QUINIDINE SULFATE-quinidine s ulfate tablet Wats on Laboratories , Inc

QUINIDINE SULFATE-quinidine s ulfate tablet Wats on Laboratories , Inc
53095A9A16450B5B147E44F5554242A6
QuinidineSulfate Tablets USP Revis ed: June 2009 Rx only 190782 DESCRIPTION Quinidine is an antimalarial schizonticide and an antiarrhythmic agent with class 1A activity; it is the disomer of quinine, and its molecular weight is 324.43.Quinidine sulfate is the sulfate salt of quinidine; its chemical name is cinchonan-9-ol, 6'-methoxy-, (9S)-, sulfate(2:1) dihydrate; its structural formula is: Its molecular formula is: C H N O •H SO •2H O; and its molecular weight is 782.96, of which 82.9% is quinidine base.Quinidine sulfate occurs as fine needle-like, white crystals, frequently cohering in masses, or fine, white powder.It is odorless, has a very bitter taste, and darkens on exposure to light.It is slightly soluble in water, soluble in alcohol and in chloroform, and insoluble in ether.Each tablet, for oral administration, contains 200 mg and 300 mg of quinidine sulfate (equivalent to 166 mg or 249 mg of quinidine base).In addition, each tablet contains the following inactive ingredients: calcium stearate, microcrystalline cellulose, sodium starch glycolate and starch (corn).CLINICAL PHARMACOLOGYPharmacokinetics and Metabolis mThe absolute bioavailability of quinidine from quinidine sulfate tablets is about 70%, but this varies widely (45 to 100%) between patients.The less-than-complete bioavailability is the result of first-pass metabolism in the liver.Peak serum levels generally appear about 2 hours after dosing; the rate of absorption is somewhat slowed when the drug is taken with food, but the extent of absorption is not changed.The volume of dis tribution of quinidine is 2 to 3 L/kg in healthy young adults, but this may be reduced to as little as 0.5 L/kg in patients with congestive heart failure, or increased to 3 to 5 L/kg in patients with cirrhosis of the liver.At concentrations of 2 to 5 mg/L (6.5 to 16.2 μmol/L), the fraction of 40 48 4 4 2 4 2

quinidine bound to plasma proteins (mainly to α -acid glycoprotein and to albumin) is 80 to 88% in adults and older children, but it is lower in pregnant women, and in infants and neonates it may be as low as 50 to 70%.Because α -acid glycoprotein levels are increased in response to stress, serum levels of total quinidine may be greatly increased in settings such as acute myocardial infarction, even though the serum content of unbound (active) drug may remain normal.Protein binding is also increased in chronic renal failure, but binding abruptly descends toward or below normal when heparin is administered for hemodialysis.

Quinidine clearance typically proceeds at 3 to 5 mL/min/kg in adults, but clearance in children may be twice or three times as rapid.The elimination half-life is 6 to 8 hours in adults and 3 to 4 hours in children.Quinidine clearance is unaffected by hepatic cirrhosis, so the increased volume of distribution seen in cirrhosis leads to a proportionate increase in the elimination half-life.

Most quinidine is eliminated hepatically via the action of cytochrome P450IIIA4; there are several different hydroxylated metabolites, and some of these have antiarrhythmic activity.

The most important of quinidine's metabolites is 3-hydroxyquinidine (3HQ), serum levels of which can exceed those of quinidine in patients receiving conventional doses of quinidine sulfate.The volume of distribution of 3HQ appears to be larger than that of quinidine, and the elimination half-life of 3HQ is about 12 hours.

As measured by antiarrhythmic effects in animals, by QT prolongation in human volunteers, or by various in vitro techniques, 3HQ has at least half the antiarrhythmic activity of the parent compound, so it may be responsible for a substantial fraction of the effect of quinidine sulfate in chronic use.

When the urine pH is less than 7, about 20% of administered quinidine appears unchanged in the urine, but this fraction drops to as little as 5% when the urine is more alkaline.Renal clearance involves both glomerular filtration and active tubular secretion, moderated by (pH-dependent) tubular reabsorption.The net renal clearance is about 1 mL/min/kg in healthy adults.When renal function is taken into account, quinidine clearance is apparently independent of patient age.

As s ays of serum quinidine levels are widely available, but the results of modern assays may not be consistent with results cited in the older medical literature.The serum levels of quinidine cited in this package insert are those derived from specific assays, using either benzene extraction or (preferably) reverse-phase high-pressure liquid chromatography.In matched samples, older assays might unpredictably have given results that were as much as two or three times higher.A typical "therapeutic" concentration range is 2 to 6 mg/L (6.2 to 18.5 μmol/L).

Mechanis ms of Action

In patients with malaria, quinidine acts primarily as an intra-erythrocytic schizonticide, with little effect upon sporozites or upon pre-erythrocytic parasites.Quinidine is gametocidal to Plasmodium vivax and P. malariae, but not to P. falciparum.

In cardiac muscle and in Purkinje fibers, quinidine depresses the rapid inward depolarizing sodium current, thereby slowing phase-0 depolarization and reducing the amplitude of the action potential without affecting the resting potential.In normal Purkinje fibers, it reduces the slope of phase-4 depolarization, shifting the threshold voltage upward toward zero.The result is slowed conduction and reduced automaticity in all parts of the heart, with increase of the effective refractory period relative to the duration of the action potential in the atria, ventricles, and Purkinje tissues.Quinidine also raises the fibrillation thresholds of the atria and ventricles, and it raises the ventricular defibrillation threshold as well.Quinidine's actions fall into class 1A in the Vaughan-Williams classification.

By slowing conduction and prolonging the effective refractory period, quinidine can interrupt or prevent reentrant arrhythmias and arrhythmias due to increased automaticity, including atrial flutter, atrial fibrillation, and paroxysmal supraventricular tachycardia.

In patients with the sick sinus syndrome, quinidine can cause marked sinus node depression and bradycardia.In most patients, however, use of quinidine is associated with an increase in the sinus rate.bradycardia.In most patients, however, use of quinidine is associated with an increase in the sinus rate.

Quinidine prolongs the QT interval in a dose-related fashion.This may lead to increased ventricular automaticity and polymorphic ventricular tachycardias, including torsades de pointes (see WARNINGS).

In addition, quinidine has anticholinergic activity, it has negative inotropic activity, and it acts peripherally as an α-adrenergic antagonist (that is, as a vasodilator).

Clinical Effects

Maintenance of sinus rhythm after conversion from atrial fibrillation: In six clinical trials (published between 1970 and 1984) with a total of 808 patients, quinidine (418 patients) was compared to nontreatment (258 patients) or placebo (132 patients) for the maintenance of sinus rhythm after cardioversion from chronic atrial fibrillation.Quinidine was consistently more efficacious in maintaining sinus rhythm, but a meta-analysis found that mortality in the quinidine-exposed patients (2.9%) was significantly greater than mortality in the patients who had not been treated with active drug (0.8%).Suppression of atrial fibrillation with quinidine has theoretical patient benefits (e.g., improved exercise tolerance; reduction in hospitalization for cardioversion; lack of arrhythmia-related palpitations, dyspnea, and chest pain; reduced incidence of systemic embolism and/or stroke), but these benefits have never been demonstrated in clinical trials.Some of these benefits (e.g., reduction in stroke incidence) may be achievable by other means (anticoagulation).

By slowing the rate of atrial flutter/fibrillation, quinidine can decrease the degree of atrioventricular block and cause an increase, sometimes marked, in the rate at which supraventricular impulses are successfully conducted by the atrioventricular node, with a resultant paradoxical increase in ventricular rate (see WARNINGS).Non-life-threatening ventricular arrhythmias: In studies of patients with a variety of ventricular arrhythmias (mainly frequent ventricular premature beats and non-sustained ventricular tachycardia), quinidine (total N=502) has been compared to flecainide (N=141), mexiletine (N=246), propafenone (N=53), and tocainide (N=67).In each of these studies, the mortality in the quinidine group was numerically greater than the mortality in the comparator group.When the studies were combined in a meta-analysis, quinidine was associated with a statistically significant threefold relative risk of death.

At therapeutic doses, quinidine's only consistent effect upon the surface electrocardiogram is an increase in the QT interval.This prolongation can be monitored as a guide to safety, and it may provide better guidance than serum drug levels (see WARNINGS).

