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.

Efficacy and safety of itacitinib versus placebo in combination with corticosteroids for initial treatment of acute graft-versus-host disease (GRAVITAS-301): a randomised, multicentre, double-blind, phase 3 trial.

BACKGROUND: Acute graft-versus-host disease (GVHD) is a common and life-threatening complication of allogeneic haematopoietic stem cell transplantation (HSCT); there is an urgent unmet need for effective therapies. We aimed to evaluate the Janus kinase 1 inhibitor itacitinib versus placebo, both in combination with corticosteroids, for initial treatment of acute GVHD. METHODS: GRAVITAS-301 was an international, double-blind, adaptive (group sequential design) phase 3 study conducted at 129 hospitals and community practices in 19 countries. Eligible patients were aged 18 years or older, had previously received allogeneic HSCT for a haematological malignancy, developed grades II-IV acute GVHD, and received up to 2 days of systemic corticosteroids. Patients were stratified by clinical standard-risk or high-risk acute GVHD and randomly assigned (1:1), via a centralised interactive voice response system, to receive either oral itacitinib (200 mg) or placebo once daily, both in addition to corticosteroids. The primary endpoint was overall response rate (ORR) at day 28 (defined as the proportion of patients with complete response, very good partial response, or partial response 28 days after the start of treatment). For sample size determination, an absolute improvement in ORR at day 28 over standard therapy of 16% was considered clinically meaningful. Efficacy analyses were performed in the intention-to-treat population; safety analyses included patients who received at least one dose of study drug. GRAVITAS-301 is registered with ClinicalTrials.gov (NCT03139604) and is complete. FINDINGS: Between July 19, 2017, and Oct 3, 2019, 439 patients were randomly assigned to receive either itacitinib plus corticosteroids (n=219; itacitinib group) or placebo plus corticosteroids (n=220; placebo group). 173 (39%) patients were female and 390 (89%) were White. At baseline, 107 (24%) of 439 patients (itacitinib 51 [23%] of 219; placebo 56 [25%] of 220) had clinical high-risk acute GVHD. The ORR at day 28 was 74% (95% CI 67·6-79·7; 162 of 219; complete response 53% [116 of 219]) for itacitinib and 66% (59·7-72·6; 146 of 220; complete response, 40% [89 of 220]) for placebo (odds ratio for ORR 1·45, 95% CI 0·96-2·20; two-sided p=0·078). Grade 3 or worse adverse events occurred in 185 (86%) of 215 itacitinib recipients and 178 (82%) of 216 placebo recipients, and most commonly included thrombocytopenia or platelet count decreased (78 [36%] vs 68 [31%]), neutropenia or neutrophil count decreased (49 [23%] vs 45 [21%]), anaemia (42 [20%] vs 26 [12%]), and hyperglycaemia (26 [12%] vs 28 [13%]). Treatment-related deaths occurred in three of 215 patients (1%) in the itacitinib group and four of 216 (2%) in the placebo group. INTERPRETATION: The observed improvement in ORR at day 28 with the addition of itacitinib versus placebo to corticosteroids did not reach the prespecified significance level. Further studies might provide additional insight into the utility of selective JAK1 inhibition for the treatment of acute GVHD. FUNDING: Incyte.

First-in-Human Phase I/IB Dose-Finding Study of Adagrasib (MRTX849) in Patients With Advanced KRASG12C Solid Tumors (KRYSTAL-1).

