Janus kinase inhibitors for atopic dermatitis: a promising treatment modality.

Atopic dermatitis (AD) is chronic, pruritic, inflammatory skin disease that affects a significant portion of the population in industrialized nations. For nonresponders to conventional therapies, AD can significantly reduce sleep quality and quality of life. AD pathogenesis is multifactorial and involves multiple immune pathways, with recent evidence of T helper (Th)2, Th17 and Th22 axis attenuation in various AD endotypes and racial subtypes. Inhibition of the conserved Janus kinase (JAK) signalling pathway represents a promising therapeutic avenue to reduce the activation of multiple proinflammatory mediators involved in AD pathogenesis. JAK inhibitors exist in both oral and topical forms with variable specificity for the receptor tyrosine kinases JAK1, JAK2, JAK3 and tyrosine kinase 2. Oral formulations include abrocitinib, upadacitinib, baricitinib and gusacitinib, and are most appropriate for patients with moderate to severe AD. Emerging topical formulation in development include ruxolitinib and deglocitinib, which may be used in patients with localized AD and also adjunctively with systemic therapy in patients with more severe disease. With observed rapidity in itch relief and accompanying dramatic reduction in inflammatory lesion count, JAK inhibitors represent a promising new treatment to revolutionize the management of AD.

The oral Janus kinase/spleen tyrosine kinase inhibitor ASN002 demonstrates efficacy and improves associated systemic inflammation in patients with moderate-to-severe atopic dermatitis: results from a randomized double-blind placebo-controlled study.

BACKGROUND: ASN002 is an oral dual inhibitor of Janus kinase and spleen tyrosine kinase, which are involved in the pathogenesis of atopic dermatitis (AD) through their regulatory role on T helper (Th)1, Th2 and Th17/Th22 pathways. OBJECTIVES: The objectives of this study were to evaluate the efficacy, safety, pharmacokinetics and effects on systemic biomarkers of ASN002 in patients with moderate-to-severe AD. Methods A total of 36 patients with moderate-to-severe AD were randomized (3 : 1) to ASN002 or placebo in the phase Ib study. Three dosage cohorts were studied over a 28-day period (20 mg, 40 mg and 80 mg once daily). RESULTS: ASN002 was superior to placebo for the proportion of patients achieving Eczema Area and Severity Index (EASI) 50 (20 mg 20%, P = 0·93; 40 mg 100%, P = 0·003; 80 mg 83%, P = 0·03; placebo 22%), EASI 75 (20 mg 0%, P = 0·27; 40 mg 71%, P = 0·06; 80 mg 33%, P = 0·65; placebo 22%) and in change from baseline in pruritus (20 mg -1·3 ± 2·1, P = 0·81; 40 mg -3·1 ± 2·7, P = 0·27; 80 mg -4·7 ± 2·1, P = 0·01; placebo -1·6 ± 1·8). Adverse events were generally mild and similar across all groups. ASN002 showed dose-dependent plasma exposure with low interpatient variability, significantly downregulated several serum biomarkers involved in Th1, Th2 and Th17/Th22 immunity, and decreased the atherosclerosis-associated biomarker E selectin/SELE. CONCLUSIONS: In patients with moderate-to-severe AD, ASN002 showed strong efficacy with rapid onset of action and associated improvements in systemic inflammation.

Dioxol and dihydrodioxin analogs of 2- and 3-phenylacetonitriles as potent anti-cancer agents with nanomolar activity against a variety of human cancer cells.

