Alzheimer's disease and clinical trials.

Alzheimer's disease (AD) is spreading its root disproportionately among the worldwide population. Many genes have been identified as the hallmarks of AD. Based upon the knowledge, many clinical trials have been designed and conducted. Attempts have been made to alleviate the pathology associated with AD by targeting the molecular products of these genes. Irrespective of the understanding on the genetic component of AD, many clinical trials have failed and imposed greater challenges on the path of drug discovery. Therefore, this review aims to identify research and review articles to pinpoint the limitations of drug candidates (thiethylperazine, CT1812, crenezumab, CNP520, and lecanemab), which are under or withdrawn from clinical trials. Thorough analysis of the cross-talk pathways led to the identification of many confounding factors, which could interfere with the success of clinical trials with drug candidates such as thiethylperazine, CT1812, crenezumab, and CNP520. Though these drug candidates were enrolled in clinical trials, yet literature review shows many limitations. These limitations raise many questions on the rationale behind the enrollments of these drug candidates in clinical trials. A meticulous prior assessment of the outcome of clinical studies may stop risky clinical trials at their inceptions. This may save time, money, and resources.

Use of PET Imaging to Assess the Efficacy of Thiethylperazine to Stimulate Cerebral MRP1 Transport Activity in Wild-Type and APP/PS1-21 Mice.

Multidrug resistance-associated protein 1 (MRP1, encoded by the ABCC1 gene) may contribute to the clearance of amyloid-beta (Aß) peptides from the brain into the blood and stimulation of MRP1 transport activity may be a therapeutic approach to enhance brain Aß clearance. In this study, we assessed the effect of thiethylperazine, an antiemetic drug which was shown to stimulate MRP1 activity in vitro and to decrease Aß load in a rapid ß-amyloidosis mouse model (APP/PS1-21), on MRP1 transport activity by means of positron emission tomography (PET) imaging with the MRP1 tracer 6-bromo-7-[11C]methylpurine. Groups of wild-type, APP/PS1-21 and Abcc1(-/-) mice underwent PET scans before and after a 5-day oral treatment period with thiethylperazine (15 mg/kg, once daily). The elimination rate constant of radioactivity (kelim) was calculated from time-activity curves in the brain and the lungs as a measure of tissue MRP1 activity. Treatment with thiethylperazine had no significant effect on MRP1 activity in the brain and the lungs of wild-type and APP/PS1-21 mice. This may either be related to a lack of an MRP1-stimulating effect of thiethylperazine in vivo or to other factors, such as substrate-dependent MRP1 stimulation, insufficient target tissue exposure to thiethylperazine or limited sensitivity of the PET tracer to measure MRP1 stimulation.

Vipera ammodytes bites treated with antivenom ViperaTAb: a case series with pharmacokinetic evaluation.

CONTEXT: In clinical practice it is difficult to differentiate between V. berus and V. ammodytes venomous bites. In the past this was not a concern, but due to the current shortage in Viperfav™ and European viper venom antiserum availability, V. a. ammodytes venomous bites have recently been treated with ViperaTAb®, which is a pharmaceutical formulation containing a monospecific ovine Fab fragments against the venom of V. berus. OBJECTIVE: To evaluate ViperaTAb® in V. a. ammodytes envenomations. MATERIALS AND METHODS: This is a prospective case series of three consecutive patients envenomed by V. a. ammodytes snakebite treated with ViperaTAb®. V. ammodytes venom, neurotoxic ammodytoxins, and Fab fragment levels were determined in serum samples and a pharmacokinetic analysis of the antivenom Fab fragments was carried out. RESULTS: Three patients bitten by V. a. ammodytes with extensive local swelling, neurological symptoms and recurrent thrombocytopenia were treated with ViperaTAb®. V. ammodytes venom was detected in serum of all three patients. Ammodytoxins were detected in the serum of only the most severely envenomed patient who developed neurological symptoms. In the presented moderate cases, a dose of 8 mL of ViperaTAb® reduced swelling and improved systemic effects, such as thrombocytopenia. However, this dose of ViperaTAb® was not effective in the most severely envenomed patient with the highest serum values of V. ammodytes venom. In this case ViperaTAb® did not stop local swelling and it had no effect on neurological signs. ViperaTAb®'s systemic clearance, distribution and elimination half-lives were 4.3-13.4 mL/h/kg, 1.2-3.2 h and 14.1-55.4 h, respectively. CONCLUSIONS: In patients envenomed by V. a. ammodytes venom, ViperaTAb® reduces moderate swelling and temporarily improves systemic effects, except neurological symptoms. ViperaTAb® application induces a decrement of V. ammodytes venom level in the blood, but did not affect serum concentration of neurotoxic ammodytoxins in the one patient with measurable concentrations.

