© 1999 by European Society of Cardiology
Copyright © 1999, European Society of Cardiology
A dilemma on Orchid Island
"Ah, Indian River country," remarked Theodore Conrad as he drove the car rental southward to Vero Beach.
"Our favorite vacation spot," affirmed Elizabeth.
"I was just thinking about a potential public health conundrum that might take place in this part of the world," added Theodore.
"Tell us about it," pleaded Thaddeus and Alexandra from the back seat.
"With pleasure...."
At the wheel of his new silver Volvo sat Seymour Lavin. Sy and his new bride, Joyce, were headed south on US 1 to their new home in Orchid Island. They had just left the Blue Gull Marina in Sebastian, where they had enjoyed a lunch of charbroiled shrimp over endive with balsamic-based vinaigrette and a bottle of their favorite California Chardonnay. With the solitude provided by closed windows and the stereo featuring a Mozart concerto, Sy and Joyce each quietly contemplated the future. Sy had a new lease on life, a new bride and a new home. He had finally come to grips with the loss of Ruth, his first wife, and her painful battle with the ravages of metastatic breast carcinoma. For more than a year after Ruth’s passing in 1994, Sy had been severely depressed, seemingly lost without his soulmate and partner. He had been unable to concentrate on his successful real estate business in Chicago. He barely coped with life. However, his grief had been assuaged 18 months later when he met 31-year-old Joyce through a mutual friend. A physical therapist, Joyce was bright, vivacious and sensitive. Her attentiveness, engaging personality and feminine charms had restored Sy’s peace of mind, and he felt like a young man again. Sy and Joyce were married on December 15, 1996, and chose to spend their winter months at their new home on the shores of Orchid Island in central Florida. They quickly assimilated themselves into the community, and by now were well known by their neighbors and acquaintances at the marina, the food market and pharmacy.
Sy glanced from the roadway over at Joyce, who like himself was caught up in thought, her eyes shielded by iridescent sunglasses. He marveled at her beauty. Her short, sleeveless white sundress was speckled with light blue periwinkles, and whether flowers or snails, it created a ravishing image for Sy – one he savored for some minutes.
The water tower and Wabasso tackle shop ahead alerted Sy to the fact that the left turn to Orchid Island was imminent. Heading eastward on Route 510, the Lavins drove past orchards of recently ripened citrus fruit delayed by an unexpected November frost. Joyce carefully crossed her tanned, slender legs for an intended effect. She shifted effortlessly to face Sy. Sitting up straight, she murmured, "Sweetie, look at these luscious grapefruits. I’ve been told they’re so healthy for you."
"Yeah," stammered Sy, stealing a glance over at his wife. Quickly recovering, he added, "You remember Sid Schwartz, my internist back in Hyde Park? He told me grapefruit juice would lower my cholesterol and improve my bad to good lipids. He called them the ratio of low to high density lipoproteins."
"Sy, we should make it a habit to drink freshly squeezed grapefruit juice whenever we can," added Joyce. "The new pink variety is sweet yet tart. Let’s replace the OJ we have at breakfast, and with our late afternoon screwdrivers. And Indian River County is a major producer of citrus fruit. We’re so fortunate to live here and have citrus available nearly year round. We can have it shipped to Chicago when we’re back in our lakefront condo."
Sy braked at the flashing stoplight and then maneuvered the Volvo onto A1A. Soon thereafter, the Lavins reached their plush beachfront estate. Their property was bounded by Sabal palms and pine trees, and as they came up the driveway, their lawn of thick, recently cut zoysia grass was dotted with blooming hibiscus that offered a cornucopia of colors: pink, red, yellow and peach flowers. Their one-acre beachfront estate provided an excellent view of the ocean with its ever-changing shapes and sounds, and was complete with swimming pool and tennis court. Sy and Joyce enjoyed a daily early morning volley on the tennis court, and at dusk a power walk along route A1A.
