Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Disopyramide”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 91 records · Page 5Linked to original sources
PubMed1993

The transport mechanism of an organic cation, disopyramide, by brush-border membranes. Comparison between renal cortex and small intestine of the rat.

The characteristics of disopyramide uptake in brush-border membrane vesicles isolated from rat renal cortex and small intestine were investigated. Transport of disopyramide into an osmotically reactive intravesicular space was observed with notable binding to the membrane surface. An outwardly directed H+ gradient stimulated disopyramide uptake, resulting in a transient uphill transport in both brush-border membranes. As for the renal brush-border membrane, the H+ gradient itself appeared to be the driving force for this stimulation of uptake. These findings suggest that disopyramide-H+ antiport is the mechanism of disopyramide action in renal cell membrane. The initial uptake was saturable (Km and Vmax of 68.0 microM and 1.25 nmol (mg protein)-1/30 s, respectively). The stimulation of disopyramide uptake by an outward H+ gradient in rat intestinal brush-border membrane was due to an interior negative H(+)-diffusion potential. A K(+)-diffusion potential (interior negative) enhanced disopyramide uptake. These results suggest that there are different mechanisms of disopyramide uptake for renal and intestinal brush-border membrane vesicles.

Animals↗
PubMed1997

Comparison of the effects of cimetidine and ranitidine on the pharmacokinetics of disopyramide in man.

The widely prescribed antiulcer agents cimetidine and ranitidine have the potential to affect the absorption, metabolism or renal excretion of disopyramide. This study investigated the effect of a single oral dose of cimetidine or ranitidine on the pharmacokinetics of disopyramide and mono-N-dealkyldisopyramide in six healthy volunteers. The treatment was conducted in a randomized cross-over design. Serum levels and urinary recoveries of disopyramide and mono-N-dealkyldisopyramide were assayed by HPLC. Cimetidine significantly elevated the maximum plasma concentration of disopyramide, the area under the plasma concentration-time curve and the total amount of disopyramide excreted unchanged in the urine, but the serum profile of mono-N-dealkyldisopyramide was not significantly affected. The effects of ranitidine on the pharmacokinetics of disopyramide and mono-N-dealkyldisopyramide were not significant. The interaction between cimetidine and disopyramide occurred mainly at the site of absorption. The results indicate that cimetidine, but not ranitidine, significantly increased the absorption of orally administered disopyramide.

Administration, Oral↗
PubMed1981

Electrophysiological effects of the optical isomers of disopyramide and quinidine in the dog. Dependence on stereochemistry.

We studied the electrophysiological effects of the optical isomers of disopyramide and quinidine on canine cardiac Purkinje fibers. Conventional microelectrode techniques were employed to study the effects of racemic disopyramide, (+)-disopyramide, (-)-disopyramide, quinidine, and quinine. Racemic disopyramide, (+)-disopyramide, and quinidine prolonged action potential duration (APD) measured at 90% repolarization. In contrast, (-)-disopyramide and quinine shortened APD. These directionally opposite effects on repolarization were observed throughout 60 minutes exposure to drug and were concentration-dependent. All five components reduced dV/dt of phase 0, increased conduction time, and increased the current requirement for all-or-none depolarization. The effects of all five compounds on dV/dt, conduction time, and current requirements were time- and concentration-dependent. Our results indicate that the stereochemical configurations of disopyramide and quinidine determine their effects on repolarization of cardiac Purkinje fibers.

Action Potentials↗
PubMed1992

Inadequate adrenergic response to disopyramide-induced hypoglycemia.

OBJECTIVE: To report a case of disopyramide-induced hypoglycemia and to discuss the observed inadequate adrenergic response in this patient. Risk factors, possible etiologies, and preventive measures are also discussed. DATA SOURCES: References from case reports and review articles as identified by MEDLINE. DATA SYNTHESIS: A wide variety of drugs has been implicated as causing hypoglycemia. The mechanism for drug-induced hypoglycemia is known for the majority of these agents. Case reports of disopyramide-induced hypoglycemia have been reported in the literature, but the mechanism of action is unclear. We report a case of disopyramide-induced hypoglycemia in which counter-regulatory hormones, serum insulin, and C-peptide concentrations were obtained. From these data, it appears that disopyramide-induced hypoglycemia results from endogenous insulin secretion, with concomitant inadequate counterregulatory response. CONCLUSIONS: Although a rare occurrence, disopyramide-induced hypoglycemia is potentially life-threatening. Patients at risk for this reaction need to be identified prior to the institution of disopyramide therapy. Patients at risk for hypoglycemia should be monitored while on disopyramide and disopyramide blood concentrations should be maintained at the lower end of the therapeutic range, or alternative agents should be considered.