[Noncardiogenic pulmonary edema in the course of poisoning with clozapine, ketoprofen and thiethylperazine]. / Niekardiogenny obrzek pluc w przebiegu zatrucia klozapina, ketoprofenem i tietylperazyna.

Pulmonary edema is a severe, potentially fatal clinical condition. It happens, when interstitial fluid is accumulating in the alveoli, impeding proper gas exchange. Typically we distinguish cardiogenic and noncardiogenic pulmonary edema. The article describes the case of severe pulmonary edema, which occurred in a young woman, free of cardiac diseases, about 30 hours after a suicidal drug poisoning (clozapine, ketoprofen, thiethylperazine). Both clozapine and ketoprofen intoxication, may be severe. Complications in these poisonings affect not only the central nervous system, but also the circulatory or respiratory system and may even occur several hours after the overdose of these drugs. The study considered the causes and possible mechanisms of pulmonary edema in poisoning with these drugs.

Valoración del conocimiento del vértigo posicional paroxístico benigno en la atención primaria y especializada de primer nivel / Evaluation of benign paroxysmal positional vertigo in primary health-care and first level specialist care

Introducción: El vértigo posicional paroxístico benigno (VPPB) es el trastorno vestibular más frecuente, pero no parece que se lo identifique bien fuera del ámbito especializado específico. Objetivo: Determinar el conocimiento del VPPB fuera de la consulta otoneurológica. Pacientes y método: Estudio retrospectivo de una serie de 69 pacientes con VPPB tratados en la consulta especializada entre junio de 2005 y diciembre de 2006, analizando las rutas de derivación, sus pormenores y los tiempos transcurridos desde el inicio de los síntomas. Resultados: 42 (61 %) pacientes llegaron por la vía convencional (atención primaria-otorrinolaringólogo extrahospitalario), 17 (25 %) procedían de urgencias (un tercio fueron ingresados); el resto procedía de consultas de pasillo o durante ingresos por otras causas (el 9 y el 5 %, respectivamente). Sólo 1 paciente fue remitido con el diagnóstico específico de VPPB. El tiempo medio de evolución de los síntomas fue de 20 ± 32 semanas, significativamente mayor (p < 0,01, test de Kruskall-Wallis) en la ruta habitual (28 semanas) que en las demás procedencias. Los VPPB remitidos más rápido eran los idiopáticos y los asociados a vestibulopatías recidivantes, y se retuvo más tiempo, con tratamientos médicos inespecíficos, a los pacientes con enfermedad previa que explicara los síntomas posicionales (postraumáticos y tras neuritis vestibular) (p < 0,01, Kruskall-Wallis). El promedio del gasto hasta la derivación fue de 364 euros, frente a los 136 euros necesarios para un tratamiento de reposición efectivo. Conclusiones: El VPPB sigue siendo una enfermedad poco conocida en la atención no especializada, por lo que se retrasan el diagnóstico y el tratamiento y se consumen recursos innecesarios para su resolución