Sitting in their screened-in porch, admiring the sights and sounds of the surf, Joyce began to massage her right thigh and shin. "Maybe it’s shinsplints from last night’s walk," she commented, wincing with pain. "That ointment we bought at the pharmacy doesn’t seem to be working for these cramps. And of late, my lower back has become stiff. I should see Dr. Ogden in Sebastian tomorrow morning. I hear he’s quite good."
"Yes, you should," Sy agreed. "He has a fine reputation with problems such as yours. Let’s just forego our evening walk and let you rest." That night, Sy was too tired for any bedroom fun and games.
The next morning, with beams of sunlight bathing the eastward facing kitchen, Joyce entered and stood facing Sy in a provocative pose, her bathrobe loosely fastened. She snuggled against his left arm as he busily worked the new electric juicer that forcefully crushed the fruit. Gazing down at her in admiration, he added, "Honey, I’ve followed your advice about grapefruits and prepared a pitcher of freshly squeezed pink grapefruit juice. It should go well with our smoked salmon and cream cheese. Besides, we’ve run out of decaf. And honey, sorry about last night. It may have been my antihistamine that made me so sleepy."
Joyce took herself over to Dr. Ogden’s in her candy-apple red BMW, her blonde pony tail trailing behind her like a flapper’s scarf in an open-aired Deusie.
Philippe Ogden, a chiropractor, was an impressive physical specimen, with tanned sinewy forearms and biceps. His well-developed pectorals and expanded chest ended in a slim waistline, his powerful quadriceps evident through casual slacks. What a hunk, Joyce thought. She related her recent symptoms to Philippe. He thoughtfully suggested that while busy with another patient, she undress and change into a gown. "On my return I will tend to your back and muscular aches using chiropractic therapy. This therapy is based on spinal manipulation, which frees nerves pinched between the vertebrae, or bones, of your spinal column".
Joyce marveled at the feel of Philippe’s powerful hands as they massaged her right and left legs, and then each of her thighs. Philippe inched closer, their bodies almost touching, as he pressed down firmly on Joyce’s flexed knee which he had brought to her chest. His eyes stared directly into hers. "Please roll over onto your tummy and I’ll continue to restore the alignment of your lumbosacral spine," Philippe told her, and then began massaging her back as she lay face down on the examining table, her chin resting on folded hands, a smile of contentment on her lovely face.
"You’re so good," she purred. "I feel better already."
"Mrs. Lavin, a word of advice," Philippe cautioned. "You can’t avoid the heat down here, and during your evening walks and morning tennis you’ll sweat a lot. I recommend you regularly take my favorite herbal tea, which reduces salt and water loss. It’s a licorice-based preparation called ‘Victory Garden.’ A number of my patients use it. Many are Muslims who celebrate Ramadan, and it helps them during their month-long fast. You can buy ‘Victory Garden’ over at Shrugg’s."
"I’ll make a note to do so," responded Joyce, gazing into his piercing eyes.
On her way home, Joyce stopped at Shrugg’s, where she also purchased decaffeinated coffee, since Sy did not sleep well after drinking regular. She bought a newspaper and a recently released legal mystery. As she browsed the paperback display of best-sellers, a breathless Hiram Salker came rushing up, his hands wringing one another as if he had just washed.
"Fine morning, eh, Mrs. Lavin?" he queried as he wiped away beads of sweat that had formed on his bald head. Hiram was built low to the ground, his bulging midriff betraying his sedentary life-style as pharmacist at Shrugg’s. Never one to miss an opportunity to schmooze with a beautiful woman, Hiram’s eyes longingly explored Joyce’s well-proportioned physique, looking for any opportunity to gaze at bare flesh.
"Good morning, Hiram. It sure is a fine day," responded Joyce as she thought about Philippe’s massage.
"Will there be anything you need from our pharmacy today?"