INDICATIONS AND USAGE

Convers ion of atrial fibrillation/flutter

In patients with symptomatic atrial fibrillation/flutter whose symptoms are not adequately controlled by measures that reduce the rate of ventricular response, quinidine sulfate is indicated as a means of restoring normal sinus rhythm.If this use of quinidine sulfate does not restore sinus rhythm within a reasonable time (see DOSAGE AND ADMINISTRATION), then quinidine sulfate should be discontinued.

Reduction of frequency of relaps e into atrial fibrillation/flutter

Chronic therapy with quinidine sulfate is indicated for some patients at high risk of symptomatic atrial fibrillation/flutter, generally patients who have had previous episodes of atrial fibrillation/flutter that were so frequent and poorly tolerated as to outweigh, in the judgment of the physician and the patient, the risks of prophylactic therapy with quinidine sulfate.The increased risk of death should specifically be considered.Quinidine sulfate should be used only after alternative measures (e.g., use of other drugs to control the ventricular rate) have been found to be inadequate.

In patients with histories of frequent symptomatic episodes of atrial fibrillation/flutter, the goal of therapy should be an increase in the average time between episodes.In most patients, the tachyarrhythmia will recur during therapy, and a single recurrence should not be interpreted as therapeutic failure.

Suppres s ion of ventricular arrhythmias

Quinidine sulfate is also indicated for the suppression of recurrent documented ventricular arrhythmias, such as sustained ventricular tachycardia, that in the judgment of the physician are life-threatening.Because of the proarrhythmic effects of quinidine, its use with ventricular arrhythmias of lesser severity is generally not recommended, and treatment of patients with asymptomatic ventricular premature contractions should be avoided.Where possible, therapy should be guided by the results of programmed electrical stimulation and/or Holter monitoring with exercise.

Antiarrhythmic drugs (including quinidine sulfate) have not been shown to enhance survival in patients with ventricular arrhythmias.

Treatment of malaria

Quinidine sulfate is also indicated in the treatment of life-threatening Plasmodium falciparum malaria.

CONTRAINDICATIONS

Quinidine is contraindicated in patients who are known to be allergic to it, or who have developed thrombocytopenic purpura during prior therapy with quinidine or quinine.

In the absence of a functioning artificial pacemaker, quinidine is also contraindicated in any patient whose cardiac rhythm is dependent upon a junctional or idioventricular pacemaker, including patients in complete atrioventricular block.

Quinidine is also contraindicated in patients who, like those with myasthenia gravis, might be adversely affected by an anticholinergic agent.

WARNINGS

Mortality

In many trials of antiarrhythmic therapy for non-life-threatening arrhythmias , active antiarrhythmic therapy has res ulted in increas ed mortality; the ris k of active therapy is probably greates t in patients with s tructural heart dis eas e.In the cas e of quinidine us ed to prevent or defer recurrence of atrial flutter/fibrillation, the bes t available data come from a meta-analys is des cribed under CLINICAL PHARMACOLOGY/Clinical Effects above.In the patients s tudied in the trials there analyzed, the mortality as s ociated with the us e of quinidine was more than three times as great as the mortality as s ociated with the us e of placebo.Another meta-analys is , als o des cribed under CLINICAL PHARMACOLOGY/Clinical Effects , s howed that in patients with various non-life-threatening ventricular arrhythmias , the mortality as s ociated with the us e of quinidine was cons is tently greater than that as s ociated with the us e of any of a variety of alternative antiarrhythmics .

Proarrhythmic effects

Like many other drugs (including all other class IA antiarrhythmics), quinidine prolongs the QT interval, and this can lead to torsades de pointes, a life-threatening ventricular arrhythmia (see OVERDOSAGE).The risk of torsades is increased by bradycardia, hypokalemia, hypomagnesemia, hypocalcemia, or high serum levels of quinidine, but it may appear in the absence of any of these risk factors.The best predictor of this arrhythmia appears to be the length of the QT interval, and quinidine C C should be used with extreme care in patients who have preexisting long-QT syndromes, who have histories of torsades de pointes of any cause, or who have previously responded to quinidine (or other drugs that prolong ventricular repolarization) with marked lengthening of the QT interval.Estimation of the incidence of torsades in patients with therapeutic levels of quinidine is not possible from the available data.

Other ventricular arrhythmias that have been reported with quinidine include frequent extrasystoles, ventricular tachycardia, ventricular flutter, and ventricular fibrillation.

Paradoxical increas e in ventricular rate in atrial flutter/fibrillation

When quinidine is administered to patients with atrial flutter/fibrillation, the desired pharmacologic reversion to sinus rhythm may (rarely) be preceded by a slowing of the atrial rate with a consequent increase in the rate of beats conducted to the ventricles.The resulting ventricular rate may be very high (greater than 200 beats per minute) and poorly tolerated.This hazard may be decreased if partial atrioventricular block is achieved prior to initiation of quinidine therapy, using conduction-reducing drugs such as digitalis, verapamil, diltiazem, or a ß-receptor blocking agent.

Exacerbated bradycardia in s ick s inus s yndrome

In patients with the sick sinus syndrome, quinidine has been associated with marked sinus node depression and bradycardia.

Pharmacokinetic cons iderations

Renal or hepatic dysfunction causes the elimination of quinidine to be slowed, while congestive heart failure causes a reduction in quinidine's apparent volume of distribution.Any of these conditions can lead to quinidine toxicity if dosage is not appropriately reduced.In addition, interactions with coadministered drugs can alter the serum concentration and activity of quinidine, leading either to toxicity or to lack of efficacy if the dose of quinidine is not appropriately modified.(See PRECAUTIONS/Drug Interactions .)

Vagolys is

Because quinidine opposes the atrial and A-V nodal effects of vagal stimulation, physical or pharmacological vagal maneuvers undertaken to terminate paroxysmal supraventricular tachycardia may be ineffective in patients receiving quinidine.

PRECAUTIONS Heart Block

In patients without implanted pacemakers who are at high risk of complete atrioventricular block (e.g., those with digitalis intoxication, second-degree atrioventricular block, or severe intraventricular conduction defects), quinidine should be used only with caution.

Drug Interactions

Altered pharmacokinetics of quinidine: Drugs that alkalinize the urine (carbonic-anhydras e inhibitors , s odium bicarbonate, thiazide diuretics ) reduce renal elimination of quinidine.

By pharmacokinetic mechanisms that are not well understood, quinidine levels are increased by coadministration of amiodarone or cimetidine.Very rarely, and again by mechanisms not understood, quinidine levels are decreased by coadministration of nifedipine.

Hepatic elimination of quinidine may be accelerated by coadministration of drugs (phenobarbital, phenytoin, rifampin) that induce production of cytochrome P450IIIA4.

Perhaps because of competition for the P450IIIA4 metabolic pathway, quinidine levels rise when C C ketaconazole is coadministered.

Coadministration of propranolol usually does not affect quinidine pharmacokinetics, but in some studies the ß-blocker appeared to cause increases in the peak serum levels of quinidine, decreases in quinidine's volume of distribution, and decreases in total quinidine clearance.The effects (if any) of coadministration of other ß-blockers on quinidine pharmacokinetics have not been adequately studied.

Hepatic clearance of quinidine is significantly reduced during coadministration of verapamil, with corresponding increases in serum levels and half-life.

Altered pharmacokinetics of other drugs: Quinidine slows the elimination of digoxin and simultaneously reduces digoxin's apparent volume of distribution.As a result, serum digoxin levels may be as much as doubled.When quinidine and digoxin are coadministered, digoxin doses usually need to be reduced.Serum levels of digitoxin are also raised when quinidine is coadministered, although the effect appears to be smaller.

By a mechanism that is not understood, quinidine potentiates the anticoagulatory action of warfarin, and the anticoagulant dosage may need to be reduced.

Cytochrome P450IID6 is an enzyme critical to the metabolism of many drugs, notably including mexiletine, some phenothiazines , and most polycyclic antidepres s ants .Constitutional deficiency of cytochrome P450IID6 is found in less than 1% of Orientals, in about 2% of American blacks, and in about 8% of American whites.Testing with debrisoquine is sometimes used to distinguish the P450IID6-deficient "poor metabolizers" from the majority-phenotype "extensive metabolizers".

