Epidemiology and outcomes of primary sclerosing cholangitis: an Australian multicentre retrospective cohort study.

BACKGROUND AND AIMS: Little is known regarding the epidemiology and outcomes of patients with primary sclerosing cholangitis (PSC) in Australia. We, therefore, evaluated the epidemiology and clinical outcomes of PSC in a large cohort of Australian patients and compared these to the general population. METHODS: We conducted a multicentre, retrospective cohort study of PSC patients at nine tertiary liver centers across three Australian states, including two liver transplant centers. RESULTS: A total of 413 PSC patients with 3,285 person-years of follow-up were included. Three hundred and seventy-one (90%) patients had large duct PSC and 294 (71%) had associated inflammatory bowel disease. A total of 168 (41%) patients developed cirrhosis (including 34 at the time of PSC diagnosis) after a median of 15.8 (95% CI 12.4, NA) years. The composite endpoint of death or liver transplantation occurred in 49 (12%) and 78 (19%) patients, respectively, with a median transplant-free survival of 13.4 (95% CI 12.2-15) years. Compared to the general population, PSC accounted for a 240-fold increased risk of development of cholangiocarcinoma (CCA) and CCA-related death. CCA risk was increased with older age of PSC diagnosis, presence of dominant stricture and colectomy. Compared to same-aged counterparts in the general population, PSC patients who were diagnosed at an older age or with longer disease duration had reduced relative survival. CONCLUSION: In this large retrospective cohort study of PSC patients in Australia, increased age and time from diagnosis was associated with increased mortality and morbidity particularly from CCA and development of cirrhosis, necessitating need for liver transplant.

Cannabinoid1 receptor in the dorsal vagal complex modulates lower oesophageal sphincter relaxation in ferrets.

Delta9-tetrahydrocannabinol (delta9-THC) is an effective anti-emetic; however, other potential gastrointestinal therapeutic effects of delta9-THC are less well-known. Here, we report a role of delta9-THC in a vago-vagal reflex that can result in gastro-oesophageal reflux, that is, gastric distension-evoked lower oesophageal sphincter (LOS) relaxation. Oesophageal, LOS and gastric pressures were measured using a miniaturized, manometric assembly in decerebrate, unanaesthetized ferrets.Gastric distension (30 ml) evoked LOS relaxation (70 +/- 8% decrease from baseline). Delta9-THC administered systemically (0.2 mg kg-1, iv.) or directly to the dorsal hindbrain surface (0.002 mg),significantly attenuated the nadir of the gastric distention-evoked LOS relaxation, and time to reach maximal response. Similar increases to maximal effect were observed after treatment with the cannabinoid receptor agonist WIN 55,212-2 (0.2 mg kg-1 iv.). The effect of systemic delta9-THC on gastric distention-evoked LOS relaxation was reversed by a selective cannabinoid1 (CBI) receptor antagonist, SR141617A (1 mg kg-1 i.v.). Since this reflex is vagally mediated, we used a CB1 receptor antiserum and immunocytochemistry to determine its distribution in ferret vagal circuitry. CBI receptor staining was present in cell bodies within the area postrema, nucleus tractus solitarius (NTS) and nodose ganglion. Intense terminal-like staining was noted within the NTS and dorsal motor vagal nucleus (DMN). Neither nodose ganglionectomy nor vagotomy altered the CB1 receptor terminal-like staining in the dorsal vagal complex. Retrogradely labelled gastric- or LOS-projecting DMN neurones did not express CBI receptors within their soma. Therefore, CBI receptor staining in the NTS and DMN is not due to primary vagal afferents or preganglionic neurones. These novel findings suggest that delta9-THC can modulate reflex LOS function and that the most likely site of action is via the CBI receptor within the NTS. This effect of delta9-THC may have implications in treatment of gastro-oesophageal reflux and other upper gut disorders.

Central mechanisms of lower esophageal sphincter control.