A small library of (Z)-2-(benzo[d][1,3]dioxol-5-yl) and (Z)-2,3-dihydrobenzo[b][1,4]dioxin-6-yl analogs of 2- and 3-phenylacetonitriles has been synthesized and evaluated for their anti-cancer activities against a panel of 60 human cancer cell lines. The dihydrodioxin analog 3j and dioxol analogs 5e and 7e exhibited the most potent anti-cancer activity of all the analogs synthesized in this study, with GI50 values of <100 nM against almost all of the cell lines in the human cancer cell panel. Of these three, only compound 3j inhibited tubulin polymerization to any degree in vitro. The binding modes of 3j and the structurally related tubulin-inhibitor DMU-212 were determined by virtual docking studies with tubulin dimer. Compound 3j docked at the colchicine-binding site at the dimer interface of tubulin. The Full-Fitness (FF) score of 3j was observed to be substantially higher than DMU-212, which agrees well with the observed anti-cancer potency (GI50 values). The mechanism by which dioxol analogs 5e and 7e exert their cytotoxic effects remains unknown at this stage, but it is unlikely that they affect tubulin dynamics. Nevertheless, these findings suggest that both dioxol and dihydrodioxin analogs of phenylacrylonitrile may have potential for development as clinical candidates to treat a variety of human cancers.

Induction of glandular stomach cancers in Helicobacter pylori-infected Mongolian gerbils by 1-nitrosoindole-3-acetonitrile.

Helicobacter pylori (H. pylori) infection and high intake of various traditional salt-preserved foods are regarded as risk factors for human gastric cancer. We previously reported that Chinese cabbage contains indole compounds, such as indole-3-acetonitrile, a mutagen precursor. 1-Nitrosoindole-3-acetonitrile (NIAN), formed by the treatment of indole-3-acetonitrile with nitrite under acidic conditions, shows direct-acting mutagenicity. In the present study, NIAN administration by gavage to Mongolian gerbils (MGs) at the dose of 100 mg/kg two times a week resulted in three adduct spots (1.6 adducts/10(8) nucleotides in total), detected in DNA samples from the glandular stomach by (32) P-postlabeling methods. Treatment with six consecutive doses of 100 mg/kg of NIAN, two times a week for 3 weeks, induced well-and moderately-differentiated glandular stomach adenocarcinomas in the MGs at the incidence of 31% under H. pylori infection at 54-104 weeks. Such lesions were not induced in MGs given broth alone, broth + NIAN or infection with H. pylori alone. Thus, endogenous carcinogens formed from nitrosation of indole compounds could be critical risk factors for human gastric cancer development under the influence of H. pylori infection.

Metabolism and disposition of [14C]dibromoacetonitrile in rats and mice following oral and intravenous administration.

1. Tissue distribution, metabolism, and disposition of oral (0.2-20 mg/kg) and intravenous (0.2 mg/kg) doses of [2-(14)C]dibromoacetonitrile (DBAN) were investigated in male rats and mice. 2. [(14)C]DBAN reacts rapidly with rat blood in vitro and binds covalently. Prior depletion of glutathione (GSH) markedly diminished loss of DBAN. Chemical reaction with GSH readily yielded glutathionylacetonitrile. 3. About 90% of the radioactivity from orally administered doses of [(14)C]DBAN was absorbed. After intravenous administration, 10% and 20% of the radioactivity was recovered in mouse and rat tissues, respectively, at 72 h. After oral dosing, three to four times less radioactivity was recovered, but radioactivity in stomach was mostly covalently bound. 4. Excretion of radioactivity into urine exceeded that in feces; 9-15% was exhaled as labeled carbon dioxide and 1-3% as volatiles in 72 h. 5. The major urinary metabolites were identified by liquid chromatography-mass spectrometry, and included acetonitrile mercaptoacetate (mouse), acetonitrile mercapturate, and cysteinylacetonitrile. 6.The primary mode of DBAN metabolism is via reaction with GSH, and covalent binding may be due to reaction with tissue sulphydryls.

Evaluation of Clinical Cardiac Safety of Itacitinib, a JAK1 Inhibitor, in Healthy Participants.

