A. Doenicke

Histamine release in dogs by Cremophor El® and its derivatives: Oxethylated oleic acid is the most effective constituent

Several preparations of Cremophor El®, several of other non-ionic detergents and several components of Cremophor El were tested for their histamine-releasing capacity in dogs. Lutensol AP 10 and a derivative of 1,2-propylenglycol were ineffective, but showed excellent properties as detergents. Thus the histamine-releasing capacity was not necessarily combined with the tenside effect of the surfactants.Oleic acid found in Tween 80 as well as in Cremophor El seems to be the most effective constituent, but the alcohol seems also to be important for the histamine-releasing capacity. The development of a non-toxic solubilizer for lipophilic drugs seems of considerable clinical interest.

POSSIBLE BENEFIT OF GR43175, A NOVEL 5-HT1-LIKE RECEPTOR AGONIST, FOR THE ACUTE TREATMENT OF SEVERE MIGRAINE

GR43175, a selective 5-HT1-like agonist, was given as an intravenous infusion in an open dose-ranging study to treat 46 attacks of severe migraine in 34 patients. The highest dose, 2 mg infused over 10 min in 24 severe attacks, resulted in rapid and complete relief of symptoms in 17 attacks (71%) and in improvement to a non-migrainous residual headache in 7 attacks. Treatment was well tolerated, the only adverse effects being transient feelings of heaviness and pressure, predominantly in the head. GR43175 may represent an important advance in the treatment of acute migraine.

Reducing pain during propofol injection : The role of the solvent

We hypothesized that the concentration of propofol in the aqueous phase may be the most important variable responsible for the pain experienced during injection of the drug.The concentration of propofol in the aqueous phase (18.57 micro gram/mL) can be decreased by increasing the fat concentration of the solvent. To test this hypothesis, 36 patients were randomly allocated to one of three groups, each receiving a different formulation of propofol. Group A received 20 mL of propofol alone in a commercial preparation (Diprivan Registered Trademark with 10 mL of saline); Group B, 20 mL of propofol to which 5 mL of long-chain triglyceride (LCT) fat emulsion and 5 mL of saline had been added; and Group C, 20 mL of propofol and 10 mL of LCT fat emulsion. The propofol emulsion was injected over 30-60 s into a dorsal vein of the hand. Patients reported pain during injection as none, mild, moderate, or severe (almost intolerable). In Group A, 8 of 12 patients reported moderate or severe pain upon injection, whereas in Group C only mild pain was reported by 6 of 12 patients. Our results suggest that a smaller concentration of propofol in the aqueous phase of the emulsion reduces pain on injection. With the addition of more lipid (10 mL), a higher percentage of propofol is absorbed by the fat particles. If solvents that permit a smaller concentration of drug in the aqueous phase of oil-in-water emulsions were used for propofol and other drugs that cause pain on injection, pain would be reduced and patient satisfaction may be increased. (Anesth Analg 1996;82:472-4)

Pharmacokinetics and pharmacodynamics of propofol in a new solvent

Pain on injection is the most commonly reported adverse event after propofol injection.In a randomized, cross-over study in two groups of 12 healthy male volunteers (24-42 yr), we compared the pharmacokinetics and pharmacodynamics of two new propofol formulations (1% and 2% concentrations) in a fat emulsion consisting of medium- and long-chain triglycerides with the standard propofol formulation. After a single intravenous bolus injection of 2 mg/kg, propofol blood levels were measured for 24 h and evaluated according to an open three-compartment model. The derived pharmacokinetic variables were not different among formulations. Additionally, electroencephalographic recordings of the onset and duration of hypnotic action were comparable with all formulations. After propofol 1% in the new formulation, fewer volunteers reported severe or moderate pain on injection (9%) than after the standard formulation (59%) (P < 0.05). We attribute this result to a lower concentration of free propofol in the aqueous phase of the new formulation. Implications: Changing the composition of the carrier fat emulsion for propofol does not have an impact on the pharmacokinetics and efficacy of propofol, but it promises to provide better patient acceptance by lowering the incidence of moderate and severe pain on injection. (Anesth Analg 1997;85:1399-403)

Definition and Classification of the Histamine-Release Response to Drugs in Anaesthesia and Surgery: Studies in the Conscious Human Subject* **

