Alternative Oral Agents in Prophylaxis and Therapy of Uterine Fibroids-An Up-to-Date Review.

Uterine fibroids (UFs) are the most common tumors of the female genital tract. The effect of UFs on the quality of life and the overall cost of treatment are significant issues worldwide. Tumor size and location are the two specific factors which influence the occurrence of symptoms, the need for, and method of, treatment (some tumors require surgery while some can be treated with selected drugs). Primary prevention and treatment of early UF disease are worthy goals that might have a great impact on health care systems. Several treatments and prophylactic methods can be used in this endeavor. This publication presents current data about lesser-known substances which may have a beneficial effect on the treatment or prophylaxis of UFs and can be administered orally, serving as an alternative to (or complement of) surgery or selective progesterone receptor modulators (SPRMs). Early prevention and treatment of UFs in women from high-risk groups should be our priority. Innovative forms of UF management are under intensive investigation and may be promising options in the near future. Many of them evaluated vitamin D, paricalcitol, epigallocatechin gallate (EGCG), elagolix, aromatase inhibitors (AIs), and cabergoline and deemed them to be safe and effective. The next step in such projects should be properly constructed randomized control trials (RCTs), carried out by successive phases.

Role of herbal bioactives as a potential bioavailability enhancer for Active Pharmaceutical Ingredients.

The current review emphasizes on the herbal bioenhancers which themselves do not possess inherent pharmacological activity of their own but when co-administered with Active Pharmaceutical Ingredients (API), enhances their bioavailability and efficacy. Herbal bioenhancers play a crucial role in enhancing the bioavailability and bioefficacy of different classes of drugs, such as antihypertensives, anticancer, antiviral, antitubercular and antifungal drugs at low doses. This paper highlights various natural compounds that can be utilized as an efficient bioenhancer. Several herbal compounds including piperine, quercetin, genistein, naringin, sinomenine, curcumin, and glycyrrhizin have demonstrated capability to improve the pharmacokinetic parameters of several potent API. This article also focuses on various United States patents on herbal bioenhancers, which has proved to be beneficial in improving oral absorption of nutraceuticals like vitamins, minerals, amino acids and certain herbal compounds. The present paper also describes proposed mechanism of action, which mainly includes absorption process, drug metabolism, and action on drug target. The herbal bioenhancers are easily available, safe, free from side effects, minimizes drug toxicity, shortens the duration of treatment, lowers the drug resistance problems and minimizes the cost of treatment. Inspite of the fact that herbal bioenhancers provide an innovative concept for enhancing the bioavailability of several potent drugs, there are numerous bioenhancers of herbal origin that are yet to be explored in several vital areas. These bioenhancers must also be implied to enhance the bioavailability and bioefficacy through routes other than the oral route of drug delivery. There is a vast array of unexploited plants which can be investigated for their drug bioenhancing potency. The toxicity profiles of these herbal bioenhancers must not be overlooked. Researches must be carried out to solve these issues and to deliver a safe and effective dose of drugs to attain desired pharmacological response.

Comparison of bevacizumab and cabergoline in the treatment of ovarian hyperstimulation syndrome in a rat model.

The aim of this study is to investigate the effects of bevacizumab in a rat model of ovarian hyperstimulation syndrome (OHSS) and compare with cabergoline. The study was performed with 24 rats in four main groups (one non-stimulated control and three OHSS treatment groups; bevacizumab, cabergoline and placebo). The rats were randomly assigned to four experimental groups (six rats per group). Efficacy of treatment was assessed on 29th day by measuring weight gain, number of eggs, presence of ascites and ovarian weight. Peritoneal fluid levels of vascular endothelial growth factor (VEGF) were measured using an enzyme-linked immunosorbent assay. Ovarian weights were significantly higher in the OHSS groups than the control group. Ovarian weights in OHSS placebo group were found to be higher than those in OHSS-treatment groups (p = 0.002). VEGF levels were found increased in the OHSS-placebo group compared with the control group (p < 0.05). This increase was not seen in the OHSS groups treated with either bevacizumab or cabergoline. We demonstrate in this study that bevacizumab can lower VEGF production and ovarian weight in rats treated with gonadotropins.

