sensations. On Oct. 10, she was placed on an experimental drug, NP-108*, a phenothiozane derivative, as are promethazine (Phenergan), chlorpromazine (Thorazine), and promazine (Sparine). After 4 days of 100, 150, 200, and 250 mg., her daily dose of NP-108 was 300 mg. orally until April 2, 1956, or 172 days in all. From Oct. 10, 1955 to April 2, 1956, her weight remained between 187 and 190 pounds, and her appetite was good. Vital signs remained stable save for occasional tachycardia. She had no physical complaints, and her mental state improved to the point where she could again work outside the hospital during the day. On April 2, 1956, she was given 3 months' convalescent leave without medication.

On

However, her symptoms recurred, and she was readmitted April 20. April 30, she weighed 189 pounds. She received meprobamate in dosage of 400, 1,200, 1,600, 2,400, and 800 mg. on successive days from May 3 through May 7 without effect on her mental state. Because the mental disturbance was accompained by increased muscle tension, tremor, and twitching of the eyelids, zoxazolamine was given in the following amounts: May 7, 500 mg.; May 8-May 12, 750 mg. daily; May 14, 1,250 mg.; May 15-17, 1,500 mg. daily; May 18-June 4, 2,000 mg. daily, and June 5, 1,000 mg. On that day, the drug was cancelled because thymol turbidity had risen from 1 unit (negative) on May 25 to 10 units (4+) on June 5. Her total dosage was 49 gm. in 30 days. Initially muscle tension and tremor diminished, but then recurred. Zoxazolamine did not alter the patient's mental state.

Her other medication during the period was glutethimide (Doriden), 500 mg., on May 26, 27, 28, June 2, 4, 5, 9, 11, 12, 16, and 17; that is, both during and after zoxazolamine administration.

Laboratory data are summarized in Table 1. In addition, on May 11, white blood cells totalled 11,800 per cubic mm., with a normal differential count and no eosinophils. On May 24, white blood cell and differential counts were virtually identical, save for 3 percent eosinophils.

During the week preceding June 5, the patient had no complaints, but her weight fell to 183 pounds. On June 5, her sclerae appeared moderately icteric, but not her skin. Abdominal examination was negative, with the liver neither palpable nor tender. The hemogram was unchanged, except for an eosinophilia of 5 percent.

On June 7, two days after zoxazolamine had been discontinued, the patient's sclerae were only questionably icteric, the rest of the physical examination remaining normal. Specifically, there was no pharyngeal injection, skin rash, adenopathy, nor palpable or tender abdominal organs. A roentgenogram disclosed no gallstones, enlarged organs, nor other abdominal abnormality.

On June 11, she weighed 178 pounds, a 5-pound loss in two weeks. Several days later, she began to note anorexia, her sole symptom at any time. Anorexia and weight loss paralleled psychiatric deterioration and an increase in smoking to 40 cigarettes a day. By July 8, long after most liver function tests had returned to normal, she weighed 166 pounds, and, on July 16, 168 pounds. Her rectal temperature, which had reached 100° only twice during October, reached or exceeded 100° on 12 days between June 12 and July 1, but not thereafter. It generally varied between 99.6° and 100.4°, reaching 101° once. Tachycardia became more frequent in June and July than previously. Physical examination on June 12 differed from that of June 5 only in the appearance of right-upper-quadrant tenderness on deep palpation and on "shock" over the rib cage. Liver and spleen were not palpable. The tender. ness persisted, reaching a maximum on July 11, after "challenge" with zoxazolamine (see below) and disappearing July 18. Otherwise, physical examina tion did not change after June 12. On June 13, her blood contained 13,900 white cells per cubic millimeter, with 66 percent neutrophils, 29 percent lymphocytes, and 4 percent eosinophils.

By July 6, the patient had received zoxazolamine for 30 days. In addition to the data in Table 1, heterophile antibody titre was normal (1:4), nonprotein nitrogen was 31 mg., albumin 4.8 gm., and globulins 2.5 mg. per 100 cc. of serum. White blood cells numbered 10,300, with 70 percent neutrophils, 24 percent lymphocytes, and 2 percent eosinophils. Liver functions, except possibly prothrombin time, had been normal for 2 weeks. At this time, she was "challenged" with small doses of zoxazolamine, beginning July 6 with 250 mg. and increasing daily by 250 mg. to 1,250 mg. on July 10, when the drug was stopped.

