Riot control agents: the tear gases CN, CS and OC-a medical review.

INTRODUCTION: 2-Chloroacetophenone (CN), o-chlorobenzylidene malonitrile (CS) and oleoresin capsicum (OC) are common riot control agents. While serious systemic effects are uncommon, exposure to high concentrations may lead to severe complications and even death. The aim of this narrative review is to summarise all main aspects of the riot control agents CN, CS and OC toxicology, including mechanisms of toxicity, clinical features and management. METHODS: OVID MEDLINE and ISI Web of Science were searched for terms associated with CN, CS and OC toxicity in humans and those describing the mechanism of action, clinical features and treatment protocols. RESULTS: CN, CS and OC are effective lacrimating agents; evidence for toxicity, as measured by the threshold for irritation, is greatest for CN, followed by CS and OC. Typically, ocular and respiratory tract irritation occurs within 20-60 s of exposure. Ocular effects involve blepharospasm, photophobia, conjunctivitis and periorbital oedema. Following inhalation, effects may include a stinging or burning sensation in the nose, tight chest, sore throat, coughing, dyspnoea and difficulty breathing. Dermal outcomes are variable, more severe for CN and include dermal irritation, bulla formation and subcutaneous oedema. Removal from the contaminated area and fresh air is a priority. There is no antidote; treatment consists of thorough decontamination and symptom-directed supportive care. Ocular exposure requires thorough eye decontamination, an eye exam and appropriate pain management. Monitoring and support of respiratory function is important in patients with significant respiratory symptoms. Standard treatment protocols may be required with patients with pre-existing respiratory conditions. Dermal exposures may require systemic steroids for patients who develop delayed contact dermatitis. CONCLUSIONS: CN, CS and OC are effective riot control agents. In the majority of exposures, significant clinical effects are not anticipated. The irritant effects can be minimised both by rapid evacuation from sites of exposure, decontamination and appropriate supportive care.

Queensland Lung Cancer Screening Study: rationale, design and methods.

BACKGROUND: Lung cancer is the leading cause of cancer-related mortality in Australia. Screening using low-dose computed tomography (LDCT) can reduce lung cancer mortality. The feasibility of screening in Australia is unknown. This paper describes the rationale, design and methods of the Queensland Lung Cancer Screening Study. AIMS: The aim of the study is to describe the methodology for a feasibility study of lung cancer screening by LDCT in Australia. METHODS: The Queensland Lung Cancer Screening Study is an ongoing, prospective observational study of screening by LDCT at a single tertiary institution. Healthy volunteers at high risk of lung cancer (age 60-74 years; smoking history ≥30 pack years, current or quit within 15 years; forced expiratory volume in 1s ≥50% predicted) are recruited from the general public through newspaper advertisement and press release. Participants receive a LDCT scan of the chest at baseline, year 1 and year 2 using a multidetector helical computed tomography scanner and are followed up for a total of 5 years. Feasibility of screening will be assessed by cancer detection rates, lung nodule prevalence, optimal management strategies for lung nodules, economic costs, healthcare utilisation and participant quality of life. CONCLUSIONS: Studying LDCT screening in the Australian setting will help us understand how differences in populations, background diseases and healthcare structures modulate screening effectiveness. This information, together with results from overseas randomised studies, will inform and facilitate local policymaking.

Voltage-gated potassium channels regulate calcium-dependent pathways involved in human T lymphocyte activation.