New prospects for drug treatment in Cushing disease.

Hypercortisolism induced by Cushing disease causes high morbidity and mortality. The treatment of choice is pituitary surgery, but it often fails to achieve cure, and other treatment modalities (radiotherapy, bilateral adrenalectomy) may therefore be required. If these treatments are not effective or while waiting for their results, hypercortisolism should be controlled with drugs. The classical drug treatments are those that act by inhibiting cortisol secretion by the adrenal gland (ketoconazole, metyrapone, mitotane, etomidate). The preliminary results of a new drug (LCI699) which is a potent enzyme inhibitor of cortisol secretion have been reported. A clinical trial of the safety and efficacy of mifepristone, a glucocorticoid receptor antagonist, has just been published. The drugs deserving more attention today are those with a direct action on the tumor by inhibiting ACTH secretion: somatostatin analogues (pasireotide), dopamine agonists (cabergoline), PPAR-γ, and retinoic acid. A special review is made of the available clinical trials with pasireotide and cabergoline.

The treatment of restless legs syndrome and periodic limb movement disorder in adults--an update for 2012: practice parameters with an evidence-based systematic review and meta-analyses: an American Academy of Sleep Medicine Clinical Practice Guideline.

A systematic literature review and meta-analyses (where appropriate) were performed to update the previous AASM practice parameters on the treatments, both dopaminergic and other, of RLS and PLMD. A considerable amount of literature has been published since these previous reviews were performed, necessitating an update of the corresponding practice parameters. Therapies with a STANDARD level of recommendation include pramipexole and ropinirole. Therapies with a GUIDELINE level of recommendation include levodopa with dopa decarboxylase inhibitor, opioids, gabapentin enacarbil, and cabergoline (which has additional caveats for use). Therapies with an OPTION level of recommendation include carbamazepine, gabapentin, pregabalin, clonidine, and for patients with low ferritin levels, iron supplementation. The committee recommends a STANDARD AGAINST the use of pergolide because of the risks of heart valve damage. Therapies for RLS secondary to ESRD, neuropathy, and superficial venous insufficiency are discussed. Lastly, therapies for PLMD are reviewed. However, it should be mentioned that because PLMD therapy typically mimics RLS therapy, the primary focus of this review is therapy for idiopathic RLS.

Cabergoline: Pharmacology, ocular hypotensive studies in multiple species, and aqueous humor dynamic modulation in the Cynomolgus monkey eyes.