Aged↗
PubMed2001

Stereoselective pharmacokinetics and pharmacodynamics of disopyramide and its metabolite in rabbits.

The extent to which interactions between enantiomers of disopyramide and between disopyramide and its metabolite, mono-N-dealkylated disopyramide (MND), contribute to stereoselectivity of the anti-arrhythmic effect has been investigated in rabbits by measuring the prolongation of the QUc interval. The plasma unbound fraction of disopyramide enantiomers was constant at a concentration range of 1.44-28.9 microM. An intravenous infusion study of the disopyramide enantiomer or racemate suggested that the S-enantiomer had a pharmacological effect, determined by linear regression analysis, approximately 3.3-times more potent than that of the R-enantiomer. Furthermore, the effect caused by racemic disopyramide was the sum of that elicited by both enantiomers individually. No significant difference was observed between the slope of linear regression analysis of intravenous infusion and that of intravenous bolus injection. Single intravenous bolus injection of MND did not affect the QUc intervals. In conclusion, the S-enantiomer of disopyramide was approximately 3.3-times more potent pharmacologically than the R-enantiomer. The relationship between plasma concentration of the disopyramide enantiomers and pharmacological effect was the sum of each enantiomer individually.

Action Potentials↗
PubMed2000

[Antiarrhythmic effects of pilsicainide hydrochloride and effects on cardiac function and ECG in dogs: comparison with disopyramide].

Antiarrhythmic effects and cardiovascular effects of pilsicainide hydrochloride were compared with those of disopyramide in a canine model of coronary ligation-induced ventricular arrhythmias and anesthetized dogs. Pilsicainide (1.25, 2.5 and 5 mg/kg) and disopyramide (2.5 and 5 mg/kg) decreased the arrhythmic ratio ¿(ventricular arrhythmias/total heart rate) x 100¿ dose-dependently. Pilsicainide at 2.5 and 5 mg/kg and disopyramide at 5 mg/kg suppressed ventricular arrhythmias more than 50%. The effective dose of pilsicainide was lower than that of disopyramide, but the effective plasma concentration of pilsicainide was between 3 and 8 micrograms/ml, which was almost the same as that of disopyramide. In anesthetized dogs, both drugs decreased LV dP/dt max in almost the same concentration-dependent manner. PQ-interval was prolonged by pilsicainide, but not by disopyramide. QRS and QTc were prolonged by both drugs in a concentration-dependent manner. However, the prolongation of QTc by disopyramide was provoked at lower plasma concentrations than by pilsicainide. Because the excessive prolongation of QTc lead to the lethal arrhythmias such as torsades de pointes, pilsicainide may be useful as an injectable antiarrhythmic agent superior to disopyramide.

Anesthesia↗
PubMed1981

Studies on the preventive method of lowered ventricular fibrillation threshold during experimental acute myocardial infarctions. A comparison between disopyramide phosphate and lidocaine.

This study was performed to investigate the prophylactic effect of disopyramide phosphate on ventricular fibrillation in acute myocardial infarction. Lidocaine and disopyramide phosphate were compared in terms of their effects on the lowered ventricular fibrillation threshold in experimental myocardial infarction produced by coronary ligation in dogs. The following results were obtained: 1) The effect of lidocaine i.v. + infusion appeared promptly and the ventricular fibrillation threshold exceeded control levels from 45 min onwards (p less than 0.01). 2) The i.m. injection of lidocaine was effective in a dose of 10 mg/Kg. The minimally effective blood level was 1.7 mcg/ml. 3) Disopyramide phosphate 5 mg/Kg i.v. produced a tendency towards recovery from 15 min onwards. After 30 min, the ventricular fibrillation threshold was significantly higher than control (p less than 0.01). 4) Disopyramide phosphate 5 mg/Kg i.m. was initially effective after 45 min. The effect was significant from 1 hour and 30 min onwards, compared with control (p less than 0.01). The minimally effective blood level was 2.4 mcg/ml. 5) Disopyramide phosphate 2 mg/Kg i.m. produced a tendency towards recovery but the difference from the control was not significant. 6) In equivalent i.m. doses, disopyramide phosphate tended to be more potent than lidocaine in increasing the ventricular fibrillation threshold. 7) In the aforementioned doses, disopyramide phosphate did not cause any marked changes in PQ interval or QT time in ECG. These results suggest that the intramuscular injection of disopyramide phosphate is a hopeful clinical treatment to prevent ventricular fibrillation in the very early stages of acute myocardial infarction.

