Pergolide Research Articles

Pharmacokinetic properties of pergolide mesylate following single and multiple-dose administration in donkeys (Equus asinus).

Donkeys with clinical signs of pituitary pars intermedia dysfunction are treated with oral pergolide mesylate despite the lack of species-specific pharmacokinetic data. To evaluate the pharmacokinetics of intragastric and oral pergolide mesylate in healthy donkeys (Equus asinus). Pharmacokinetic study. Six healthy donkeys were administered pergolide mesylate (Prascend®) at 2 μg/kg bodyweight (bwt) intragastrically once, then once daily per os (PO) for 5 days. Blood samples were collected at 0, 10, 20, 30 and 45 min and 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36 and 48 h after the single intragastric dose, once daily immediately before the PO dose, and then again at the above times after Day 5 of once daily oral dosing. Plasma pergolide concentration was quantified via ultra-performance liquid chromatography-tandem mass spectrometry. Pergolide concentration versus time data after the first and last doses were analysed based on noncompartmental pharmacokinetics using commercial software. Paired t-tests were used to compare single and multiple doses (p< 0.05). In a follow-up study, a single oral dose was then administered to two donkeys followed by concurrent blood sampling from the jugular and cephalic veins to evaluate the effect of route of administration on pergolide pharmacokinetics. Cmax , Tmax AUC, and t½λz differed significantly (p≤ 0.03) after single and multiple doses, with significantly lower Cmax (0.16 ± 0.16 ng/ml) and t½λz (9.74 ± 1.35 h) after intragastric dosing on Day 1 than after 5 days of oral dosing (3.74 ± 2.26 ng/ml and 16.35 ± 5.21 h, respectively). Pergolide plasma concentrations were higher in jugular vein samples compared to cephalic vein samples after a single oral dose. Small sample size; varied administration routes. Pergolide mesylate (dosed at 2μg/kg bwt) is bioavailable in donkeys after intragastric and PO administration. Differences in pharmacokinetics were noted after multiple doses, related to different routes of administration and sublingual absorption of pergolide.

Management of pituitary pars intermedia dysfunction in practice: A clinical audit

In horses/ponies with pituitary pars intermedia dysfunction (PPID), pergolide mesylate treatment, with monitoring of therapeutic response, is recommended by contemporaneous literature and equine endocrinologists. However, it is unknown whether these recommendations are adhered to in private practice. This clinical audit aimed to compare treatment and monitoring of PPID cases in veterinary practice against available recommendations. Case data and basal plasma adrenocorticotropic hormone (ACTH) concentrations from all equids tested for PPID between 2012 and 2016 from a single veterinary practice in the UK were obtained. Records were reviewed and information on treatment and monitoring over the subsequent 2–6 years was extracted and compared with published recommendations. After exclusions, the audit population was 480 animals (median age, 20 years). The most common presenting signs were laminitis and/or historical laminitis (51.2%) and hypertrichosis and/or delayed coat shedding (24.5%). Based on seasonally adjusted reference intervals for basal ACTH concentration, 51.7% (n = 248) of animals were classified as positive, 37.1% (n = 178) as negative and 11.3% (n = 54) as equivocal for PPID. Records were available for 459 animals; of which pergolide treatment was initiated in 78.7% (n = 185/235) of positive cases, 19.2% (n = 10/52) of equivocal cases and 6.4% (n = 11/172) of cases classified as negative. Overall, 87.2% (n = 129/148) of cases commenced treatment as per recommendations. Only 77.7% (n = 160/206) of pergolide-treated animals had documented PPID monitoring and of these, only 48.1% (n = 77/160) had follow-up basal ACTH testing in the first 1–3 months following diagnosis. The findings confirm that management of PPID in veterinary practice fell below contemporaneous recommendations, especially for monitoring.