Itacitinib is a JAK1-selective inhibitor in phase 3 development in graft-versus-host disease. A post hoc electrocardiogram (ECG) analysis and a plasma concentration-QTc (C-QTc) analysis were performed to assess cardiac safety using data from the first-in-human itacitinib study. The study included 2 cohorts of 12 healthy participants each in an interleaving dosing design with single doses of 10-300 mg or placebo; 500 and 1000 mg doses were subsequently added with 12 participants randomized to itacitinib or placebo. Continuous Holter recordings were collected from 1 hour predose to 8 hours postdose on each dosing day, and ECG intervals were blindly extracted to match timed pharmacokinetic samples. Data showed no hysteresis, and a prespecified linear mixed-effects C-QTc model was used with change-from-baseline QTcF (QT interval corrected for heart rate by Fridericia's method) as the dependent variable, plasma itacitinib concentrations and centered baseline QTcF as continuous covariates, treatment and time as categorical factors, and a random intercept per participant. The estimated slope of the C-QTc relationship was not significantly different from zero: 0.0002 milliseconds per nM (90%CI, -0.00019 to 0.00054 milliseconds). No clinically meaningful effects on cardiac conduction (PR and QRS intervals) or any categorical PR or QRS outliers were observed. A QTc effect exceeding the threshold of concern (10 milliseconds) can be excluded for itacitinib plasma concentrations up to ∼13 000 nM (∼7200 ng/mL), which is well above the maximum concentration expected with the highest proposed therapeutic dose of itacitinib either with concomitant use of cytochrome P450 3A4 inhibitors or in patients with impaired hepatic function.

Neurotoxicological evaluation of two disinfection by-products, bromodichloromethane and dibromoacetonitrile, in rats.

The Safe Drinking Water Act requires that the U.S. EPA consider noncancer endpoints for the assessment of adverse human health effects of disinfection by-products (DBPs). As an extension of our studies in which we demonstrated neurotoxicity at relatively low levels of dibromo- and dichloroacetic acids, we examined the potential neurotoxicity of other classes of DBPs. Bromodichloromethane (BDCM) and dibromoacetonitrile (DBAN) were administered to male and female F-344 rats via drinking water for 6 months. During exposure, rats were tested for neurobehavioral effects using a functional observational battery and motor activity, followed by perfusion fixation for neuropathological evaluation at the end of exposure. Calculating for chemical loss, fluid consumption, and body weight, average intakes were approximately: 9, 27, and 72mg/(kgday) BDCM, and 5, 12, and 29mg/(kgday) DBAN. Fluid consumption was decreased in most treatment groups, but body weight gain was altered only at the high concentrations. There were few neurobehavioral changes, and these were not considered toxicologically relevant. Of the general observations, there was only minimally decreased body tone in DBAN-treated high-dose males. Treatment-related neuropathological findings were not observed. Lowered fluid consumption was the most sensitive and consistent endpoint in the present studies. Thus, unlike the haloacetic acids, neurotoxicity may not be a concern for toxicity of halomethanes or haloacetonitriles.

Tolerance to dichloroacetonitrile-induced neurotoxicity in streptozotocin-induced diabetic rats.

Diabetes mellitus has potential to alter the toxicity of hazardous chemicals. Dichloroacetonitrile (DCAN) is one of high-risk nitrogenous disinfection by-products. This study evaluated the neurotoxicity of DCAN (11, 44 and 88mg/kg) in normoglycaemic and streptozotocin (STZ)-induced diabetic rats via orally for 28days. STZ diabetes prolonged the median survival time and total lethal time after DCAN (88mg/kg) exposure when compared with that observed in normoglycaemic rats. DCAN altered motor activity and induced anxiety behaviour in normoglycaemic rats; but it did not exaggerate behavioural changes in STZ diabetic rats. DCAN -induced brain oxidative damage by compensatory increase glutathione content and decrease malonaldehyde levels; but it did not induce oxidative damage in diabetic rats. STZ diabetes slowed down the pathological pace of DCAN-induced brain mitochondrial dysfunction by decreasing reactive oxygen species and increasing cytochrome C oxidase activity. In conclusion, the present study indicated that STZ diabetic rats are resistant to DCAN-induced neurotoxicity at the dosage and with the dosage schedule in 28-day subacute toxicity test.

