- Email: [email protected]
CYTOMEGALIC INCLUSION DISEASE TREATED WITH IDOXURIDINE AND NOVOBIOCIN
39 Neither their clinical condition
nor
liver-function
tests
improved during this period. Colchicine, 1 to 2 mg. per day, was given to the 7 patients. When they developed diarrhcea colchicine was stopped for 1 or 2 days. After 2 weeks of treatment all patients showed a striking clinical improvement, and most of them were discharged in fair condition and have continued taking only colchicine. Bilirubin, which was high in 6 patients (1-0 to 5-5 mg. per 100 ml.), returned to almost normal values ( < 0,5 mg.) in 5 of them. When bilirubin was higher than 4 tc 5 mg. the fall after colchicine treatment was 50% or more during che lst week of treatment. In patients with bilirubin values close to 1 mg. per 100 ml. the fall was slower. Serum-glutamic-oxaloacetic transaminase and serum-glutamic-pyruvic transaminase were normal in 3 patients and only slightly raised (100 to 600 u. per ml.) in the other 4, in whom they returned to normal values ( < 60 U. per ml.) after 2 weeks of treatment. In 1 patient who had been under treatment for more than 3 weeks serum-albumin rose from 1-6 g. per 100 ml. to normal (>3-5 g. per 100 ml.). These preliminary findings suggest that a further trial of colchicine in chronic liver disease would be worth while. We have already begun a double-blind trial in a group of patients who had a liver biopsy before treatment. This will enable us to evaluate not only the clinical and laboratory changes caused by the drug but also histological modifications in the liver after 2 or 3 months of treatment. Departamento de Biologia Celular Centro de Investigación y de Estudios Avanzados del IPN, México 14. D.F.
Departamento de Gastroenterologia Instituto Nacional de Nutrición, México 22, D.F.
MARCOS
ROJKIND.
MISAEL URIBE DAVID KERSHENOBICH.
CYTOMEGALIC INCLUSION DISEASE TREATED WITH IDOXURIDINE AND NOVOBIOCIN
S1R,-’1’here is no established treatment for congenital cytomegalic inclusion disease (c.l.D.). Only a few studies, including adequate virological monitoring, of antiviral chemotherapy have been reported. 1-4 Few physicians have treated more than an occasional case. The use of the antiviral agent, idoxuridine (5-iodo-2’-deoxyuridine), in C.LD. has met with limited success.1,2 A report5 that novobiocin enhanced the antiviral activity of idoxuridine against herpes simplex and vaccinia viruses in vitro suggested the use of this combined therapy in c.l.D. A 1-day-old White male infant because of progressive lethargy. He
referred to this clinic the product of a normal mild non-specific maternal was
was
pregnancy complicated only by a illness in the first month of pregnancy. Delivery was precipitous at 41 weeks. At birth, hepatosplenomegaly, mild jaundice,
small purpuric lesions over the face and thorax, petechise on the soft palate, a grade 2/6 whining systolic murmur, and an undescended right testis were noted. Birth-weight was 2-67 kg.; the head circumference was 32 cm. When seen here, the infant was lethargic and had a poor The anterior fontanelle was patent and desucking reflex. pressed. No chorioretinitis was observed, and X-rays of the skull and chest were normal. The initial laboratory data included: hemoglobin 22 g. per 100 ml.; leucocyte-count 17,800 per c.mm.; platelet-count 48,000 per c.mm.; bilirubin, direct 5-7 and indirect 5-85 mg. per 100 ml.; serum glutamic-oxaloacetic trans1.
Conchie,
A. F.,
Barton, B. W., Tobin, J.
O’H. Br.
med. J. 1968, iv
162. 2. 3.
Barton, B. W., Tobin, J. O’H. Ann. N.Y. Acad. Sci. 1970, 173, 90 Plotkin, S. A., Stetler, H. Antimicrob. Agents Chemother. 1969, 9
4.
Kraybill, E. N., Sever, J. L., Avery, G. B., Movassaghi,N. J. Pediat 1972, 80, 485. Chang, T. W., Weinstein, L. Antimicrob. Agents Chemother. 1970 10, 165.