Lower esophageal sphincter (LES) tone is decreased during swallowing, during transient LES relaxations (TLESRs), and before emesis, and this decrease is due primarily to increasing inhibitory vagal output to the LES. Reflex-evoked relaxation of the LES is mediated by long-loop vagovagal reflexes that are coordinated by the dorsal vagal complex in the hindbrain medulla. A sequence of events occurs. Central control of TLESRs has not been studied directly; the information on how drugs may work centrally to reduce TLESRs is extrapolated from knowledge of how the brain evokes LES relaxation. Reduction of the frequency of TLESRs by a GABAB agonist, baclofen, is due to inhibition of vagal afferents, information transfer between the nucleus tractus solitarius and dorsal motor nucleus of the vagus, and vagal efferent outflow. Preliminary data show that cannabinoid receptor activation reduces information transfer between the nucleus tractus solitarius and dorsal motor nucleus of the vagus. The potential therapeutic usefulness of these types of agents that reduce TLESRs by acting centrally is promising.

Lower oesophageal sphincter relaxation evoked by stimulation of the dorsal motor nucleus of the vagus in ferrets.

An understanding of the neural control of lower oesophageal sphincter (LOS) relaxation is clinically relevant because transient LOS relaxations (TLOSRs) are a mechanism of acid reflux into the oesophagus. Preganglionic motor neurones innervating the LOS are localized in the dorsal motor nucleus of the vagus (DMV). Based on a single study in cats, it is now widely accepted that these neurones are functionally organized into two separate populations, such that stimulation of the caudal and rostral DMV evokes LOS relaxation and contraction, respectively. Our goal was to map the functional LOS responses to chemical stimulation in the DMV and nucleus tractus solitarius (NTS) of ferrets, an animal model commonly used for conscious studies on TLOSRs, and to test whether DMV-evoked LOS relaxation is mediated through hexamethonium-sensitive vagal-inhibitory pathways to the LOS. We used miniaturized manometry with Dentsleeve to monitor LOS and oesophageal pressures in decerebrate unanaesthetized ferrets. LOS relaxation was evoked readily in response to gastric insufflation, which shows that the vago-vagal reflex was intact in this preparation. Microinjections of l-glutamate (12.5 nmol L-1 in 25 nL) were made into the DMV from approximately - 1.5 to + 2.0 mm relative to the obex. Microinjections into the caudal (- 1.5 to + 0.0 mm behind obex) and intermediate (+ 0.1 to + 1.0 mm rostral to obex) DMV both significantly decreased LOS pressure, and complete LOS relaxation was noted in 28/32 and 11/18 cases, respectively. LOS relaxation responses to DMV microinjection were highly reproducible and abolished by bilateral vagotomy or hexamethonium (15 mg kg-1 intravenously). A nitric oxide synthase inhibitor (l-NAME 100 mg kg-1 intramuscularly) significantly increased the time taken to reach the maximal response. Increases in LOS pressure (24 +/- 4 mmHg; n = 3) were obtained only when stimulation sites were located equal to greater than 1.5 mm rostral to the obex. LOS relaxation (- 78 +/- 10%; n = 6) was evoked by stimulation of the NTS but not immediately outside of the NTS (11 +/- 27%; n = 5). We conclude that there is a very extensive population of 'inhibitory' motor neurones in the DMV that may account for the predominant vagal-inhibitory tone in ferrets. As NTS stimulation evokes LOS relaxation and the predominant response to DMV stimulation is also LOS relaxation, this vago-vagal reflex may involve an excitatory interneurone between the NTS and DMV vagal inhibitory output.

Site of action of GABA(B) receptor for vagal motor control of the lower esophageal sphincter in ferrets and rats.

