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.

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.

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.

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.

D(1) dopamine receptor agonists are more effective in alleviating advanced than mild parkinsonism in 1-methyl-4-phenyl-1,2,3, 6-tetrahydropyridine-treated monkeys.

Selective D(1) dopamine receptor agonists exert antiparkinsonian effects in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) monkey model of Parkinson's disease and in human Parkinson's disease. Motor impairment in idiopathic Parkinson's disease progresses from mild to severe, but the therapeutic potential of D(1) dopamine receptor agonists in early and advanced stages of parkinsonism is not known. To compare the effectiveness of D(1) agonists at different levels of impairment, we developed a model of mild and advanced parkinsonism in nonhuman primates and a rating scale that differentiated the two models. D(1) dopamine receptor agonists (SKF 81297, dihydrexidine) and D(2) dopamine receptor agonists [quinelorane, (+)-PHNO were administered to monkeys (Macaca fascicularis) displaying either mild parkinsonism (two doses of 0.6 mg/kg i.v. MPTP 1 month apart) or advanced parkinsonism (three doses of 0.6 mg/kg i.v. MPTP within 10 days). In normal monkeys (n = 3), SKF 81297 and dihydrexidine did not promote increased motor activity. In advanced parkinsonism (n = 4), D(1) and D(2) dopamine agonists effectively reversed the motor deficits. In contrast, the therapeutic benefits of D(1) agonists SKF 81297 and dihydrexidine were relatively limited in mild parkinsonism (n = 4). The D(2) agonists quinelorane and (+)-PHNO alleviated some symptoms in mild parkinsonism but also reduced balance and induced more dyskinesias than did D(1) agonists. Mild and advanced parkinsonism in nonhuman primates can be produced with fixed dosing regimens of MPTP. Based on the therapeutic efficacy and side effect profiles derived from these models, D(1) agonists are more promising for the treatment of advanced than of mild Parkinson's disease.

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.

Benzo[c]phenanthridine alkaloids sanguinarine and chelerythrine: biological activities and dental care applications.

This article reviews chemical, pharmacological, and toxicological research relating to two principal benzo[c]phenanthridine alkaloids, namely sanguinarine and chelerythrine, in the period 1980-1994. The medical applications of these alkaloids in relation to their biological activities are discussed.

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.

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.

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.

Notes on the routine intravenous use of isometamidium in the control of bovine trypanosomiasis on the Kenya coast.

Various chemotherapeutic regimes were used to control trypanosomiasis in 3,000 Boran cattle on an estate on the Kenya coast. Recently the therapeutic use of isometamidium by the intravenous route was adopted to treat individual trypanosome-infected cattle. This was in order to overcome tissue reactions encountered after intramuscular injection and also to control a "thin cow" syndrome attributed to chronic trypanosomiasis. Toxic side effects were eliminated by careful attention to the intravenous technique which was safely used in calves, pregnant cattle and bulls. Weekly blood sampling and treatments of infected individuals resulted in a reduction of cases from 2,187 to 208 out of 46,495 and 46,329 samples examined in 1985 and 1986 respectively. The standard of management was very high and although this routine successfully controlled bovine trypanosomiasis on this estate its application elsewhere is likely to be limited.

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.

Antiemetic efficacy of levonantradol compared to delta-9-tetrahydrocannabinol for chemotherapy-induced nausea and vomiting.

The antiemetic efficacy of im levonantradol, a synthetic cannabinoid, given at a dose of 1 mg every 4 hours, was compared to oral delta-9-tetrahydrocannabinol (THC) given at a dose of 15 mg every 4 hours in a double-blind crossover study. Twenty-six patients receiving emetogenic cancer chemotherapy were evaluated. For each drug, 28% of treated patients had no nausea. The median number of emetic episodes with levonantradol was 2.0 versus 3.0 for THC (P = 0.06). Side effects occurred in 91.7% and 97.3% of levonantradol and THC patients, respectively, with drowsiness and dizziness most commonly seen. Side effects were generally well-tolerated, with only 13.9% of levonantradol and 21.6% of THC patients discontinuing treatment because of side effects. Levonantradol appears to be at least as effective an antiemetic as THC and is the only cannabinoid available for parenteral use.

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.

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.

A randomised multicentre single blind comparison of a cannabinoid anti-emetic (levonantradol) with chlorpromazine in patients receiving their first cytotoxic chemotherapy.

One hundred and eight patients selected to receive combinations of highly emetic cytotoxic chemotherapy for malignant disease were included in a study of anti-emetic therapy. The patients were randomly allocated to receive levonantradol (0.5, 0.75 or 1 mg) or chlorpromazine (25 mg) prior to receiving their first course of cytotoxic therapy. The appropriate anti-emetic was administered 2 hr prior to the start of chemotherapy, 2 hr after chemotherapy and subsequently at 4-hourly intervals for a further 8 hr. The extent of anorexia, nausea and vomiting along with other side-effects were assessed at regular intervals by physicians and nursing staff during the 24 hr following chemotherapy. In addition, a self-assessment questionnaire was completed by the patients. Levonantradol (0.5 mg) was superior to chlorpromazine (25 mg) as an anti-emetic. Both were reasonably well tolerated, although at this dose of levonantradol 22% of patients experienced dysphoric reactions. At higher doses of levonantradol the proportion of patients experiencing these reactions rose to 50%, but without a concomitant increase in antiemetic activity. Neither drug achieved satisfactory control of vomiting in patients receiving combinations containing cis-platinum. We conclude that levonantradol (0.5 mg) is a more effective anti-emetic than chlorpromazine (25 mg) in patients receiving cytotoxic chemotherapy. However, its use cannot be recommended due to its high incidence of unacceptable central nervous system side-effects.

Levonantradol for the treatment of chemotherapy-induced nausea and vomiting.

Twenty patients with cancer previously unresponsive to antiemetic treatment of chemotherapy-induced nausea and vomiting were treated with the new tetrahydrocannabinoid Levonantradol. 15 patients experienced substantial relief and 10 of them preferred the drug for further courses. These observations suggest that Levonantradol can be beneficial to patients refractory to conventional antiemetic therapy.