Animals↗
PubMedDate not supplied

Clinical pharmacokinetics of disopyramide.

Disopyramide is an antiarrhythmic agent with proven efficacy in the management of atrial and ventricular arrhythmias. The drug is well absorbed and undergoes virtually no first-pass metabolism. Peak concentrations are achieved approximately 0.5 to 3.0 hours after a dose. Absorption is reduced and slightly slowed in patients with acute myocardial infarction. Disopyramide is excreted as unchanged drug (two-thirds) or as the metabolite mono-N-desisopropyldisopyramide, with elimination via both renal and biliary routes. Elimination half-life is approximately 7 hours in normal subjects and patients, but is prolonged in patients with renal insufficiency (creatinine clearance less than 60 ml/min). Disopyramide exhibits complex protein binding. It is bound to alpha 1-acid glycoprotein (AAG), an acute phase reactant, and binds in a concentration-dependent (saturable) manner. The unbound fraction is reduced in the presence of elevated concentrations of AAG, as are found in acute myocardial infarction and in some chronic haemodialysis patients and renal transplant recipients. Free disopyramide concentrations are low relative to total concentration in these patients. Because the pharmacological effects of disopyramide are determined by unbound drug, changes in the unbound fraction could make total disopyramide concentrations misleading as a guide to therapy. Changes in protein binding do not, however, alter free disopyramide or metabolite concentrations, both of which are dependent only on dosage and intrinsic clearance. Free drug concentration measurement could potentially improve therapeutic monitoring, but is as yet of unproven clinical value. Disopyramide is cleared more rapidly in children than in adults, and therefore children require higher dosages to attain therapeutic concentrations.

Aged↗
PubMed1987

Fatal disopyramide intoxication from suicidal/accidental overdose.

Disopyramide is an oral antiarrhythmic drug which reduces conduction velocity, prolongs duration of action potential and the effective refractory period, and exerts vagolytic properties. The drug is usually well absorbed orally. The principal use of the drug is to suppress ventricular extrasystoles with usual oral dosage of 100 to 200 mg every 6 h, until blood levels of 2 to 4 micrograms/mL are attained. The use of the drug for suicide is uncommon as it is a prescription drug. Two cases of fatal disopyramide intoxication seen at the Los Angeles County Medical Examiner's Office will be discussed followed by a review of the literature of fatal suicidal disopyramide overdose. Case 1 was a 31-year-old male pharmacist with known history of depression and no history of heart disease. His decomposed remains were found with a suicide note and with several disopyramide tablets. At autopsy the blood level for disopyramide was 146 micrograms/mL. Case 2 is a 40-year-old male with history of alcoholism and prior suicidal attempts who regularly took disopyramide to control ventricular arrhythmias. He apparently ingested 36 100-mg tablets of disopyramide before his final collapse. At autopsy his blood level of disopyramide was 63 micrograms/mL.

Adult↗
PubMed1980

A stable isotope dilution assay for disopyramide and its [13C, 15N]labelled analogue in biological fluids.

The mass spectra of disopyramide phosphate and two stable isotopically labelled analogues have been obtained using electron impact and chemical ionization. The low isotopic purity of [13C, 15N)disopyramide phosphate was shown to be due to the low isotopic purity of the 15N label. A stable isotope dilution assay for disopyramide and [13C, 15N]disopyramide in biological fluids has been developed using [2H14]disopyramide phosphate as the internal standard. This assay will be used to analyse samples obtained after the co-administration of disopyramide phosphate intravenously and [13C, 15N]disopyramide phosphate orally to several animal species.