BACKGROUND & AIMS: Stimulation of gamma-aminobutyric acid B metabotropic receptors (GBRs) by baclofen reduces the incidence of transient lower esophageal sphincter (LES) relaxations. The GBR effect may be a result of a central site of action in the dorsal vagal complex, where upper gastrointestinal vagal reflexes are integrated. Therefore, we first localized GBR immunostaining in the dorsal vagal complex. Next, we tested the hypothesis that baclofen modulates LES motor tone via GBR expressed by vagal efferent neurons. METHODS: An antibody against the human GBR1b isoform was characterized and used for immunocytochemistry in rats and ferrets. Functional studies involved microinjection of L-glutamate into the caudal dorsal motor nucleus of the vagus to evoke an LES relaxation in decerebrate unanesthetized ferrets. RESULTS: In both species, GBR1b was expressed in preganglionic motor neurons and, in ferrets, the receptor was highly expressed in identified LES-projecting preganglionic neurons. GBR1b immunostaining was also pronounced in the subnucleus centralis of the nucleus tractus solitarius. This distribution implicates GBR in control of the esophageal phase of swallowing at the level of the central program generator. In functional studies, centrally evoked LES relaxation (-73% +/- 8% mm Hg) was significantly attenuated after 7 micromol/kg intravenous baclofen (-37% +/- 10%; N = 5). CONCLUSIONS: These data all suggest that GBR agonists inhibit LES relaxation via a site of action associated with vagal motor outflow to the LES.

Organization and neurochemistry of vagal preganglionic neurons innervating the lower esophageal sphincter in ferrets.

The motor control of the lower esophageal sphincter (LES) is critical for normal swallowing and emesis, as well as for the prevention of gastroesophageal reflux. However, there are surprisingly few data on the central organization and neurochemistry of LES-projecting preganglionic neurons. There are no such data in ferrets, which are increasingly being used to study LES relaxation. Therefore, we determined the location of preganglionic neurons innervating the ferret LES, with special attention to their relationship with gastric fundus-projecting neurons. The neurochemistry of LES-projecting neurons was also investigated using two markers of "nontraditional" neurotransmitters in vagal preganglionic neurons, nitric oxide synthase (NOS), and dopamine (tyrosine hydroxylase: TH). Injection of cholera toxin B subunit (CTB)-horseradish peroxidase (HRP) into the muscular wall of the LES-labeled profiles throughout the rostrocaudal extent of the dorsal motor nucleus of the vagus (DMN) The relative numbers of profiles in three regions of the DMN from caudal to rostral are, 43 +/- 5, 67 +/- 11, and 113 +/- 30). A similar rostrocaudal distribution occurred after injection into the gastric fundus. When CTB conjugated with different fluorescent tags was injected into the LES and fundus both labels were noted in 56 +/- 3% of LES-labeled profiles overall. This finding suggests an extensive coinnervation of both regions by vagal motor neurons. There were significantly fewer LES-labeled profiles that innervated the antrum (16 +/- 9%). In the rostral DMN, 15 +/- 4% of LES-projecting neurons also contained NADPH-diaphorase activity; however, TH immunoreactivity was never identified in LES-projecting neurons. This finding suggests that NO, but not catecholamine (probably dopamine), is synthesized by a population of LES-projecting neurons. We conclude that there are striking similarities between LES- and fundic-projecting preganglionic neurons in terms of their organization in the DMN, presence of NOS activity and absence of TH immunoreactivity. Coinnervation of the LES and gastric fundus is logical, because the LES has similar functions to the fundus, which relaxes to accommodate food during ingestion and preceding emesis, but has quite different functions from the antrum, which provides mixing and propulsion of contents for gastric emptying. The presence of NOS in some LES-projecting neurons may contribute to LES relaxation, as it does in the case of fundic relaxation. The neurologic linkage of vagal fundic and LES relaxation may have clinical relevance, because it helps explain why motor disorders of the LES and fundus frequently occur together.

Hyperfunctioning parathyroid carcinoma.

Primary hyperparathyroidism is rarely caused by carcinoma. We report a patient who manifested many of the clinical and radiographic features of the disease. When encountering symptomatic hypercalcemia with or without a palpable neck mass, carcinoma should be considered in the differential diagnosis. Patient survival depends on an aggressive surgical approach to the primary lesion and recurrent disease.

Central control of lower esophageal sphincter relaxation.