Introduction: Benign paroxysmal positional vertigo (BPPV) is the most common cause of vestibular vertigo, but it is not well known in routine clinical practice. Objective: To determine the awareness of BPPV outside the ENT clinic. Patients and method: Retrospective study of sixty-nine patients treated for BPPV between June 2005 and December 2006 at the specialist clinic. We analyzed the routes and details for their referral and the time elapsed since the start of the symptoms. Results: 42 patients (61 %) were referred through the conventional route (primary health-care or non-hospital ENT); 17 patients (25 %) came from the emergency room (one third of them were admitted); the remainder were patients hospitalized for some other problem (5 %) or informal consultations (9 %). Only one patient had been referred with a specific diagnosis of BPPV. The onset of vertigo symptoms before treatment was, on average, 20 weeks (SD, 32 weeks) and was significantly longer among patients coming from primary care (28 weeks) as compared with the other groups (P < .01, Kruskall-Wallis test). The mean time to referral was shorter among patients with idiopathic BPPV or with BPPV secondary to recurrent vestibulopathy whereas it was more prolonged among patients with a concomitant pathology capable of justifying the presence of positional symptoms, such as vestibular neuritis or post-traumatic BPPV (P < .01, Kruskall-Wallis test). The medical cost of treating BPPV prior to referral has been calculated at 1364 per individual (mostly for non-specific medical treatments) instead of the 1136 needed for effective positional treatment. Conclusions: BPPV continues to be a poorly understood pathology outside specialist neuro-otologic clinics, leading to delays in diagnosis and treatment, as well as the unnecessary consumption of resources

Drug treatment during pregnancy and isolated orofacial clefts in hungary.

OBJECTIVE: To evaluate the possible association between all kinds of drug treatments during pregnancy and isolated cleft lip with or without cleft palate (CL/P) and posterior cleft palate (PCP) in the offspring. SETTING: The dataset of the large population-based Hungarian Case-Control Surveillance of Congenital Abnormalities, 1980-1996, was evaluated. PARTICIPANTS: One thousand three hundred seventy-four cases with isolated CL/P and 601 with PCP, plus 38,151 population controls (without birth defects) and 20,868 malformed controls with other defects. INTERVENTION: In this observation case-control study the data collection was based on prospective medical records particularly prenatal logbook, retrospective maternal data via a self-reported questionnaire, and home visits of nonresponding mothers. MAIN OUTCOME MEASURES: Isolated CL/P and PCP associated with drug treatments during pregnancy. RESULTS: An increased risk for isolated CL/P was found in cases born to mothers treated with amoxicillin, phenytoin, oxprenolol, and thiethylperazine during the second and third month of pregnancy, i.e., the critical period of isolated CL/P. Risk of isolated PCP was increased in mothers with oxytetracycline and carbamazepine treatment during the third and fourth month of pregnancy, i.e., the critical period of PCP. CONCLUSIONS: This study confirmed the orofacial cleft (OFC) inducing effect of phenytoin, carbamazepine, oxytetracycline, and thiethylperazine and suggested a possible association between OFCs and oxprenolol and amoxicillin. However, drugs may have only a limited role in the origin of isolated OFCs.

Anaphylactic reaction and unrelated, subsequent, known side effects during therapy with thiethylperazine.

We report the first case presenting with successive anaphylactic reaction and extra-pyramidal syndrome after treatment with thiethylperazine maleate (thiethylperazine). Both reactions were caused due to this anti-emetic drug, but an additive effect of clemastine fumarate, prescribed to treat the anaphylactic reaction, is suggested by the sequence of events. We discuss the importance of knowing the pharmacological similitudes of common prescribed drugs in order to avoid the occurrence of side effects.

Thiethylperazine-induced parkinsonism: in vivo demonstration of dopamine D2 receptors blockade.

Thiethylperazine (Torecan) is a piperazine phenothiazine employed to relieve vertigo. Its use may be associated with extrapyramidal side effects (dystonia, akathisia, tardive dyskinesia) (Sulkava, 1984), but parkinsonism has rarely been described. We describe a woman who, 1 month after the onset of thiethylperazine treatment, developed parkinsonism that disappeared 2 months after withdrawal of the drug. However, cerebral single-photon emission computed tomography (SPECT) with the dopamine (DA) D2 receptors ligand 123I-iodobenzamide (123I-IBZM) revealed a persistent reduced DA D2 receptors activity (by 45%) in the basal ganglia (BG), which may be clinically not effective.

Case-control study of teratogenic potential of thiethylperazine, an anti-emetic drug.

