Narciclasine as well as other Amaryllidaceae isocarbostyrils are promising GTP-ase targeting agents against brain cancers.

The anticancer activity of Amaryllidaceae isocarbostyrils is well documented. At pharmacological concentrations, that is, approximately 1 µM in vitro and approximately 10 mg/kg in vivo, narciclasine displays marked proapoptotic and cytotoxic activity, as does pancratistatin, and significant in vivo anticancer effects in various experimental models, but it is also associated with severe toxic side effects. At physiological doses, that is, approximately 50 nM in vitro and approximately 1 mg/kg in vivo, narciclasine is not cytotoxic but cytostatic and displays marked anticancer activity in vivo in experimental models of brain cancer (including gliomas and brain metastases), but it is not associated with toxic side effects. The cytostatic activity of narciclasine involves the impairment of actin cytoskeleton organization by targeting GTPases, including RhoA and the elongation factor eEF1A. We have demonstrated that chronic treatments of narciclasine (1 mg/kg) significantly increased the survival of immunodeficient mice orthotopically xenografted with highly invasive human glioblastomas and apoptosis-resistant brain metastases, including melanoma- and non-small-cell-lung cancer- (NSCLC) related brain metastases. Thus, narciclasine is a potentially promising agent for the treatment of primary brain cancers and various brain metastases. To date, efforts to develop synthetic analogs with anticancer properties superior to those of narciclasine have failed; thus, research efforts are now focused on narciclasine prodrugs.

Safety and efficacy of three trypanocides in confirmed field cases of trypanosomiasis in working equines in The Gambia: a prospective, randomised, non-inferiority trial.

BACKGROUND: Globally, working equines have a continued and growing socioeconomic role in supporting the livelihoods of between 300-600 million people in low income countries which is rarely recognised at a national or international level. Infectious diseases have significant impact on welfare and productivity in this population and equine trypanosomiasis is a priority disease due to its severity and prevalence. Strategies are required to improve the prevention, diagnosis, management and treatment of trypanosomiasis in equines and more data are required on the efficacy and safety of current trypanocidal drugs. METHODS: A prospective randomised, open-label non-inferiority trial was performed in The Gambia on horses and donkeys that fulfilled 2/5 clinical inclusion criteria (anaemia, poor body condition, pyrexia, history of abortion, oedema). Following randomised trypanocidal treatment (diminazene diaceturate, melarsomine dihydrochloride or isometamidium chloride), animals were observed for immediate adverse drug reactions and follow-up assessment was performed at 1 and 2 weeks. Blood samples underwent PCR analysis with specific Trypanosoma sp. primers. Treatment efficacy was assessed by measuring changes in clinical parameters, clinicopathological results and PCR-status post-treatment after evaluating for bias. Using PCR status as the outcome variable, non-inferiority of isometamidium treatment was determined if the upper bound limit of a 2-sided 95% CI was less than 10%. RESULTS: There was a significant beneficial effect upon the Trypanosoma sp. PCR positive population following trypanocidal treatment for all groups. The findings of clinical evaluation and PCR status supported a superior treatment effect for isometamidium. Melarsomine dihydrochloride efficacy was inferior to isometamidium. There were immediate, self-limiting side effects to isometamidium in donkeys (26%). Diminazene had the longest duration of action as judged by PCR status. CONCLUSIONS: The data support the continued use of isometamidium following careful dose titration in donkeys and diminazene for trypanosomiasis in equines using the doses and routes of administration reported.

A single 20 mg dose of dihydrexidine (DAR-0100), a full dopamine D1 agonist, is safe and tolerated in patients with schizophrenia.