The effect of pergolide mesylate on adrenocorticotrophic hormone responses to exogenous thyrotropin releasing hormone in horses

Thyrotropin releasing hormone (TRH) stimulation testing is often used to support a diagnosis of pituitary pars intermedia dysfunction (PPID) in horses although it is unclear whether or not repeat TRH stimulation testing post-treatment is a valid means of assessing response to medical therapy. Laboratory submissions from 64 suspected equine PPID cases were examined including the initial pre-treatment TRH stimulation test and a follow up test within 100 days of starting medical therapy with pergolide. In a subset of cases, further follow-up tests were examined beyond 100 days of starting treatment. Results from tests conducted between 1 July and 30 November were excluded.Significant improvements were seen in both the baseline and TRH-stimulated adrenocorticotrophic hormone (ACTH) concentrations within 100 days with no further improvements seen in the subset of cases examined thereafter. Although 88% (n = 56/64) of all cases showed a decreased response to TRH post-treatment, only 24% (n = 9/38) of horses with positive pre-treatment TRH stimulation tests normalised following treatment, with a further 34% (n = 13/38) improving into an equivocal test outcome category. Most commonly (42%; n = 16/38), horses with positive pre-treatment TRH stimulation tests remained positive following treatment, although 75% (n = 12/16) of these showed a numerically lower post-treatment response to TRH. These results will help inform practitioners of expected changes in TRH stimulation test results when assessing response of horses with PPID to medical therapy with pergolide.

Pharmacokinetics and pharmacodynamics of pergolide mesylate after oral administration in horses with pituitary pars intermedia dysfunction

Published information on the pharmacokinetic and pharmacodynamic properties of pergolide is limited. The aim of this study was to investigate the pharmacokinetic and pharmacodynamic properties of oral pergolide in horses with pituitary pars intermedia dysfunction (PPID). The study design was a nonrandomized clinical trial. Six horses with PPID diagnosed by thyrotropin-releasing hormone (TRH) stimulation tests received pergolide at 4 μg/kg for 18 d. Plasma samples for determination of pergolide and ACTH concentration were collected 0.5 h before and 2 and 12 h after each administration of pergolide. Maximum plasma concentrations after the first oral dose of pergolide (0.104–0.684 ng/mL; median 0.261 ng/mL; interquartile range [IQR] 0.184–0.416 ng/mL) were not significantly different to the maximum steady-state concentration at day 18 (0.197–0.628 ng/mL; median 0.274; IQR 0.232–0.458 ng/mL). Chronic administration was not associated with drug accumulation (R = 1.09) and pergolide concentration reached steady state within 3 d. Throughout, concentrations of pergolide fluctuated considerably, with median plasma peak concentrations more than four times higher than median trough concentrations. Plasma ACTH concentration reduced significantly within 12 h of administration with further reductions occurring up to 10 d after the initiation of treatment. Although there were parallel fluctuations in the concentrations of pergolide and ACTH, timing of ACTH measurement in relation to the administration of pergolide did not have a significant effect. Alterations in the response to TRH were identified at 8 d with no further change being identified at 18 d. A small number of horses were studied. Oral pergolide results in significant suppression of pars intermedia activity within hours. Pergolide and ACTH concentrations fluctuated in tandem although correlation was poor. Fluctuations in pergolide concentration were consistent with a terminal elimination half-life of less than 12 h. To reduce the level of fluctuation of ACTH, twice-daily dosing of pergolide may be more appropriate.

Pharmacokinetics and Pharmacodynamics of Oral Pergolide Mesylate In Horses With Pituitary Pars Intermedia Dysfunction

Pharmacokinetics and Pharmacodynamics of Oral Pergolide Mesylate In Horses With Pituitary Pars Intermedia Dysfunction

Effects of chronic exposure to octamethylcyclotetrasiloxane and decamethylcyclopentasiloxane in the aging female Fischer 344 rat