The aims of the current studies were to determine the in vitro and in vivo ocular and non-ocular pharmacological properties of cabergoline using well documented receptor binding, cell-based functional assays, and in vivo models. Cabergoline bound to native and/or human cloned serotonin-2A/B/C (5HT(2A/B/C)), 5HT(1A), 5HT(7), alpha(2B), and dopamine-2/3 (D(2/3)) receptor subtypes with nanomolar affinity. Cabergoline was an agonist at human recombinant 5HT(2), 5HT(1A) and D(2/3) receptors but an antagonist at 5HT(7) and alpha(2) receptors. In primary human ciliary muscle (h-CM) and trabecular meshwork (h-TM) cells, cabergoline stimulated phosphoinositide (PI) hydrolysis (EC(50)=19+/-7 nM in TM; 76 nM in h-CM) and intracellular Ca(2+) ([Ca(2+)](i)) mobilization (EC(50)=570+/-83 nM in h-TM; EC(50)=900+/-320 nM in h-CM). Cabergoline-induced [Ca(2+)](i) mobilization in h-TM and h-CM cells was potently antagonized by a 5HT(2A)-selective antagonist (M-100907, K(i)=0.29-0.53 nM). Cabergoline also stimulated [Ca(2+)](i) mobilization more potently via human cloned 5HT(2A) (EC(50)=63.4+/-10.3 nM) than via 5HT(2B) and 5HT(2C) receptors. In h-CM cells, cabergoline (1 microM) stimulated production of pro-matrix metalloproteinases-1 and -3 and synergized with forskolin to enhance cAMP production. Cabergoline (1 microM) perfused through anterior segments of porcine eyes caused a significant (27%) increase in outflow facility. Topically administered cabergoline (300-500 microg) in Dutch-belted rabbit eyes yielded 4.5 microMM and 1.97 microM levels in the aqueous humor 30 min and 90 min post-dose but failed to modulate intraocular pressure (IOP). However, cabergoline was an efficacious IOP-lowering agent in normotensive Brown Norway rats (25% IOP decrease with 6 microg at 4h post-dose) and in conscious ocular hypertensive cynomolgus monkeys (peak reduction of 30.6+/-3.6% with 50 microg at 3h post-dose; 30.4+/-4.5% with 500 microg at 7h post-dose). In ketamine-sedated monkeys, IOP was significantly lowered at 2.5h after the second topical ocular dose (300 microg) of cabergoline by 23% (p<0.02) and 35% (p<0.004) in normotensive and ocular hypertensive eyes, respectively. In normotensive eyes, cabergoline increased uveoscleral outflow (0.69+/-0.7 microL/min-1.61+/-0.97 microL/min, n=13; p<0.01). However, only seven of the eleven ocular hypertensive monkeys showed significantly increased uveoscleral outflow. These data indicate that cabergoline's most prominent agonist activity involves activation of 5HT(2), 5HT(1A), and D(2/3) receptors. Since 5HT(1A) agonists, 5HT(7) antagonists, and alpha(2) antagonists do not lower IOP in conscious ocular hypertensive monkeys, the 5HT(2) and dopaminergic agonist activities of cabergoline probably mediated the IOP reduction observed with this compound in this species.

Pharmacologic prevention of aspiration pneumonia: a systematic review.

BACKGROUND: Aspiration pneumonia is a common cause of morbidity and mortality. Several approaches, including bed positioning, dietary changes, and oral hygiene, have been proposed to prevent aspiration pneumonia, yet few data are available on the efficacy of pharmacologic interventions in reducing the rate of aspiration. OBJECTIVE: This study was a systematic literature review of the pharmacologic prevention of aspiration pneumonia. METHODS: We searched MEDLINE (1996-2006); EMBASE (1974-2006); Cumulative Index to Nursing & Allied Health Literature (CINAHL) (1982-2006); Health Services Technology, Administration, and Research (HealthSTAR) (1975-2006); and the Cochrane Library for relevant articles. References of all included articles were reviewed. Studies were included if they had a prospective, controlled design with a primary outcome of prevention of aspiration pneumonia. Surrogate outcomes that had a direct link to decreasing the incidence of aspiration pneumonia were considered. Selected articles were reviewed independently by 2 authors. RESULTS: Of 1108 studies reviewed, 20 were analyzed. Angiotensin-converting enzyme inhibitors may be beneficial in selected patients at high risk for aspiration. Capsaicin may be a low-risk approach to stimulate swallowing and cough reflexes. Amantadine, cabergoline, and theophylline may cause serious adverse events, and their routine use for prevention of aspiration pneumonia is not recommended. Cilostazol should not be used because of the increased risk for bleeding. CONCLUSIONS: Limited information is available on benefits and risks to guide an evidence-based approach to the pharmacologic prevention of aspiration pneumonia. Considering the high incidence of aspiration pneumonia in older adults, large randomized clinical trials on the effectiveness of pharmacologic interventions are warranted.

Cabergoline scavenges peroxynitrite enhanced by L-DOPA therapy in patients with Parkinson's disease.