The lower esophageal sphincter is innervated by both parasympathetic (vagus) and sympathetic (primarily splanchnic) nerves; however, the vagal pathways are the ones that are essential for reflex relaxation of the lower esophageal sphincter (LES), such as that which occurs during transient LES relaxations. Vagal afferent sensory endings from the distal esophagus and LES terminate in the hindbrain nucleus tractus solitarius. The preganglionic motor innervation of the LES arises from the dorsal motor nucleus of the vagus. Together these nuclei comprise the dorsal vagal complex within which there is a neural network coordinating reflex control of the sphincter. Vagal efferent preganglionic neurons to the gastrointestinal tract are organized viscerotopically in the dorsal motor nucleus of the vagus. Stimulation of the dorsal motor nucleus of the vagus caudal to the opening of the fourth ventricle results in relaxations, whereas stimulation in the rostral portion of the nucleus evokes contractions of the LES. Few details are known about the neural circuitry that links sensory information from the stomach and esophagus within the nucleus tractus solitarius to these separate populations of neurons within the dorsal motor nucleus of the vagus. The motor vagal preganglionic output is primarily cholinergic, which ultimately stimulates excitatory or inhibitory motor neurons that control the smooth muscle tone. Excitatory neurons evoke muscarinic receptor-mediated muscle contraction. Inhibitory neurons evoke nitric oxide or vasoactive intestinal polypeptide-mediated relaxation of the lower esophageal sphincter. However, other neurotransmitters are found in vagal preganglionic neurons, including norepinephrine/dopamine and nitric oxide. A subpopulation of nitric oxide synthase-containing vagal preganglionic neurons innervate the upper gastrointestinal tract and mediate relaxation. The neurotransmitters and circuitry controlling lower esophageal sphincter pressure are important to characterize, because part of the dorsal vagal complex is outside of the blood-brain barrier and is a potential target for pharmacologic intervention in the treatment of such disorders as gastroesophageal reflux disease.

Excitation of dorsal motor vagal neurons evokes non-nicotinic receptor-mediated gastric relaxation.

Vagal stimulation results in both gastric motor excitatory and non-adrenergic non-cholinergic (NANC) inhibitory responses. The NANC pathway involves preganglionic cholinergic neurons, which act through nicotinic receptors to ultimately evoke gastric smooth muscle relaxation via release of nitric oxide (NO) and other neurotransmitters. Within the dorsal motor nucleus of the vagus (DMN), some preganglionic neurons also contain NO synthase. The NO synthase-containing neurons innervate the gastric fundus where adaptive relaxation occurs. This study tests the hypothesis that chemical stimulation of vagal motor neurons in animals, in which nicotinic receptors are blocked, evokes an NO-dependent gastric relaxation. A cell body excitant, N-methyl-D-aspartate (NMDA, 0.03-3 nmol), was microinjected into the DMN in anesthetized rats while recording intragastric pressure (IgP). The first group received NMDA before and after administration of a ganglionic blocker, hexamethonium bromide (15 mg/kg, i.v.) and atropine (1.0 mg/kg). Significant dose-dependent increases in IgP and gastric motility occurred before hexamethonium after the 0.3 and 3 nmol doses of NMDA. After hexamethonium, 0.3 and 3 nmol NMDA evoked significant decreases in IgP. A second group of rats was hexamethonium-pretreated and received NMDA microinjection into the DMN before and after an NO synthase inhibitor, N(G)-nitro-L-arginine methyl ester (10 mg/kg, i.v.). The NMDA-evoked decrease in IgP was completely abolished by the NO synthase inhibitor. These data support the novel idea that NO synthase-containing preganglionic neurons mediate gastric relaxation that is independent of nicotinic receptors.

A phase I evaluation of multitargeted antifolate (MTA, LY231514), administered every 21 days, utilizing the modified continual reassessment method for dose escalation.