When drugs whose metabolism is P450IID6-dependent are given to poor metabolizers, the serum levels achieved are higher, sometimes much higher, than the serum levels achieved when identical doses are given to extensive metabolizers.To obtain similar clinical benefit without toxicity, doses given to poor metabolizers may need to be greatly reduced.In the cases of prodrugs whose actions are actually mediated by P450IID6-produced metabolites (for example, codeine and hydrocodone, whose analgesic and antitussive effects appear to be mediated by morphine and hydromorphone, respectively), it may not be possible to achieve the desired clinical benefits in poor metabolizers.

Quinidine is not metabolized by cytochrome P450IID6, but therapeutic serum levels of quinidine inhibit the action of cytochrome P450IID6, effectively converting extensive metabolizers into poor metabolizers.Caution must be exercised whenever quinidine is prescribed together with drugs metabolized by cytochrome P450IID6.

Perhaps by competing for pathways of renal clearance, coadministration of quinidine causes an increase in serum levels of procainamide.

Serum levels of haloperidol are increased when quinidine is coadministered.

Presumably because both drugs are metabolized by cytochrome P450IIIA4, coadministration of quinidine causes variable slowing of the metabolism of nifedipine.Interactions with other dihydropyridine calcium-channel blockers have not been reported, but these agents (including felodipine, nicardipine, and nimodipine) are all dependent upon P450IIIA4 for metabolism, so similar interactions with quinidine should be anticipated.

Altered pharmacodynamics of other drugs: Quinidine's anticholinergic, vasodilating, and negative inotropic actions may be additive to those of other drugs with these effects, and antagonistic to those of drugs with cholinergic, vasoconstricting, and positive inotropic effects.For example, when quinidine and verapamil are coadministered in doses that are each well tolerated as monotherapy, hypotension attributable to additive peripheral α-blockade is sometimes reported.

Quinidine potentiates the actions of depolarizing (succinylcholine, decamethonium) and nondepolarizing (d-tubocurarine, pancuronium) neuromus cular blocking agents .These phenomena are not well understood, but they are observed in animal models as well as in humans.In addition, in vitro addition of quinidine to the serum of pregnant women reduces the activity of pseudocholinesterase, an enzyme that is essential to the metabolism of succinylcholine.

Non-interactions of quinidine with other drugs: Quinidine has no clinically significant effect on the pharmacokinetics of diltiazem, flecainide, mephenytoin, metoprolol, propafenone, propranolol, quinine, timolol, or tocainide.

Conversely, the pharmacokinetics of quinidine are not significantly affected by caffeine, ciprofloxacin, digoxin, diltiazem, felodipine, omeprazole, or quinine.Quinidine's pharmacokinetics are also unaffected by cigarette smoking.

Information for patients

Before prescribing quinidine sulfate as prophylaxis against recurrence of atrial fibrillation, the physician should inform the patient of the risks and benefits to be expected (see CLINICAL PHARMACOLOGY).Discussion should include the facts: that the goal of therapy will be a reduction (probably not to zero) in the frequency of episodes of atrial fibrillation; and that reduced frequency of fibrillatory episodes may be expected, if achieved, to bring symptomatic benefit; but that no data are available to show that reduced frequency of fibrillatory episodes will reduce the risks of irreversible harm through stroke or death; and in fact that such data as are available suggest that treatment with quinidine sulfate is likely to increase the patient's risk of death.

Carcinogenes is , Mutagenes is , Impairment of Fertility

Animal studies to evaluate quinidine's carcinogenic or mutagenic potential have not been performed.

Similarly, there are no animal data as to quinidine's potential to impair fertility.

Pregnancy

Pregnancy Category C

Animal reproductive studies have not been conducted with quinidine.There are no adequate and wellcontrolled studies in pregnant women.Quinidine should be given to a pregnant woman only if clearly needed.

Human placental transport of quinidine has not been systematically studied.In one neonate whose mother had received quinidine throughout her pregnancy, the serum level of quinidine was equal to that of the mother, with no apparent ill effect.The level of quinidine in amniotic fluid was about three times higher than that found in serum.In another case, the levels of quinidine and 3-hydroxyquinidine in cord blood were about 30% of simultaneous maternal levels.

Labor and Delivery

Quinine is said to be oxytocic in humans, but there are no adequate data as to quinidine's effects (if any) on human labor and delivery.

Nurs ing Mothers

Quinidine is present in human milk at levels slightly lower than those in maternal serum; a human infant ingesting such milk should (scaling directly by weight) be expected to develop serum quinidine levels at least an order of magnitude lower than those of the mother.On the other hand, the pharmacokinetics and pharmacodynamics of quinidine in human infants have not been adequately studied, and neonates' reduced protein binding of quinidine may increase their risk of toxicity at low total serum levels.Administration of quinidine should (if possible) be avoided in lactating women who continue to nurse.

Geriatric Us e

Safety and efficacy of quinidine in elderly patients has not been systematically studied.

Pediatric Us e

In antimalarial trials, quinidine was as safe and effective in pediatric patients as in adults.

Notwithstanding the known pharmacokinetic differences between children and adults (see CLINICAL PHARMACOLOGY, Pharmacokinetics and Metabolis m), children in these trials received the same doses (on a mg/kg basis) as adults.

Safety and effectiveness of antiarrhythmic use in pediatric patients have not been established.

ADVERSE REACTIONS

Quinidine preparations have been used for many years, but there are only sparse data from which to estimate the incidence of various adverse reactions.The adverse reactions most frequently reported have consistently been gastrointestinal, including diarrhea, nausea, vomiting, and heartburn/esophagitis.In one study of 245 adult outpatients who received quinidine to suppress premature ventricular contractions, the incidences of reported adverse experiences were as shown in the table below.The most serious quinidine-associated adverse reactions are described above under WARNINGS.

Vomiting and diarrhea can occur as isolated reactions to therapeutic levels of quinidine, but they may also be the first signs of cinchonis m, a syndrome that may also include tinnitus, reversible highfrequency hearing loss, deafness, vertigo, blurred vision, diplopia, photophobia, headache, confusion, and delirium.Cinchonism is most often a sign of chronic quinidine toxicity, but it may appear in sensitive patients after a single moderate dose.

A few cases of hepatotoxicity, including granulomatous hepatitis, have been reported in patients receiving quinidine.All of these have appeared during the first few weeks of therapy, and most (not all) have remitted once quinidine was withdrawn.

Autoimmune and inflammatory s yndromes associated with quinidine therapy have included fever, urticaria, flushing, exfoliative rash, bronchospasm, psoriaform rash, pruritus and lymphadenopathy, hemolytic anemia, vasculitis, pneumonitis, thrombocytopenic purpura, uveitis, angioedema, agranulocytosis, the sicca syndrome, arthralgia, myalgia, elevation in serum levels of skeletal-muscle enzymes, and a disorder resembling systemic lupus erythematosus.

Convulsions, apprehension, and ataxia have been reported, but it is not clear that these were not simply the results of hypotension and consequent cerebral hypoperfusion.There are many reports of syncope.Acute psychotic reactions have been reported to follow the first dose of quinidine, but these reactions appear to be extremely rare.

Other adverse reactions occasionally reported include depression, mydriasis, disturbed color perception, night blindness, scotomata, optic neuritis, visual field loss, photosensitivity, and abnormalities of pigmentation.

OVERDOSAGE

Overdoses with various oral formulations of quinidine have been well described.Death has been described after a 5-gram ingestion by a toddler, while an adolescent was reported to survive after ingesting 8 grams of quinidine.

The most important ill effects of acute quinidine overdoses are ventricular arrhythmias and hypotension.

Other signs and symptoms of overdose may include vomiting, diarrhea, tinnitus, high-frequency hearing loss, vertigo, blurred vision, diplopia, photophobia, headache, confusion, and delirium.

Arrhythmias

Serum quinidine levels can be conveniently assayed and monitored, but the electrocardiographic QT interval is a better predictor of quinidine-induced ventricular arrhythmias.