Macromolecular adduction by trichloroacetonitrile in the Fischer 344 rat following oral gavage.

Male Fisher 344 rats were administered 1- or 2-[14C]trichloroacetonitrile (TCAN) by oral gavage. DNA was isolated from the liver, kidneys and stomach and several protein fractions (globin, albumin and globulins) were isolated from blood. TCAN binds to both the DNA and the blood proteins in a dose-related manner. More radiolabel was associated with the DNA when the carbon at C2 position was labeled, than at C1 position. However, the position of the radiolabel did not influence the levels of radioactivity associated with the blood proteins. The stomach exhibited the highest level of DNA binding, followed in order by the liver and kidney. TCAN binding level was higher in DNA isolated from rats killed at 24 h than at 4 h after administration. In contrast, the three blood proteins showed similar binding levels, regardless of the exposure time. Radioactivity associated with DNA was not incorporated into the nitrogen bases (i.e. via de novo synthesis) and a covalent binding index (mumol chemical bound/mol nucleotide phosphate per mmol/kg body wt. of chemical administered) of 30-120 was observed for various tissues. Most of the radioactivity (60-80%) associated with globin could be released and separated from the protein by the treatment with concentrated ammonium hydroxide and precipitation of protein by organic solvent. Three peaks were observed in the HPLC elution profiles of the radioactivity released from the globin. Trichloroacetic acid co-eluted with one of these released products (peak II), however, the chemical identity of the material under the major peak (peak III) and peak I are still uncharacterized.

Anilino-(2-bromophenyl) acetonitrile: a promising orally effective antileishmanial agent.

Visceral leishmaniasis (VL) or kala-azar is a worldwide disseminated intracellular infection caused by the hemoflagellate protozoan parasites Leishmania donovani. Chemotherapeutic scenario presents a deplorable picture and demands an urgent search for a new and safe anti-VL drugs, preferably active by oral route. In search of new antileishmanial agents, a total of 16 compounds belonging to the anilino-(substituted phenyl)-acetonitrile class were tested in vitro in promastigote/macrophase-amastigote systems and in vivo in L. donvoani/hamster model for their antileishmanial activity. Compound 3, anilino-(2-bromophenyl)-acetonitrile, exhibited most promising activity both in vitro at a concentration of 100 microg/ml (82.33 and 94.36% in promastigote and macrophase-amastigote systems, respectively) and in vivo at a dose of 50 mg/kg for 5 days (82.11 and 80% by i.p. and p.o. routes, respectively), hence this compound was investigated in detail. To maximize its bioavailability, dissolution profile, absorption, the compound was also tested in vivo as its soluble form. But no enhancement in activity was observed. From the results of different parameters for example ED(50) and LD(50) etc. compound 3 appears to be a potent orally effective compound which could further be investigated to establish its potential as a candidate molecule of antileishmanial therapy.

An assessment of the release of inorganic cyanide from the fragrance materials benzyl cyanide, geranyl nitrile and citronellyl nitrile applied dermally to the rat.

Organonitriles are widely used as components of fragrances that are incorporated into consumer products, many of which are for human topical use. Some organontriles are readily broken down metabolically to potentially toxic inorganic cyanide. Studies were therefore undertaken to assess whether this occurs with three representative fragrance nitriles, namely, benzyl cyanide, geranyl nitrile and citronellyl nitrile when applied dermally to the rat. The nitriles (benzyl cyanide, 150 mg/kg; geranyl and citronellyl nitriles, 400 mg/kg) were applied to the shaved backs of rats and maintained under occlusion for 24 h. Urine samples were collected for 0-24 h, 24-48 h and 48-72 h from the time of first application. These samples were analysed for thiocyanate, a biomarker for cyanide formation in vivo, as described previously (Potter, J., Smith, R.L., Api, A.M., 2000. Urinary thiocyanate levels as a biomarker for the generation of inorganic cyanide from benzyl cyanide in the rat. Food and Chemical Toxicology 39, 141-146). In the case of benzyl cyanide, there was a marked increase in urinary thiocyanate levels attributable to the release of cyanide in vivo. The amount of thiocyanate recovered was equivalent to 37% of the dose for males and 32% for females. For geranyl nitrile there was no significant increase in urinary thiocyanate excretion and there was only a marginal increase in the case of citronellyl nitrile that was equivalent to 0.40% of the applied dose for males and 0.29% for females.