PURPOSE: Adagrasib (MRTX849) is an oral, highly selective, small-molecule, covalent inhibitor of KRASG12C. We report results from a phase I/IB study of adagrasib in non-small-cell lung cancer, colorectal cancer, and other solid tumors harboring the KRASG12C mutation. MATERIALS AND METHODS: Patients with advanced KRASG12C-mutant solid tumors were treated with adagrasib 150 mg orally once daily, 300 mg once daily, 600 mg once daily, 1,200 mg once daily, or 600 mg orally twice a day using an accelerated titration design, which transitioned to a modified toxicity probability interval design when a predefined degree of toxicity was observed or target adagrasib exposure was achieved. Safety, pharmacokinetics, and clinical activity were evaluated. RESULTS: Twenty-five patients were enrolled and received at least one dose of adagrasib. The recommended phase II dose (RP2D) was 600 mg twice a day on the basis of safety, tolerability, and observed pharmacokinetics properties. No maximum tolerated dose was formally defined. After a median follow-up of 19.6 months, eight of 15 patients (53.3%; 95% CI, 26.6 to 78.7) with RECIST-evaluable KRASG12C-mutant non-small-cell lung cancer treated at 600 mg twice a day achieved a confirmed partial response. The median duration of response was 16.4 months (95% CI, 3.1 to not estimable). The median progression-free survival was 11.1 months (95% CI, 2.6 to not estimable). One of two patients with KRASG12C-mutant colorectal cancer treated at 600 mg twice a day achieved a partial response (duration of response, 4.2 months). At the RP2D, the most common treatment-related adverse events (any grade) were nausea (80.0%), diarrhea (70.0%), vomiting (50.0%), and fatigue (45.0%). The most common grade 3-4 treatment-related adverse event was fatigue (15.0%). CONCLUSION: Adagrasib 600 mg twice a day was well tolerated and exhibited antitumor activity in patients with advanced solid tumors harboring the KRASG12C mutation.

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.

The Effect of Renal Impairment on the Pharmacokinetics and Safety of Itacitinib.

Itacitinib is a novel, selective, Janus kinase 1 inhibitor in development for treatment of graft-versus-host disease. The objective of this study was to assess pharmacokinetics and safety of 300-mg itacitinib dosed in participants with normal renal function (n = 10), severe renal impairment (n = 8), and end-stage renal disease (ESRD) on hemodialysis (n = 8). Serial plasma and urine samples (urine from normal and severe groups only) were collected before dosing until 72 hours after dosing. In the ESRD group, itacitinib was evaluated in 2 periods, when dosed before (period 1) and after (period 2) a hemodialysis session. Geometric mean ratios (90% confidence interval) in participants with severe renal impairment, ESRD period 1 and ESRD period 2 relative to participants with normal renal function were 1.65 (1.13-2.39), 0.71 (0.49-1.03), and 0.83 (0.57-1.20) for maximum plasma drug concentration and 2.23 (1.56-3.18), 0.81 (0.57-1.16), and 0.95 (0.66-1.35) for area under the plasma concentration-time curve from time zero to infinity. Itacitinib was well tolerated, and 3 grade 1 treatment-emergent adverse events were reported over the course of the study. Given the magnitude of exposure changes in participants with severe renal impairment or ESRD and the historic risk-benefit profile, no dose adjustment is recommended for itacitinib in patients with impaired renal function, although the final dosage recommendation will be based on cumulative pharmacokinetics and safety from this study and from the pivotal graft-versus-host disease trial. Additionally, itacitinib may be administered to patients undergoing dialysis regardless of the time of dialysis.

Disruption of the behavioral satiety sequence by simmondsin.

Simmondsin, a cyanoglycoside from jojoba meal, reduces food intake after oral administration. To diagnose if it acts by inducing satiation or by creating abnormal physiological effects, an observational study was undertaken to investigate the effects of simmondsin on feeding and other behaviors. Particular attention was paid to the behavioral sequence associated with satiety (BSS). At first contact, simmondsin non-significantly reduced food intake by 17% and had little effect on feeding and associated behaviors. The behavioral structure was preserved and a small shift of the onset of resting to the left was observed, suggesting a small satiative action of simmondsin at first contact. Simmondsin given for the second time caused a more pronounced food intake reduction of 52% due to a reduction in eating duration, mean bout intake and mean bout length, and to an increase in latency to eat. At second contact, simmondsin caused a strong switching in active behaviors, disrupting the BSS. The simmondsin-induced hyperactivity suggests that simmondsin produces aversiveness with second contact. Our results indicate that simmondsin exerts multiple effects. It probably facilitates a small natural process of satiation/satiety at first contact, but creates abnormal physiological effects resulting in aversive reactions from second contact on.

Atorvastatin: A Review of Analytical Methods for Pharmaceutical Quality Control and Monitoring.