"Yes, as a matter of fact there is. Dr. Ogden suggested I pick up an herbal tea called ‘Victory Garden.’ It’s an over-the-counter preparation, isn’t it?"
"Why, yes," Hiram said, walking over to the herbal preparations counter. "May I ask what will you be using it for?"
" Well, Mr. Lavin and I are quite health conscious. We exercise regularly," she said with a flirtatious twinkle in her eye, knowing full well the effect it would have on this little man. "Working out is not only good for cardiovascular fitness, it’s also good for controlling our cholesterol level. Dr. Ogden suggested we take this tea to conserve salt and water when working out in the Florida sun."
"That’s a fine idea, Mrs. Lavin," noted Hiram. To reinforce his concern, he added, "We also have some pure licorice candies from the Netherlands that you might want to try." Adding a touch of wisdom, he noted, "Your husband should drink grapefruit juice regularly. It’s been shown to lower cholesterol, and you don’t want Mr. Lavin to have a heart attack during one of your workouts."
"We began such a regimen just today. We have grapefruit juice with breakfast and with our afternoon cocktail," noted Joyce. "It’s very kind of you to think of that."
"My pleasure," Hiram said, his eyes traveling up Joyce’s dark blue leotard-clad legs and firm thighs to her running shorts with their widely cut leg openings. "Please call on me anytime I can be of service," he said licking his lips. "I would even make a housecall for you, Mrs. Lavin." His eyes reached her chest and stopped there. "May I call you Joyce?" he added.
"Hiram, you’re too kind. Something you just said reminded me of a saying Mr. Lavin told me about bald men. Let’s see, how does it go? Oh, yes. Those with a bald spot at the back of their head are so sexy. Those whose baldness is expressed at their scalp line are so cerebral." She paused for effect. "And then those men who are bald all over think they’re sexy." Joyce turned and made her exit.
Based on the advice of Philippe and Hiram, the Lavins embarked on their new health care routine. Afternoon showers created the ambience and opportunity for Sy and Joyce to be cozy. Sy had recently forsaken his antihistamine. Later in the week, he and Joyce each developed leg cramps after their workouts.
"I need to revisit with Dr. Ogden," noted Joyce. "These cramps in my calves are killing me."
"As you wish, my dear," Sy said. "I’ll just tough it out. The cramps will probably disappear as we continue our regular exercises."
He added with a twinkle in his eye, "I will, however, go over to Shrugg’s. Since I stopped taking my antihistamine, my stuffy nose and teary eyes have become a nuisance. I’m going to need a pill that doesn’t make me sleepy. I’ll call Sid Schwartz about such a preparation and he can call Hiram with the prescription."
On Saturday morning, Sy was over at Shrugg’s. "Hiram, how goes it, my friend?"
"Fine," responded a somewhat reserved Hiram. "And how is the missus?" he added, with just a touch of sarcasm.
"Reasonably well, thank you, except for recurring leg cramps. Hiram, I need an antihistamine without sedative effects. Dr. Schwartz, my internist in Chicago, should have called in a prescription."
"Yes he did, Mr. Lavin. This particular preparation blocks H1 histamine receptors but doesn’t enter the brain. Drowsiness is not a feature of this drug. You should take one tablet at breakfast and one in the late afternoon."
"Thanks, Hiram. I’ll give it a try."
The Lavins spent the remainder of Saturday at home. Joyce enjoyed her new novel while Sy watched an intercollegiate football game, smoking his favorite Feunte cigar. The restful day served their intermittent leg cramps well. "This new antihistamine seems to be working," reported Sy.
"I’m glad. I like it when you’re not so sleepy, dear," purred Joyce. "By the way, I invited Stuart to visit with us for a few days. A surprise for your birthday next Sunday. We’ll keep it a small affair. I’ve only invited a few guests over."
"That’s so nice of you, honey. It’ll be good to see my son and hear how he’s managing the business back in the windy city. His extravagant lifestyle notwithstanding, I worry about his love of horses at the track, and I’ll be damned if I’ll bail him out again. When will we have to pick Stuart up at the airport?"