The necessary treatment of hemodynamically unstable polymorphic ventricular tachycardia (including torsades de pointes) is withdrawal of treatment with quinidine and either immediate cardioversion or, if a cardiac pacemaker is in place or immediately available, immediate overdrive pacing.After pacing or cardioversion, further management must be guided by the length of the QT interval.

Quinidine-associated ventricular tachyarrhythmias with normal underlying QT intervals have not been adequately studied.Because of the theoretical possibility of QT-prolonging effects that might be additive to those of quinidine, other antiarrhythmics with Class I (disopyramide, procainamide) or Class III activities should (if possible) be avoided.Similarly, although the use of bretylium in quinidine overdose has not been reported, it is reasonable to expect that the α-blocking properties of bretylium might be additive to those of quinidine, resulting in problematic hypotension.

If the post-cardioversion QT interval is prolonged, then the pre-cardioversion polymorphic ventricular tachyarrhythmia was (by definition) torsades de pointes.In this case, lidocaine and bretylium are unlikely to be of value, and other Class I antiarrhythmics (disopyramide, procainamide) are likely to exacerbate the situation.Factors contributing to QT prolongation (especially hypokalemia, hypomagnesemia, and hypocalcemia) should be sought out and (if possible) aggressively corrected.Prevention of recurrent torsades may require sustained overdrive pacing or the cautious administration of isoproterenol (30 to 150 ng/kg/min).

Hypotens ion

Quinidine-induced hypotension that is not due to an arrhythmia is likely to be a consequence of quinidine-related α-blockade and vasorelaxation.Simple repletion of central volume (Trendelenburg positioning, saline infusion) may be sufficient therapy; other interventions reported to have been beneficial in this setting are those that increase peripheral vascular resistance, including α-agonist catecholamines (norepinephrine, metaraminol) and the Military Anti-Shock Trousers.

Treatment

To obtain up-to-date information about the treatment of overdose, a good resource is your certified Regional Poison-Control Center.Telephone numbers of certified poison-control centers are listed in the Physicians' Desk Reference (PDR).In managing overdose, consider the possibilities of multiple-drug overdoses, drug-drug interactions, and unusual drug kinetics in your patient.

Accelerated removal

Adequate studies of orally-administered activated charcoal in human overdoses of quinidine have not been reported, but there are animal data showing significant enhancement of systemic elimination following this intervention, and there is at least one human case report in which the elimination half-life of quinidine in the serum was apparently shortened by repeated gastric lavage.Activated charcoal should be avoided if an ileus is present; the conventional dose is 1 gram/kg, administered every 2 to 6 hours as a slurry with 8 mL/kg of tap water.Although renal elimination of quinidine might theoretically be accelerated by maneuvers to acidify the urine, such maneuvers are potentially hazardous and of no demonstrated benefit.

Quinidine is not usefully removed from the circulation by dialysis.

Following quinidine overdose, drugs that delay elimination of quinidine (cimetidine, carbonicanhydrase inhibitors, thiazide diuretics) should be withdrawn unless absolutely required.

DOSAGE AND ADMINISTRATION

Treatment of P. falciparum malaria

Quinidine sulfate tablets are used in one of the approved regimens for the treatment of life-threatening P. falciparum malaria.The central component of the regimen is Quinidine Gluconate Injection, and the regimen is described in the package insert of Quinidine Gluconate Injection.

Convers ion of atrial fibrillation/flutter to s inus rhythm

Especially in patients with known structural heart disease or other risk factors for toxicity, initiation or dose-adjustment of treatment with quinidine sulfate should generally be performed in a setting where facilities and personnel for monitoring and resuscitation are continuously available.Patients with symptomatic atrial fibrillation/flutter should be treated with quinidine sulfate only after ventricular rate control (e.g., with digitalis or ß-blockers) has failed to provide satisfactory control of symptoms.

Adequate trials have not identified an optimal regimen of quinidine sulfate for conversion of atrial fibrillation/flutter to sinus rhythm.In one reported regimen, the patient first receives two tablets (400 mg; 332 mg of quinidine base) of quinidine sulfate every six hours.If this regimen has not resulted in conversion after 4 or 5 doses, then the dose is cautiously increased.If, at any point during administration, the QRS complex widens to 130% of its pre-treatment duration; the QT interval widens to 130% of its pre-treatment duration and is then longer than 500 ms; P waves disappear; or the patient develops significant tachycardia, symptomatic bradycardia, or hypotension, then quinidine sulfate is discontinued, and other means of conversion (e.g., direct-current cardioversion) are considered.

Reduction of frequency of releas e into atrial fibrillation/flutter

In a patient with a history of frequent symptomatic episodes of atrial fibrillation/flutter, the goal of therapy with quinidine sulfate should be an increase in the average time between episodes.In most patients, the tachyarrhythmia will recur during therapy with quinidine sulfate, and a single recurrence should not be interpreted as therapeutic failure.

Especially in patients with known structural heart disease or other risk factors for toxicity, initiation or dose-adjustment of treatment with quinidine sulfate should generally be performed in a setting where facilities and personnel for monitoring and resuscitation are continuously available.Monitoring should be continued for two or three days after initiation of the regimen on which the patient will be discharged.

Therapy with quinidine sulfate should be begun with 200 mg (equivalent to 166 mg of quinidine base) every six hours.If this regimen is well tolerated, if the serum quinidine level is still well within the laboratory's therapeutic range, and if the average time between arrhythmic episodes has not been satisfactorily increased, then the dose may be cautiously raised.The total daily dosage should be C reduced if the QRS complex widens to 130% of its pre-treatment duration; the QT interval widens to 130% of its pre-treatment duration and is then longer than 500 ms; P waves disappear; or the patient develops significant tachycardia, symptomatic bradycardia, or hypotension.

Suppres s ion of ventricular arrhythmias

Dosing regimens for the use of quinidine sulfate in suppressing life-threatening ventricular arrhythmias have not been adequately studied.Described regimens have generally been similar to the regimen described just above for the prophylaxis of symptomatic atrial fibrillation/flutter.Where possible, therapy should be guided by the results of programmed electrical stimulation and/or Holter monitoring with exercise.

HOW SUPPLIED

Sulfate Tablets USP 200 mg are 12/32", scored, round, white tablets imprinted DAN DAN and 5438 supplied in bottles of 100 and 1000.Quinidine Sulfate Tablets USP 300 mg are 14/32", scored, round, white tablets imprinted DAN DAN and 5454 supplied in bottles of 100.Dispense in well-closed, light-resistant container with child-resistant closure.Store at 20° -25°C (68° -77°F).[See USP controlled room temperature.]Protect from light and moisture.
CManufactured By:Wats on Pharma Private LimitedVerna, Salcette Goa 403 722 INDIADistributed By:Wats on Pharma, Inc.Corona, CA 92880 USARevised: June 20091907820609BPRINCIPAL DISPLAY PANELNDC 0591-5438-01QuinidineSulfateTablets USP200 mgWatson 100 TabletsRx only
Route of Ad minis tration


Variation, Variability, and the Origin of the Avian Endocranium: Insights from the Anatomy of Alioramus altai (Theropoda: Tyrannosauroidea)
Published August 10, 2011

Gabe S Bever email@example.com
Department of Geology and Geophysics
Yale University
New Haven, ConnecticutUnited States of America

Division of Paleontology
American Museum of Natural History
New YorkNew York

United States of America

Stephen L Brusatte
Division of Paleontology
American Museum of Natural History
New YorkNew York

United States of America

Department of Earth and Environmental Sciences
Columbia University
New YorkNew YorkUnited States of America

Amy M Balanoff
Division of Paleontology
American Museum of Natural History
New YorkNew York

United States of America

Department of Earth and Environmental Sciences
Columbia University
New YorkNew YorkUnited States of America

Mark A Norell
Division of Paleontology
American Museum of Natural History
New YorkNew York