Background: Atorvastatin, a lipid-regulating drug, was the best-selling drug in the world in the early 2000s. Thus, monitoring of this drug is important because it is accessible to a large portion of the population. In addition, its quality control is fundamental to provide quality medicines. Method of analysis can be the first step in the rational use of pharmaceuticals. Objective/Methods: In this context, a critical review of analytical methods present in the literature and official compendia for the pharmaceutical quality control of atorvastatin was made. Results: Among the analytical methods most used in the evaluation of atorvastatin, HPLC is highlighted, followed by HPLC coupled to MS, and spectrophotometry in UV. Tablets are the most studied pharmaceutical samples, and plasma is the most studied biological matrix. In the literature, studies with atorvastatin-based pharmaceutical products are more common than biological materials. Acetonitrile is the organic solvent most commonly used in the methods surveyed to evaluate atorvastatin. Conclusions: Currently, awareness of the impact that the analytical choice has on the health of the operator and the environment is growing. Therefore, the suitability of existing methods for the determination of atorvastatin can be made to adhere to the current analytical chemistry. In this way, the analytical, environmental, and human consciousness will remain united. Highlights: Although the literature shows interesting methods from an economic and environmental point of view, such as UV, Vis miniaturized, and TLC, they can still be improved to meet the requirements of the current sustainable analytical chemistry.

Paradoxial response to dopaminergic agents in parkinsonism.

A patient with the classical stigmata of parkinsonism was treated on three separate occasions with levodopa, a combination of levodopa and carbidopa, and lergotrile mesylate, a direct-acting dopamine-receptor agonist. All three treatment regimens resulted in dose-related increases in parkinsonian features. To our knowledge, this response has not been previously described. Lergotrile did not alter CSF homovanillic acid concentration. It is suggested that this rare paradoxical motor response to dopaminergic agents may be associated with dysfunction of the postsynaptic dopamine receptor site.

Lergotrile in the treatment of parkinsonism.

Lergotrile mesylate, a direct-acting dopamine agonist, was administered for up to 10 months to 25 patients with Parkinson disease. Of six patients not receiving levodopa concurrently, five showed definite improvement in parkinsonian signs and symptoms. These results are the first clear indication that lergotrile is efficacious, independently of any interaction with levodopa, in the treatment of Parkinson disease. The drug was also effective in relieving some complications of long-term levodopa therapy. Lergotrile was more effective in alleviating on-off problems than in reversing loss of levodopa efficacy. Side effects of lergotrile included exacerbation of hallucinations, dyskinesias, hypotension, and alterations in liver function tests.

Studies on the antiparkinsonism efficacy of lergotrile.

The antiparkinsonian activity of lergotrile mesylate, a presumed dopaminergic receptor stimulating agent, was investigating in monkeys with surgically induced tremor and in parkinsonian patients. The administration of lergotrile resulted in a dose-dependent reduction in the intensity of tremor in the monkeys. In 13 patients with Parkinson's disease treated with lergotrile (up to 12 mg a day), overall improvement was observed in five. Tremor was the main clinical feature to benefit, and the improvement reached statistical significance. In a subgroup of four patients treated with a higher dose of lergotrile (up to 20 mg a day), further improvement in rigidity and bradykinesia was noted, but again, only improvement in tremor was statistically significant. Adverse effects included orthostatic hypotension, behavioral alterations, and nausea and vomiting. These were severe enough to result in drug withdrawal in three patients.

The treatment of hyperprolactinemia with a new ergot derivative, lergotrile mesylate.

Lergotrile mesylate is an ergot alkaloid derivative modified to eliminate the vasoconstrictive properties of the parent compound while preserving the properties that inhibit pituitary secretion. Administration of the drug to women with amenorrhea-galactorrhea resulted in the lowering of serum prolactin concentrations. The duration of action was short, so that prolactin levels were near base line 6 to 8 hours after a 2.0-mg dose and morning prolactin concentrations were not persistently suppressed. Initial therapy was accompanied by the development of postural hypotension. Tolerance to this side effect of the drug developed after several days of treatment with gradually increasing doses. In one patient, long-term treatment resulted in reduction of breast secretions, resumption of menses, and conception.