"It’s all taken care of. You can sleep in Sunday morning and leisurely read the newspaper while I run over to Melbourne to get him. I want you to have your rest. I’ve planned something special for your birthday."
A week passed with the Lavin’s enjoying Florida’s warm temperatures as contrasted to the frigid, snowy weather in Chicago, which they read about in the newspaper with smug satisfaction.
Sy awoke Sunday morning earlier than expected. The digital clock radio indicated it was 8:05 a.m. Joyce had already departed. Strange. Why had she left so early, he wondered. Stuart’s plane was not due in until 11:16 a.m., and Melbourne was only 38 miles away.
Stuart’s arrival late Sunday morning was a pleasant reunion. There was much to learn about family and friends in Chicago. Then Stuart was given a personalized tour of the new house.
"It’s a lovely new home. I’m happy for you, Dad." He took Sy over to a corner of the room. "Dad, I’d like to speak privately with you, if I may. A rundown of the business. He looked over at Joyce. ‘Men’s talk – if you don’t mind."
Stuart and Sy went outside to sit on the porch while Joyce retired to the living room and resumed reading her legal thriller.
"Dad, the business is fine. All those properties you bought and converted into parking decks are high yield, low maintenance. What a brilliant strategy." He swallowed hard. "But Dad, I need your help. I’ve incurred some personal expenses that have me strapped. I’m seriously worried."
"Damn it. Not again!" shouted an irate Sy. "Your losses at the race track cannot be condoned. And you’re probably bedding several bimbos with your lascivious lifestyle. You’ve got to quit this craziness. The only way I can get your attention is to not help you this time."
"Fine!" Stuart shouted back. "Where are you when I need you? This is serious! I’m in debt for one hundred thousand dollars! And the next thing I know, you’ll have your new toy inherit your estate, leaving me out in the cold."
"Go rest, young man," Sy told him, gritting his teeth. "Take a walk on the beach. I need time to think. And try to be civil when our guests arrive later this afternoon."
Sy flopped into his favorite soft recliner and gave out a heavy sigh. Joyce, noting his brooding mood, looked to provide comfort. "Sy, I’ll prepare our afternoon screwdrivers now, yours with a double dose of vodka."
"Thank you. That sounds good," he replied. "When are our guests arriving?"
"It’s 4:00 p.m. now. We’ll gather together poolside around 6:00. I’ve called Fig Leaf’s to cater the whole affair. Nothing for you to worry about, my dear."
But worry he did. He had to clear his mind. Stuart was in desperate need. How could he turn his back on his only child? The vodka provided much-needed sleep to clear his mind and find a possible solution to the dilemma. He awoke at 5:43 p.m., freshened up and quickly took his medication in anticipation of tonight’s outdoor dose of pollen. Fortunately, the guests were fashionably late. They included Mike and Sally Calhoun, a recently retired law enforcement officer and his wife from New York City, whom Sy and Joyce had met at the marina; Gopal and Geeta Shankar, a cardiologist and his wife who lived next door; and David and Michelle Davis, lawyers in Vero Beach who helped manage the Lavin estate. All were standing around the pool engaged in polite conversation with Joyce and Stuart as Sy approached with an iced pitcher of screwdrivers. Without warning, he went down in a heap, not 10 feet from his guests. Gopal sprang into action. Finding no pulse, he began manual chest compressions. Mike effortlessly joined in to provide ventilation. Geeta used their cellular phone to immediately alert fire rescue, who arrived minutes later. Paramedics maintained cardiopulmonary resuscitation (CPR), established intravenous access and applied ECG leads. Gopal found Torsades de Pointes on Sy’s ECG, a form of ventricular tachycardia with QRS complexes appearing at a rate of 200 bpm and of changing amplitude that twisted around the isoelectric line. He immediately applied electrical shock to the chest that successfully restored sinus rhythm. There was no ECG evidence of acute myocardial infarction, but the QT interval was markedly prolonged and there were prominent U waves. Gopal gave intravenous magnesium sulfate. Sy’s blood pressure recovered and spontaneous ventilation returned, but he was too groggy to communicate effectively. "Joyce," asked Gopal, "is your husband taking any medications?"