OBJECTIVE: Thiethylperazine is a commonly used anti-emetic drug during pregnancy in Hungary. One experimental study in mice and rats found an increased occurrence of cleft palate after the use of thiethylperazine during pregnancy but the human data of thiethylperazine have not been reported. Thus, the aim of the study was to investigate the possible human teratogenic effect of thiethylperazine. DESIGN: Case-control approach. SETTING: The teratogenic potential of thiethylperazine was evaluated in the population-based large data set of the Hungarian Case-Control Surveillance of Congenital Abnormalities between 1980 and 1996. SAMPLE: Of 38,151 newborn infants without any congenital abnormalities (control group), 746 (2.0%) had mothers who were treated with thiethylperazine, while of 22,843 cases with congenital abnormalities, 411 (1.8%) had mothers who were treated with thiethylperazine during pregnancy. METHODS: Case-control pair analysis. MAIN OUTCOME MEASURES: Different congenital abnormalities. RESULTS: The pairs of cases with congenital abnormalities and their matched controls without congenital abnormalities were compared and this approach showed a somewhat higher rate of cleft lip +/- palate (OR: 2.0 with 95% CI: 1.0-4.0) in infants born to mothers with thiethylperazine treatment during the first trimester of pregnancy. CONCLUSION: Our data do not indicate clear teratogenic effect of thiethylperazine, however, a weak association was found between thiethylperazine use and cleft lip +/- palate.

Acatisia inducida por tietilperazina en paciente embarazada / Akathisia induced by thiethylperazine in a pregnant patient

La acatisia es un efecto lateral neurológico agudo común a diversos fármacos que actúan a nivel dopaminérgico, su manifestación fundamental es la inquietud psicomotora, es importante diagnosticar y tratar precozmente este síndrome. Tietilperazina es una fenotiazina cuyo efecto antiemético es usado en diversas circunstancias clínicas, presentamos el caso de una paciente hospitalizada por hiperemesis gravídica que es derivada a psiquiatría por la presencia de síntomas aparentemente ansiosos. El examen clínico permite sospechar acatisia por Tietilperazina Torecan®, el cuadro cede completamente con la suspensión del fármaco. Nos parece interesante comunicar este caso por la implicancia para los especialistas.

Akatisia is an common neurological complication of treatment with dopaminergic drugs, subjetive feeling of restlessness is their main symptom, it's important to recognize this syndrome early and to treat immediately. Thietylperazine is an phenothiazine drug with antiemetic effect used for medical practice, we present a case of 35 years old pregnancy inpatient referred to psychiatrist for anxiety, the diagnosis was akatisia induced by thietylperazide.

Cinqüenta anos de medicamentos antipsicóticos em psiquiatria: II - fenotiazinas piperazínicas / Fifty yearts of antipsychotic drugs in psychiatry: II - piperazine phenothiazines

Na iminência de uma nova era na terapêutica psiquiátrica, com a redescoberta da clozapina e a introduçäo de novos antipsicóticos atípicos, é feito um balanço sistemático das substância desenvolvidas nos últimos 50 anos. As substâncias introduzidas até o presente säo reunidas nos grupos-tioxantênicos com estrutura aparentada às fenotiazinas), tioxantenos, butirofenonas, difenilbutilpiperidinas, benzamidas, indóis, dibenzoxazepinas - e nos grupos químicos mais recentes - dibenzodiazepinas, benzisoxazólicos, tienobenzodiazepinas, dibenzotiazepinas, benzisotiazólicos, didroindolonas, imidazolidinonas -, além de compostos ainda em desenvolvimento. Neste artigo, o segundo da série concebida com esta finalidade, säo examinados os derivados fenotiazínicos com cadeia lateral piperazínica, carfenazina, clorimpifenina, dixirazina, flufenazina, metofenazina, oxaflumazina, perazina, perfenazina, proclorperazina, tietilperazina, tiopropazato, tioproperazina e trifluperazina. Com base em bibliografia básica específica, säo discutidos aspectos técnicos e revisado o conhecimento cientíco acumulado através da experimentaçäo e da utilizaçäo clínica destes compostos, desde seu lançamento até a presente data, com informaçöes sistemáticas sobre fórmula estrutural, fórmula molecular, nomes químicos, nomes fantasia e códigos de cada composto, além de dados sobre sua eventual comercializaçäo no país

Subacute cutaneous lupus erythematosus associated with cinnarizine and thiethylperazine therapy.

We report the case of a woman who developed subacute cutaneous lupus erythematosus (SCLE) after exposure to the sun while taking cinnarizine and thiethylperazine. The patient recalled that 10 years previously, a similar eruption had appeared after sunbathing, while she was taking only cinnarizine. SCLE development in this patient was probably drug related and there is some evidence that cinnarizine played an important pathogenic role.