United States of America

Variation, Variability, and the Origin of the Avian Endocranium: Insights from the Anatomy of Alioramus altai (Theropoda: Tyrannosauroidea)
Published August 10, 2011Received May 18, 2011; Accepted July 14, 2011;Editor: Daphne Soares, University of Maryland, United States of America Funding: This work was funded by the American Museum of Natural History, Yale University, and the National Science Foundation (Graduate Research Fellowship to SLB, Doctoral Dissertation Improvement Grants DEB 1110357 and DEB 0909970 to SLB and MAN and AMB and MAN, respectively, and DEB-9300700 and ATOL 0228693 to MAN). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. * ¤ Current address: Department of Anatomy, New York College of Osteopathic Medicine, Old Westbury, New York, United States of America
The internal braincase anatomy of the holotype of Alioramus altai, a relatively small-bodied tyrannosauroid from the Late Cretaceous of Mongolia, was studied using high-resolution computed tomography. A number of derived characters strengthen the diagnosis of this taxon as both a tyrannosauroid and a unique, new species (e.g., endocranial position of the gasserian ganglion, internal ramification of the facial nerve). Also present are features intermediate between the basal theropod and avialan conditions that optimize as the ancestral condition for Coelurosauria-a diverse group of derived theropods that includes modern birds. The expression of several primitive theropod features as derived character states within Tyrannosauroidea establishes previously unrecognized evolutionary complexity and morphological plasticity at the base of Coelurosauria. It also demonstrates the critical role heterochrony may have played in driving patterns of endocranial variability within the group and potentially reveals stages in the evolution of neuroanatomical development that could not be inferred based solely on developmental observations of the major archosaurian crown clades. We discuss the integration of paleontology with variability studies, especially as applied to the nature of morphological transformations along the phylogenetically long branches that tend to separate the crown clades of major vertebrate groups.Citation: Bever GS, Brusatte SL, Balanoff AM, Norell MA (2011) Variation, Variability, and the Origin of the Avian Endocranium: Insights from the Anatomy of Alioramus altai (Theropoda: Tyrannosauroidea). PLoS ONE 6(8): e23393.

Introduction

The potential of developmental systems to produce morphological variation (i.e., variability) is not static but changes through ontogeny and phylogeny [1,2]. This dynamism has important consequences not only for evolutionary mechanics and evolvability [1,3] but also for the practical ability of biologists to precisely infer historical patterns of morphological change. The vertebrate neurocranium, for example, develops early in skeletal ontogeny, probably in response to the structural needs of the rapidly developing central nervous system [4]. This accelerated early growth is followed by a long period of negative allometry where ossification of the cartilaginous neurocranium and otic capsules and the subsequent maturation of associated ossified structures are largely delayed relative to that of other cranial partitions. The probability that in any given specimen the expression of braincase features is influenced by one of the many possible types of variation thus differs from that of other skeletal modules, even if the specimen is in a late stage of postnatal development [5]. Considering the importance of this region (both as the skeletal seat of the brain and primary sense organs and as a source of phylogenetically informative characters), the critical role paleontology plays in breaking up the long periods of evolutionary time often separating major crown clades, and the fact that any study of the fossil record likely requires comparing specimens of different ontogenetic ages, the potential implications of dynamic variability are obvious and significant. Grasping these implications requires a better understanding of developmental dynamics in extant lineages. It also requires the careful study of those extinct clades occupying critical positions on the tree, whose fossil record includes specimens with a diverse taxonomic and ontogenetic distribution. Tyrannosauroids are beginning to be one such clade [6].

While not implying directionality to the tree, the position of Tyrannosauroidea as a basal coelurosaur lineage [7][8][9][10][11][12] makes them a group where one would at least hope to find features intermediate between plesiomorphic states present in noncoelurosaurian theropods and highly derived morphologies characterizing maniraptoran lineages close to the crown (i.e., the origin of Aves, sensu [13]). The braincase of Tyrannosaurus rex long has been a subject of anatomical interest (e.g., [14][15][16][17]), but detailed comparative studies of endocranial anatomy among Tyrannosauroidea, especially using modern tools of anatomical visualization such as high-resolution X-ray computed tomography (CT), has only recently begun. This is true despite the fact that braincases are known for many tyrannosauroid species [18].

Several of these specimens are established as reflecting different points along the tyrannosaur growth curve [19,20]. Recently, important contributions on this subject were published [21,22] based largely on specimens of Tyrannosaurus, Gorgosaurus libratus, and the taxonomically controversial 'Nanotyrannus' lancensis specimen (Cleveland Museum of Natural History [CMNH] 7541, probably a juvenile Tyrannosaurus [23]) as well as several recently discovered taxa. These studies are critical in establish a comparative framework to which new specimens can be added and initial hypotheses of phylogenetic and ontogenetic transformations tested.

Our goal is to further address phylogenetic and ontogenetic variability in tyrannosauroids by describing the endocranial anatomy of the ontogenetically young holotype of Alioramus altaia new tyrannosauroid from the Late Cretaceous of Mongolia that is nested deep within Tyrannosauridae as a close relative of the Daspletosaurus torosus-Tarbosaurus bataar-Tyrannosaurus clade [24]. This position places it within the Gorgosaurus-Tyrannosaurus phylogenetic bracket (equivalent to Tyrannosauridae) established by [21]. A detailed description of the well-preserved braincase will be published elsewhere. The purpose of this paper is to describe the most salient features of the internal braincase anatomy that have direct bearing on phylogenetic transformations within Tyrannosauroidea and that provide insights into the origin and early evolutionary history of coelurosaurian neuroanatomy. Discussion of these features will then be used as a springboard to address wider, more theoretical issues regarding the dynamics of morphological variation and the interpretation of evolutionary transformations in a phylogenetic context.

Results

General observations

The holotype of Alioramus altai (Institute of Geology, Mongolian Academy of Sciences [IGM] 100/1844) was collected at Tsaagan Khushuu, Nemegt Formation (Maastrichtian) during the Mongolian Academy of Sciences-American Museum of Natural History 2001 expedition. It is estimated to represent a nine-year-old juvenile/subadult based on a count of lines of arrested growth [24]. The partial skeleton has a nearly complete braincase preserving all expected neurocranial and dermal elements except the ethmoid complex ( Fig. 1). This midline element was present in life-but perhaps only as a cartilaginous structure-based on a clear frontal scar that marks the contact of the ethmoid ring with the dermal skull roof and delimits the rostrocaudal and mediolateral extent of the olfactory bulbs [25]. The braincase exhibits some clockwise distortion around the long axis of the skull that is independent of the overlying dermal roof, but overall, it is remarkable in its preservational quality, especially for a relatively small-bodied tyrannosauroid. A high-resolution CT scan resulted in remarkable contrast between matrix and bone, allowing a detailed study of the internal braincase anatomy. This anatomy includes the conformation of the endocranial cavity, the cranial nerve roots and venous sinuses, the osseous labyrinth of the inner ear, and the extensive system of internal pneumatic sinuses that invest nearly all of the neurocranial elements (Fig. 2). Descriptive observations are based on a cranial orientation in which the lateral semicircular canal is held horizontally. This configuration results in the head being held in a slightly downturned position in agreement with Gorgosaurus and Tyrannosaurus and in marked contrast to tyrannosauroid outgroups [21].

As in other tyrannosauroids, the endocast is long, narrow, and apomorphically lacks a strong midbrain angle (Figs. 3, 4). Dural sinuses cover the hind-and midbrain regions and include a dorsal peak whose prominence is matched only by an adult specimen of Tyrannosaurus rex (American Museum of Natural History, Fossil Fishes Amphibians, Reptiles and Birds 5117 [14]). A prominent floccular lobe (cerebellar auricle) extends caudolaterally from the cerebellar region of the hindbrain to lie between the semicircular canals of the inner ear. This tabular-shaped cavity is relatively large compared to the same structure in Tyrannosaurus, Gorgosaurus, and 'Nanotyrannus' and more closely resembles the floccular cavity of Tarbosaurus [21,26,27]. The path of the rostral middle cerebral vein is somewhat unclear, but it did not penetrate the laterosphenoid through its own canal as in Gorgosaurus and Tyrannosaurus [21]. It either exited with a branch of the trigeminal nerve (cranial nerve [cn] V), which is plesiomorphic for Theropoda, or through the prootic; either position would be derived within Tyrannosauroidea. Rostral to the transverse sinus is a pair of small but distinctive ventrolateral swellings interpreted to be the optic lobes. The development and position of these structures, in combination with a moderate expansion of the cerebral hemispheres, supports the hypothesis that the exaggerated cerebral expansion resulting in the caudolateral displacement of the optic lobes characteristic of avialans and other maniraptorans began at the base of Coelurosauria [17]. The olfactory tracts are extremely short and broad and do not support the tentative idea of Witmer and Ridgely [21] that broad tracts in T. rex and CMNH 7541 relate directly to their apomorphically broad and short skulls, because the skull of Alioramus altai is relatively narrow and long (it is the proportionally longest skull, compared to height, of any known tyrannosauroid specimen). The large olfactory bulbs compare closely to those of other tyrannosauroids [21,22,25,28].