The role that potassium channels play in human T lymphocyte activation has been investigated by using specific potassium channel probes. Charybdotoxin (ChTX), a blocker of small conductance Ca(2+)-activated potassium channels (PK,Ca) and voltage-gated potassium channels (PK,V) that are present in human T cells, inhibits the activation of these cells. ChTX blocks T cell activation induced by signals (e.g., anti-CD2, anti-CD3, ionomycin) that elicit a rise in intracellular calcium ([Ca2+]i) by preventing the elevation of [Ca2+]i in a dose-dependent manner. However, ChTX has no effect on the activation pathways (e.g., anti-CD28, interleukin 2 [IL-2]) that are independent of a rise in [Ca2+]i. In the former case, both proliferative response and lymphokine production (IL-2 and interferon gamma) are inhibited by ChTX. The inhibitory effect of ChTX can be demonstrated when added simultaneously, or up to 4 h after the addition of the stimulants. Since ChTX inhibits both PK,Ca and PK,V, we investigated which channel is responsible for these immunosuppressive effects with the use of two other peptides, noxiustoxin (NxTX) and margatoxin (MgTX), which are specific for PK,V. These studies demonstrate that, similar to ChTX, both NxTX and MgTX inhibit lymphokine production and the rise in [Ca2+]i. Taken together, these data provide evidence that blockade of PK,V affects the Ca(2+)-dependent pathways involved in T lymphocyte proliferation and lymphokine production by diminishing the rise in [Ca2+]i that occurs upon T cell activation.

Improvement after angioplasty and stenting of pulmonary arteries due to sarcoid mediastinal fibrosis.

We describe a series of cases referred to our institution with working diagnoses of chronic thrombo-embolic pulmonary hypertension (CTEPH) for consideration of surgical pulmonary thrombo-endarterectomy (PTE). Investigations in two cases revealed extrinsic compression of the pulmonary arteries from massive mediastinal lymphadenopathy (mediastinal fibrosis) due to underlying sarcoidosis. Angioplasty and stenting of the pulmonary arteries were performed in all cases with sustained haemodynamic and functional improvement. This highlights the value of new imaging modalities in delineating causes of pulmonary hypertension, and demonstrates an interventional approach for selected cases.

Treatment options and strategies for acute severe pulmonary embolism.

Pulmonary thromboembolism (PE) is the third most frequent cause of cardiovascular death after ischaemic heart disease and stroke. In fatal PE, 2/3 of patients die within first hour of presentation. There is a clinical impetus to rapidly recognize, risk-stratify and appropriately treat patients with acute severe PE. Current recommendations present conflicting classification systems, and there is often some confusion in the clinical evaluation and management of patients with acute severe PE. This review presents a series of real clinical cases, which illustrate the available treatment options, ranging from conservative therapy to thrombolysis through to percutaneous catheter fragmentation and open surgical embolectomy. We evaluate the evidence for the various strategies and propose an algorithm for clinicians with a focus on early risk stratification and timely referral. This is particularly relevant to regional and remote centres, as well as secondary and tertiary institutions.

Ibogaine for treating drug dependence. What is a safe dose?

The indole alkaloid ibogaine, present in the root bark of the West African rain forest shrub Tabernanthe iboga, has been adopted in the West as a treatment for drug dependence. Treatment of patients requires large doses of the alkaloid to cause hallucinations, an alleged integral part of the patient's treatment regime. However, case reports and case series continue to describe evidences of ataxia, gastrointestinal distress, ventricular arrhythmias and sudden and unexplained deaths of patients undergoing treatment for drug dependence. High doses of ibogaine act on several classes of neurological receptors and transporters to achieve pharmacological responses associated with drug aversion; limited toxicology research suggests that intraperitoneal doses used to successfully treat rodents, for example, have also been shown to cause neuronal injury (purkinje cells) in the rat cerebellum. Limited research suggests lethality in rodents by the oral route can be achieved at approximately 263mg/kg body weight. To consider an appropriate and safe initial dose for humans, necessary safety factors need to be applied to the animal data; these would include factors such as intra- and inter-species variability and for susceptible people in a population (such as drug users). A calculated initial dose to treat patients could be approximated at 0.87mg/kg body weight, substantially lower than those presently being administered to treat drug users. Morbidities and mortalities will continue to occur unless practitioners reconsider doses being administered to their susceptible patients.

Sodium-calcium exchange in sarcolemmal vesicles from tracheal smooth muscle.