Octamethylcyclotetrasiloxane (D4) and decamethylcyclopentasiloxane (D5) are used as intermediates or monomers in the synthesis of silicon-based polymers for industrial or consumer applications. D4 and D5 may remain as residual monomer in these polymers at less than 1000ppm and may therefore be present as a minor impurity in consumer products. For D5, in addition to the manufacture of polymers, its uses include intentional addition to consumer products, personal care products and some dry- cleaning solvents. Two-year rodent chronic bioassays were conducted with both substances and borderline increases in the incidence of uterine tumors were observed, specifically, benign uterine adenoma with D4 and adenocarcinoma with D5. The effects profile and induction of uterine tumors share some similarity with that seen with chronic exposure to dopamine agonists. The current study investigated the potential for D4 and D5 to elicit dopamine agonist-like effects on estrous cyclicity. Separate groups of reproductively senescent female Fischer 344 rats (F344) were exposed via vapor inhalation to D4 (700ppm, 9.3mg/L) or D5 (160ppm, 2.1mg/L) or to a diet containing 0.0045, 0.045, or 4.5ppm pergolide mesylate (PM), a potent dopamine agonist used here as a reference substance, from 11 through 24 months of age. The primary focus was to characterize the effects of D4 and D5 exposure on estrous cyclicity relative to that observed with PM. As a monitoring effort, circulating endogenous estradiol, progesterone, prolactin and corticosterone levels were evaluated monthly. A blood sample from each rat was obtained via tail vein in the afternoon after the daily inhalation exposure period once every 4 weeks. Histomorphologic examination of the major organs including the reproductive tract was conducted on all animals at study termination.This study has shown that chronic exposure to D4 and D5 can affect cyclicity in the reproductively senescent F344 rat. For each substance the effect on cyclicity involved reduction in the incidence of pseudopregnancy with a shift toward cycles more typical of younger animals. D4 and D5 induced an increase in estrous cycle repetition whereas D4 also increased the incidence of extended estrus. These shifts resulted in animals entering proestrus/estrus significantly more times over the duration of the study than seen in the control group. Similar effects were observed with the reference substance, PM. However, distinct differences in the timing and magnitude of the effects on the estrous cycle and impact on prolactin, progesterone, estradiol, and corticosterone suggest that D4 and D5 are not classical dopamine agonists even though a similar increased incidence of proestrus/estrus was also observed with PM. These results may prove important with respect to understanding D4- and D5-induced uterine tumor response in the F344 rat, given the relationship between increased incidence of uterine endometrium stimulation by endogenous estrogen as a consequence of extended or more frequent proestrus/estrus, uterine tumor risk, and questions of relevance to humans. Recent publications have summarized the existing data on D4 and D5, with emphasis on exploring the biological relevance of the uterine tumors (Klaunig et al., 2016a,b; Franzen et al., 2017; Dekant and Klaunig, 2016; Dekant et al., 2017). The authors concluded that although the mode of action has not yet been fully established, the data, including the findings from this study, indicate that the D4- and D5-induced uterine tumors observed in the rodent chronic bioassays have no relevance for human risk characterization based not only on the distinct species differences in regulation of the reproductive systems, but also the high exposure levels and duration required for expression in rats.

Large pituitary adenoma in an 8‐year‐old Arabian stallion

SummaryAn 8‐year‐old Arabian stallion weighing 361 kg presented to Louisiana State University Veterinary Teaching Hospital with a 3‐month history of weight loss, exercise intolerance, long hair coat and recent history of seizures and aimless wandering in the pasture. An initial presumptive diagnosis of pituitary pars intermedia dysfunction (PPID) was made based on clinical signs. The initial examination revealed weight loss and loss of body condition (BCS 3/9), hypertrichosis, muscle wasting and reluctance to move when prompted. A neurological examination revealed dull mentation with no evidence of proprioceptive deficits in the limbs. Mild hyperglycaemia and a stress leucogram were noted on initial biochemical panel and haematology, respectively. Plasma adrenocorticotrophic hormone (ACTH) concentrations before and after thyrotropin releasing hormone (TRH) stimulation were markedly increased. Rapid slice computed tomography (CT) scan of the head before and after contrast revealed a large mass in the region of the pituitary gland suggestive of macroadenoma causing PPID. Prior to imaging, treatment consisted of supportive nursing care. Due to size of the pituitary gland (measuring 4.6 × 4.6 × 3.8 cm) and the presence of seizure‐like activity and dull mentation, the stallion was subjected to euthanasia. A necropsy was not performed. Pituitary macroadenomas in horses affected with PPID, who show neurological signs such as seizure‐like activity, dull mentation and aimless wandering, might have a poor prognosis and treatment with pergolide mesylate might not reduce pituitary gland size or relieve clinical signs. A CT scan is indicated in horses with neurological signs suspected of PPID to further evaluate pituitary gland size and surrounding structures and rule out other causes to better assess prognosis.

