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Acid–base disturbances
Published in Martin Andrew Crook, Clinical Biochemistry & Metabolic Medicine, 2013
Mechanical ventilation may be needed. Respiratory stimulants such as doxapram or nikethamide are not without side effects, for example they may lower the epilepsy threshold. Medroxyprogesterone can increase respiratory drive and has been used in pickwickian syndrome (obesity–hypoventilation). Oxygen therapy may be indicated if the patient is hypoxic and, in patients with COPD who fulfil the criteria for O2 therapy, this may decrease mortality and reduce pulmonary hypertension. However, as discussed later, O2 therapy should be used with caution if there is hypercapnia (raised PCO2), which may aggravate the acidosis.
Stimulants, antidepressants, antimanics, anticonvulsants, and psychotomimetic agents
Published in Bev-Lorraine True, Robert H. Dreisbach, Dreisbach’s HANDBOOK of POISONING, 2001
Bev-Lorraine True, Robert H. Dreisbach
The fatal dose of picrotoxin may be as low as 20 mg or 2–3 cocculus kernals (0.5 g). In the treatment of drug-induced coma in which the convulsive threshold is raised, doses of picrotoxin over 300 mg in 24 h are likely to induce severe toxicity. The fatal dose of pentylenetetrazole may be as low as 1 g. The maximum dose should be limited to 6 g in 24 h. The fatal dose of nikethamide has not been established.
Arvid Carlsson (1923–2018)
Published in Andrew P. Wickens, Key Thinkers in Neuroscience, 2018
Carlsson was born in Uppsala, Sweden, to parents who were both historians. His father, Gottfrid, specialised in Nordic politics of the late Middle Ages and was appointed professor of history at the University of Lund when Carlsson was 3 years old. Carlsson’s mother Lizzie, also a doctorate, was interested in the legal status of Swedish women during the same historical period – although she had given up her career aspirations to raise a family. Despite this, she had kept a keen interest in her subject and during her seventies would publish two books and a number of articles on historical matters, which resulted in a honorary degree from the University of Uppsala. Carlson recounts that he grew up in a loving stable environment with his two brothers and sister, and all of whom would have a university education. Carlson chose to study medicine as did his younger brother – although he had no real motive to do this, other than having a vague idea of believing science might be more useful than arts. He began his medical studies in 1941, at the University of Lund, in the “deep south” of Sweden, a town that Carlsson thought was somewhat reminiscent of Oxford. At this time, World War II was raging in much of Europe, and Carlsson’s study became interrupted for a couple of years because of military service. Returning to clinical training in 1944, Carlsson was also one of the first medics to examine the emaciated prisoners of Nazi concentration camps whom had managed to reach Sweden through the humanitarian efforts of Count Folke Bernadotte.1 Right from the start of his medical studies, Carlsson had a hankering to do research, and in the same year, he obtained an unpaid position as an assistant in the laboratory of pharmacologist Gunnar Ahlgren. Here, Carlsson was given the task of examining the action of the convulsant pentylenetetrazol. It would lead to his first paper in 1946. Carlsson then studied the stimulant nikethamide (Coramine),2 a drug used medically to counteract tranquilizer overdoses. He found that its lethal action followed a circadian rhythm – the first time a drug’s action had been shown to be influenced by time of day. Another area of research that Carlsson entered into (around 1948) concerned the effects of calcium on bone metabolism. In fact, this work would form the basis of his MD thesis, which he finally completed in 1951.
The powder in the basement: how an unlabeled poison inspired federal legislative change
Published in Clinical Toxicology, 2022
Keahi M. Horowitz, Robert G. Hendrickson, Adam Blumenberg
By all accounts the evening meal of November 18th began normally. Hospital residents gathered at communal dining tables within their respective wards awaiting food from the kitchen. According to reports, many patients rejected their dinners due to a “salty or soapy taste, while others complained of numbness of the mouth [3].” One nurse, Allie Wassel, sampled some of the eggs and immediately instructed her ward to stop eating – an act which likely saved their lives [4]. However, the other wards were not so fortunate. Within 15 min, one patient had died and over 260 others were becoming acutely symptomatic. Dr. Evans, the superintendent, and Dr. Lidbeck, one of the house physicians, were called to the hospital to find a gruesome scene. Patients throughout multiple wards were crying out with marked abdominal pain, bloody emesis, bloody bowel movements, carpopedal spasm, pallor, generalized weakness, muscular paralysis, and shallow breathing. Some were becoming cyanotic [3]. In response, the hospital staff immediately started providing multiple empiric therapies, including “salt and sodium bicarbonate…nikethamide, epinephrine, caffeine with sodium benzoate, neosynephrin [sic] subcutaneously, 50 percent dextrose intravenously, whisky by mouth, and external heat”. By the end of the night 47 patients had died with no clear cause. Autopsies permitted on 6 of deceased patients would later reveal mucosal edema, hyperemia, petechial hemorrhages, and “congestion of the abdominal viscera [3].”
In vitro and in silico computational methods for assessing vaginal permeability
Published in Drug Development and Industrial Pharmacy, 2023
Eleni Tsanaktsidou, Marios Krestenitis, Christina Karavasili, Constantinos K. Zacharis, Dimitrios G. Fatouros, Catherine K. Markopoulou
Based on w × c [1] vs w × c [2] plots which reveal the ± influence of a variable (Table 4), an important group of factors that contribute negatively to in vitro permeability, are those related to the lipophilic character of a compound. Both logP and logD (at pH 4.5 which is approximately the normal vaginal pH) coefficients determine the distribution of a molecule between aqueous and lipophilic phase and characterize its lipophilicity. In conjunction with already published work, these are the main factors influencing drug penetration across biological membranes [30]. Indeed, as the lipophilicity of a compound increases, the tendency for its molecule to diffuse along the vaginal epithelial barrier appears to decrease [31]. The phenomenon is due to the repulsive forces that develop with the polar surface of the mesothelial cell wall. Consequently, low hydrophilicity and high LogP values lead to poor permeability. Similar behavior has been observed in both PLS models A and B (Figure 3), of the present research, where compounds included in PLS model A and display high lipophilicity (e.g. 4-chlorotestosterone, bromobenzene, mebendazole), exhibited zero permeation through the artificial membrane. In contrary, significantly higher permeability values were achieved for compounds with low or even negative (nikethamide, o-nitroaniline, 2-methylimidazole and 2-methylimidazole) logD values. Milica Radan and coworkers in their recent study [8] on the blood-brain barrier (BBB), they found (using QSPR models) that lipophilicity (ALogP2, squared Ghose-Crippen octanol partition coefficient) has a significant parabolic effect on permeability, as a decrease in permeability was observed for compounds with very high as well as very low ALogP2 values. Although the number of observations (18 obsarvations) in their study was statistically small and the experiments were conducted in a non-polar membrane (BBB), a corresponding attempt was also made in the present work. Thus, in an overview plot (Figure 4) the Papp values of the 108 observations were correlated with their LogP. According to the results, a slight tendency to decrease Papp at relatively more extreme values of lipophilicity is revealed. Specifically, substances with LogP values from 0.2 to 2.0 generally have high permeability (Figure 4, Area a), while for LogP values outside this range, their permeability varies from case to case (probably influenced by other properties) as shown in Figure 4 –Area c). Finally, substances with extreme values of lipophilicity 0.2 > LogP > 3.8 show reduced Papp (Figure 4, Area b).