Sarcolemmal vesicles prepared by a new procedure from bovine tracheal smooth muscle were found to have a Na-Ca exchange activity that is significantly higher than that reported for different preparations from other types of smooth muscle. The exchange process system co-purified with 5'-nucleotidase, a plasma membrane marker enzyme, and was significantly enriched (over 100-fold) compared to mitochondria (cytochrome-c oxidase) but only slightly enriched (4-fold) compared to sarcoplasmic reticulum (NADPH-cytochrome-c reductase). The Na+ dependence of Ca2+ transport was demonstrated through both uptake and efflux procedures. The uptake profile with respect to Ca2+ was monotonic with a linear vo VS. vo.S-1 plot. The resultant Km of Ca2+ from the airway sarcolemmal vesicles (20 microM) was similar in magnitude to the Km of cardiac sarcolemmal vesicles (30 microM). Tracheal vesicles demonstrated a Vmax of 0.3-0.5 nmol.mg-1.s-1 which is significantly higher than that reported in preparations from other smooth muscle types. Furthermore, two processes found to stimulate cardiac Na-Ca exchange, pretreatment with either a mixture of dithiothreitol and Fe2+ or with chymotrypsin, were ineffective on the tracheal smooth muscle. Thus, the Na-Ca exchanger identified in tracheal smooth muscle appears to be different from that observed in cardiac muscle, implying that regulation of this activity may also be different.

Comparison of pharmacokinetics and pharmacodynamics of short- and long-term glyburide therapy in NIDDM.

OBJECTIVE: To examine the pharmacokinetics and pharmacodynamics of glyburide after single- and multiple-dose administration in patients with type II diabetes. RESEARCH DESIGN AND METHODS: Twenty patients with type II diabetes between 40 and 70 years of age participated in the study. A 24-h pharmacokinetic evaluation including a 4-h Sustacal tolerance test was conducted before instituting glyburide therapy (baseline), after the first 2.5-mg test dose of glyburide and at weeks 6 and 12 of chronic glyburide therapy. Glyburide doses were titrated with a target goal of achieving a fasting plasma glucose of < or = 7.8 mmol/l or to reach maximum daily doses of 20 mg. RESULTS: A significant prolongation in the elimination half-life (t1/2: week 0, 4.0 +/- 1.9 h; week 6, 13.7 +/- 10.5 h; and week 12, 12.1 +/- 8.2 h) and an increased volume of distribution of glyburide was observed during chronic dosing. These results strongly suggest possible drug accumulation. No differences in pharmacokinetic parameters were noted between evaluations at week 6 or week 12. Changes in pharmacodynamic response of glucose, insulin, and C-peptide to chronic glyburide therapy were observed. Glyburide therapy significantly reduced plasma glucose levels at weeks 6 and 12 (percent changes in AUC0-->4. glucose from baseline: week 0, -3 +/- 11%; week 6, -29 +/- 13%; and week 12, -26 +/- 19%). Pancreatic insulin secretion was acutely enhanced and maintained during long-term therapy. Responsiveness to therapy as assessed by the ratio of AUC0-->4.glucose:AUC0-->4.C-peptide was significantly improved at all weeks compared with baseline. No pharmacodynamic response differences were observed between the week 6 and the week 12 evaluations. CONCLUSIONS: This study demonstrates that significant differences in glyburide pharmacokinetics and pharmacodynamics exist between single-dose and steady-state conditions. These differences support the need for careful dosage titration of glyburide to achieve a desired therapeutic response in patients with type II diabetes.

Delayed seizure-like activity following analytically confirmed use of previously unreported synthetic cannabinoid analogues.

Synthetic cannabinoid use has become widespread, leading to increased burdens on health care providers. Symptoms range from agitation and psychosis to seizures and acute kidney injury. We report a case where a patient was assessed and treated twice within 12 h for seizures following synthetic cannabinoid intoxication. Blood sample determinations showed low concentrations of analogues not previously reported, some of which are legal. Clinicians should be aware that synthetic cannabinoids may cause an array of severe health consequences. Given the ever evolving structure of available analogues, clinicians must also be prepared for other unexpected adverse effects.