Equine pituitary pars intermedia dysfunction: current perspectives on diagnosis and management.

Equine pituitary pars intermedia dysfunction (PPID) is a neurodegenerative disease of the hypothalamus, resulting in the loss of dopaminergic inhibition of pars intermedia. An oxidative stress injury of unknown etiology has been suggested to initiate the neurodegeneration. While hypertrichosis (formerly known as hirsutism) is considered pathognomic for advanced disease, the antemortem diagnosis of subclinical and early disease has continued to prove difficult. Numerous tests have been used with varying sensitivities and specificities. The overnight dexamethasone suppression test, originally documented to have 100% sensitivity and specificity in horses with advanced disease, has proven to be less valuable in identifying early disease. Basal plasma adrenocorticotropin concentrations have improved sensitivity and specificity when sampled during the autumn months, and α-melanocyte-stimulating hormone, while not yet commercially available, shows promise as a sensitive and specific single sample test. Recent advances in our knowledge include the strong association between laminitis and hyperinsulinemia, both common clinical signs associated with PPID. The pathogenesis of hyperinsulinemia, laminitis, and their association with this disease is a focus of current research. The dopamine agonist pergolide mesylate is still the mainstay of medical management, with studies on oral bioavailability, pharmacokinetics, and long-term survival rates now published.

Effect of prior exposure to dopamine agonists on treatment with gabapentin enacarbil in adults with moderate-to-severe primary restless legs syndrome: pooled analyses from 3 randomized trials.

BackgroundDopamine agonists (DAs) are a first-line therapy for moderate-to-severe restless legs syndrome (RLS), but these treatments may lead to complications, such as augmentation and impulse control disorders, requiring switching to another therapeutic class. Here we assess efficacy and tolerability of gabapentin enacarbil (GEn) in adults with moderate-to-severe primary RLS, with or without prior DA exposure.MethodsData from 3 trials were pooled. Patients were identified as DA-naive or DA-exposed, based on prior treatment with ropinirole, pramipexole, rotigotine, or pergolide mesylate, and the dopamine precursor levodopa. Details on prior treatment duration and dose were unavailable. Patients with a history of augmentation were excluded. Within DA-naive/DA-exposed patients we investigated the co-primary end points from the pivotal trials: mean change from baseline to week 12 in International RLS (IRLS) Rating Scale total score and proportion of responders (“much”/“very much” improved) on the investigator-rated Clinical Global Impression–Improvement (CGI-I) scale. Safety was also assessed.Results671 patients were randomized (DA-naive: placebo, n = 194; GEn 600 mg, n = 131; GEn 1200 mg, n = 214; DA-exposed: placebo, n = 50; GEn 600 mg, n = 30; GEn 1200 mg, n = 52). Across treatment arms, no significant differences between DA-naive and DA-exposed subgroups in IRLS Rating Scale total score change from baseline at any visit were seen, except week 1 in the placebo group (−6.1 DA-naive vs −3.4 DA-exposed, P = .020). No significant differences in the odds of CGI-I response at week 12 between DA-naive vs DA-exposed patients in any treatment group were seen; however, with placebo there was a nonsignificant trend toward fewer responders among DA-exposed (34.0%) vs DA-naive (44.3%) patients. Both GEn doses significantly improved the IRLS Rating Scale total score change from baseline and CGI-I response vs placebo, regardless of prior DA exposure. The most common treatment-emergent adverse events were dizziness and somnolence.ConclusionsPrior DA exposure had no significant effect on efficacy or tolerability of GEn (600 or 1200 mg) in this pooled analysis of adults with moderate-to-severe primary RLS. These data support the use of GEn in DA-exposed and DA-naive patients.Trial registrationClinicalTrials.gov NCT00298623, NCT00365352, and NCT01332305

Pharmacokinetics of pergolide after intravenous administration to horses.