The potential of dopamine D(1) receptor agonists to have beneficial effects on cognitive function has been suggested by a body of preclinical evidence. We now report the use of dihydrexidine (DAR-0100), the first full D(1) agonist, in a pilot study assessing single low dose safety and tolerability in patients with schizophrenia. A within-subject cross-over design was used in 20 adults (18-65 years) with SCID-IV diagnosed schizophrenia. Subjects were outpatients with a moderate level of residual negative symptoms, and were on stable dosing of non-D(1)-blocking antipsychotic drugs. Following screening, subjects were hospitalized for 48 h, and at 0800 h each morning scanned on a 3 T MRI scanner for resting brain perfusion, followed by a Blood Oxygen Level Dependent (BOLD) fMRI scan during an N-Back working memory task. They then received 20 mg subcutaneously (SC) of dihydrexidine or placebo over 15 min, followed by 45 min of intermittent MRI scans of perfusion and BOLD activity during the working memory task. Blood was drawn for serum drug levels and subjects were evaluated for clinical and cognitive changes. The procedure was repeated using the opposite challenge 2 days later. Dihydrexidine was well tolerated with no serious adverse events although three subjects had mild dizziness and five subjects experienced nausea. There was no significant effect of drug on clinical interview ratings or delayed (afternoon) neuropsychological performance. No medication interactions were seen. Thus, a single subcutaneous dose of dihydrexidine is tolerated and safe in patients with schizophrenia and does not produce delayed clinical or neuropsychological improvements.

Antioxidant Effect of Ukrain Versus N-Acetylcysteine Against Acute Biliary Pancreatitis in An Experimental Rat Model.

Purpose/Aim: Oxidative stress plays an important role in the pathogenesis of acute pancreatitis (AP). We compared the therapeutic effects of Ukrain (NSC 631570) and N-acetylcysteine (NAC) in rats with AP. MATERIALS AND METHODS: Forty male Sprague Dawley rats were divided into four groups: controls; AP; AP with NAC; and AP with Ukrain. AP was induced via the ligation of the bile-pancreatic duct; drugs were administered intraperitoneally (i.p.) 30 min and 12 h after AP induction. Twenty-four hours after AP induction, animals were sacrificed and the pancreas was excised. Levels of malondialdehyde (MDA) and nitric oxide (NO), and activity levels of tumor necrosis factor (TNF)-α, and myeloperoxidase (MPO) were measured in tissue samples. Total oxidant status (TOS), total antioxidant status (TAS), and total bilirubin, as well as activity levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), amylase and lipase were measured in serum samples. Pancreatic tissue histopathology was also evaluated. RESULTS: Test drugs reduced levels of MDA, NO, TNF-α, total bilirubin, AST, ALT, TOS and MPO, amylase and lipase activities (P < 0.001), and increased TAS (P < 0.001). Rats treated with test drugs attenuated AP-induced morphologic changes and decreased pancreatic damage scores compared with the AP group (P < 0.05). Both test drugs attenuated pancreatic damage, but the therapeutic effect was more pronounced in rats that received Ukrain than in those receiving NAC. CONCLUSIONS: These results suggest that treatment with Ukrain or NAC can reduce pancreatic damage via anti-inflammatory and antioxidant effects.

Effects of the D1 dopamine receptor agonist dihydrexidine (DAR-0100A) on working memory in schizotypal personality disorder.