Brompiperidinophenothiazine, supplied by Sandos Pharmaceuticals, Hanover, NJ.

By July 11, she had developed no symptoms, and physical examination was unchanged, save for more marked right-upper-quadrant tenderness, to deep palpation and to "shock," than on June 5. This disappeared by July 18. She was not icteric nor were liver or spleen palpable. Thus, the administration of 3.75 gm. of zoxazolamine failed to reproduce the laboratory picture of hepatotoxicity, though liver tenderness definitely increased. Not only did the indices of hepatocellular function cephalin flocculation and thymol turbidity-remain negative, but serum bilirubin and alkaline phosphatase continued their gradual recession.

Her subsequent course combined physical recovery with mental deterioration, the latter improving after topectomy.

Comment.-Liver damage of primarily hepatocellular type, with a minor obstructive component, appeared after 4 weeks of zoxazolamine therapy. Clipical manifestations were slight, comprising anorexia, weight loss, tachycardia (possibly all 3 were psychogenic), low-grade fever, transient scleral icterus, and right-upper-quadrant tenderness.

As explanations for the total picture, bacterial hepatitis and infectious mononucleosis are unlikely. While viral hepatitis cannot be excluded, against it may be adduced the somewhat elevated white blood cell count, apparently normal for this patient, with normal differential count and lymphocyte morphology; prompt return of liver functions (except possibly prothrombin time) to normal in 10 days, without bed rest or special diet. Homologous serum hepatitis is unlikely, since she had no blood studies or injections between Nov. 23, 1955, and May 11, 1956. Exposure to infectious hepatitis might have occurred during her residence in a girls' club, April 2-19, but there were no known cases there nor on the patient's ward between April 1 and July 31.

A drug effect, therefore, seems most possible. There was no known exposure to potential hepatotoxins other than her medications. No case of liver damage has been reported for glutethimide among over 100,000 users' (though one case of unexplained transient jaundice occurred during its use), or, to our knowledge, for meprobamate among several million users. Glutethimide was given sporadically in small doses both during and after zoxazolamine; its continued use did not prevent the prompt subsidence of abnormal laboratory findings after zoxazolamine was withheld. Meprobamate was given in modest dosage for 5 days which ended a full month before the abnormal findings appeared. It is thus unlikely that either glutethimide or meprobamate was the primary agent. Their possible potentiating or synergizing role must remain unsettled.

(See footnotes, pp. 663 and 664.)

The same may be said for NP-208 (brom piperidinophenothiazine), an experimental phenothiazine derivative. No case of liver disease has been attributed to NP-208' to NP-207, (piperidinochlorphenothiazine), a close analogue; or to promazine 10, 10-(y-dimethylamino-n-prophyl) phenothiazine. The jaundice caused by chlorpromazine is cholestatic or obstructive rather than primary hepatocellular, as here. And finally, the patient suffered no liver impairment during 6 months on NP-208 or in the month following its withdrawal (in April), while receiving no medication. Her signs of liver impairment appeared in June. Thus, zoxazolamine appears implicated as an etiologic agent. Liver disease appeared after 1 month of its administration. After zoxazolamine was withheld, laboratory tests (except for prothrombin time) reverted to normal promptly, the clinical manifestations more slowly. Small challenging doses did not reproduce the whole picture, but liver tenderness definitely increased, disappearing in 1 week after the drug was again withheld.

CASE 3

A 38-year-old Italian mechanic was admitted April 2, 1956, for 5 years of progressive weakness and spasticity of the legs. In 1951 at another hospital, a herniated nucleus pulposus had been excised from between the 6th and 7th cervical vertebrae, with some relief. However, after a neck injury 6 months later, his symptoms progressed to paraplegia. His health otherwise was excellent, and he drank no alcohol. Physical examination on admission, except as related to his neurological deficit, was within normal limits, as were urinalysis and hemogram.