PURPOSE: To determine toxicities, maximally tolerated dose (MTD), pharmacokinetic profile, and potential antitumor activity of MTA, a novel antifolate compound which inhibits the enzymes thymidylate synthase (TS), glycinamide ribonucleotide formyltransferase (GARFT), and dihydrofolate reductase (DHFR). METHODS: Patients with advanced solid tumors were given MTA intravenously over 10 min every 21 days. Dose escalation was based on the modified continual reassessment method (MCRM), with one patient treated at each minimally toxic dose level. Pharmacokinetic studies were performed in all patients. RESULTS: A total of 37 patients (27 males, 10 females, median age 59 years, median performance status 90%) were treated with 132 courses at nine dose levels, ranging from 50 to 700 mg/m(2). The MTD of MTA was 600 mg/m(2), with neutropenia and thrombocytopenia, and cumulative fatigue as the dose-limiting toxicities. Hematologic toxicity correlated with renal function and mild reversible renal dysfunction was observed in multiple patients. Other nonhematologic toxicities observed included mild to moderate fatigue, anorexia, nausea, diarrhea, mucositis, rash, and reversible hepatic transaminase elevations. Three patients expired due to drug-related complications. Pharmacokinetic analysis during the first course of treatment at the 600 mg/m(2) dose level demonstrated a mean harmonic half-life, maximum plasma concentration (Cpmax), clearance (CL), area under the curve (AUC), and apparent volume of distribution at steady state (Vdss) of 3.08 h, 137 microg/ml, 40.0 ml/min per m(2), 266 microg. h/ml, and 7.0 l/m(2), respectively. An average of 78% of the compound was excreted unchanged in the urine. Partial responses were achieved in two patients with advanced pancreatic cancer and in two patients with advanced colorectal cancer. Minor responses were obtained in six patients with advanced colorectal cancer. CONCLUSIONS: The MTD and dose for phase II clinical trials of MTA when administered intravenously over 10 min every 21 days was 600 mg/m(2). MTA is a promising new anticancer agent.

Vagally-regulated gastric motor activity: evidence for kainate and NMDA receptor mediation.

Blockade of GABA(A) receptors in the dorsal vagal complex produces marked gastric motor excitation. This effect is abolished by a prior microinjection of a non-selective excitatory amino acid receptor antagonist. Here we present functional evidence for kainate and NMDA receptor-mediated gastric excitation in the dorsal vagal complex. Microinjections into the dorsal vagal complex were performed in alpha-chloralose-anesthetized rats using multi-barrelled glass micropipettes while recording intragastric pressure and motility. Kainic acid (30 and 100 pmol in 30 nl) and NMDA (100 and 300 pmol) produced dose-related increases in intragastric pressure and motility. The gastric responses to kainate (30 pmol) and NMDA were selectively abolished by prior microinjection 6,7-dinitroquinoxaline-2,3-dione (600 pmol, 60 nl) and DL-2-amino-5-phosphanopentanoic acid (2 nmol), respectively. Atropine (1 mg/kg, i.v.) pretreatment blocked kainate-, NMDA- and L-glutamate-induced gastric excitation. Thus, both kainate- and NMDA-receptors in the dorsal vagal complex can independently cause vagally-mediated gastric motor excitation.

A phase I and pharmacokinetic study of LY231514, the multitargeted antifolate.

LY231514 is a novel antifolate that principally inhibits thymidylate synthase, but with additional folate-dependent enzyme targets. A Phase I study of single-agent LY231514 administered as a daily i.v. infusion over 10 minutes for 5 days, repeated every 3 weeks, was conducted to evaluate the maximum tolerated dose, pharmacokinetic profile, and antitumor activity of the drug using this schedule. Thirty-eight patients with advanced malignancies that were refractory or not amenable to standard therapy were treated with a total of 116 courses of LY231514, escalating treatment doses through 10 dose levels, from 0.2-5.2 mg/m2/day. No objective clinical responses were observed, although minor antitumor activity not fulfilling the response criteria was seen in three patients. A maximum tolerated dose of 4.0 mg/m2/day was determined, with neutropenia as the predominant dose-limiting toxicity. Reversible disturbances of liver biochemistry, fulfilling the protocol definitions of dose-limiting toxicity, were also observed. Other toxicities included diarrhea, mucositis, skin rash, and fatigue. Pharmacokinetic studies were performed at all treatment levels. Analysis showed a linear relation between administered dose and both maximum plasma concentration (Cmax) and area under the plasma concentration/time curve. The drug was cleared with a day 1 total body clearance of 108.9 +/- 38.8 ml/min/m2, with plasma concentrations declining with a mean harmonic terminal half-life of 1.4 +/- 0.98 h. When given by this schedule, LY231514 is tolerable, and Phase II studies are in progress.