To determine the pharmacokinetics of pergolide after IV administration to horses. 8 healthy adult horses. Pergolide mesylate was administered IV at a dose of 20 μg/kg (equivalent to 15.2 μg of pergolide/kg) to each horse, and blood samples were collected over 48 hours. Pergolide concentrations in plasma were determined by means of high-performance liquid chromatography-tandem mass spectrometry, and pharmacokinetic parameters were determined on the basis of noncompartmental methods. After IV administration of pergolide, mean ± SD clearance, elimination half-life, and initial volume of distribution were 959 ± 492 mL/h/kg, 5.64 ± 2.36 hours, and 0.79 ± 0.32 L/kg, respectively. With an elimination half-life of approximately 6 hours, twice-daily dosing may be more appropriate than once-daily dosing to reduce peak-trough fluctuation in pergolide concentrations. Further pharmacodynamic and pharmacokinetic studies of pergolide and its metabolites will be necessary to determine plasma concentrations that correlate with clinical effectiveness to determine the therapeutic range for the treatment of pituitary pars intermedia dysfunction.

Cluster Screening: An Effective Approach for Probing the Substrate Space of Uncharacterized Cytochrome P450s

Cytochrome P450 monooxygenases (P450s) are versatile enzymes with high potential for biocatalysis. The number of newly annotated P450 genes has been increasing constantly, and these thus represent a rich resource for new biocatalysts. However, the substrate scopes of newly identified P450s are often not known, and thus their exploitation is difficult. Herein we describe an approach, named "cluster screening", and its application for the primary characterization of two P450s: CYP154E1 and CYP154A8. A library comprising 51 compounds was designed and organized into nine groups according to their chemical properties. The activities of both P450s in vitro were maintained with suitable nonphysiological redox partners, and the cluster library was screened with these enzymes for product formation. From this library, 30 compounds tested positive for CYP154E1 and 23 were positive for CYP154A8. Cluster screening distinguishes subtle differences in activity and selectivity of enzymes as closely related as those of the same P450 family. For example, the alkaloid pergolide mesylate was converted by CYP154E1 (4 %) but not by CYP154A8. A building block of vitamin D3 , Grundmann's ketone, was converted by both enzymes, although conversion was higher with CYP154E1 (100 vs 53%).

Pharmacokinetics of Pergolide Mesylate in Horses

AimsPergolide mesylate is the treatment of choice for equine pituitary pars intermedia dysfunction (PPID) and veterinary preparations are now licensed for this use in a number of countries. Pharmacokinetic properties of the drug have not been established completely in horses and current dosing recommendations are based upon clinical experience. This study aimed to establish the pharmacokinetic properties of the drug following intravenous administration.MethodsEight healthy Thoroughbred or Standardbred geldings were administered 0.02 mg/kg bwt pergolide mesylate via an intravenous jugular catheter. Blood samples were collected over a period of 48 h from a catheter in the contralateral jugular vein for determination of plasma pergolide concentrations. Pergolide concentrations in plasma were determined using a high‐performance liquid chromatography–tandem mass spectrometry assay. Maximum concentration of pergolide was determined directly from the data. Other pharmacokinetic parameters were determined for each horse by use of noncompartmental analysis with a commercial software program. Area under the curve was calculated by the linear trapezoidal rule. The terminal elimination rate constant and terminal half‐life were calculated by means of log‐linear regression. Initial volume of distribution, mean residence time, and clearance were calculated using standard noncompartmental formulae.ResultsSee Table . Results Mean (± s.d.) Maximum concentration (Cmax) 14.90 ± 5.02 Terminal elimination rate constant (λ) (h−1) 0.14 ± 0.06 Terminal half‐life (h) 5.80 ± 2.26 Area under the curve 0‐∞ (ng*h/ml) 18.63 ± 7.30 Mean residence time (h) 6.30 ± 2.43 Clearance (ml/h/kg bwt) 964.30 ± 460.95 Initial volume of distribution (l/kg bwt) 1.13 ± 0.39 ConclusionsVolume of distribution and half‐life for pergolide in horses are shorter than reported previously. There is no rationale for administering a loading dose of pergolide mesylate; however, based on its pharmacokinetic properties twice daily dosing with pergolide mesylate may be more appropriate than once daily dosing.Ethical animal researchApproved by the Animal Care and Ethics Committee, Charles Sturt University. Sources of funding: Internal funding. Competing interests: Although not used in the current study, David Rendle has acted as a paid speaker and consultant for Boehringer Ingelheim, manufacturers of Prascend: the licensed form of pergolide in Europe and the USA.