N-linked oligosaccharides are not required for hormone binding of the lutropin receptor in a Leydig tumor cell line and rat granulosa cells.

We have examined roles of carbohydrates of the lutropin receptor in a murine Leydig tumor cell line (MLTC) and primary cultures of rat granulosa cells. We approached this issue by deglycosylating mature receptors with glycosidases and by preventing glycosylation of nascent receptors with tunicamycin B2, an inhibitor of protein glycosylation but not protein synthesis. Deglycosylation of mature receptors with neuraminidase, N-glycanase or both did not affect ligand binding capacity. Regardless of glycosidase treatment, the number of hormone binding sites was similar. The Kas for native receptors, asialoreceptors and aglycoreceptors, are also comparable, being 2.0 x 10(9) M-1, 1.9 x 10(9) M-1 and 1.7 x 10(9) M-1 respectively. In contrast, cells treated with tunicamycin B2 failed to bind the hormone. These results demonstrate that N-oligosaccharides of mature lutropin receptors are not required for ligand binding. In addition, our data suggest, for the first time, that N-glycosylation of the receptor may be necessary for expressing functional receptors on the cell surface and that there exist striking similarities in roles of oligosaccharides of lutropin and its receptor.

Structure of the luteinizing hormone receptor gene and multiple exons of the coding sequence.

The genomic structure of the LH receptor is important to our understanding of its expression mechanisms, functional domains, relationships with other hormone receptors, and evolution. We have isolated four overlapping cosmid clones and six subgenomic clones of the rat LH receptor gene. They span a total of 95.6 kilobases (kb) and extend from 23 kb upstream of the translation start site to 13 kb down-stream of the stop codon. In addition, part of the human LH receptor gene has been isolated. The coding region of the rat hormone receptor gene spans over 60 kb and consists of 11 exons and 10 introns. Southern blots hybridized with exon 1 and exon 11 probes as well as gene dose analyses demonstrate that a single copy gene encodes the rat LH receptor. Sequence comparison suggests that the porcine and human LH receptor genes have similar, if not identical, exon-intron structures. There is no consensus cAMP-responsive element within 600 basepairs up-stream of the translation start site in spite of the cAMP responsiveness of the LH receptor gene. There are, however, unconventional cAMP-responsive elements in the region: one which is identical, several which are homologous to the activating protein-2-binding elements, CCCCAGGC, and several sequences which are similar to the G-rich cAMP-responsive element found in P450c21, a steroid 21-hydroxylase. The first 10 exons encode the N-terminal half of the molecule, while exon 11 encodes the C-terminal half of the molecule. This last exon is the same in the rat and human genes. The DNA and amino acid sequences of the first 10 exons show significant similarities and reveal repetitive sequence motifs. They have similar sizes which occur in the range of 69 and 183 bases; 8 of them are from 69-81 bases. Despite these remarkable similarities, structural predictions of exons 1-10 show a diversity of structures. The N-terminal half of the LH receptor appears to have a folded structure, with frequent turns and an extensive surface area. Part of the surface is predicted to be covered by amphiphilic helices and beta structures, types of secondary structure frequently found at the interfaces between subunits or between 2 interacting molecules. The introns dividing these exons also share many similarities.(ABSTRACT TRUNCATED AT 400 WORDS)

Ketoconazole effects on methylprednisolone disposition and their joint suppression of endogenous cortisol.

The effects of ketoconazole and methylprednisolone on endogenous cortisol were studied in eight normal subjects. Intravenous methylprednisolone sodium succinate was given alone in doses of 15 or 30 mg. The methylprednisolone dose was reduced by 57% when ketoconazole was administered chronically for 1 week to seek equivalent methylprednisolone AUCs by compensating for the expected reduction in methylprednisolone clearance. Ketoconazole decreased clearance by 46% and increased mean residence time by 37%. The ratio of the cortisol AUC during each drug treatment compared with baseline conditions was used to assess the net extent and duration of cortisol suppression. This cortisol AUC ratio was reduced from 0.45 (methylprednisolone) to 0.39 (methylprednisolone plus ketoconazole), suggesting that ketoconazole modestly enhanced (P less than 0.01) cortisol suppression. Based on the reduction in methylprednisolone clearance and cortisol AUC by ketoconazole, a 50% lower dose of methylprednisolone during concomitant therapy with ketoconazole is recommended.