SummaryIn 2 clinical studies in 40 conscious human volunteers and 164 orthopedic patients histamine-release responses were diagnosed, defined and classified. Polygeline (Haemaccel) in its now outdated formulation [40] was chosen as a clinical histamine releaser. The main interest was not concentrated on the extreme, the “classical” anaphylactic response, but on theaverage histamine-release response found in clinical experiments with so many drugs in the last 10 years.In human volunteers 600 ng/kg histamine was i. v. injected. Indicants for a systemic anaphylactoid reaction with the highest incidence ratio were tachycardia, plasma histamine levels >1 ng/ml, “metallic taste”, flush, congestion of head, “wet eyes” and tears, hypertension and headache. Following polygeline none of these subjects developed a life-threatening reaction, but 12 showed a systemic response, 11 a cutaneous reaction and 17 were non-responders. Indicants for a systemic anaphylactoid reaction with the highest incidence ratio were plasma histamine levels >1 ng/ml, tachycardia, wheals, sensation of heat, narrowness of throat, hypertension, headache and wet eyes or tears.In a prolective, cohort study in the orthopedic patients 3 subjects with life-threatening reactions, 27 with systemic response, 96 with cutaneous reaction and 38 non-responders were included. Indicants with the highest incidence ratio were tachycardia, plasma histamine levels >1 ng/ml, erythema and wheals, cough, flush, stuffy nose and facial oedema. With this trial the indicants for diagnosing a systemic histamine release response in volunteers were validated in patients to a large extent.Thus the average histamine-release response was defined by clinical signs such as tachycardia and mild hypertension, scattered hives such as spots of erythema and wheals, respiratory symptoms in the laryngeal and nasal region, such as cough, narrowness in the throat, stuffy nose and sneezingand by pathological plasma histamine levels (>1 ng/ml). In addition histamine-release responses were differentiated as cutaneous responses, systemic responses and life-threatening responses by clinical and operational criteria and by plasma histamine levels. Using clinical trials and medical decision making procedures the incidence of systemic histamine-release responses in patients higher by two orders of magnitude than in other studies reported hitherto.ZusammenfassungIn 2 klinischen Studien bei 40 wachen Freiwilligen und 164 orthopädischen Patienten wurde versucht, Histaminfreisetzungsreaktionen zu diagnostizieren, zu definieren und zu klassifizieren. Haemaccel in einer heute klinisch nicht mehr verwendeten Zubereitung [40] wurde als klinischer Histaminfreisetzer verwendet. Das Hauptinteresse galt nicht der extremen, der klassischen anaphylaktischen Reaktion, sondern einer durchschnittlichen Histaminfreisetzung, die in klinischen Untersuchungen der letzten 10 Jahre mit so vielen Arzneimitteln gefunden wurde.Bei den Freiwilligen wurden 600 ng/kg Histamin intravenös verabreicht. Indikatoren für eine systemische anaphylaktoide Reaktion mit der höchsten Inzidenzrate waren Tachykardie, Plasmahistaminspiegel über 1 ng/ml, metallischer Geschmack, Flush, Kopfdruck, feuchte Augen oder Tränen, Hypertension und Kopfschmerzen. Nach Haemaccel-Infusion zeigte keiner der Probanden eine lebensbedrohliche Reaktion, aber 12 eine systemische und 11 eine Hautreaktion, während bei 17 keine Symptome gefunden werden konnten. Indikatoren mit der höchsten Inzidenzrate waren wiederum Plasmahistaminspiegel über 1 ng/ml, Tachykardie, Quaddeln, Hitzegefühl, Enge im Hals, Hypertension, Kopfschmerzen und Tränen.In einer prolektiven Cohortstudie wurden aus 600 orthopädischen Patienten 164 ausgewählt: 3 hatten eine lebensbedrohliche Reaktion, 27 eine systemische und 96 eine Hautreaktion, 38 Patienten zeigten keine Symptome. Indikatoren mit der höchsten Inzidenzrate waren wiederum Tachykardie, Plasmahistaminspiegel über 1 ng/ml, Erytheme und Quaddeln, Husten, Flush, verstopfte Nase und Gesichtsödem. Damit wurden durch die Patientenstudie die Indikatoren für eine systemische Histaminfreisetzungsreaktion in Probanden zu einem großen Teil validiert. So läßt sich eine durchschnittliche Histaminfreisetzungsreaktion als eine systemische anaphylaktoide Reaktion charakterisieren, mit klinischen Symptomen wie Tachykardie und leichte Hypertension, verstreuten Effloreszenzen, respiratorischen Symptomen im Bereich des Kehlkopfs und der Nasenschleimhautund durch pathologische Plasmahistaminspiegel (>1 ng/ml). Außerdem wurden die Histaminfreisetzungsreaktionen in kutane, systemische und lebensbedrohliche Reaktionen eingeteilt, wobei klinische und operationale Kriterien sowie Plasmahistaminspiegel für die Klassifikation verwendet wurden.

Propofol in an Emulsion of Long- and Medium-chain Triglycerides: The Effect on Pain

IMPLICATIONS In a test of two formulations of propofol for induction, patients experienced less pain with the formulation in Intralipid (Propofol-Lipuro 1%) than with Diprivan 1%.

H1 and H2 Blockade: A Prophylactic Principle in Anaesthesia and Surgery Against Histamine-Release Responses of Any Degree of Severity: Part II

: In the perioperative period, histamine release was shown in numerous situations and pathological states. They include diseases or complications of diseases, preparation and premedication of patients, induction of anaesthesia, maintenance of anaesthesia and surgery, and administration of drugs and treatment in the immediate postoperative period. A premedication with histamine H1 and H2 receptor antagonists was developed which in five controlled clinical trials blocked histamine-release responses of all grades of severity. These included single spots of erythema or a wheal up to life-threatening reactions or even death of the patient or laboratory animal. The necessity for a new premedication was investigated by methods of medical decision-making considering the incidence of the reactions, classification of severity, efficiency of prophylaxis and treatment of anaphylactoid reactions, and side-effects. As a result, the premedication with dimethpyrindene (Forhistal, Fenistil) plus cimetidine (Tagamet) was recommended in a series of patients at risk: those with a history of hypersensitivity reactions to intravenous agents or atopy, patients with a second I.V. drug exposure within a few days, those undergoing surgery with a high risk of histamine release, patients of greater than 70 years age, and poor-risk patients with preoperative cardiac, respiratory or liver insufficiency and shock.