Long-term or high-dose L-DOPA therapy in patients with Parkinson's disease (PD) may accelerate degeneration of dopaminergic neurons, possibly by increasing oxidative stress. To investigate the effects of cabergoline on peroxynitrite-mediated oxidative damage caused by L-DOPA, the concentration of 3-nitrotyrosine in cerebrospinal fluid (CSF) of 18 PD patients was compared with that in 20 normal controls. The concentration of 3-nitrotyrosine in patients following L-DOPA therapy was significantly higher than in untreated PD patients and controls. On the other hand, the concentration in PD patients after cabergoline therapy was significantly lower than in PD patients after L-DOPA therapy alone. These data suggest that cabergoline scavenges peroxynitrite induced by L-DOPA in patients with PD.

Correlation between 5-HT7 receptor affinity and protection against sound-induced seizures in DBA/2J mice.

Audiogenic seizures can be induced in DBA/2J mice following intense auditory stimulation. A number of neurotransmitters, including 5-hydroxytryptamine (5-HT), are believed to be involved in mediating this effect since it has been shown previously that depletion of 5-HT or blockade of 5-HT receptors protects DBA/2J mice from these audiogenic seizures. The present study was undertaken to determine whether antagonism of the newly identified 5-HT7 receptor may protect DBA/2J mice from audiogenic seizures by attempting to correlate in vivo potency of compounds with their affinity at the 5-HT7 receptor. All compounds used in the correlation were shown to be antagonists at the 5-HT7 receptor and a statistically significant correlation was observed between 5-HT7 affinity and doses for half-maximal response (ED50) for protection of DBA/2J mice from sound-induced seizures (r = 0.80; P < 0.05). No significant correlation was observed between in vivo activity and affinity at either 5-HT1A, 5-HT2A or 5-HT2C receptors. It is also unlikely that interactions between the 5-ht5 receptor will protect DBA/2J mice from audiogenic seizures since metergoline and mesulergine which are both active in this in vivo model have no affinity for the 5-ht5 receptor. There are similarities between the pharmacology of the 5-HT7 receptor and that of the 5-HT1A receptor, however the correlation between the in vivo potency in DBA/2J mice and 5-HT1A affinity was not significant. Furthermore, the 5-HT1A receptor antagonist WAY 100135 did not protect DBA/2J mice from audiogenic seizures at doses that antagonise 5-HT1A receptor-mediated effects in mice. These data suggest that antagonism of 5-HT7 receptors may protect against audiogenic seizures in DBA/2J mice although a definitive conclusion must await studies with selective 5-HT7 antagonists.

[The interaction of dopamine and opioid receptors in the re-establishing of an amnesic and forgotten memory trace by quinpirole]. / Vzaimodeistvie dofaminovykh i opioidnykh retseptorov pri vosstanovlenii amnezirovannogo i zabytogo sleda pamiati kvinpirolom.

The present study evaluated the contribution of delta and kappa opioid receptors to the dopamine-mediated reestablishment of an amnestic and forgotten memory trace. Using passive avoidance as a memory index, the pretraining injection of leukephalin was determined to enhance the efficiency of quinpirole, a selective dopamine D-2 receptor agonist, to reactivate the memory retrieval in amnesia and forgetfulness. In contrast, pretreatment with dynorphin attenuated the retrieval by enhancing the effect of the pretesting injection of quinpirole in amnesia. Quinpirole was found to be more effective in attenuating amnesia than forgetfulness.

[Effect of quinpirole on the retrieval of a memory trace in amnesia]. / Vliianie kvinpirola na vosproizvedenie sleda pamiati pri amnezii.

In experimental studies on mice it was shown that quinpirole, a selective agonist of dopaminergic postsynaptic D-2 receptors, possessed a pronounced antiamnestic activity. Administration of quinpirole before testing on 2nd and 22nd days reactivated the retrieval of passive avoidance impaired by an amnestic agent. The drug effect depended on the duration of "psychogenic" amnesia. It is suggested that the postsynaptic dopaminergic D-2 receptors are actively involved in the neurochemical mechanisms of memory trace retrieval.

