and Rat Model Kinetic Characteristics

BackgroundParkinson's disease is a neurodegenerative disorder, and a major cause of disability. Levodopa, a prodrug of dopamine, remains the gold standard in the pharmacological management of Parkinson's disease. Despite several attempts to improve the clinical efficacy of levodopa, new oral levodopa formulations are needed to overcome irregular absorption and variable plasma concentrations.ObjectiveThe aim of this study was to evaluate the in vitro and in vivo kinetic properties of chitosan-coated hydroxypropylmethyl cellulose microparticles of levodopa (and carbidopa).MethodsMicroparticles were formulated by encapsulating levodopa powder in chitosan-coated hydroxypropylmethyl cellulose using the spray-drying method. Levodopa microparticles were evaluated for size, zeta potential, drug loading capacity, encapsulation efficiency and in vitro release. In evaluating in vivo pharmacokinetics, Sprague Dawley rats were administered either levodopa/carbidopa powder, levodopa/carbidopa microparticles, or Sinemet CR (a controlled release formulation of levodopa/carbidopa). The dose of respective formulations administered was 20/5 mg/kg; 20 mg levodopa combined with 5 mg carbidopa per kilogram body weight of animals. Treatments were administered via the oral route every 12 hours. Blood samples were collected after predetermined times following the third dose. Plasma was obtained from blood collected, and levodopa levels determined by HPLC. Pharmacokinetic parameters, including Cmax, Tmax, AUC, and t½ of the various formulations, were estimated.ResultsThe mean (SD) size of levodopa microparticles was 0.5 (0.05) µm with polydispersity index of 0.41 and a zeta potential of 10.8 mV. Of the expected 20% drug loading, the actual drug loading capacity of levodopa microparticles was found to be 19.1%, giving an encapsulation efficiency of 95.7%. The in vitro release kinetics of levodopa microparticles showed a controlled and sustained release, with about 80% release occurring after 12 hours. In vivo pharmacokinetic studies showed that rats administered levodopa/carbidopa microparticles had greater AUC (612.7 [17.42] ng.h/mL) and higher Cmax (262.4 [38.86] ng/mL) compared with Sinemet CR: AUC 354.7 (98.09) ng.h/mL and Cmax 95.5 (20.87) ng/mL. However, Sinemet CR had a much longer half-life (6.1 [2.58] hours) compared with levodopa/carbidopa microparticles (2.0 [0.31] hours).ConclusionsFindings from this study suggest that chitosan-coated hydroxypropylmethyl cellulose microparticles of levodopa/carbidopa may give relatively high levels of levodopa in circulation. (Curr Ther Res Clin Exp. 2020; 81:XXX–XXX)© 2020 Elsevier HS Journals, Inc.

CVT-301 for the treatment of Parkinson’s disease

ABSTRACTIntroduction: For patients with Parkinson’s disease (PD), the treatment of motor and nonmotor fluctuations is tantamount to maintaining quality of life. Subcutaneous apomorphine has been the only commercially available rescue therapy for the treatment of OFF episodes. In December 2018, CVT-301 (Inbrija), an inhaled formulation of levodopa (LD), was approved by the FDA for this indication.Areas covered: In this review, the authors summarize the armamentarium available to address motor fluctuations in PD, including medications in development. The authors discuss the pharmacological properties of CVT-301 as well as its efficacy and safety as reported in phase I, II, and III studies.Expert opinion: More than 20 medications or surgical procedures are available or in development to address motor fluctuations in PD. Deep brain stimulation (DBS) is an invasive but effective intervention at the end of the treatment spectrum. Less invasive therapies are used in combination to ameliorate motor fluctuations. Rescue therapies can help patients taking oral medications who experience delayed onset symptom relief (delayed ON), and unexpected wearing OFF by providing rapid and durable symptoms relief. CVT-301, an inhaled LD formulation, provides a safe and effective delivery mechanism that may be preferred by patients over subcutaneous injections.

Pharmacokinetic drug evaluation of CVT-301 for the treatment of Parkinson’s disease

ABSTRACTIntroduction: Levodopa (LD), in combination with a decarboxylase inhibitor, is a mainstay and the most effective therapeutic agent in the treatment of Parkinson’s disease (PD). Unfortunately, during chronic treatment with this agent, ON–OFF phenomena and dyskinesia appear. Despite the many medical treatment options available, unpredictable OFF episodes can still occur and be severe and disabling. A rescue therapy that provides a rapid and predictable ON response for patients with OFF periods would be of great value for such patients.Areas covered: CVT-301 is a self-administered dry powder aerosol inhaled formulation of LD that is being developed as a self-administered treatment for OFF periods. The PK profile of CVT-301, the efficacy, and the safety highlighted in randomized clinical trials will be reviewed.Expert opinion: CVT-301 may offer several potential advantages including increased systemic bioavailability through pulmonary absorption, rapid onset of action, avoidance of first-pass drug metabolism and less plasma-level variability.List of Abbreviations: PD: Parkinson’s disease; LD: Levodopa; CD: Carbidopa; AADC: aromatic L-amino acid decarboxylase; IR: immediate-release; FPD: fine particle dose; GI: gastrointestinal; PK: pharmacokinetic; CVs: coefficient of variation; UPDRS: Unified Parkinson’s Disease Rating Scale; AEs: adverse events; FEV: forced expiratory volume; FVC: forced vital capacity; DLCO: diffuse lung CO ; tmax: time to maximum concentration