Cranial nerve roots

The cranial nerve roots in IGM 100/1844 exhibit a basically conservative pattern with a few notable exceptions. The glossopharyngeal nerve (cn IX) exits the endocranial cavity through a separate opening in the otoccipital (fused exoccipital and opisthotic) caudal to the cochlear branch of the vestibulocochlear nerve (cn VIII) and rostral to the medial aperture of the cavum metoticum (Fig. 5). The small canal runs a short distance caudolaterally and penetrates the rostromedial wall of the recessus scalae tympani. There is no caudal path for this nerve through the pneumatized crista tuberalis to the vagal canal, so it appears the nerve maintains a rostral position and exits the braincase laterally through the foramen pseudorotunda. A rostral path for cn IX through the recessus scalae tympani is known in other tyrannosauroid and some non-tyrannosauroid theropods (21,29), but it is unclear whether any of these taxa also express the independent medial canal of IGM 100/1844 or if their glossopharyngeal nerves communicate with the recessus scalae tympani through the medial aperture of the cavum metoticum. An independent medial canal through the rostromedial margin of the recessus scalae tympani is tentatively considered an autapomorphy of Alioramus altai.

The gasserian ganglion lies fully within the endocranial cavity, so that the ophthalmic (cn V 1 ) and maxillomandibular (cn V 2-3 ) branches of the trigeminal nerve (cn V) exit the cavity separately ( Fig. 6). This is a derived feature shared with avialans, but because a single trigeminal opening characterizes the other known coelurosaur groups, paired canals can be considered an ambiguous tyrannosauroid synapomorphy [16,21,22,30,31].

A character in IGM 100/1844 currently considered an unambiguous tyrannosaur synapomorphy is the presence of a lateral fossa in the prootic that houses the external foramina of the maxillomandibular canal of the trigeminal nerve and the canal for the facial nerve (cn VII) (Fig. 6) [21,22,31]. The presence of this lateral fossa in the basal tyrannosauroids Dilong paradoxus and Guanlong wucaii is currently unclear [6,32,33]. Its expression may be diagnostic of a more exclusive clade within Tyrannosauroidea, perhaps Tyrannosauridae. The narrowing of this fossa into a foramen may be a late-stage ontogenetic transformation in tyrannosaurids [31], and the more fossa-like morphology expressed in IGM 100/1844 attests to its relative immaturity. To be precise, in IGM 100/1844 the fossa houses only the canal transmitting the palatine ramus of the facial nerve (cn VII 1 ) because the geniculate ganglion was fully enclosed inside the prootic. This internal position results in separate canals for the palatine and hyomandibular branches (cn VII 2 ) of the facial nerve, with the hyomandibular ramus exiting the braincase behind the prootic fossa near the otic recess. This is autapomorphic in Alioramus altai, as theropods (including all other tyrannosauroids) retain the highly conservative position of the geniculate ganglion within the postnatal remnant of the cranioquadrate space. When osseous signatures of the theropod palatine and hyomandibular nerves are present, they generally take the form of grooves on the lateral surface of the prootic (e.g., [31,34]).

Significant variation involving the cranial nerve roots is found in the area surrounding the infundibulum where IGM 100/1844 retains a plesiomorphic sinus cavernosus (Fig. 7). This sinus lies in the lateral margin of the pituitary fossa and clearly accepted the oculomotor (cn III) and abducens nerves (cn VI) and their associated vasculature. It probably also transmitted the cranial branches of the carotid arteries [35]. This is the common morphology in archosaurs generally, and in non-coelurosaurian theropods, but was previously unknown in coelurosaurs, including other tyrannosauroids [21,29,[35][36][37]. The derived condition, retained in the crown, and expressed in all other coelurosaurs preserving this region, is the absence of a sinus cavernosus with the abducens nerve positioned lateral to the pituitary fossa [21]. The abducens canal in CMNH 7541 approximates the lateral margin of the pituitary fossa, tempting Witmer and Ridgely [21] to score the specimen as exhibiting the plesiomorphic condition. They refrained, regarding the situation as reflecting a transformation of the derived coelurosaurian morphology or an artifact of postmortem damage to the skull. The configuration in IGM

Osseous labyrinth

The complete osseous labyrinth of IGM 100/1844 (Fig. 8) is similar to that of other tyrannosauroids in possessing an elongate rostral semicircular canal whose caudodorsal expansion and resultant twisting of the common crus is intermediate between that of non-coelurosaurian theropods and the exaggerated condition of maniraptorans [21,38]. In contrast, the rostral expansion of this canal is restricted in IGM 100/1844 and results in the common crus retaining the plesiomorphic vertical orientation. This morphology is shared with non-coelurosaurian theropods and Gorgosaurus, but differs from the strongly angled common crus of T. rex, CMNH 7541, and maniraptorans. The lateral canal of IGM 100/1844 is not strongly bowed as in other tyrannosauroids and maniraptorans but exhibits the relatively straight orientation and strong caudal hook characteristic of non-coelurosaurian theropods. The osseous labyrinth of IGM 100/1844 is congruent with the hypothesis of [21] that a long, slender, and straight cochlear cavity is synapomorphic for tyrannosauroids.

Neurocranial pneumaticity

The neurocranial elements of IGM 100/1844 are extensively pneumatized and house the five sinus recesses typical of tyrannosauroids (Fig. 2). The morphology of the internal cavities   associated with these recesses is also conservative, again with a few notable exceptions. For example, the rostral tympanic sinus contains a significant dorsal diverticulum that passes between the ophthalmic and maxillomandibular canals. This condition is shared with Gorgosaurus and CMNH 7541 but is lacking in Daspletosaurus and Tyrannosaurus [21]. The basisphenoid recess pneumatizes the basipterygoid processes and retains the plesiomorphic caudal fossa that is highly reduced or absent in Tyrannosaurus and Tarbosaurus [16,21,39]. The subsellar sinus invests the entire length of the cultriform process of the parasphenoid so that its three-dimensional reconstruction reflects the shape of the process nearly perfectly. This sinus is restricted to the proximal base of the cultriform process in Tyrannosaurus, whereas it extends distally into the process in CMNH 7541, Gorgosaurus, and now IGM 100/1844. The subcondylar sinus of IGM 100/1844 is like that of CMNH 7541 and differs from the condition in both Gorgosaurus and Tyrannosaurus in being confluent with the rostral tympanic sinus and joining the caudal tympanic sinus to pneumatize the crista tuberalis [21].

Discussion

Character transformations

The internal braincase anatomy of Alioramus altai preserves a number of derived features that strengthen its diagnosis as both a tyrannosauroid and a unique species. We note, however, that the braincase in the only other species of Alioramus, A. remotus [40], is not well described nor has it been CT scanned. The unique neurocranial features of A. altai may therefore diagnose a monophyletic Alioramus. The presence of a reduced midbrain angle, a long, slender, and straight cochlear cavity, a gasserian ganglion positioned fully within the endocranial cavity, and a prootic fossa accepting the external foramina of the maxillomandibular canal and at least a branch of the facial canal are all characters present in IGM 100/1844 that optimize as tyrannosauroid synapomorphies based on the small number of tyrannosauroid taxa whose endocranial anatomy has been studied to date [14,16,21,22,26,27,31]. Whether these characters are diagnostic of Tyrannosauroidea or some more exclusive tyrannosauroid clade depends on the unstudied internal braincase anatomy of phylogenetically basal tyrannosauroids, such as Dilong and Guanlong [6,32,33]. The degree to which the subsellar sinus   pneumatizes the cultriform process, the absence of an independent path of the rostral middle cerebral vein through the laterosphenoid, the presence of an independent medial path of the glossopharyngeal nerve, and the ramification of the facial canal within the ossified otic capsule are all unique characters that further support the status of A. altai as a new species. The last two autapomorphies are currently unambiguously unique to A. altai among all theropods.