[Therapeutic trial in acute cochlear deafness. A comparative study of Ginkgo biloba extract and nicergoline]. / Essai thérapeutique dans les surdités cochléaires aiguës. Etude comparative de l'extrait de Ginkgo biloba et de la nicergoline.

Ischemia and the metabolic disorder it entails would seem to be the pathogenic mechanism behind acute cochlear deafness, irrespective of the triggering process. The prognosis is entirely dependent on the rapid initiation of an effective treatment. At the end of a double-blind therapeutic trial comparing Ginkgo biloba extract and a standard alpha blocker (nicergoline), a significant recovery was observed in both therapeutic groups, but improvement was distinctly better in the Ginkgo biloba group.

The effects of nicergoline on spontaneously hypertensive rats and their offspring.

Six consanguine monogamous SHR couples (G1) were treated from 5 weeks of age on with an alpha blocker, nicergoline, 0.1 mg/kg/day i.p.. Male rats were treated without interruption; treatment was withheld in female rats from delivery to weaning. They were compare to six similar SHR couples who were only daily i.p. injected with the same volume of solvent in the same conditions as controls, as well as with naive (untreated) rats. Second (G2) and third (G3) generation rats (untreated) were studied. In G1 rats, systolic blood pressure (SBP), heart rate, heart weight/body weight ratio and bulbar noradrenaline content were decreased (compared to control or naive rats), while plasma renin activity (PRA) and hypothalamic noradrenaline content were not changed. In G2 rats, SBP and PRA were decreased, all other parameters being unchanged. No parameter was changed in G3 rats. This appears to be the first report of a preventive effect of antenatal treatment on the development of hypertension in SHR.

Experiences with a new ergoline (CF 25-397) in parkinsonism.

Studies on rats with unilateral nigral lesions suggest that a new ergoline, CF 25-397, is a dopaminergic agonist that might improve parkinsonism. CF 25-397 induces less stereotyped behavior than other dopaminergic agents in rats, and might therefore cause less dyskinesia than levodopa in man. We investigated the clinical actions of CF 25-397 in nine patients. During treatment, severe deterioration resulted in hypokinesia and rigidity; five patients showed marked dysphagia and dysphonia. There was statistically significant deterioration in four timed tests. Mild improvement, not statistically significant, was noted in tremor. These results indicate that clinical implication of the response to potential therapeutic agents in rodent models of parkinsonism must be interpreted with caution.

Comparative effects of a series of prolactin inhibitors, 17beta-estradiol and 2alpha-methyldihydrotestosterone propionate, on growth of 7,12-dimethylbenz(a)anthracene-induced rat mammary carcinomas.

Eight ergot alkaloids and ergoline derivatives, effective prolactin inhibitors, were tested for activity against DMBA-induced rat mammary carcinomas. Compounds were administered daily, 5 times/week for 4 weeks, and rats were observed for an additional 4 weeks. Groups treated with androgen and estrogen were used as positive controls. Those ergot compounds and ergolines that proved to be highly effective in reducing tumor size or in inducing regression of tumors to nonpalpability were Deprenon (D-6-methyl-8-ergolin-I-ylacetic acid amide) and ergocryptine; effective to an intermediate degree were Dironyl [N-(D-6-methyl-8-isoergolin-I-yl)-N',N'-diethylurea], ergocornine, and Lysenyl [N-(D-6-methyl-8-isoergolenyl)-N',N'-diethyl-urea]; and effective to a minimal degree were Lergotrile (2-chloro-6-methylergoline-8beta-acetonitrile), CB-154, and 6605-VUFB (D-6-methyl-8-cyanomethylergolin-I). Remission of many individual carcinomas was brief, and duration of complete regression (all tumors in the rat were nonpalpable) was less than 10 weeks.