Alpha1-acid glycoprotein concentration and protein binding in trauma.

Alpha 1-Acid glycoprotein (AAG) concentrations were measured every 2 to 3 days in eight trauma patients and seven healthy subjects for approximately 3 wk. Mean AAG concentrations in the trauma patients rose from 100 mg/dl to a peak value of 243 mg/dl at 10 to 14 days. AAG levels averaged more than 200 mg/dl at 15 to 21 days. Mean AAG concentration in healthy subjects was 70 mg/dl with little inter- or intraindividual variability. Lidocaine was added to all serum samples from four of the patients and to selected samples from all of the healthy subjects and protein binding was determined. The binding ratio (bound concentration/free concentration) correlated strongly with AAG concentration in the trauma patients (r = 0.92), in the healthy subjects (r = 0.84), and in both groups combined (r = 0.96). AAG concentration and binding ratio for each of the four patients individually also correlated (P less than 0.05 in all cases). The change in free fraction associated with this increase in AAG was approximately doubled in each patient. Similar findings with drugs commonly used in trauma patients would be expected to alter serum concentration-response relationships significantly.

Mechanisms of nonlinear disposition kinetics of sulfamethazine.

Five healthy male subjects received oral doses of 10 and 40 mg/kg of sulfamethazine (SMZ) approximately 14 days apart in a nonrandomized crossover study. Blood and urine samples were collected for at least 24 and 72 hr, respectively. All samples were assayed by the Bratton-Marshall procedure for SMZ and apparent N-acetylsulfamethazine (NSMZ). Recovery of total drug (SMZ + NSMZ) in urine was 88.9% following the low and 79.5% following the high dose. The low and high dose plasma concentration time curves were not readily superimposable (i.e., nonlinear kinetic behavior was observed). The data suggest that several mechanisms contribute to the nonlinearity. Specifically, a dose-dependent decrease in absorption rate displaced the plasma concentration-time curve to the right in some subjects, whereas apparent metabolic clearance (Clm) decreased with increasing dose (estimated assuming dose = amount of SMZ + NSMZ in urine to 72 hr) in all subjects (0.35 ml/min/kg for the low and 0.23 for the high dose). Still greater dose-dependent effects were found when apparent Clm of unbound drug was determined, since free fraction rose from 0.11 to 0.30 over the observed plasma concentration range. Renal clearance (ClR) of Smz appeared to be a complex function of time. In the low dose study it ranged from an average of 0.071 ml/min/kg at 2 hr to 0.146 ml/min/kg at 6 hr after drug. After the high dose comparable values were 0.083 and 0.128. Interindividual variability and pronounced nonlinear kinetics of SMZ after 40 mg/kg suggest that this dose is probably a poor choice for the determination of acetylator phenotype.

Effects of ketoconazole on methylprednisolone pharmacokinetics and cortisol secretion.

The disposition of methylprednisolone was examined in six normal subjects after the injection of 20 mg iv methylprednisolone sodium succinate. Disposition studies were performed both without and with ketoconazole, 200 mg/day, for 6 days. Ketoconazole increased the methylprednisolone AUC and mean residence time (by 135% and 66%, respectively) and decreased clearance (60%), the terminal phase slope, and the volume of distribution. These findings are typical of macrolide antibiotic alteration of methylprednisolone disposition and consistent with reports of inhibition of drug metabolism by ketoconazole. Methylprednisolone reduced the 24-hour cortisol AUC by 44%, but morning cortisol concentrations returned to normal. Ketoconazole with methylprednisolone further reduced the 24-hour cortisol AUC and suppressed morning cortisol concentrations. Thus ketoconazole inhibits methylprednisolone disposition and extends the adrenal suppression effects of this corticosteroid.