Animals↗
PubMed1980

The absorption of disopyramide in animals determined using a stable isotope co-administration technique.

The stable isotope co-administration technique for estimating the bioavailability of drugs has been investigated in a series of experiments using rhesus monkeys. The compound chosen for study was disopyramide phosphate. A cross-over study was designed whereby the animals received disopyramide phosphate (administered intravenously at 5 mg kg-1) and [13C, 15N]disopyramide phosphate (administered orally at 5 mg kg-1), with a wash-out period between doses. A co-administration study was carried out whereby both the oral and intravenous doses were administered together. The co-administration study was repeated. The results from the cross-over study showed [13C, 15N]disopyramide to have an oral availability of 4.9 +/- 0.9% (by comparing areas under the plasma concentration versus time curves). The bioavailability was estimated to be 5.7 +/- 0.3% comparing totals excreted in urine over 48 h. The bioavailability of the oral dose was calculated as 8.2 +/- 2.5% (comparing areas under plasma concentration versus time curves) and 9.3 +/- 3.0% (comparing totals excreted in urine) after co-administration. The differences between these results and the cross-over results were examined in a further study, using oral administration only. The animals were dosed orally with a solution containing both disopyramide phosphate (5 mg kg-1) and [13C, 15N]disopyramide phosphate (5 mg kg-1). No differences were observed between the plasma concentration versus time curves or urinary excretion for either isotope. It is unlikely that the discrepancy in bioavailability is due to absorption, metabolism or exretion of the oral dose. It is probable that the high concentration of disopyramide obtained after the intravenous dosage affects the disposition of the oral dose, and this gives the higher figure.

Administration, Oral↗
PubMed1998

Cisapride counteracts the anticholinergic effect of disopyramide on the guinea pig isolated small but not large intestine.

This study examines the influence of the prokinetic agent cisapride on the disopyramide's effect on the isolated duodenum and ileum, as well as on the ascending colon of the guinea pig. Acetylcholine produced the well known stimulatory effect on the intestinal parts with EC50 values 9.6 x 10(-8), 7 x 10(-9) and 1.1 x 10(-6) M for the duodenum, ileum and ascending colon, respectively. Disopyramide inhibited, in a concentration-dependent manner, the contractile responses of the intestinal parts to acetylcholine. Cisapride, at concentrations ranging from 5 x 10(-9) M to 10(-6) M, significantly reversed the above inhibitory effect of disopyramide on the guinea pig duodenum and ileum and produced a parallel leftward shift of the concentration-response curve for acetylcholine in the presence of disopyramide. However, cisapride was not found able to reverse the inhibitory effect of disopyramide on the ascending colon. In conclusion, cisapride may counteract the inhibitory effect of disopyramide on the guinea pig duodenum and ileum, probably by facilitating the cholinergic neurotransmission, while it is not able to reverse the disopyramide's inhibitory effect on the guinea pig ascending colon.

Acetylcholine↗
PubMed1988

Nicorandil shortens action potential duration and antagonises the reduction of Vmax by lidocaine but not by disopyramide in guinea-pig papillary muscles.

Conventional microelectrode techniques were used to examine whether or not nicorandil, which shortens action potential duration (APD), modifies the lidocaine- or disopyramide-induced time-dependent reduction of Vmax in guinea-pig papillary muscles. First, effects of 0.1 and 1 mmol/l nicorandil were examined on the frequency dependence of Vmax and on the recovery process of Vmax. Second, the frequency-dependent reduction of Vmax by 20 mumol/l antiarrhythmic drugs was examined in the presence and absence of 1 mmol/l nicorandil at stimulation frequencies of 1/120 Hz - 5 Hz. Third, the recovery process of Vmax in the presence of 20 mumol/l antiarrhythmic drugs was examined, with and without 1 mmol/l nicorandil, by applying test stimuli at various diastolic intervals after conditioning stimuli. 1 mmol/l nicorandil greatly shortened APD90 to 30-40% of control without changing the frequency dependence of Vmax, the recovery process of Vmax, and the resting potential. The lidocaine-induced, frequency-dependent reduction of Vmax was significantly antagonised by 1 mmol/l nicorandil, but the disopyramide-induced reduction was not. The recovery process of Vmax slowed in the presence of lidocaine was antagonised by 1 mmol/l nicorandil as follows: the time to get the full recovery of Vmax was shortened by nicorandil with a significant decrease in the zero time-intercept (from 0.54 to 0.38) but with an insignificant change in the recovery time constant (from 130 ms to 121 ms). In contrast, the recovery process of Vmax slowed in the presence of disopyramide (a zero time intercept of 0.13 and a recovery time constant of 50 s) was not significantly antagonised by 1 mmol/l nicorandil. In conclusion, nicorandil having an action potential-shortening action antagonises the lidocaine-induced, time-dependent reductions of Vmax, but not the disopyramide-induced reductions. These results suggest that: (1) lidocaine and disopyramide preferentially bind to inactivated and activated sodium channels, respectively, because lidocaine's effects are dependent on and disopyramide's effects are independent of APD (during which sodium channels are in the inactivated state); and (2) nicorandil is a useful drug for estimating whether a sodium channel-blocking action of class I antiarrhythmic drugs is due to an inactivated channel block or an activated channel block. These time-dependent reductions of Vmax by both lidocaine and disopyramide were well simulated by the guarded receptor hypothesis.