Formulation of levodopa containing dry powder for nasal delivery applying the quality-by-design approach

The aim of this work was to carry out preliminary experiments for preparation of levodopa (LEVO)-containing intranasal powder. The experiments were designed according to the Quality by Design (QbD) concept. Based on prior risk assessment, LEVO and chitosan (CH) or sodium hyaluronate (HA) as mucoadhesive matrix formers were co-milled using planetary ball mill to prepare microparticles as drug delivery systems. The rotation speed, the milling time and the drug-additive ratio were evaluated to be the most relevant milling factors - as a result of the initial risk assessment; which were set according to a factorial design. The effects of critical process parameters and excipients were investigated on the particle size and surface characteristics of products, and on the crystallinity, in vitro dissolution and permeability of LEVO. Milling in the presence of higher amount of HA resulted in smaller average particle size of powders (D50 = 13.068 μm) and higher initial dissolution and permeation of LEVO compared to CH-containing formulations (D50 = 21.667 μm).

Pulmonary Safety and Tolerability of Inhaled Levodopa (CVT-301) Administered to Patients with Parkinson's Disease.

Background: CVT-301, an inhaled levodopa (LD) formulation, is under development for relief of OFF periods in Parkinson's disease (PD). Previously, we reported that CVT-301 improved OFF symptoms relative to placebo. In this study, we evaluate pulmonary function in patients treated with a single dose of CVT-301 or placebo for 3 hours, or received multiple doses/day for 4 weeks.Methods: As part of two phase 2 studies, pulmonary safety and tolerability of CVT-301 were evaluated in PD patients experiencing motor fluctuations (≥2 hours OFF/day), Hoehn and Yahr stage 1–3, and forced expiratory volume in 1 second/forced vital capacity ratio ≥75% of predicted (in ON state). In study A, patients received single doses of oral carbidopa/LD and each of the following via the inhaled route: placebo and 25 and 50 mg LD fine particle dose (FPD) CVT-301. In study B, patients received up to 3 inhaled doses/day of 35 mg (weeks 1–2) and 50 mg LD FPD CVT-301 (weeks 3–4) versus placebo. Assessments included spirometry and treatment-emergent adverse events (TEAEs).Results: In study A, (n = 24) mean age ± standard deviation was 61.3 ± 7.4 years, mean time since diagnosis was 10.5 ± 4.6 years, and mean duration of LD treatment 8.4 ± 3.7 years. Assessment of pulmonary function (predose to 3 hours postdose) showed that spirometry findings were within normal ranges, regardless of treatment groups, or motor status at screening. In study B, (n = 86) mean age was 62.4 ± 8.7 years, time since PD diagnosis was 9.4 ± 3.9 years, and duration of LD treatment 7.8 ± 3.9 years. Longitudinal assessment of pulmonary function over 4 weeks showed no significant difference in spirometry between CVT-301 versus placebo groups. In both studies, the most common CVT-301 TEAE was mild-to-moderate cough (study A: 21%; study B: 7% vs. 2% in placebo). Other common TEAEs in study B were dizziness and nausea.Conclusion: Acute and longitudinal assessment of pulmonary function showed that CVT-301 treatment was not associated with acute airflow obstruction in this population. CVT-301 was generally safe and well tolerated.

Extended-release oral capsule of carbidopa-levodopa in Parkinson disease.

Motor fluctuations complicate the treatment of patients with Parkinson’s disease receiving levodopa. Extended-release carbidopa–levodopa has a pharmacokinetic profile that provides a more continuous levodopa serum concentration. Patients taking this formulation can expect longer duration of action and fewer doses per day, similar clinical improvement when compared to other levodopa formulations, and with a theoretically lower risk of developing motor fluctuations. Several studies, including three randomized control trials provide evidence for the efficacy, safety and tolerability of extended release carbidopa–levodopa in patients with both early and advanced Parkinson’s disease are reviewed here. Also provided is guidance for dosing of and conversion to extended release carbidopa–levodopa as well as a discussion of its place in the clinical practice.

Diagnosis and Management of Parkinson's Disease.

Despite numerous efforts to identify specific and sensitive biomarkers, the diagnosis of Parkinson's disease (PD) is still based on clinical criteria that include the presence of a combination of cardinal motor features (tremor, rigidity, bradykinesia, and postural instability), other motor features (including freezing of gait and abnormal postures), and numerous nonmotor features. In addition, the presence of atypical features may suggest an alternative diagnosis. Levodopa therapy remains the gold standard in the management of motor features of PD. New formulations of levodopa and novel delivery systems are currently being evaluated and gradually introduced in clinical practice in an attempt to prevent or treat levodopa-related motor complications. Dopamine agonists also play an important role as monotherapy in mild or adjunctive therapy in moderately advanced disease. As the disease progresses and patients develop complications from levodopa therapy, specifically motor fluctuations and dyskinesias, deep brain stimulation becomes an alternative therapeutic option. Clinical trials of experimental therapeutics are currently fueling the PD therapeutic pipeline.