"Only an antihistamine," she responded tearfully. "He’s been well otherwise. Will he be okay?"
"We’ll take him to the hospital for observation. You can ride with us in the ambulance. And I will need more information. Sy’s chaotic heart rhythm that accounted for this cardiac arrest and his abnormal ECG are puzzlesome," said a serious Gopal as the ambulance drove off.
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Gopal sat at the nurses’ station in the CCU, reviewing the information at hand. Sy, a 66-year-old male, would likely have coronary artery disease and be at risk of sudden cardiac death. But Torsades with prolonged QT interval? This had him flummoxed. He knew the appearance of Torsades was associated with congenital or acquired prolongation of ventricular repolarization. Prolonged QT interval accompanies certain medications, including ‘antiarrhythmic’ agents such as quinidine and procainamide, and electrolyte disturbances such as hypokalemia. Serum electrolyte levels were pending. The prominent U wave was suggestive of hypokalemia. But why K+ loss when Joyce denied Sy had recently experienced diarrhea or vomiting? Increased urinary excretion? Sy was not on a diuretic. Serum K+ proved to be 3.4 meq/l and was corrected. He must be receiving something that promotes urinary K+ excretion, thought Gopal. I’d better talk to his wife some more.
"Joyce, Sy is stable and regaining full consciousness. The arrhythmia has not reappeared. I need to ask several questions, please."
"Certainly, I’m so pleased he’s improving. Sy has never had a heart attack that we know of, or a history of high blood pressure."
"He’s losing K+. Probably through his kidneys, perhaps his sweat, likely both. I need to find out why. Does Sy exercise regularly? Has he had leg cramps of late?"
"As a matter of fact, both Sy and I experienced leg cramps, although mine are a more chronic problem. We thought it was related to our daily workouts. And come to think of it, these cramps appeared since we began taking herbal tea with licorice. It’s called ‘Victory Garden.’ We also like licorice candy from Holland."
Licorice. This was an important clue to K+ loss, thought Gopal. But the marked prolongation of the QT interval? There had to be something more than hypokalemia. "Has Sy been dieting?"
"No. We are careful with our diet, but no store-bought supplements or fads you read about in the papers. To help reduce our cholesterol we take grapefruit juice (GFJ) twice a day. Would that matter?" asked a puzzled Joyce.
"I don’t believe so." Citrus fruit and Torsades? "It seems unlikely" remarked Gopal. "But let me check into it. And tell me the name of the antihistamine Sy is taking."
"It’s called terfenadine."
Gopal began with the Physicians’ Desk Reference (PDR) at the nurses’ station. Terfenadine indeed is implicated in QT prolongation and ventricular arrhythmias, including Torsades, and sudden cardiac death. These rare complications are seen in association with increased terfenadine levels that accompany its concomitant administration with certain antibiotics, such as ketoconazole or itraconazole, clarithromycin, erythromycin or troleandomycin.
These drug interactions, however, were not at play in Sy’s case. Could GFJ be implicated? There was nothing in the PDR on this possibility. He would contact the pharmacist at Shrugg’s. Next he would conduct an on-line search of the pharmaceutical database, and if that failed, a search on the worldwide web for grapefruits and the heart.
"Hello, this is Dr. Gopal Shankar," he said as he connected with Shrugg’s. "May I speak to the pharmacist please?"
"Hiram Salker, pharmacist, speaking."
"Dr. Salker, Dr. Shankar here. I have an unusual question for you. Are you aware of any reports that would link consumption of GFJ with increased bioavailability of terfenadine?"