Effects of cocaine on adrenal sympathetic nerve discharge in anesthetized rats.

Cocaine increases the circulating levels of plasma catecholamines, presumably via the activation of the sympathoadrenal axis. However, a number of reports have shown that the predominant response to cocaine is a generalized decrease in sympathetic nerve activity. One possible explanation for the increase in plasma catecholamines may be that the adrenal sympathetic nerve is less sensitive to the sympathoinhibitory actions of cocaine than are other nerves. This study compared the effects of cocaine on adrenal and renal sympathetic nerve discharge (SND) recorded simultaneously in pentobarbital-anesthetized rats. Cocaine produced dose-related decreases in both renal and adrenal SND; however, the decreases in adrenal SND were significantly smaller than in renal SND. Cocaine also elicited pressor responses in these rats. The decreases in adrenal SND were similar in baroreceptor intact and sinoaortically denervated rats, indicating that pressor-mediated baroreceptor reflex activation was not responsible for the decrease in adrenal SND. In a separate group of rats, i.v. administration of desipramine decreased both adrenal and renal SND. As with cocaine, the decreases in adrenal SND after desipramine were smaller, suggesting that the differences in the neural responses did not reflect a differential local anesthetic effect of cocaine on the two nerves. In conclusion, these studies showed that cocaine decreases adrenal SND in pentobarbital-anesthetized rats. However, the adrenal sympathetic nerve is less sensitive than the renal nerve to the sympathoinhibitory actions of cocaine. Whether the adrenal SND remaining after cocaine contributes to the increase in plasma catecholamines produced by this drug remains to be determined.

Intracisternal antisense oligonucleotides to TRH receptor abolish TRH-evoked gastric motor excitation.

Thyrotropin-releasing hormone (TRH) from the nucleus raphe obscurus (nROb) innervates the dorsal vagal complex (DVC) and activates gastric motor function. Assessment of the importance of TRH has been hampered by the lack of TRH receptor antagonists. To overcome this, rats were given intracisternal antisense oligonucleotides against the first 18 bases of TRH receptor mRNA, mismatch oligonucleotides, or saline. Rats were anesthetized, and L-glutamate (15 nmol), TRH (1 and 10 pmol), and saline were microinjected into the DVC and nROb while gastric motor function was monitored. Intracisternal TRH mRNA antisense oligonucleotides abolished the gastric excitatory affects of microinjection of TRH, but not L-glutamate, into the DVC, and the response to TRH recovered after 2 wk of no antisense treatment. Chemical stimulation of the nROb increased intragastric pressure in saline- and mismatch- but not antisense-treated animals. These studies demonstrate that intracisternal TRH receptor antisense oligonucleotides produce a selective and reversible "knockdown" of responsiveness to exogenous TRH in the DVC, as well as to excitation of an endogenous TRH pathway controlling gastric function. It also provides a new tool for assessment of TRH pathways in hindbrain control of gastric function.

Identification of phospholipase A2 and neurotoxic activities in the venom of the New Guinean small-eyed snake (Micropechis ikaheka).

The Papua New Guinean small-eyed snake (Micropechis ikaheka) is recognised as a cause of life-threatening envenoming in certain parts of New Guinea. The clinical features suggest the presence of toxins acting at the neuromuscular junction and on muscle. We have used the mouse phrenic nerve hemidiaphragm preparation, a phospholipase A2 assay, and 125I-neurotoxin-binding radioimmunoassays to look for toxic activities in the crude venom and in preliminary high-performance liquid chromatography (HPLC) fractions. Micropechis ikaheka venom at 1 and 3 micrograms/ml completely abolished nerve-evoked muscle twitch within 70 min at 37 degrees C. There was also a sustained contracture of the muscle and some reduction in twitch tension evoked by direct stimulation; these were explained by the presence of phospholipase A2 activity. The venom inhibited the binding of 125I-alpha-bungaro-toxin to detergent-extracted human muscle acetylcholine receptor (AChR), and inhibited acetylcholine receptor function in a muscle cell line. It also inhibited binding of 125I-omega-conotoxin GVIA to detergent-extracted human frontal cortex voltage-gated calcium channels, but this appeared to be dependent on the phospholipase A2 activity. Identification of the main neurotoxic fractions following HPLC are shown.