Qualidade por Design Analítico (AQbD) aplicado no desenvolvimento e otimização de métodos cromatográficos / Analytical Quality by Design (AQbD) applied in the development and optimization of chromatographic methods

O guia Q8(R2) do guia ICH descreve Qualidade por Design (QbD) como "uma abordagem sistemática para desenvolvimento farmacêutico que começa com objetivos predefinidos e enfatiza produto, entendimento e controle dos processos, baseado em dados científicos sólidos e gestão do risco da qualidade". Os métodos analíticos são considerados parte integrante do desenvolvimento farmacêutico. Assim, a Qualidade por Design Analítico (AQbD) é justificável e recomendada para obter flexibilidade regulatória, reduzir os resultados fora de especificação, obter um alto grau de robustez e um método analítico econômico. O Planejamento de Experimentos (DoE) é um conjunto de ferramentas estatísticas que inclui delineamentos de triagem e otimização, no qual os fatores são sistematicamente variados para determinar seus efeitos nas respostas, o que permite a determinação de quais fatores são os mais significantes, a identificação de qual configuração de fatores resulta em respostas otimizadas e a identificação de interações entre os fatores. As abordagens QbD e AQbD permitem a melhoria contínua ao longo do ciclo de vida do produto farmacêutico e do método analítico, inclusive para reduzir a variabilidade do produto, melhorar o desempenho do processo, reduzir resultados fora da especificação, melhorar o desempenho analítico, entre outros. O Cloridrato de Verapamil foi escolhido como molécula teste para desenvolvimento do projeto. Na primeira etapa do estudo foi realizado uma triagem com 13 fatores e 20 experimentos, utilizando o delineamento Plackett-Burman, seguiu-se para a próxima etapa com 7 fatores e 16 experimentos através do delineamento fatorial fracionado (Res.: IV). A etapa de otimização foi realizada com 3 fatores e 20 experimentos utilizando o delineamento central composto. Após todas as etapas do estudo, as seguintes condições foram consideradas ideais: Fase móvel A - Tampão formiato de amônio 10 mM pH 3,0, Fase móvel B - Amoníaco 2,0% em acetonitrila, eluição do tipo gradiente, coluna cromatográfica XSelect CSH C18 (100mm x 4,6mm x 3,5 µm), fluxo de 0,7 mL/min, volume de injeção de 2 µL para teor e 10 µL para produtos de degradação. Os métodos desenvolvidos são robustos, validados e indicativos de estabilidade

The ICH guide Q8 (R2) describes Quality by Design as "a systematic approach to pharmaceutical development that begins with predefined goals and emphasizes product, understanding and control of processes, based on solid scientific data and Quality Risk Management ". Analytical methods are considered an integral part of pharmaceutical development. Thus, the application of QbD approach to analytical method development is justifiable and a recommended strategy to attain regulatory flexibility, to reduce out-of-specification results, to achieve a high degree of robustness and a cost-effective analytical method. DoE is a set of statistical tools which include screening designs and optimization designs. In DoE approach, the controlled input factors are systematically varied to determine their effects on the output responses, which allows the determination of the most important input factors, the identification of input factors setting leading to optimized output responses, and the identification of interactions between input factors. The QbD and AQbD approach allows the continuous improvement throughout the lifecycle of pharmaceutical product and analytical method, including to reduce product variability, to improve process performance, to reduce out-of-specification results, to improve analytical performance, among others. Verapamil Hydrochloride was chosen as a test molecule for the development of the project. In the first phase of the study, a 13-factor and 20-experiment screening was performed using the Plackett-Burman design, followed by the 7-factor and 16-experiment next stage through fractional factorial design (Res .: IV). The optimization step was performed with 3 factors and 20 experiments using the composite central design. After performing all the study steps, the following conditions were considered ideal: Mobile Phase A - 10 mM ammonium formate buffer pH 3.0, Mobile Phase B - 2.0% ammonia in acetonitrile, gradient elution, column chromatographic XSelect CSH C18 (100mm x 4.6mm x 3.5µm), flow rate of 0.7ml / min, injection volume of 2µL for assay and 10µL for degradation products. The methods developed are robust, validated and stability indicating

Intoxicación aguda por acetonitrilo / Acute intoxication by acetonitrile

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Unusual occupational toxins.

Occupational and environmental medicine affords encounters with many unusual toxins, ranging from exotic metals to rocket fuels. Twelve of the most unusual industrial toxins are reviewed here and their clinical manifestations and treatments explored: acetonitrile, acrylonitrile, boron hydrides, dimethylaminopropionitrile, dimethylformamide, hydrazines, methyl isocyanate, 2-nitropropane, phosphine, Stalinon, tellurium, and vanadium.