Pharmacological enhancement of prefrontal D1 dopamine receptor function remains a promising therapeutic approach to ameliorate schizophrenia-spectrum working memory deficits, but has yet to be rigorously evaluated clinically. This proof-of-principle study sought to determine whether the active enantiomer of the selective and full D1 receptor agonist dihydrexidine (DAR-0100A) could attenuate working memory impairments in unmedicated patients with schizotypal personality disorder (SPD). We performed a randomized, double-blind, placebo-controlled trial of DAR-0100A (15 mg/150 ml of normal saline administered intravenously over 30 min) in medication-free patients with SPD (n=16) who met the criteria for cognitive impairment (ie, scoring below the 25th percentile on tests of working memory). We employed two measures of verbal working memory that are salient to schizophrenia-spectrum cognitive deficits, and that clinical data implicate as being associated with prefrontal D1 availability: (1) the Paced Auditory Serial Addition Test (PASAT); and (2) the N-back test (ratio of 2-back:0-back scores). Study procedures occurred over four consecutive days, with working memory testing on Days 1 and 4, and DAR-0100A/placebo administration on Days 2-4. Treatment with DAR-0100A was associated with significantly improved PASAT performance relative to placebo, with a very large effect size (Cohen's d=1.14). Performance on the N-back ratio was also significantly improved; however, this effect rested on both a non-significant enhancement and diminution of 2-back and 0-back performance, respectively; therefore interpretation of this finding is more complicated. DAR-0100A was generally well tolerated, with no serious medical or psychiatric adverse events; common side effects were mild to moderate and transient, consisting mainly of sedation, lightheadedness, tachycardia, and hypotension; however, we were able to minimize these effects, without altering the dose, with supportive measures, eg, co-administered normal saline. Although preliminary, these findings lend further clinical support to the potential of D1 receptor agonists to treat schizophrenia-spectrum working memory impairments. These data suggest a need for further studies with larger group sizes, serum DAR-0100A levels, and a more comprehensive neuropsychological battery.

A double-blind, placebo-controlled, dose-ranging study to investigate the safety and efficacy of CY 208-243 in patients with Parkinson's disease.

We carried out a double-blind rising dose study of a D-1 dopamine agonist, CY 208-243, in 6 parkinsonian patients. Deficits monitored by Columbia scores were significantly improved at single doses ranging from 5 to 40 mg, though efficacy was low. Used alone, CY 208-243 was not a satisfactory therapeutic agent, and toxicity data precluded further increases in dosage.

Oral levonantradol in the treatment of chemotherapy-induced emesis: preliminary observations.

Levonantradol, a new synthetic cannabinoid, was examined for antiemetic effectiveness in 27 patients with refractory chemotherapy-induced emesis. Thirty-one courses of levonantradol were administered orally beginning 2 hours before chemotherapy and continuing every 4 hours for a minimum of 12 to 24 hours at one of three different dose levels. At the 0.5-mg dose, 14 patients were evaluable with seven partial response (50 per cent) and one complete response (7 per cent). At the 1.0-mg dose, 11 patients were evaluable with five partial responses (45 per cent) and three complete responses (27 per cent). Only one patient has thus far been treated at the 1.5-mg dose with no response noted. Side effects observed included somnolence (90 per cent), dry mouth (83 per cent), dizziness (67 per cent), decreased concentration (40 per cent), dysphoria (33 per cent), and altered perception (30 per cent). Euphoria ("high") was infrequent (9 per cent). No relationship between dose (0.5 and 1.0 mg) and side effects was observed. There was a suggestion of improved antiemetic efficacy at the 1.0-mg dose. Although this study is preliminary, it appears that levonantradol is a relatively well-tolerated oral antiemetic that deserves further evaluation.

Clinical experience with levonantradol hydrochloride in the prevention of cancer chemotherapy-induced nausea and vomiting.

Reports suggesting that delta 9-tetrahydrocannabinol (THC) had a potent antiemetic effect in patients treated with cancer chemotherapeutic agents led to the synthesis of other cannabinol derivatives with possibly less side effects. We report here our initial observations with the antiemetic levonantradol in 12 patients with advanced solid tumors receiving cytotoxic polychemotherapy. All patients had a history of vomiting and nausea without successful treatment with standard antiemetic drugs in previous, identical chemotherapy cycles. No other antiemetic or psychoactive drugs were given. Patients received 1 mg levonantradol i.m. 2 hours before as well as 2 and 6 hours after cytotoxic treatment. When compared to the last course of chemotherapy with alternate antiemetic drugs, we found that 11/12 patients had less nausea and vomiting when treated with levonantradol. 8/12 Patients considered the antiemetic treatment with levonantradol better than the one given before. The following side effects were observed: 4 patients complained of pain and local irritation after injection. 2 patients showed a fall in blood pressure, especially orthostatic hypotension. 8 patients complained of sedation and drowsiness. 7 patients experienced psychic side effects, such as decrease of vigilance and reaction, altered sense of timing, body image distortions and even depersonalization. Levonantradol is a potent antiemetic drug but its applicability, especially in outpatients, may be complicated by a high incidence of side effects.