Blockade of alpha-2 adrenergic receptors in the rostral ventrolateral medulla attenuates the sympathoinhibitory response to cocaine.

The purpose of this study was to determine whether neurons in the rostral ventrolateral medulla play a role in the sympathoinhibitory response elicited by i.v. administration of cocaine and, if so, to identify the type(s) of receptors involved. Adrenergic antagonists were microinjected bilaterally into the rostral ventrolateral medulla in pentobarbital-anesthetized rats in an attempt to block the decrease in sympathetic nerve discharge (SND) elicited by cocaine (1 mg/kg i.v.). After the bilateral microinjection of saline, cocaine elicited a -56 +/- 5% (mean +/- S.E.) decrease in SND lasting 36 +/- 3 min. Cocaine also increased arterial pressure (21 +/- 3 mm Hg). Prior microinjection of the alpha-2 adrenergic antagonist idazoxan (0.3, 3 or 10 nmol) did not alter the magnitude of the sympathoinhibitory response to cocaine; however, the duration of the response was significantly reduced by all 3 doses (range 21 +/- 3 to 11 +/- 2 min). Similarly, microinjection of the alpha-2 adrenergic antagonist piperoxan (10 nmol) decreased the duration (from 45 +/- 8 to 23 +/- 4 min), but not the magnitude of the sympathoinhibitory response. Microinjection of either the alpha-1 adrenergic antagonist terazosin (0.24 nmol) or the beta adrenergic receptor antagonist propranolol (2 nmol) did not attenuate the decrease in SND elicited by cocaine. The cocaine-mediated pressor response was not affected by any of the antagonist treatments. These data show that the decrease in SND elicited by cocaine is mediated centrally and involves, at least in part, the activation of alpha-2 adrenergic receptors in the rostral ventrolateral medulla.

The depletion of monoamines blocks the sympathoinhibitory response to cocaine.

Recent studies have shown that cocaine decreases, rather than increases sympathetic nerve discharge (SND). Whether these sympathoinhibitory responses are the result of cocaine's actions on monoaminergic transmission (i.e. blockade of neuronal uptake or stimulation of transmitter release) or its local anesthetic actions is not known. The purpose of the present study was to determine the degree to which cocaine's actions on monoaminergic transmission are involved in mediating the sympathoinhibitory response to this drug. We examined the mean arterial pressure, heart rate and splanchnic sympathetic nerve responses elicited by cocaine (1 mg/kg, i.v.) in pentobarbital-anesthetized rats depleted of monoamines. Monoamines were depleted by administering reserpine (10 mg/kg, i.p.) either 24, or 48 and 24 h before the experiment. The rats were also given alpha-methyl-p-tyrosine (200 mg/kg, i.p.) 2 h before the experiment. Vehicle-treated rats served as controls. Depletion of monoamines markedly reduced resting arterial pressure and heart rate and significantly attenuated the pressor response and tachycardia elicited by tyramine (1 mg/kg, i.v.). In control rats, cocaine elicited marked (-64 +/- 4%) and prolonged (44 +/- 4 min) decreases in SND. The magnitude (-34 +/- 11%) and duration (23 +/- 6 min) of these responses were significantly attenuated after 1 day of monoamine depletion. After 2 days of depletion, the sympathoinhibitory response was abolished and was replaced by a small, brief increase in SND (10 +/- 3%). The pressor responses were similar in control and depleted rats, while the bradycardic response (-33 +/- 4 bpm) was significantly reduced after 1 and 2 days of monoamine depletion to -20 +/- 3 and -15 +/- 2 bpm, respectively. We conclude that a functionally intact monoaminergic system is essential for the sympathoinhibitory response to cocaine. Whether the pressor responses result from a non-monoaminergic or a reserpine and/or alpha-methyl-p-tyrosine resistant catecholaminergic mechanism is unknown.