IGM 100/1844 shares with other tyrannosauroids a number of endocranial features intermediate in their development between the plesiomorphic condition present in non-coelurosaurian theropods and the highly derived morphologies characteristic of nontyrannosauroid coelurosaurs, including avialans. These include an intermediate expansion of the cerebrum (with comparable caudolateral displacement of the optic lobes), intermediate caudodorsal expansion of the rostral semicircular canal, and a slightly downturned orientation of the head. Each of these conditions can be inferred (based on an ordered character state reconstruction) to represent the ancestral coelurosaurian morphology.

Features that vary within tyrannosauroids also inform the nature of neuroanatomical transformations between non-coelurosaurian theropods and maniraptorans. Optic lobes, for example, are not visible in all tyrannosauroids (e.g., [26]) and may be obscured in the most mature specimens by a late postnatal expansion of the cranial roof and thickening of the surrounding dural envelope that may also decrease the apparent relative size of the flocculus [21]. This hypothesis is congruent with the clear optic lobes and relatively large floccular cavity of the skeletally immature IGM 100/1844. This variation suggests that a late-stage shift in developmental timing played a role in the early history of the cerebral-optic lobe configuration so exaggerated in avialans and other maniraptorans. This shift may have been a paedomorphic truncation of the expanding cranial vault and underlying dural envelope, a hypermorphic inflation of the cerebrum at the expense of the dural envelope, or some combination of the two. Regardless of the pathway, the result is a relative expansion of the cerebrum that is closely associated with increased cognition and likely played an important role in the evolutionary success of maniraptorans [15,41].

The plesiomorphic features expressed in IGM 100/1844 indicate previously unrecognized evolutionary complexity and morphological plasticity in the transition from basal theropod neuroanatomy to that of maniraptorans. For example, the presence of a sinus cavernosus supports Alioramus altai as lying phylogenetically outside of Coelurosauria. But, when considered as a feature of the deeply nested tyrannosauroid IGM 100/1844 (and possibly CMNH 7541, which is also an ontogenetically young specimen), the presence of this sinus suggests theropod evolution went through a period at the base of Coelurosauria where the developmental pathways (genetic-epigenetic interactions during ontogeny [42]) responsible for patterning the diencephalic region exhibited a relatively high level of variability. This variability is retained to some degree in Tyrannosauroidea and can be expected to characterize at least the early history of its sister taxon (the clade of non-tyrannosauroid coelurosaurs) before becoming secondarily reduced, eventually resulting in the seemingly fixed loss of a cavernous sinus that is conserved in Aves (Fig. 9). A similar pattern can be inferred for the evolution of a straight versus strongly bowed lateral semicircular canal and a vertical versus strongly angled common crus of the osseous labyrinth.

In each of these characters, it is a transformational increase in variability at or near the base of Coelurosauria followed by a transformational reduction or loss of that variability during subsequent coelurosaurian evolution (after the divergence of tyrannosauroids) that represents the underlying synapomorphies presaging the 0 to 1 state changes reflected in phylogenetic character matrices and used to characterize broad patterns of theropod morphological evolution. In this sense, the polymorphic 0/1 condition for tyrannosauroids can be conceptualized as a derived feature that is intermediate between the 0 and 1 states of non-coelurosaurian theropods and maniraptorans, respectively. Because the 0/1 state (i.e., high variability) would only emerge at the clade level, its presence would not necessarily change the phylogenetically informative nature of 0 to 1 or 1 to 0 transformations occurring within that clade-in other words, homoplasies can be phylogenetically informative [43,44].

The relatively young ontogenetic ages of both IGM 100/1844 and CMNH 7541 suggests that their unique expression of these plesiomorphic states may simply reflect ontogenetic variation.  Modern crocodilians and birds both lack postnatal variation with regards to the presence and absence of the sinus cavernosus, respectively. The variation observed in tyrannosauroids suggests the initial loss of the sinus along the avian stem occurred as a latestage ontogenetic transformation (terminal addition) that was subsequently pushed to earlier developmental stages. Eventually, this resulted in the absence of postnatal variation characteristic of the avian crown. Between the evolution of the derived condition as a terminal ontogenetic state and the heterochonic shift(s) that pushed this transformation out of postnatal development exists a period of increased variability where expression of the plesiomorphic and derived conditions can be expected in a typical collection of fossil specimens reflecting different stages of the growth curve.

Concentrated homoplasy, variability, and pattern interpretation

A Darwinian model of evolution predicts that the origin of a morphological structure will generally be accompanied by a period of increased variability in the developmental pathway(s) associated with that feature. It is possible that these periods of high variability can at times be maintained long enough to influence broad patterns of phylogenetic history [45,46]. Such extended ''zones of variability'' should produce distinctively high levels of homoplasy near the origin of a derived feature followed by a canalization of morphological expression. The opening and closing of these zones likely reflect phylogenetically informative transformations (i.e., 0R1, 1R2) in the molecular architecture of development that increase and subsequently decrease variability in the system (e.g., [47]).

In the transformation of the sinus cavernosus, horizontal semicircular canal, and common crus to the derived states retained in modern birds, the anatomy of Alioramus altai contributes to a pattern of variation that is congruent with the predicted pattern if a zone of variability was in place at the base of Coelurosauria. The phylogenetic duration of this zone is currently unclear, but the expression of the plesiomorphic morphology in specimens lying along at least the phylogenetic stem of the Maniraptoriformes clade (Ornithomimosauria + Maniraptora) should be expected. Even if an alternative evolutionary interpretation is preferred-for example, that the late-stage transformation in tyrannosauroids is a derived developmental trajectory not ancestral to those theropods more closely related to birds-the tyrannosauroid transformational pattern still establishes morphological and developmental complexity for these characters at the base of the coelurosaur tree and supports heterochrony as an important mechanism in driving patterns of neuroanatomical variability.

The extended maintenance of high variability, with its associated expectation of high levels of homoplasy, may be an important component of large-scale patterns of morphological and ecological evolution. In a study of rates of character change and morphological disparity (overall anatomical variety) in early Triassic-Jurassic archosaurian relatives of birds and crocodiles based on a 400+ discrete character dataset, the major clade of crocodile-line archosaurs (Crurotarsi or Pancrocodylia) had both significantly greater morphological disparity and a significantly higher incidence of homoplasy than bird-line archosaurs (Ornithodira or Panaves [13], including primitive theropod dinosaurs) [48]. These results suggest that homoplasy is a principal driver of large-scale morphological variation (morphospace occupation) in at least one clade of fossil vertebrates. In other words, those lineages with more homoplasy are able to occupy a greater range of morphospace and experiment with a greater number of body plans (and presumably ecological activities, if morphospace occupation roughly correlates with ecological niche occupation) than those species with less homoplasy. It may be expected, therefore, that taxa nested within an extended ''zone of variability,'' may be able to explore greater morphological and ecological opportunities (depending on the nature of the characters, or character complexes, affected). This tantalizing possibility awaits further testing with other empirical case studies, as well as integration of developmental, paleontological, and phylogenetic data.

The rapid rate at which our understanding of morphological evolution is progressing is largely a reflection of the data generated by developmental biologists, who are isolating the mechanisms of morphological change at the molecular level, and by paleontologists, whose unique ability to empirically study the distribution of characters in deep time is critical to establishing the tempo and mode of these mechanistic transformations in developmental pathways. The role of paleontology is especially crucial when long periods of evolutionary history separate the origins and radiations of modern groups [49]. Conceptualizing the patterns of morphological variation and homoplasy derived from anatomical studies, such as this one on Alioramus altai, as a reflection of evolving variability in developmental networks [44,[50][51][52] increases the potential of paleontology to inform the nature of morphological transformations and the molecular changes that underlie them. This can only strengthen the relationship between fossil and developmental data [53].