[Dyskinesis after a single dose of thiethylperazine during the first trimester of pregnancy]. / Dyskinezy po jednorazowym zastosowaniu tietyloperazyny w pierwszym trymestrze ciazy.

A case of a 22-year female patient with poly-symptomatic reversible dyskinetic syndrome following a single thiethylperazine (Torecan) dose is presented. The patient was 10 weeks pregnant. Detoxication abolished extrapyramidal symptoms within 7 hours. Possible mechanism of such an adverse reaction to thiethylperazine is discussed.

Candida albicans test for the screening of phototoxicity in anthistamines / 대한피부과학회지

BACKGROUND: Antihistamine drugs are used widely in many conditions. Although some antihistamines may cause a photosensitive reaction,many physicians are not awae of it. OBJECTIVE: For examination of the phototoxic potential of antihistamines, we performed the Candida albiecrns test which is simple, cheap, and good for the screening of many drugs. MEHTODS: Thirty microliters of each solute of various antihistamines were applied to the Sabraud dextrose agar plate in which Candida albicans were applied diffusly. Four hours after the application, 60J/cm fo UVA was irradiated for two days. The irradiated. plates and nonirradiated control ones were incubated in a dark room for 48 hours, and examined for lear zones arround the drug, which means a positive results for the phototoxic potential of the drugs. RESULTS: Mequitazine, thiethylperazine, perphenazine and cllorromazine showed positive results, whereas others did not. An additional Candida albicans test using 0.1%, 0.01%, and 0.001% of the positive drugs revealed tht chlorpromazine, thiethylperazine aderphenazine showed positive results at 0.1%, but negative at 0.01 and 0.001%. Mequitazine was niegative at 0.1, 0.01, and 0,001%, Additional studies of the Candida albicans test using 5% and 10% of the diphenhydramine and dimenhydrinate, those were known photosensitizers but they slowed negative results at this study and revealed very weak posit,ive result in 10% diphenhydramine. CONCLUSION: A photosensitive reaction such as photoallergy and persistent light react,ion may be triggered by the phenothiazine antihistamines. Negative result in 1%, and very weak positive results in 10% diphenhydramine may be due to different mechanism of phototoxicity, or the low phototoxic potential of diphenhydrainine.

Sensitive determination of phenothiazines in body fluids by gas chromatography with surface ionization detection.

Fourteen phenothiazine derivatives were tested for their detection by gas chromatography (GC) with surface ionization detection (SID). The sensitivity of GC-SID was highest with trimeprazine and levomepromazine, which contain aliphatic tertiary amino side chains, and lowest with thiethylperazine and thioproperazine, which contain sulphur residues. Chlorpromazine, trimeprazine and promazine showed excellent linearity between the SID response and the drug amount in the range 0.25-3.0 pmol on-column. Their detection limits were as low as ca. 5-10 pg (15-30 fmol) on-column (250-500 pg per ml of body fluid). A detailed procedure for isolation of phenothiazines from human whole blood and urine using Sep-Pak C18 cartridges, before the GC with SID, is also presented. The recoveries of the drugs (100 pmol), which were added to 1 ml of whole blood or urine, were more than 79%. The baselines remained steady as the column temperature was increased.

Progressive loss of antiemetic efficacy during subsequent courses of chemotherapy.

The maintenance of the antiemetic efficacy of a combined protocol (intravenous methylprednisolone, oral thiethylperazine and oral amitriptyline) during six consecutive courses of adjuvant FAC chemotherapy (5-fluorouracil, doxorubicin, cyclophosphamide) was analysed in 107 female breast cancer patients who completed the six planned courses of treatment. A continuous decrease in complete (no vomiting episodes) and major protection rate (0-2 vomiting episodes) was evident during chemotherapy. Complete protection rate decreased from 62.6% in the first course to 48.6% in the sixth (P less than 0.05, chi 2 test). The respective figures for major protection rate were 76.6% and 58% (P less than 0.01, chi 2 test). These data, together with other from the literature, should be taken into consideration when reviewing the overall results of current antiemetic trials, which usually only mention the results obtained in the first course of chemotherapy.