Pulmonary pharmacology.

This article reviews the basic principles of pharmacodynamics and pharmacokinetics, with a special emphasis on the pharmacologic considerations that must be taken into account when treating the patient with respiratory disease who is also pregnant or nursing the neonate. A description of the four classes of therapeutic agents used for COPD is given with a discussion of the scientific evidence for their safety during pregnancy. The understanding of asthma suggests that bronchodilators relieve the symptoms, while antiinflammatories suppress the disease. Direct administration to the target tissue by inhalation of the bronchodilators (beta-adrenoreceptor agonists and anticholinergics) and immunosuppressors (corticosteroids and cromolyn) leads to low systemic levels of these drugs, which reduces fetal drug exposure. Oral administration of beta-adrenoreceptor agonists, corticosteroids, and theophylline may be necessary to obtain sufficient maternal lung function and ensure adequate oxygenation of the fetus. This must be carefully weighed against the potential fetal and maternal risks involved with increased systemic levels of these drugs. A brief description of classes of drugs used for upper respiratory diseases (antihistamines, alpha-adrenergic agonists, corticosteroids, antitussives, and expectorants) and their safety during pregnancy is also given. There is concern that most alpha-adrenergic agonists increase blood pressure at therapeutic doses needed to relieve nasal congestion. Therefore, for pregnant patients requiring decongestants, opinion favors administration of pseudoephedrine, which has the most favorable therapeutic index, to reduce potential cardiovascular adverse reactions in the fetus. Intranasal administration of the newer corticosteroids, which have limited absorption, is useful for suppression of allergic rhinitis, while minimizing the risk of adverse reactions. The purpose of this article has been to provide pharmacologic/toxicologic information about commonly used respiratory drugs. This will to enable the clinician to make an educated decision regarding the choice of therapy for respiratory disorders to ensure that fetal and maternal outcomes are optimal.

Sympathetic nerve responses elicited by cocaine in anesthetized and conscious rats.

Recent evidence suggests that cocaine decreases rather than increases sympathetic nerve discharge (SND). The purpose of the present study was to provide the first complete characterization of the dose-response relationships of cocaine (0.005-3 mg/kg, IV) for arterial pressure, heart rate, and lumbar, splanchnic, or renal SND in pentobarbital-anesthetized rats. Cocaine was also tested in conscious rats. In pentobarbital-anesthetized rats cocaine elicited prolonged (lasting up to 56 min), dose-dependent decreases in SND on all three nerves. The splanchnic nerve was significantly more sensitive to the inhibitory actions of cocaine than was the lumbar nerve. Cocaine increased arterial pressure and elicited bradycardia at doses above 0.5 mg/kg. Comparison of the dose-response curves of cocaine for splanchnic SND in sham-operated and sinoaortically deafferentated (SAD) rats showed that the baroreceptor reflex made only a minor contribution to the magnitude of sympathoinhibitory response. However, the duration of the sympathoinhibitory response was significantly shorter in SAD than in sham animals. In conscious rats, cocaine (0.1 and 1.0 mg/kg) elicited a pattern of neural and cardiovascular responses similar to that seen in anesthetized rats, except that the prolonged sympathoinhibitory responses were preceded by a brief (lasting < 10 s) increase in SND. From these data we conclude that cocaine produces prolonged decreases in SND in conscious and anesthetized rats. These sympathoinhibitory responses do not appear to result from baroreceptor reflex activation and may involve a central mechanism of action.

Occult malignancy presenting as metastatic disease to the hand and wrist.

Osseous metastases to the hand and wrist are uncommon. Most cases represent the manifestation of known malignancy with disseminated disease. Less commonly, acrometastases are the initial presentation of malignancy. In both instances, diagnosis of malignancy is frequently not considered either clinically or radiographically. This results in a delay in diagnosis and in inappropriate therapy. Three cases of occult malignancy presenting as acrometastases are reported. The author stresses the importance of considering this diagnosis when faced with any aggressive lytic or blastic lesion of the hand and wrist in a patient in the fifth decade of life or older.