Materials and Methods

Specimen and CT scanning IGM 100/1844 was collected under the auspices of an institutional agreement between the American Museum of Natural History and Mongolian Academy of Science. All specimens collected under the terms of this agreement receive Mongolian Figure 9. Phylogenetic tree showing the distribution of the plesiomorphic sinus cavernosus (0) in Theropoda. The sinus is invariably present in non-coelurosaurian theropods and invariably lost (1) in non-tyrannosaur coelurosaurs. The secondary loss of the sinus in Alioramus altai and possibly CMNH 7541 is interpreted as reflecting a period in theropod evolution in which the developmental pathways responsible for patterning the diencephalic region exhibited relative high levels of variability. This variability is retained in Tyrannosauroidea and might be expected to characterize at least the early history of its sister taxon. The variability in this case may be driven in part by heterochrony in which the original loss of the sinus occurred as a terminal addition to the ontogenetic sequence and was subsequently eliminated from postnatal ontogeny. Tree topology reflects generally accepted relationships with Theropoda [6][7][8][9][10][11][12]. doi:10.1371/journal.pone.0023393.g009

Figure 1 .
1The braincase of Alioramus altai (IGM 100/1844) (modified from fig. 2 of [22]). Dorsal (A), left lateral (B), ventral (C), and occipital (D) views. bo, basioccipital; bs, basisphenoid; ls, laterosphenoid; os, orbitosphenoid; ot, otoccipital; pa, parietal; pf, prefrontal; pr, prootic; so, supraoccipital. doi:10.1371/journal.pone.0023393.g001

Figure 2 .
2Stereopairs of the articulated braincase of Alioramus altai (IGM 100/1844). Dorsal (A), right lateral (B), and ventral (C) views. The images are reconstructed from the CT data with the bones rendered transparent to show the internal structures examined in this study. atr, anterior tympanic recess; bsr, basisphenoid recess; ctr, caudal tympanic recess; ec, endocranial cavity; scr, subcondylar recess; ssr, subsellar recess. doi:10.1371/journal.pone.0023393.g002

Figure 3 .
3Stereopairs of the braincase of Alioramus altai (IGM 100/1844) rendered transparent. This rendering reveals casts of the endocranial cavity, cranial nerve roots, selected vasculature, and the inner ear in dorsal (A), right lateral (B), and ventral (C) views, and the endocast with labeled structures in right lateral view (D). The upper right scale bar refers to A-C. doi:10.1371/journal.pone.0023393.g003100/1844 is nearly identical to that of non-coelurosaurian theropods (e.g., Majungasaurus crenatissimus[29]), although the point at which the abducens nerve enters the pituitary fossa may lie closer to the lateral margin of the fossa than in non-coelurosaurian theropods. This more lateral position may reflect a secondary invasion of the pituitary fossa by the abducens nerve, but it also may reflect an intermediate state in the transition from the plesiomorphic theropod condition (abducens passes through the pituitary fossa) and the one expressed in other coelurosaurs (abducens passes lateral to the fossa), including other tyrannosauroids. Regardless of the interpretation, the abducens nerve passed through the pituitary fossa in IGM 100/1844 making the presence of a sinus cavernosus a variable morphology among tyrannosaurs.

Figure 4 .
4Right lateral view of labeled endocranial casts of Alioramus altai (IGM 100/1844

Figure 5 .
5Two horizontal slices through the left cavum metoticum of Alioramus altai (IGM 100/1844). The slices sample the upper (A) and middle (B) regions of this space. The glossopharyngeal nerve (cn XI) enters the recessus scalae tympani through a foramen that is independent of the medial aperture of the cavum metoticum. Rostral is to the left. doi:10.1371/journal.pone.0023393.g005

Figure 6 .
6Morphology of the cranial nerve roots in Alioramus altai (IGM 100/1844). (A) Digital reconstruction of the cranial nerve roots in right dorsolateral view. (B) Horizontal CT slice showing the position of the gasserian ganglion and the split paths of the ophthalmic and maxillomandibular branches of the trigeminal nerve through the braincase. C) External view of the left lateral surface of the braincase showing the position of the prootic fossa, which accepts the lateral opening of the maxillomandibular branch of the trigeminal nerve and the palatine branch of the facial nerve.

Figure 7 .
7The diencephalic region of the braincase and endocranial cast of Alioramus altai (IGM 100/1844). The braincase is rendered in right anteroventrolateral view shows the position of the sinus cavernosus. The red arrow shows the point at which the abducens nerve enters the pituitary fossa. Dotted line delimits the sinus cavernosus as expressed on the external surface of the braincase. II, optic canal; III oculomotor canal, III B , position of external opening of oculomotor canal within sinus cavernosus; IV, trochlear canal; VI, abducens canal; VI B , position of external opening of oculomotor canal within sinus cavernosus; ptf, pituitary fossa. doi:10.1371/journal.pone.0023393.g007

Figure 8 .
8Stereopairs of the right osseous labyrinth of Alioramus altai (IGM 100/1844). The renderings are in lateral (A), medial (B), rostral (C), caudal (D), dorsal (E), and ventral (F) views. Reconstruction of the facial canal (purple), cavum metoticum (blue), and the independent medial path of the glossopharyngeal nerve (orange) are included in the medial and lateral views.

). These casts include the endocranial cavity, cranial nerve roots, selected vasculature, and inner ear. II, optic canal; III, oculomotor canal; IV, trochlear canal; V, trigeminal canals; VI, abducens canal; VII, facial canals; XII, hypoglossal canal; cm, cavum metoticum, includes lateral paths of glossopharyngeal and vagus nerves; cmv, caudal middle cerebral vein canal; ch, cerebral hemisphere; dp, dorsal peak (dural sinus); ie, inner ear; ob, olfactory bulb; ocs, occipital sinus; ocv, orbitocerebral vein; ol, optic lobe; ptf, pituitary fossa; rmv, rostral middle cerebral vein canal. doi:10.1371/journal.pone.0023393.g004

II, optic canal; III, oculomotor canal; IV, trochlear canal; V 1 , ophthalmic ramus of the trigeminal canal; V 2/3 , maxillomandibular ramus of the trigeminal canal; VI, abducens canal; VII 1 , palatine ramus of facial canal; VII 2 , hypoglossal ramus of facial canal; X, vagal canal; XII, hypoglossal canal; atr, anterior tympanic recess; chc, cochlear canal; csc, caudal semicircular canal; cts, caudal tympanic sinus; dhv, dorsal head vein canal; fl, floccular canal; fm, foramen magnum; gg, fossa housing gasserian ganglion; lsc, lateral semicircular canal; or, otic recess; ptf, pituitary fossa; rsc, rostral semicircular canal; rmv, rostral middle cerebral vein canal; rst, recessus scalae tympani. doi:10.1371/journal.pone.0023393.g006

VII, facial canals; VIII vestibulocochlear canals; IX, glossopharyngeal canal; ccr, common crus; chc, cochlear canal; csc, caudal semicircular canal; fpr, fenestra pseudorotunda; fv, fenestra vestibuli; jc, vagal canal; lsc, lateral semicircular canal; rsc, rostral semicircular canal. doi:10.1371/journal.pone.0023393.g008
PLoS ONE | www.plosone.org
August 2011 | Volume 6 | Issue 8 | e23393
AcknowledgmentsWe thank Amy Davidson who physically prepared the braincase and Mick Ellison who photographed it. CT scanning was performed by Matt Colbert (The University of Texas at Austin) and facilitated by Justin Sipla (The University of Texas El Paso). Larry Witmer (Ohio University) made available important comparative CT data. We thank Xu Xing (Institute of Vertebrate Paleontology and Paleoanthropology, Beijing) for access to specimens in his care. Larry Witmer and an anonymous reviewer greatly improved the manuscript with their critical comments and suggestions.Author ContributionsAcademy catalogue numbers and are returned to Mongolia. The braincase of IGM 100/1844 was scanned at The University of Texas High-Resolution X-ray Computed Tomography Facility, Austin. Scanning occurred along the sagittal axis using a voltage of 450 kV and amperage of 3 mA. A total of 431 slices were recovered at an image resolution of 1,024 X 1,024 pixels. The slice thickness and interslice spacing is 0.25 mm with a reconstructed field of view of 301.6 mm. Reslicing of the data along the horizontal and coronal axes and all digital segmentation was performed using VG StudioMax 1.2.1. The reconstruction of all movies (www.digimorph.org/specimens/Alioramus_altai) was performed using VG StudioMax 2.0.1.
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