For muscle spasm he was placed on zoxazolamine, 1.6 gm., and for anxiety, on chlorpromazine, 75 mg. a day. After preliminary studies, a laminectomy was performed April 13, with removal of extensive scar material from around the cord. He received 500 cc. of blood, as well as 1000 cc. dextrose in water. Postoperative medications included 2 weeks of penicillin and streptomycin, plus 3 weeks of sulfisoxazole (Gantrisin) and tetracycline (Achromycin) for urinary-tract infection accompanying an inlying catheter. He also received occasional chloral hydrate for sleep. For increasing spasticity, z tazolamine was increased to 2 gm. daily on May 3, and 3 gm. daily on May 18. Chlorpromazine dosage remained at 75 mg. a day until June 30, when it was stopped. His post-operative course was complicated by pneumonitis May 25, responding in 6 days to penicillin and tetracycline; by tonsillitis June 4, clearing shortly on penicillin; and by a persistent urinary-tract infection with organisms resistant to all drugs except chloramphenicol.

On July 3, while on zoxazolamine, penicillin, and tetracycline, his temperature rose to 105°F., and he became nauseated and vomited. He was icteric, with a nontender liver felt 2 finger-breadths below the costal margin. The spleen was not palpable then nor at any time during his hospitalization. His blood contained 41,600 white cells per cubic mm., with 90 percent neutrophils; the urine was strongly positive for bile, but contained no urobilinogen. When blood cultures showed E. coli, on July 6, chloramphenicol, 2 gm., and streptomycin, 1 gm. a day were added, and tetracycline and zoxazolamine discontinued. Within 5 days he was afebrile and feeling well, but jaundice and nontender liver enlargement persisted.

His laboratory findings are summarized in table 2. In addition, electrolytes (Na, Cl, K, and CO2) and nonprotein nitrogen were normal throughout; one cholesterol determination was 205 and a single calcium, 9.6 mg. per 100 cc.; Vitamin K was not used; and repeated stool specimens showed no occult blood, ova, nor parasites. Amebic complement fixation was negative as were a skeletal survey and flat film of the abdomen for gallstones.

Zoxazolamine was reinstituted July 18. Four days later, he became anorectic, restless, nauseated, and vomited. (Penicillin and streptomycin had been cancelled July 18, leaving chloramphenicol as the sole antibiotic during the next few weeks.) Jaundice deepened, and he had 3 days of pruritus. On July 25, his temperature rose to 101° F., and his liver became tender and larger than before. Zoxazolamine was stopped July 25, and 2 days later he became afebrile and remained so. His appetite returned, while nausea, vomiting, and right-upperquadrant discomfort disappeared. The liver again became smaller and no longer tender, though still enlarged.

On Aug. 10, be developed anemia and thrombocytopenia, treated by transfusion and withholding chloramphenicol.

(See footnotes, pp. 663 and 664.)

Comment.-While this patient may have had homologous serum hepatitis complicated by an E. coli septicemia, there is no practical way to prove viral rather than drug etiology. The douor had given transfusions some years before without incident, nor had he been ill or jaundiced since. In any case, the patient's hepatotoxicity, predominantly of parenchymatous rather than obstructive type, developed while on zoxazolamine for 2 months, improved in a few days after zoxazolamine was withheld, promptly worsened on its reinstitution, and again cleared when it was withheld. This evidence suggests a hepatotoxic effect of zoxazolamine, whether the drug was the primary etiologic agent here or not.

A 24-year-old truck driver, of Czech descent, was hospitalized June 30, 1956, because of paraplegia due to spinal cord compression sustained in a shallow dive half an hour before. Previous health had been excellent, without known exposure to infection. His most recent injection had been for a dental procedure in January. For some 4 years, he had drunk a few glasses of beer and one of whisky nightly, with good food intake. Physical examination and laboratory data on admission were normal except as related to his recent trauma. He was treated by bed rest in neck traction, with later physiotherapy.

Medications consisted of codeine and aspirin for pain, chloral hydrate for sleep, penicillin and sulfisoxazole (Gantrisin) for prophylaxis during constant bladder drainage. Drainage was discontinued July 26, sulfisoxazole July 30. On July 4, meprobamate, 3.2 gm. a day, was begun for restlessness, and was continued throughout his hospitalization. On July 11, he developed acute epididymitis, treated by tetracycline (Achromycin), 1 gm. a day for 7 days. Likewise on July 11, he developed acute superficial thrombophlebitis of the right calf and received warfarin sodium (Coumadin) thereafter until Sept. 3.