Antiemetic effect of intramuscular levonantradol in patients receiving anticancer chemotherapy.

Positive results of investigations of the antiemetic activity of delta-9-tetrahydrocannabinol (THC) in patients receiving cancer chemotherapy have led to the development of levonantradol, a synthetic derivative of THC. We assessed both the antiemetic activity and toxicity of intramuscular levonantradol in patients receiving cancer chemotherapy who were refractory to conventional antiemetic therapy. An open dose-finding study was conducted using initial doses of 0.5 mg. Doses were escalated by 0.5 mg when an incomplete response with no toxicity was observed. Of the 28 patients initially treated, 25/28 (89 per cent) achieved a complete or partial antiemetic response at doses ranging from 0.5 to 1.5 mg. There was no difference in response rate with respect to age or patient size. Of the 31 patients evaluable for toxicity, six reported none. Dysphoria, the dose-limiting toxicity, occurred in five patients (16 per cent) at 1.0 to 1.5-mg doses. The most commonly reported side effects were somnolence (48 per cent) and dry mouth (32 per cent). We conclude that intramuscular levonantradol is an effective antiemetic at doses as low as 0.5 mg.

Dose ranging evaluation of the antiemetic efficacy and toxicity of intramuscular levonantradol in cancer subjects with chemotherapy-induced emesis.

A phase II double-blind placebo-controlled, randomized dose-ranging trial was undertaken to determine the antiemetic efficacy and toxicity of the synthetic cannabinoid levonantradol at doses of 0.5, 1.0, 1.5, and 2.0 mg. Intramuscular levonantradol was prophylactically administered in random dosing to 20 subjects with a documented history of refractory emesis due to chemotherapy in advanced cancer. The selected dose was administered prior to the chemotherapy and was serially repeated over 12 hours, and efficacy and toxicity data were evaluated for 24 hours. Significant (P less than 0.01) antiemetic activity over placebo was observed with all doses of levonantradol administered, and a dose-effect response was not observed. Doses up to 2.0 mg were well tolerated, and observed toxicity increased with increased doses and with repeated dosing. Psychomimetic effects were mild and tolerable, and the limiting side effects were somnolence and hypotension.

Levonantradol for chemotherapy-induced emesis: phase I-II oral administration.

Thirty five patients were enrolled into a Phase I-II study of oral levonantradol being tested as an antiemetic for chemotherapy patients who were refractory to the aggressive use of standard antiemetic agents. Sixty-nine total courses were given. Dysphoric reactions (fear, anxiety, hallucinations) were the most serious side effects, and were most prevalent at the highest dose tested (2.0 mg q4h). Somnolence, a "high" feeling, hypotension were also noted. Antiemetic responses were seen at 0.5, 1.0, 1.5 and 2.0 mg dose levels: the two intermediate doses gave responses comparable to those previously reported for oral THC. It is suggested that a combination of oral and parenteral levonantradol may prove to be a very effective program to relieve the otherwise disabling problems of persistent nausea and vomiting.

Evaluation of intramuscular levonantradol and placebo in acute postoperative pain.

Double-blind administration of a single intramuscular dose of 1.5, 2.0, 2.5, or 3.0 mg levonantradol or placebo to 56 patients with moderate to severe postoperative or trauma pain showed significant analgesic effects of each dose of levonantradol as compared to placebo (P less than 0.05). However, no significant dose response was observed. Compared to 2/16 patients on placebo, 23/40 patients (57 per cent) on levonantradol reported one or more side effect. Drowsiness was most frequent. Dry mouth, dizziness, "weird dreams," mild hallucinations, nervousness, apprehension and confusion occurred less frequently. Changes in resting heart rate and blood pressure were minor and general acceptability was good.