Action Potentials↗
PubMed1991

Efficacy of disopyramide in conversion and prophylaxis of post-thyrotoxic atrial fibrillation.

Rhythm conversion in patients with post-thyrotoxic atrial fibrillation (AF) has been performed with disopyramide in order to evaluate the conversion rate and to test its effect on the maintenance of sinus rhythm after cardioversion. The duration of AF ranged from 9 to 122 months (mean 31.8 months). Of 81 patients, 12 (15%) with relatively short duration AF were converted to sinus rhythm with disopyramide. The remaining 69 patients required DC cardioversion, which restored sinus rhythm in 58 patients. The 58 DC-converted patients were divided into two groups: a disopyramide group (D group) and a non-disopyramide group (non-D group). The D group received disopyramide 300 mg per day for 3 months after DC cardioversion and the non-D group did not receive anti-arrhythmic drugs. During the early observation period, only one patient relapsed in the D group into AF, but 5 successive patients in the non-D group reverted to AF, forcing discontinuation of the non-D protocol. A second DC cardioversion performed on 3 of those 5 patients was followed by maintenance therapy with disopyramide 300 mg per day, and they remained in sinus rhythm. With the inclusion of those three subjects, sinus rhythm was still present in 44 of the total of 58 patients converted by DC (76%) at the time of follow-up (64 months). Thus, disopyramide was effective in rhythm conversion and it was essential for the maintenance of sinus rhythm after cardioversion in patients with post-thyrotoxic AF.

Adolescent↗
PubMed1983

Plasma concentration of disopyramide given as capsules and controlled release tablets.

Steady state plasma levels and clinical effects of disopyramide have been compared following administration of standard capsules and controlled release (CR) tablets. Nineteen patients (29-70 years) with atrial or ventricular arrhythmias were treated for two weeks with disopyramide capsules 200 mg t.i.d. and then with CR tablets 300 mg b.i.d. for 14 weeks. After treatment either with capsules or CR tablets, plasma concentrations of disopyramide and its metabolite N-deisopropyldisopyramide were similar within 1 dosage interval. Maximum and minimum concentrations of the parent drug were 10.1 +/- 0.9 mumol/l (mean +/- SEM) and 5.7 +/- 0.5 mumol/l with CR tablets, and 10.2 +/- 0.5 mumol/l and 5.6 +/- 0.5 mumol/l with standard capsules. The bioavailability of disopyramide was the same after capsules and CR tablets. Disopyramide, independent of the formulation, produced good antiarrhythmic effects. The side-effects reported on questioning were mainly of the anti-cholinergic type and there was no significant difference between the formulations with respect to their incidence, type or severity. Of 16 patients who stated a preference for one of the dosage forms, 11 prefered the CR tablets. The study confirms the good antiarrhythmic effect of disopyramide and shows that the CR preparation permits twice daily administration of disopyramide.

Adult↗
PubMed1991

Electrophysiologic effects of FPL 13210 on canine Purkinje fiber action potential duration and Vmax comparison to disopyramide.