[Aminoacetonitrile and fetogenesis of the rat. III. Malformations of the osseous skeleton (author's transl)]. / Aminoacetonitril und Fetogenese der Ratte. III. Fehlbildungen des knöchernen Skelettes.

The paper describes disturbances of ossification and malformations of the osseous skeleton of rat fetuses after application of 300 mg aminoacetonitrile/kg body weight during fetogenesis (days 15--19). Malformations are inducible at all days proved: Single doses of the lathyrogenic agent (intraperitoneally applicated) produce severe scoliosis, bending of extremities, wristdrop of the fore paws, shortening of the lower jaw, cleft palate and distorsion of the ribs. This paper is a continuation of 2 preceding parts dealing with general parameters of reproduction and gross anomalies after application of aminoacetonitrile, and disturbances of internal organ systems.

A comparative randomized double-blind clinical trial of isoaminile citrate and chlophedianol hydrochloride as antitussive agents.

The efficacy and safety of a new centrally acting antitussive agent, isoaminile citrate, was compared with that of chlophedianol hydrochloride in a double-blind, randomized interpatient study. A total of 66 patients participated, two and four patients were lost to follow-up with isoaminile and chlophedianol, respectively. In the experimentally induced cough in 12 normal human subjects, isoaminile (40 mg) was as effective as chlophedianol (20 mg), but its duration of action was somewhat longer. One subject developed allergic skin rash with chlophedianol and was withdrawn from the study. In 60 patients with cough associated with chest diseases, isoaminile (40 mg, 3 x daily) was as effective as chlophedianol (20 mg, 3 x daily) in suppressing cough as judged from the 3-h and 24-h cough counts. The increase in PEFR at day 7 of treatment was somewhat more marked with chlophedianol as compared with isoaminile. None of the drugs interfered with the expectoration process. The side effects observed were few, mild in nature, and did not require a decrease in dose or withdrawal of treatment in any of the patients. Isoaminile citrate was concluded to be an effective and relatively safe antitussive agent. Isoaminile citrate, alpha(isopropyl)-alpha-(beta-dimethylaminoproyl) phenylacetonitrile citrate, is a centrally acting antitussive agent. In animal experiments this drug was as efficacious as codeine but was devoid of any respiratory depressant effect [Krause 1958, Kuroda et al. 1971]. This controlled double-randomized interpatient study was designed to test the comparative efficacy and safety of isoaminile and chlophedianol, another centrally acting antitussive, in humans.

[The influencing of blastogenesis and embryogenesis in rats through aminoacetonitrile]. / uber die Beeinflussung von Blastogenese und Embryogenese der Ratte durch Aminoacetonitril

The study was designed to determine the influence of the lathyrogenic substance aminoacetonitrile on blastogenesis and embryogenesis of the Wistar rat. 91 female Wistar rats, weighing from 190 through 380 g, received a single injection of 300 mg aminoacetonitrile (AAN)/kg body weight. Substance was given intraperitoneally on days 5, 7, 9, 11 or 13 of pregnancy. The detection of sperms in the vaginal smears was counted as day 1 post coitum. Animals were sacrificed on day 21 of pregnancy. The following parameters served as a base of interpretation: fetal body weight, numbers of implantations, resorptions, dead and living fetuses. Malformations were detected by outer inspection for gross anomalies, by the razor blade technique for internal malformations, and by skeletal preparations. All results were evaluated by statistical means. AAN influences pregnancy and fetal development. The rates of fetal resorptions are enhanced after application of AAN beyond the 7th day p. c. The maximum of fetal death is reached on day 11 p. c. There is no influence on the mean implantation number. With the exception of the 5th day of development AAN reduces the number of living fetuses. After application of AAN on day 13 p.c. the mean body weight decreases significantly. All over the investigated range malformations can be observed. Abnormalities of internal organs are frequent: Hydrocephalus, hydronephrosis, situs inversus. Malformations of the skeletal system are only observable on days 5, 7 and 9: sternal fissure, supernumerary ribs, destruction of the lumbar spine. AAN does not induce gross anomalies of the fetus.

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).