Effects of dibromoacetonitrile on rats following 13-week drinking water exposure.

The subchronic toxicity of dibromoacetonitrile (DBAN), a disinfection by-product in drinking water, was studied in the rat. Male (180+/-18 g) and female (152+/-9 g) Sprague-Dawley rats (10 animals per group) were fed DBAN in organic-free distilled water at concentrations of 0.1, 1, 10 and 100 ppm for 13 weeks. Control rats received organic-free distilled water only. Water intakes in the highest dose males and females were reduced by 25 and 32% as compared to the controls, respectively (P<0.05), with no significant reductions in food consumption and body weight gain. The organ to body weight ratio was significantly increased in the highest-dose males and females for kidneys but not for the brain, liver, spleen, thymus and testicles. In the males, decreases were detected in serum uric acid levels at 1 and 100 ppm, and in urinary uric acid at 10 and 100 ppm. Decreased serum protein was detected in the highest-dose males and decreased serum LDH was found in the highest-dose females. Both the white blood cell and lymphocyte counts were significantly elevated in the highest-dose females. A significant increase in hepatic catalase activity was observed only in males starting at 1 ppm, and increased palmitoyl-CoA oxidase (PCO) activity was found in males and females of the highest dose group. In the males, decreased thiobarbituric acid reactive substance (TBARS) level was detected in the liver at 1.0 and 100 ppm groups, while increased TBARS was found in the serum at 100 ppm DBAN. No treatment-related changes were detected in the activities of hepatic benzyloxyresorufin O-dealkylase (BROD), pentoxyresorufin O-dealkylase (PROD) and ethoxresorufin O-deethylase (EROD), and in hepatic UDP-glucuronosyltransferase (UDPGT) and glutathione S-transferases (GST). Although DBAN is a potent inhibitor of hepatic aldehyde dehydrogenase (ALDH) and GST in vitro, there was no evidence of suppression of these enzymes in the treated animals. Mild histological changes were detected in animals receiving the highest dose, consisting of collapsed angularity, increased epithelial height in the thyroid of both sexes, and cytoplasmic vacuolation and nuclear vesiculation in the thyroid of females, increased myeloid to erythroid ratio in the bone marrow of both sexes, and cytoplasmic inclusions in the proximal tubules of male kidneys. In summary, treatment effects occurred predominantly at 100 ppm and included in both sexes: increased kidney weights, histological changes in the thyroid and bone marrow, and increased peroxisomal enzyme activities; and in males: decreased serum and urinary uric acid levels, and indication of oxidative stress. The no-observed-adverse-effect level (NOAEL) was therefore judged to be 10 ppm, equivalent to 1.11 and 1.21 mg/kg/day in the males and females, respectively.

Anticancer effects of KI-10F: a novel compound affecting apoptosis, angiogenesis and cell growth in colon cancer.