Double-blind multiple-dose crossover study of the antiemetic effect of intramuscular levonantradol compared to prochlorperazine.

Twenty cancer patients who received chemotherapy were entered into a double-blind crossover design antiemetic study comparing 1 mg levonantradol, an investigational synthetic cannabinoid, to 10 mg prochlorperazine. Sixteen patients completed the crossover. For each antiemetic course, four doses of each study medication were given intramuscularly 2 hours before chemotherapy and then 2, 6, and 10 hours after chemotherapy administration. There were no statistical differences in patients' responses to levonantradol and prochlorperazine. The frequency of side effects was greater with levonantradol than with prochlorperazine. The most common side effect of levonantradol were somnolence, dry mouth, dizziness, tachycardia, postural hypotension, and blurred vision, while those for prochlorperazine were somnolence, dry mouth, and tachycardia.

Levonantradol, a new antiemetic with a high rate of side-effects for the prevention of nausea and vomiting in patients receiving cancer chemotherapy.

Levonantradol, a new antiemetic compound pharmacologically related to the cannabinoids, was given to 17 patients who had experienced severe and protracted nausea and vomiting during previous courses of cancer chemotherapy, and to six patients receiving a first course of strongly emetic cytostatic treatment. Eight patients were partially protected from acute gastrointestinal disturbances. Of the 23 patients, 21 exhibited some toxicity, with six patients exhibiting major affective side-effects and 13 patients complaining of pain at the injection site. Levonantradol is an active antiemetic compound. Due to the rate of side-effects observed in our study however, we would not recommend use of this agent as an antiemetic drug.

Therapeutic and prophylactic activity of isometamidium chloride against a tsetse-transmitted drug-resistant clone of Trypanosoma congolense in Boran cattle.

An investigation was conducted on the therapeutic and prophylactic activity of isometamidium chloride (SamorinR) in Boran (Bos indicus) cattle against a Trypanosoma congolense clone, IL 3270. This clone was derived, without drug selection, from a stock originally isolated in Burkina Faso and has previously been shown to be resistant to isometamidium in both cattle and mice using an infection and treatment regimen. A group of 5 cattle were treated intramuscularly with 1.0 mg kg-1 isometamidium chloride and 28 days later challenged with Glossina morsitans centralis infected with T. congolense IL 3270. All 5 cattle and 17 untreated cattle challenged on the same day became parasitaemic by day 16 post challenge, indicating that prophylaxis did not extend to 28 days post treatment. The cattle were then treated with isometamidium chloride at one of the following doses and by different routes of administration; 1.0 or 2.0 mg kg-1 intramuscularly, 0.25, 0.5, 0.75 or 1.0 mg kg-1 intravenously. Infections relapsed in all cattle at an interval of 12-21 days following treatment, with the exception of those treated with 2.0 mg kg-1 intramuscularly in which the development of relapse infections was delayed. Similar studies were also conducted with a highly sensitive clone of T. congolense, IL 1180. Infections in cattle with this clone were eliminated by intravenous treatment with 0.25 mg kg-1 isometamidium chloride or intramuscular treatment with 0.5 mg kg-1 isometamidium chloride. Thus, although intravenous administration of isometamidium eliminated a fully sensitive infection, treatment by this route appeared not to enhance the therapeutic efficacy of the drug in the treatment of a T. congolense clone which expresses a high level of resistance.

Effects of the full dopamine D1 receptor agonist dihydrexidine in Parkinson's disease.