Effects of Pergolide Mesylate on Plasma Adrenocorticotropic Hormone Concentration in Horses with Pituitary Pars Intermedia Dysfunction

AimsPituitary pars intermedia dysfunction (PPID) is a common degenerative neuropathy of horses associated with ageing. Pergolide mesylate (pergolide) is the only licensed treatment for PPID in the UK; however, published evidence of its efficacy is limited to small case series and anecdotal reports. This study evaluated adrenocorticotropic hormone (ACTH) responses in horses treated with pergolide and investigated factors that may influence response to treatment.MethodsA retrospective review of submissions to The Liphook Equine Hospital Laboratory was performed from January 2007 to December 2012 and cases in which ACTH concentration was measured before and after instigation of pergolide treatment were identified. Data were analysed using Rv.2.15 software (R Development Core Team). Improvement was defined as a reduction of ACTH concentration of ≥75%, or a return of ACTH concentration to within seasonally adjusted reference intervals.ResultsA total of 2122 cases satisfied the inclusion criteria. Improvement was identified in 54.8% of horses at the first follow‐up assessment; however, ACTH concentration returned to within reference intervals in only 28%. Equids with a higher ACTH concentration pretreatment were more likely to improve (odds ratio [OR] 1.01, 95% confidence intervals [CI] 1.00–1.02; P = 0.027), but less likely to return to within the reference interval (OR 0.97; 95% CI 0.96–0.98; P&lt;0.001). Older equids were significantly less likely to improve (OR 0.56, 95% CI 0.46–0.67; P&lt;0.001). Improvement was more likely after a cumulative dose of 50 mg (OR 1.59, 95% CI 1.10–2.29; P = 0.013) and duration of treatment was positively associated with treatment response (P = 0.039). A daily dose &gt;0.5 μg/kg bwt was less likely to be associated with a reduction in ACTH concentration (OR 0.86, 95% CI 0.77–0.96; P = 0.009). Native breeds, mini and draught horses were more likely to return to the reference range than other breeds (OR 1.6, 95% CI 1.24–2.07; P&lt;0.001). Neither gender nor season were associated with response to treatment.Conclusions and practical significancePergolide is an effective means of reducing ACTH concentration in equids with PPID.Ethical animal researchNot required by this Congress: retrospective clinical study. Sources of funding: None. Competing interests: Rendle and Durham have acted as paid speakers and consultants for Boehringer Ingelheim, manufacturers of Prascend, the licensed equine pergolide product.

Comparison of hair follicle histology between horses with pituitary pars intermedia dysfunction and excessive hair growth and normal aged horses

Pituitary pars intermedia dysfunction (PPID) in older equids is commonly recognized by a long hair coat that fails to shed. The aim of this study was to compare hair follicle stages in PPID-affected horses with excessively long hair coats with the stages of normal aged horses (controls) and to compare hair follicle stages in PPID-affected horses after 6 months of treatment with pergolide mesylate with those of control horses. Eight PPID-affected horses and four normal, age-matched, control horses. Skin biopsies were collected from the neck and rump of PPID-affected and control horses. A diagnosis of PPID was established based on hair coat changes and supportive overnight dexamethasone suppression test results. Skin biopsies were repeated after 6 months of treatment with pergolide. The number of hair follicles in anagen (A) or telogen (T) was counted for each skin biopsy using transverse sections. Pretreatment biopsies had a greater percentage of A follicles (neck 96%, rump 95%) and a lower percentage of T follicles (neck 4%, rump 5%) in PPID-affected horses than in control horses (A, neck 15%, rump 25%; and T, neck 85%, rump 75%). After treatment with pergolide, all PPID-affected horses had improved shedding, and the percentages of A follicles (neck 69%, rump 70%) and T follicles (neck 31%, rump 30%) were not different from untreated control horses (A, neck 68%, rump 82%; and T, neck 32%, rump 18%). These findings document that excessive hair growth (hypertrichosis) in PPID-affected horses is due to persistence of hair follicles in A. Furthermore, treatment with pergolide improved shedding and reduced the percentage of A follicles in PPID-affected horses.