The anticancer effect of a new pyrazole derivative, KI-10F (2-(4-(2-(4-(dimethylamino) phenyl)pyridin-4-yl)-5-(3-methoxy-5-methylphenyl)-1H-pyrazol­1-yl) acetonitrile)•3.5HCl) was evaluated in human colon cancer cells. KI-10F strongly suppressed the growth of human colon cancer cells and induced apoptosis by increasing the proportion of sub-G1 presenting apoptotic cells as well as causing cell cycle arrest at the G2/M phase. Apoptosis by KI-10F was confirmed by observation of an increase in the expression of cleaved caspase-3, caspase-8, caspase-9 and Bax, and the decrease of Bcl-2. Decreased expression of HIF-1α and VEGF, and the inhibition of HUVEC tube formation and migration showed that KI-10F effectively inhibited the angiogenesis process. Furthermore, in vivo study in a mouse xenograft model showed that KI-10F produced a stronger antitumor activity than 5-FU, a conventional anticancer drug prescribed for the treatment of colon cancer. The effects of KI-10F on tumor proliferation (PCNA), angiogenesis (CD34) and apoptosis (cleaved caspase-3) were evaluated by immunohistochemistry using isolated tumor tissue samples. Taken together, our results demonstrated that KI-10F induces apoptosis and inhibits cell growth and angiogenesis both in vitro and in vivo. We suggest that KI-10F is an effective chemotherapeutic candidate for use against colon cancer.

Simmondsin for weight loss in rats.

OBJECTIVE: To investigate the safety and efficacy for weight loss of simmondsin, a dietary supplement extracted from the seed of the jojoba plant (Simmondsia chinensis). ANIMALS: Sprague-Dawley male rats were fed various levels of simmondsin for 8 weeks (lean rats) or 16 weeks (high fat-induced obese rats). MEASUREMENTS: Food intake, body weight and composition, histopathology, hematology parameters. RESULTS: Simmondsin produced a clear dose-response effect on food intake and body weight. No remarkable histopathologic changes were noted in the liver, kidney and spleen. One lean animal, in the 0.5% group, had approximately a 20% depression in red bone marrow cells. Significant effects on hematology parameters were seen almost exclusively in groups consuming simmondsin at the highest level (0.5%) and these effects appeared to be reversed by removing simmondsin from the diet. CONCLUSION: Simmondsin at both the 0.15% level and the 0.25% level significantly reduced food intake and body weight without apparent negative effects. At dose levels much higher than therapeutic levels, there seemed to be reversible effects on circulating red and white blood cells. Future studies should determine long-term effects of lower doses on blood cell parameters.

Acetonitrile serum concentrations and cyanide blood levels in a case of suicidal oral acetonitrile ingestion.

Acute acetonitrile toxicity is mainly dependent on the release of cyanide via hepatic metabolism. Although evaluated in animals, few data are available concerning the toxicokinetic parameters of acetonitrile and acetonitrile-liberated cyanide in human. This paper reports a case of suicidal oral acetonitrile ingestion of about 5 mL without severe symptoms of intoxication in a previously healthy adult male with a body weight of 60 kg. Acetonitrile serum concentrations as well as cyanide blood levels were determined over the whole hospitalization. The elimination half-lives calculated from these data were 32 h for acetonitrile and 15 h for cyanide. After sodium thiosulfate bolus application, the cyanide blood level rapidly decreased to 10% of the initial value, indicating that sodium thiosulfate sufficiently detoxifies acetonitrile-liberated cyanide. Since cyanide levels again increased to maximal values about 4.5 h after sodium thiosulfate application, continued thiosulfate therapy is required as predicted by the long elimination half-lives of acetonitrile and acetonitrile-liberated cyanide. Determination of cyanide and acetonitrile concentrations is recommended for the estimation of optimal individual sodium thiosulfate dosage.

Inhalation toxicology of acute exposure to aliphatic nitriles.

Male CD-1 mice were exposed for 60 min to toxic concentrations of acetonitrile, propionitrile, or n-butyronitrile and were maintained for the following 14 d. The LC50 values for acetonitrile, propionitrile, and n-butyronitrile were 2,693, 163, and 249 ppm, respectively. Pretreatment with Na2S2O3 or NaNO2, two common inorganic cyanide antagonists, can provide significant (p < 0.05) protection against the mortality associated with exposure to lethal concentrations of these nitriles. Administration of Na2S2O3 consistently provided a greater measure of protection than did NaNO2 against nitrile poisoning. Pretreatment with a heptatotoxic dose of CCl4 can protect mice against death from inhalation of lethal concentrations of these nitriles. The present results are compared with those of previous studies, and the conclusions support the rationale for administration of inorganic cyanide antagonists to individuals poisoned by inhalation of acetonitrile, propionitrile, or n-butyronitrile.