The contribution of dopamine D1 receptor stimulation to the motor effects of dopaminergic drugs in patients with Parkinson's disease remains undetermined. The authors of this article studied the clinical efficacy, pharmacokinetics, and tolerability of the full D1 receptor agonist dihydrexidine, (+/-)-trans-10,11-dihydroxy-5,6,6a,7,8,12b-hexahydrobenzo[a] phenanthridine hydrochloride in a double-blind, placebo-controlled trial in four patients with Parkinson's disease. Single intravenous doses were carefully titrated according to a fixed schedule ranging from 2 mg to the highest tolerated dose (or a maximum of 70 mg) infused over either 15 or 120 minutes. The only patient to achieve a plasma drug concentration greater than 100 ng/ml had a brief but definite motor improvement accompanied by choreic dyskinesias similar to the response to levodopa. Dose-limiting adverse effects, including flushing, hypotension, and tachycardia, were observed in all cases, especially with rapid infusions. No nausea or emesis occurred. Pharmacokinetic studies yielded a plasma half-life < 5 minutes. These preliminary data suggest that dihydrexidine has a marginal therapeutic window for providing an antiparkinsonian effect, although it remains uncertain how much of this effect is attributable to pure D1 receptor stimulation.

Phase 1 trial of levonantradol in chemotherapy-induced emesis.

Levonantradol is a synthetic cannabinoid with demonstrated preclinical antiemetic activity. The current phase I trial was undertaken to determine: 1) the maximally tolerated dose; 2) the side effects at the different dosage levels; and 3) to evaluate the antiemetic efficacy of levonantradol in patients receiving emesis-producing chemotherapy. Thirty-four patients received 52 courses of levonantradol. Concurrent chemotherapy most frequently consisted of high dose cisplatin (120 mg/m2), either alone or in combination with other agents. Levonantradol dosage was escalated through seven treatment levels (0.5-4.0 mg per dose) and was given intramuscularly every 4 hours. Toxicity was similar to that observed with other cannabinoids and primarily consisted of dizziness (65%), burning and erythema at the injection site (48%), mild sedation (44%), orthostatic hypotension (37%), dysphoria (29%), and urinary retention (10%). Marked urinary retention occurred in three of seven patients at the 4.0 mg per dose level, and two of 24 patients at either the 2.5 mg and 3.0 mg levels. Major or minor antiemetic responses (0-2 or 3-5 emetic episodes, respectively) occurred in 23% of patients receiving cisplatin and in 53% of patients receiving non-cisplatin containing chemotherapy. Intramuscular levonantradol can be given safely at doses up to 3.0 mg/kg, with toxicity and antiemetic efficacy similar to that observed with other cannabinoids.

Isometamidium in pigs: disposition kinetics, tissue residues and adverse reactions.

The disposition and adverse effects of the anti-trypanosomal drug isometamidium in pigs were evaluated. Following intramuscular administration of the drug at doses of 0.5, 15 and 35 mg kg-1, the drug was rapidly absorbed within 15 to 30 minutes to reach maximum plasma concentrations of 12 to 477 (n = 6), 302 to 655 (n = 4) and 1620 (n = 1) ng ml-1, respectively. No drug was detectable in plasma (less than 5 ng ml-1) 24 hours after drug administration at the three doses used. The half-lives of disappearance of the drug from plasma during the terminal phase were 7.12 h for the pigs given a dose of 15 mg kg-1, and 7.20 h for the pig which received a dose of 35 mg kg-1. At all the intramuscular injection sites, high drug concentrations were found six weeks after administration. The most dramatic adverse reactions observed were: one death after intramuscular administration at a dose of 35 mg kg-1 to two animals, and two deaths after intravenous administration at a dose of 2 mg kg-1 to two animals. For all these cases, the immediate cause of death was acute cardiovascular collapse. Biochemical analyses and gross and histological examinations showed that the animals that tolerated the high doses of 15 and 35 mg kg-1 given intramuscularly had extensive and severe tissue damage at the injection sites. Significant increases in plasma gamma-glutamyltransferase and alanine aminotransferase following drug administration suggested a degree of hepatobiliary damage.