Histamine release and hypotensive reactions in dogs by solubilizing agents and fatty acids: Analysis of various components in cremophor El and development of a compound with reduced toxicity

Anaphylactoid reactions in man following administration of drugs solubilized with cremophor El® (polyethylenglycolglycerol riconoleate) are a considerable clinical problem. Since these reactions occur in dogs on first exposure and in pigs on second exposure, the ‘dog model’ was used in this communication to analyse components and chemical modifications of cremophor El and its components for their clinical effects, their hypotensive actions and their histamine-releasing capacity.Two series of experiments in 1978 and 1980 were performed in 144 adult mongrel dogs of both sexes. In these studies histamine release wasnot related to the effect of the solubilizing agents as tensides and was elicited by rather low doses (about 10–100 mg/kg i.v.). The effect of these substances on blood pressure and on blood histamine levels was connected with distinct chemical features: the most potent compounds were oxethylated and additionally esterified unsaturated or hydroxylated fatty acids.Several phases in hypotensive reactions were observed, including an immediate response, a delayed blood pressure response and a late response about 15–20 min after injection. Only the delayed response was associated with histamine release. The combination of cardiovascular effects and histamine release was fatal on some occasions indicating that histamine release can be dangerous.Compared to cremophor El, the tenside effect was equal, but the toxicity was reduced in oxethylated 12-hydroxystearic acid. It is recommended that this solubilizer should be used in further extended studies in animals and — if these are successful—in clinical trials.

Elevated plasma histamine concentrations in surgery: causes and clinical significance

SummaryHistamine concentrations in plasma, whole blood and various tissues of human subjects, monkeys, pigs and dogs were determined by fluorometric methods before, during and after surgical operations. Following intraabdominal surgery in 6 of 22 patients elevated plasma histamine levels were found several hours after the end of operation. Some of the causes of histamine release in surgery were found to be premedication by atropine, intravenously administered anaesthetics, infusion of plasma substitutes and manipulation on the gut. Acute blood losses were without effect on the plasma histamine levels. Clinical symptoms and pathophysiological reactions, such as tachycardia, hypotension, increased gastric secretion and anaphylactoid reactions could be related to the release of histamine in some circumstances.ZusammenfassungHistaminkonzentrationen in Plasma, Vollblut und verschiedenen Geweben von Mensch. Affe, Schwein und Hund wurden vor, während und nach Operationen mit fluorometrischen Methoden gemessen. nach intraabdominellen eingriffen wurden bei 6 von 22 Patienten erhöhte Plasmahistaminspiegel noch Stunden nach der Operation gefunden.Als Ursachen der Histaminfreisetzung bei Operationen wurden nachgewiesen: Prämedikation durch Atropin, Anästhesieeinleitung mit intravenös verabreichten Kurznarkotika, Infusion von Plasmasubstituten und Manipulationen am Darm. Akuter Blutverlust war ohne Einfluß auf die Plasmahistaminspiegel. Klinische Symptome und pathophysiologische Reaktionen, wie Tachykardie, arterielle Hypotension, erhöhte Magensekretion und anaphylaktoide Reaktionen konnten auf Histaminfreisetzung unter bestimmten Umständen zurückgeführt werden.

A comparison of two formulations for etomidate, 2-hydroxypropyl-beta-cyclodextrin (HPCD) and propylene glycol.

The unphysiologic osmolality of commercial preparations of etomidate dissolved in propylene glycol has limited its use as a drug to induce anesthesia. We wanted to determine whether hydroxypropyl-beta-cyclodextrin (HPCD) is a more suitable solvent than propylene glycol by comparing pharmacokinetics, pharmacodynamics, and side effects of etomidate preparations in each solvent. Twenty-four healthy, male volunteers, randomly assigned to either the male volunteers, randomly assigned to either the HPCD or the propylene glycol group received etomidate, 0.3 mg/kg, dissolved in one of the two test solvents. We recorded arterial blood pressure, heart rate, electrocardiogram, electroencephalogram, pain on injection, myoclonic movements, and venous sequelae. Systolic and diastolic blood pressure and heart rate were similar in both groups. Frequency and severity of pain on injection differed significantly between groups. In the propylene glycol group, five subjects suffered venous sequelae: in three, thrombophlebitis resolved after 5 days; in one, after 10 days; and in the other, after 12 days. In the HPCD group, only one subject suffered severe pain on injection and none had venous sequelae. We conclude that HPCD may be superior to propylene glycol as a solvent for etomidate. HPCD is associated with less pain, less thrombophlebitis, and no hemolysis without clinically important alteration of pharmacokinetics or pharmacodynamics of etomidate.