Pergolide block of the cloned Kv1.5 potassium channels

Pergolide mesylate, an ergot-derivative dopamine receptor agonist, is prescribed for the management of patients with Parkinson's disease. Pergolide caused vasoconstriction in a pulmonary artery. Kv1.5 channel is highly expressed in pulmonary arterial smooth muscle cells, where it plays an important role as a determinant of vascular tone. In the present study, we investigated the effects of pergolide on Kv1.5 stably expressed in Chinese hamster ovary cells using the whole-cell patch-clamp technique. The Kv1.5 block by pergolide was concentration-, time-, voltage-, and use-dependent. Pergolide blocked Kv1.5 currents in a concentration-dependent manner, with an IC(50) value of 15.4 μM and a Hill coefficient of 1.7. The activation and inactivation of Kv1.5 were significantly accelerated by pergolide in a concentration-dependent manner. The apparent association and dissociation rate constants were 0.43 μM(-1) s(-1) and 8.34 s(-1), respectively, with a K (D) value of 19.1 μM. Pergolide slowed deactivation kinetics of Kv1.5, resulting in a tail crossover phenomenon. The block of Kv1.5 by pergolide was voltage-dependent, increasing significantly at test potentials from -10 to +10 mV, whereas the current was reduced slightly with a shallower voltage dependence in the range between +20 and +50 mV (δ = 0.34). There was a significant hyperpolarizing shift in the voltage dependence of steady-state inactivation of Kv1.5. Pergolide produced a use-dependent Kv1.5 block at 1 and 2 Hz, and also slowed the time course for recovery from inactivation. These results suggest that pergolide has an affinity for the open and inactivated states of Kv1.5 channels.

Pharmacological Modulation of the Short-Lasting Effects of Antagonistic Direct Current-Stimulation Over the Human Motor Cortex

Combined administration of transcranial direct current-stimulation (tDCS) with either pergolide (PER) or d-cycloserine (d-CYC) can prolong the excitability-diminishing effects of cathodal, or the excitability enhancing effect of anodal stimulation for up to 24 h poststimulation. However, it remains unclear whether the potentiation of the observed aftereffects is dominated just by the polarity and duration of the stimulation, or the dual application of combined stimulation and drug administration. The present study looks at whether the aftereffects of oral administration of PER (a D1/D2 agonist) or d-CYC (a partial NMDA receptor agonist), in conjunction with the short-duration antagonistic application of tDCS (either 5 min cathodal followed immediately by 5 min anodal or vice versa), that alone only induces short-lasting aftereffects, can modulate cortical excitability in healthy human subjects, as revealed by a single-pulse MEP (motor-evoked-potential) paradigm. Results indicate that the antagonistic application of tDCS induces short-term neuroplastic aftereffects that are dependent upon the order of the application of short-duration stimulation. The administration of d-CYC resulted in a marked inhibition of cortical excitability under the application of tDCS in both stimulation orders. Intake of PER resulted in an increase in cortical excitability in both stimulation orientations, but was non-significant compared to the placebo condition. These results indicate that the aftereffects of tDCS are dependent upon the order of stimulation applied, and also demonstrate the prolongation of tDCS aftereffects when combined with the administration of CNS active drugs.