The frequency-dependent effects of FPL 13210, a new disopyramide derivative, were examined in isolated canine cardiac Purkinje fibers paced at a frequency of 2 Hz and following abrupt changes in pacing cycle length. At 2 Hz, FPL 13210 depressed Vmax, while shortening action potential duration measured at 50% of repolarization (APD50) and not affecting duration measured at 90% of repolarization (APD90). These effects were concentration dependent over the range of 1-30 microM. The depression of Vmax produced by 5 microM FPL 13210 was not significantly different than that produced by 18 microM disopyramide while the preparations were paced constantly at 2 Hz. At these concentrations, recovery of Vmax was slowed by both FPL 13210 and disopyramide. The slow time constant estimated for this relation after exposure to FPL 13210 was approximately 6.5 times longer than that estimated following administration of disopyramide. In addition, APD90s evoked by early premature stimuli in the presence of 5 microM FPL 13210 were longer than those produced in the absence of drug when the diastolic intervals longer than 100 ms produced shorter APD90s after FPL 13210 administration. Therefore, when FPL 13210 is compared to disopyramide using concentrations selected to produce equivalent degrees of Vmax depression, FPL 13210 produced effects on APD90 that were opposite to those produced by disopyramide when the diastolic interval was longer than normal. These effects of FPL 13210 would suggest that this compound should be classified as a class Ic antiarrhythmic agent, unlike disopyramide, a class Ia antiarrhythmic agent.

Action Potentials↗
PubMed1982

Use of radionuclide ventriculography for assessment of changes in myocardial performance induced by disopyramide phosphate.

Disopyramide phosphate may precipitate heart failure in susceptible patients with cardiomegaly. To identify those at risk, gated radionuclide ventriculography (RVG) was performed in two groups. Eleven patients without evidence of structural heart disease constituted group 1, and 12 with impaired ventricular function made up group 2. RVG was carried out before and 2 hours after administration of a single 300-mg dose of disopyramide orally. After disopyramide mean left ventricular ejection fraction (EF) decreased in the 12 patients in group 2 (35% to 26%) (p less than 0.01); depression of function was most pronounced in regions with the poorest baseline value. Of the 11 patients in group 1 (mean EF 60%), EF was reduced after disopyramide in only one. Serum levels of drugs were comparable in patients in both groups (3.1 vs. 3.7 micrograms/ml). We conclude that (1) patients with left ventricular dysfunction are particularly susceptible to the depressant effects of disopyramide; (2) RVG is a sensitive technique for detecting disopyramide-induced changes in ventricular performance; and (3) RVG before and shortly after a dose of disopyramide orally may help to identify those patients at high risk.

Adolescent↗
PubMed1986

Long-term therapy with disopyramide phosphate: side effects and effectiveness.

In this study, the safety and efficacy of long-term therapy with disopyramide phosphate were evaluated in 40 patients with documented, recurrent, symptomatic tachyarrhythmias. Twenty-one (53%) of the patients had organic heart disease, and nine of these patients had compensated congestive heart failure. The tachyarrhythmias which were treated were paroxysmal supraventricular tachycardia (21 patients), paroxysmal atrial fibrillation (six patients), and paroxysmal ventricular tachycardia (13 patients). In each patient there was evidence, from continuous ECG monitoring or electrophysiologic testing, that disopyramide would be effective therapy, and each patient was able to tolerate disopyramide (no side effects or tolerable side effects) during an initial trial period of 1 to 2 weeks. Dosages of disopyramide were 400 to 1600 mg/day (994 +/- 320 mm/day). During long-term therapy, side effects were reported by 28 (70%) of the patients. The side effects were usually anticholinergic, and were usually a continuation of side effects noted during the initial trial period. None of the patients had idiosyncratic reactions to disopyramide. Most of the patients found side effects to be tolerable; however, in seven patients it was necessary to discontinue disopyramide after 1 to 8 (6 +/- 3) months. Actuarial incidence of intolerable side effects was 21 +/- 7% at 12 months. Nine (22%) of the 40 patients had symptomatic recurrences of tachyarrhythmia after 3 to 32 (15 +/- 9) months of therapy. Actuarial incidence of drug ineffectiveness was 32 +/- 10% at 24 months. Disopyramide was both effective and tolerated in 24 (60%) of the patients, who were followed for 2 to 64 (23 +/- 16) months.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