"Why, no. Is there a problem? Is Mr. Lavin sick?"
"There is no problem. Thank you for your help." How did Hiram know I was calling about Sy Lavin? thought Gopal.
Gopal’s computerized literature search indicated there now was an emerging body of evidence that linked GFJ with altered pharmacokinetics of dihydroperidine calcium channel blockers. Earlier in 1996, several reports identified enhanced bioavailability of terfenadine and QT prolongation with GFJ consumption. Additionally, GFJ has the potential, like licorice, to enhance urinary K+ excretion.
The next morning on rounds, Gopal went to the CCU. Sy had fully recovered and there was no recurrence of Torsades or other ventricular arrhythmias. "Sy, do you know anyone who would wish you harm?"
"No. My son Stuart is a bit tempestuous, but he’s okay."
"Do you know Hiram Salker over at Shrugg’s?"
"Why, yes I do. Why do you ask?"
"Oh, good morning, Mrs. Lavin," Gopal said as Joyce entered Sy’s room. "We were just talking about Hiram Salker. Do you know him?"
"I do, indeed," sighed Joyce.
"Would Hiram have known that either or both of you were taking ‘Victory Garden,’ and that you favored GFJ twice a day?"
"I don’t think so," said Sy.
"That’s not correct, honey. I mentioned this to Hiram several weeks ago when I purchased the herbal tea. He proceeded to recommend the licorice candies to me."
"And when you purchased terfenadine for your allergies, Sy, did Hiram indicate there was a possible interaction with GFJ and that K+ wasting associated with the combination of licorice and GFJ could further predispose you to an irregular heartbeat?"
"No, he did not."
"I believe I shall talk to the authorities," said Gopal.
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Terfenadine (T) is a second-generation selective H1 receptor antagonist with few central nervous system effects. It also is a potent antagonist of the delayed rectifier K+ current in cardiac myocytes. Elevated levels of T is the proposed mechanism for repolarization abnormalities, including QT prolongation, that predispose to ventricular tachycardia, including Torsades.
T, a pro-drug, is biotransformed by cytochrome CYP3A4 in the intestine. Inhibition of this step allows for accumulation of unmetabolized T. GFJ and its flavonoids (e.g, naringin), in particular, inhibit CYP3A4. The flavonoid composition of GFJ is enhanced when ripening fruit is exposed to freezing temperatures, and is at a peak during early development. In producing GFJ, forceful mechanical compression increases the presence of compounds derived from fruit tissues high in naringin, as contrasted with GFJ obtained solely from juice vesicles by hand-squeezed fruit without pulp. Increments in the time to maximum concentration and area under the concentration–time curve of T, together with QT prolongation, are observed when T is coadministered with GFJ.
Flavonoids also inhibit renal 11 β-hydroxysteroid dehydrogenase, the guardian enzyme that preserves the specificity of the promiscuous steroid receptor for mineralocorticoids. This enzyme is inhibited by flavonoids and glycyrrhizic acid, the active principle of licorice. In combination, GFJ and large dose licorice, derived in Sy’s case from two sources – herbal tea and imported candies known to have a high concentration of licorice – would permit more plentiful glucocorticoids to act as mineralocorticoids and predispose to hypokalemia and ventricular arrhythmias.
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The U.S. manufacturer of T has recently withdrawn this agent from the marketplace. The Food and Drug Administration (FDA) has requested that generic formulations of T likewise be withdrawn. In the UK, the Committee on Safety of Medicines has recommended that the status of T be changed to prescription only.
In 1996, the Michigan Court of Appeals ruled that a retail pharmacy may be held liable to a patient based on its commercial advertisement on computer-detected harmful drug interactions. In so doing, the pharmacy and its pharmacist each assumed a responsibility in monitoring a patient’s drug regimen. A failure to do so is actionable under the theories of negligence and fraud.
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