Pharmacokinetics and pharmacodynamics of methylprednisolone in obesity.

Methylprednisolone pharmacokinetics and its directly suppressive effects on plasma cortisol, blood histamine (basophils), and circulating helper T cells were evaluated in six obese (at least 35% above ideal body weight) men and six nonobese male volunteers. Methylprednisolone doses of 0.6 mg/kg total body weight were administered as the 21-succinate sodium salt. Absolute clearance (in liters per hour) of methylprednisolone was 40% less in the obese subjects. Total volume of distribution (Vss) of methylprednisolone was unchanged (about 120 L), but when normalized for total body weight, Vss per kilogram was less in obesity. The patterns of cortisol, blood histamine, and helper T cell responses after methylprednisolone administration were similar in both groups, but more profound effects were observed in the obese subjects. Pharmacodynamic models were applied for these immediate effects of methylprednisolone based on the premise that receptor interactions of steroids are followed by rapid suppression of the circadian rhythm of cortisol and recirculation of basophils and helper T cells, which persist until inhibitory concentrations (IC50) of methylprednisolone disappear. Similar IC50 values for the three effects were obtained in both groups, indicating no intrinsic pharmacodynamic differences in sensitivity to these methylprednisolone effects in obesity. However, methylprednisolone should be administered on the basis of ideal body weight, and the dosing interval should be potentially lengthened because of decreased methylprednisolone clearance in obesity.

Chloramphenicol sodium succinate kinetics in critically ill patients.

Chloramphenicol sodium succinate (SCAP) kinetics were studied in 10 critically ill patients. High-performance liquid chromatography was used to assay SCAP and chloramphenicol (CAP) in serum and urine. Total body (ClTB), metabolic (ClM), and renal (ClR) clearances of SCAP were variable. Correlations were found between creatinine clearance (Clcr) and ClTB, ClM, and ClR of SCAP (r = 0.92, p less than 0.001; r = 0.84, p less than 0.005; and r = 0.84, p less than 0.005). Recovery of SCAP in the urine also demonstrated large interpatient variability. Between 6.5% and 43.5% of the SCAP dose was recovered in the urine of 6 patients. This variability could not be explained by incomplete urine collection or by differences in renal function. Renal excretion of SCAP was shown to influence CAP serum levels. CAP ClTB was diminished, but no relationship was found between routine liver function studies and CAP ClTB. Therefore we caution the use of such relationships in using CAP in critically ill patients.

Pharmacokinetics and pharmacodynamic modeling of direct suppression effects of methylprednisolone on serum cortisol and blood histamine in human subjects.

Pharmacodynamic models for "directly suppressive" effects of methylprednisolone are based on the premise that receptor interactions of steroids are followed by immediate suppression of either the circadian secretion of cortisol or the constant rate recirculation of histamine-containing basophils that persists until inhibitory concentrations of methylprednisolone disappear. Methylprednisolone doses of 0, 10, 20, and 40 mg were given as the 21-succinate sodium salt in a balanced crossover study to six normal men. Plasma steroid concentrations and blood histamine were measured simultaneously. Both forms of methylprednisolone exhibited linear kinetic parameters. One dynamic model quantitates the baseline circadian pattern and the decline and return of cortisol with similar parameter estimates for all three dose levels. A similar model describes the monoexponential decline and the log-linear return to steady-state baseline of blood histamine. Similar inhibitory concentration values for both effects approximated the equilibrium dissociation constant of in vitro steroid receptor binding. The new models are more physiologically appropriate for these steroid effects than three other models that are commonly employed in pharmacodynamics. Steroid effects generally appear to be receptor mediated with either nongene immediate responses or gene-mediated delayed effects. These models allow quantitation of the rapid effects of steroids with simple equations and common fitted parameters for all steroid dose levels.