CGMP level in idiopathic Parkinson’s disease patients with and without cardiovascular disease – A pilot study

We have previously found that average serum cGMP level in unselected patients with Parkinson’s disease (PD), particularly in patients treated with a combination of l-DOPA and the dopamine agonist pergolide mesylate, is markedly higher than that in healthy controls. Here we compared serum cGMP and total testosterone levels between l-DOPA/pergolide mesylate-treated male idiopathic PD patients without and with cardiovascular disease (iPD, n = 10, and iPD-CVD, n = 10, respectively) and age-matched healthy volunteers (n = 10). There was no difference in PD-related disability between the two patient groups as assessed by UPDRS motor score and Hoehn-Yahr staging. Whereas none of the patients showed hypoandrogenemia, PD patients compared to controls revealed significantly lower serum testosterone levels, and iPD-CVD patients showed significantly lower levels than iPD patients. Serum cGMP levels were but moderately while significantly higher in the two groups of PD patients than in the controls, and were the highest in the iPD-CVD group. For all study groups combined, there was a high negative correlation between total testosterone level and cGMP level. Our data indicate that blood total testosterone level is negatively correlated with general health status in PD patients, whereas the reverse is true for blood cGMP level.

Effects of pergolide mesylate on transduction efficiency of PEP-1-catalase protein

The low transduction efficiency of various proteins is an obstacle to their therapeutic application. However, protein transduction domains (PTDs) are well-known for a highly effective tool for exogenous protein delivery to cells. We examined the effects of pergolide mesylate (PM) on the transduction of PEP-1-catalase into HaCaT human keratinocytes and mice skin and on the anti-inflammatory activity of PEP-1-catatase against 12- O-tetradecanoylphorbol-13-acetate (TPA)-induced inflammation using Western blot and histological analysis. PM enhanced the time- and dose-dependent transduction of PEP-1-catalase into HaCaT cells without affecting the cellular toxicity. In a mouse edema model, PEP-1-catalase inhibited the increased expressions of inflammatory mediators and cytokines such as cyclooxygenase-2, inducible nitric oxide synthase, interleukin-6 and -1β, and tumor necrosis factor-α induced by TPA. On the other hand, PM alone failed to exert any significant anti-inflammatory effects. However, the anti-inflammatory effect of co-treatment with PEP-1-catalase and PM was more potent than that of PEP-1-catalase alone. Our results indicate that PM may enhance the delivery of PTDs fusion therapeutic proteins to target cells and tissues and has potential to increase their therapeutic effects of such drugs against various diseases.

Multitemperature Stability and Degradation Characteristics of Pergolide Mesylate Oral Liquid

The stability of pergolide mesylate in an oral aqueous liquid was studied. Stability and solubility data were used to determine the degradation characteristics of the drug in this formulation. Samples were stored in the dark at 35°C, 45°C, and 60°C. At 1, 2, 4, 8, 12, and 16 weeks, samples were removed and stored in a −80°C freezer for high performance liquid chromatography (HPLC) assay at a later date. The initial drug concentration of 0.30 mg/mL was determined by assay after storage at −80°C. A solubility of 6.9 mg/mL was found for pergolide mesylate in the oral liquid at room temperature with a relative standard deviation (RSD) of 4.0%. The degradation process is considered first-order at 25°C and 35°C. At higher temperatures (45°C and 60°C), a color change and curvature at the latter time points in degradation profiles are ascribed to the presence of methylcellulose. The activation energy calculated for degradation of pergolide mesylate in the oral liquid was 21.3 kcal/mol. The time to reach 90% potency (t90) values were calculated to be 43 days and 3 days, respectively, for storage at 25°C and 35°C. Drug concentrations up to ~6 mg/mL can be maintained as a solution at room temperature with this formulation.

Field study into the efficacy of a medicinal plant based complex for management of Equine Cushings Syndrome in ageing horses

Pituitary Pars Intermedia Dysfunction (PPID), known as Equine Cushings Syndrome, is characterized by elevated plasma glucocorticoid concentration due to adenoma or hyperplasia of the pars intermedia of the pituitary gland. Clinical signs include hirsutism, hyperhidrosis, muscle atrophy, chronic infections, polyuria, polydipsia and laminitis [1]. The dopamine agonist pergolide mesylate is the conventional therapy of choice. Compliance is poor due to expense, poor prognosis and adverse events [2].