羟氨苄青霉素引起大疱性类天疱疮样疹

Drugs with low water solubility are predisposed to low and variable oral bioavailability and, therefore, to variability in clinical response. Despite significant efforts to "design in" acceptable developability properties (including aqueous solubility) during lead optimization, approximately 40% of currently marketed compounds and most current drug development candidates remain poorly water-soluble. The fact that so many drug candidates of this type are advanced into development and clinical assessment is testament to an increasingly sophisticated understanding of the approaches that can be taken to promote apparent solubility in the gastrointestinal tract and to support drug exposure after oral administration. Here we provide a detailed commentary on the major challenges to the progression of a poorly water-soluble lead or development candidate and review the approaches and strategies that can be taken to facilitate compound progression. In particular, we address the fundamental principles that underpin the use of strategies, including pH adjustment and salt-form selection, polymorphs, cocrystals, cosolvents, surfactants, cyclodextrins, particle size reduction, amorphous solid dispersions, and lipid-based formulations. In each case, the theoretical basis for utility is described along with a detailed review of recent advances in the field. The article provides an integrated and contemporary discussion of current approaches to solubility and dissolution enhancement but has been deliberately structured as a series of stand-alone sections to allow also directed access to a specific technology (e.g., solid dispersions, lipid-based formulations, or salt forms) where required.

Strategies to Address Low Drug Solubility in Discovery and Development

Protein nanoparticles as drug carriers in clinical medicine.

Taxanes are standard treatment for metastatic breast cancer; however, the solvents used as vehicles in these formulations cause severe toxicities The FDA recently approved a solvent-free formulati

http://www.protocol-online.org/forums/uploads/monthly_11_2009/msg-6644-1257363554.ipb

Albumin-bound paclitaxel: a next-generation taxane

ol triricinoleate 35) and polysorbate 80 (Tween 80; polyoxyethylene-sorbitan-20-monooleate) are widely used as drug formulation vehicles, including for the taxane anticancer agents paclitaxel and docetaxel. A wealth of recent experimental data has indicated that both solubilisers are biologically and pharmacologically active compounds, and their use as drug formulation vehicles has been implicated in clinically important adverse effects, including acute hypersensitivity reactions and peripheral neuropathy. CrEL and Tween 80 have also been demonstrated to influence the disposition of solubilised drugs that are administered intravenously. The overall resulting effect is a highly increased systemic drug exposure and a simultaneously decreased clearance, leading to alteration in the pharmacodynamic characteristics of the solubilised drug. Kinetic experiments revealed that this effect is primarily caused by reduced cellular uptake of the drug from large spherical micellar-like structures with a highly hydrophobic interior, which act as the principal carrier of circulating drug. Within the central blood compartment, this results in a profound

Pharmacological effects of formulation vehicles : implications for cancer chemotherapy.

Incidence and clinical importance of perioperative histamine release: randomised study of volume loading and antihistamines after induction of anaesthesia

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.

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.

Objective and design:Patient recruitment is a major problem in clinical trials. In a survey, the attitude of a public sample towards clinical trials was assessed.

Attitude towards clinical trials: results of a survey of persons interested in research.

Acute cholecystitis is an often unrecognized and potentially life-threatening complication seen among ICU patients with multiple injury. To investigate the epidemiology of this entity and to evaluate significant etiologic precursors, a prospective clinical and sonographic study was performed in 45 consecutive patients (mean age, 29 years) treated for multiple trauma (mean ISS, 27) in the ICU. Eight of 45 patients developed a cholecystitis during intensive care treatment (18%). Six patients recovered with conservative therapy; in two instances a cholecystectomy was necessary. There was no mortality as a result of cholecystitis. A significant relationship between the severity of the initial trauma (p less than 0.05), the number of blood transfusions (p less than 0.01), and the incidence of acute cholecystitis was found. Other factors such as prolonged shock, respiratory failure, or parenteral alimentation were less prevalent and were not temporally related to the onset of the disease. All patients had large amounts of narcotics administered over a prolonged period, so that narcotic-induced biliary stasis appeared to be another eminent factor involved in the genesis of posttraumatic cholecystitis. Our results lead to the conclusion that acute cholecystitis occurs with an unexpectedly high incidence and that a high remission rate can be expected following conservative treatment provided that appropriate serial ultrasound examinations are performed.

Ch. Ohmann

Papers

Incidence and clinical importance of perioperative histamine release: randomised study of volume loading and antihistamines after induction of anaesthesia

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.

Attitude towards clinical trials: results of a survey of persons interested in research.

Acute cholecystitis: a complication in severely injured intensive care patients.

Histamine Release in Anaesthesia and Surgery: A New Method to Evaluate its Clinical Significance with Several Types of Causal Relationship