On July 17, because of muscle spasm, he was placed on zoxazolamine, 2 gm. a day, until Aug. 8, when the drug was withdrawn because anorexia, nausea, and epigastric distress had developed. He was not jaundiced, and physical examination was within normal limits except for right-upper-quadrant tenderness to palpation and "punch." Blood counts were normal on July 8 and 9, white cells totalling 7200 per cubic mm., within 54 percent neutrophils, 38 lymphocytes, 7 percent monocytes, and 1 percent eosinophils. His urine contained no bile. Except for the bromsulfalein test, all liver functions were normal-namely, cephalin flocculation, thymol turbidity, serum bilirubin, cholesterol, alkaline phosphatase, and phosphorus the latter two, on both Aug. 10 and Aug. 13. On Aug. 10, there was 23 percent retention of bromsulfalein after 30 minutes.

After zoxazolamine was withdrawn, the symptoms and sole clinical sign (rightupper-quadrant tenderness) promptly disappeared. On Aug. 18, less than 5 percent of bromsulfalein was retained.

(See footnotes, pp. 663 and 664.)

Beginning Aug. 22, he was "challenged" with zoxazolamine, 1 gm. a day for 9 days and 2 gm. a day thereafter until Sept. 21. On Aug. 29, his bromsulfalein retention was 7 percent in 30 minutes, and cephalin flocculation and thymol turbidity were both negative. On Sept. 4, there was again definite right-upperquadrant tenderess to deep palpation and punch; bromsulfalein retention was 6 percent in 30 minutes. On Sept. 6 and again on Sept. 13, right-upper-quadrant tenderness was absent, and bromsulfalein, cephalin flocculation, and thymol turbidity tests were normal.

Comment. The abnormal findings here appeared after 5 weeks of meprobainate and 3 of zoxazolamine. The patient had anorexia, nausea, epigastric distress, right-upper-quadrant tenderness and on one occasion bromsulfalein retention of 23 percent after 30 minutes. These slight manifestations of hepatotoxicity disappeared promptly on withholding zoxazolamine and did not reappear (save for transient right-upper-quadrant tenderness) after 4 weeks' "challenge" with zoxazolamine, while meprobamate was continued. The objective evidence for hepatotoxicity here is far from convincing, resting on a single, unchecked laboratory value.

CASE 4

A 72-year-old retired Jewish male was admitted Sept. 8, 1956, for increasing jaundice, anorexia, and nausea, of 1 month's duration. Two years before admission, he developed Parkinson's disease, which slowly progressed. Two months before admission, he was begun on meprobamate, 800 mg., and zoxazolamine, 1 gm. a day, with neurological improvement. This regimen lasted for about 6 weeks to 2 months. One month before admission he noted nausea, and 3 weeks before admission, anorexia, indigestion, weakness, and occasional drowsiness. A few days before admission, jaundice, dark urine, and clay-colored stool were noted. He drank no alcohol, had lost no weight, and had been exposed to no known infection, injection, or potential hepatotoxin other than his drugs. Six weeks before admission, his teeth had been cleaned and one or two were filled, but without analgesics.

On admission, he was deeply jaundiced, with a nontender liver palpable 2 fingerbreadths below the right costal margin. Spleen and lymph nodes were normal, as were the remainder of the physical examination and his vital signs. Hemoglobin was 15.5 gm. per 100 cc., white blood cells 8700 per cubic mm., with 82 percent neutrophils and 18 percent lymphocytes. The urine contained 1+ albumin, occasional red and white blood cells, and bile. Treatment consisted of bed rest and withholding all drugs except occasional chloral hydrate for sleep. Laboratory data are summarized in Table 3. In addition, blood urea nitrogen was 11 mg. and cholesterol 283 mg. per 100 cc. A subsequent urinalysis was negative. On Sept. 11 and 13, his liver was barely palpable. His appetite and comfort improved as his jaundice receded.

Comment.-Hepatotoxicity of parenchymatous type developed after some 4 weeks of zoxazolamine and meprobamate, clearing when the drugs were withheld. The patient's age and Parkinsonism precluded zoxazolamine "challenge."