Developmental toxicology of acetonitrile in the Syrian golden hamster.

Pregnant hamsters were exposed to acetonitrile by inhalation, ingestion, or ip injection during the early primitive streak stage of embryogenesis. Inhalation of 1,800 or 3,800 ppm acetonitrile for 60 min failed to induce malformations in the near-term offspring whereas inhalation of 5,000 or 8,000 ppm acetonitrile was associated with production of severe axial skeletal (dysraphic) disorders. One fetus afflicted with extrathoracic ectopia cordis was recovered from a dam exposed to 8,000 ppm acetonitrile. An oral or ip dose of 100-400 mg/kg acetonitrile in hamsters of equivalent gestational age also caused malformations identical to those noted following inhalation exposure. Some dams exposed to the highest concentrations or doses of acetonitrile displayed overt signs of poisoning. Multiple injections of sodium thiosulfate antagonized the mortality and signs of intoxication associated with acetonitrile treatment. Offspring of thiosulfate-treated hamsters exposed to acetonitrile failed to exhibit the marked teratogenic response that was associated with exposure to equivalent concentrations or doses of acetonitrile alone. Elevated concentrations of cyanide and thiocyanate were detected in all tissues studied at 2.5 hr after an oral or ip dose of acetonitrile. Cyanide was liberated when acetonitrile was incubated in vitro with hamster liver slices or NADPH-fortified hepatic microsomal preparations. The results suggested that in vivo liberation of cyanide from acetonitrile was responsible for the production of terata.

Simple high-performance liquid chromatographic method for the determination of PGT/1A, a new immunostimulating drug, in biological fluids.

This paper describes a simple high-performance liquid chromatographic method for the determination of PGT/1A (3-L-pyroglutamyl-L-thiazolidine-4-carboxylic acid), a new immunostimulating drug, in plasma and urine. The column was packed with LiChrospher-NH2 (5 microns), the mobile phase was 0.02 M monobasic potassium phosphate (pH 3.2 with concentrated phosphoric acid)-acetonitrile (25:75, v/v), the flow-rate was 1.2 ml/min, the detection wavelength was 210 nm and the apparatus was a Varian Model 5000. Plasma (1 ml) was added to 1.2 ml of acetonitrile and the supernatant injected; the urine was diluted 1:5. The retention time of PGT/1A was 9.4 min in plasma and 9.9 min in urine. The method was validated for recovery, accuracy and reproducibility. The results after intravenous injection in twelve volunteers are also given.

Comparison between lergotrile and bromocriptine in parkinsonism.

The therapeutic and adverse effects of two ergot derivatives, bromocriptine and lergotrile, were compared in idiopathic parkinsonism. At both low (50 mg daily) and high (150 mg daily) dosage there was a similar but not identical profile of response. Initially, lergotrile tended to induce more severe but always transient hypotension. At higher doses, bromocriptine caused more dyskinesia. Neurological deficits improved with increasing doses up to an average daily level of 80 to 150 mg of ergot derivatives combined with levodopa, 450 to 1,150 mg, and carbidopa, 45 to 115 mg. However, efficacy often declined at the highest doses of antiparkinsonian agents. Adverse effects caused by ergot derivatives are more common with dosages greater than 100 mg per day. In general, the best overall therapeutic results with bromocriptine and lergotrile were obtained in the dose range of 50 to 100 mg daily for each. It is concluded that bromocriptine and lergotrile are similar in their therapeutic properties and that both are comparable in efficacy to levodopa plus carbidopa (though optimal results are commonly obtained by combining submaximal doses of levodopa with ergot derivatives). The role for each drug in the treatment of parkinsonism is likely to be determined by factors such as cost (bromocriptine) and hepatotoxicity (lergotrile).