372.
5.
Age, cloys
Upper: Effect of treatment on bilirubin (mg. per 100 ml.), heemoglobin (g. per 100 ml.), and platelet-count (per c.mm.). Lower: Cytomegalovirus in urine and throat cultures in terms of 50% tissue-culture infective doses (T.C.LD.so) in WI-38 cells.
aminase,
372 units per
litre; and IgM, 1-05
mg. per ml.
The
initial clinical impression of a congenital viral infection was confirmed by the demonstration of typical cytomegalic inclusionbearing cells in the urinary sediment, the production of the classic cytopathic effects of cytomegalovirus (c.M.v.) in WI-3S cell cultures inoculated with the patient’s urine, and an initial
complement-fixing antibody titre to c.M.v. Because of the severity of the disease,
of 1/16. a trial of idoxuridine and novobiocin was recommended to the parents; the experimental nature of the therapy was specifically defined, and they fully agreed to the drug trial.*Treatment was begun when the infant was 16 days old. A total of 600 mg. of idoxuridine per kg. body-weight was given by intravenous infusion divided over seven days, and a total of 280 mg. of novobiocin was given during the same seven days in divided doses (20 mg. intramuscularly each morning and 20 mg. in 10 ml. of saline intravenously each evening after the idoxuridine infusion). Except for thrombocytopenia (platelets, 40,000 per c.mm.), the infant continued to do well throughout the treatment period (see accompanying figure). The platelet-count remained low after therapy, and eventually a generalised petechial rash developed, associated with gingival bleeding and a decrease in hxmoglobin concentration to 9-8 g. per 100 ml. Prednisone (5 mg. a day) was started on day 29 and continued for one month; it produced a good bone-marrow response. At age 3 months the infant was smiling, holding his head up, and observing his hands; he had rolled over once. Thereafter, development progressively lagged. By 18 months he was saying a few single words and following a few simple commands, but he had difficulty sitting alone and he had not yet crawled. Reflex changes were in keeping with his chronological age. The liver gradually decreased in size, becoming normal at 7 months. Bilirubin levels returned to normal. The spleen, however, remained enlarged and firm throughout the period of observation. Virological findings are shown in the figure. Before treatment, c.M.v. was not recovered from stool or cerebrospinal fluid. Virus persisted in the urine and throat despite treatment, but the amount decreased considerably; the virus was no longer recoverable after twelve months. At age 7 months, when the patient had * Permission for use of idoxuridine and Drug Administration.
was
obtained from the Food
40
clinically
apparent chickenpox, c.M.v. could not be recovered from the throat or urine. At a follow-up examination five weeks later, C.M.V. was recovered from the urine and a rhinovirus from the throat. Complement-fixing antibody titre to c.M.v. was 1/4 at 9 months of age.
Accumulating evidence suggests that c.M.v. produces broad spectrum of disease in general and in the congenitally infected infantIn 2 of 3 patients treated with idoxuridine viuria decreased 2 as in our patient, but the clinical response was disappointing. However, these patients were severely damaged, and treatment began at 14 weeks in 2 cases and at 2t years in the 3rd. We agree with Barton and TobinZ that idoxuridine should be used only in selected cases. Our patient was ideal for antiviral chemotherapy. He had severe disease without irreparable damage to the central nervous system. Therapy was specifically directed to protecting the central nervous system, allowing repair of visceral damage, and inhibiting viral replication and excretion. The poor clinical responses in the published cases 1,2 and the in-vitro data suggesting enhanced antiviral activity with both idoxuridine and novobiocin 6 prompted our use of the combination. No serious complications arose. Whether the thrombocytopenia with slight bleeding was drug-induced or secondary to the infection is unknown. Although the head circumference was small at birth, it was not out of proportion to birth-weight and size, and it was not until later that we judged our patient a
truly microcephalic.
INHIBITION OF INSULIN RELEASE BY DIPHENYLHYDANTOIN AND DIAZOXIDE IN A PATIENT WITH BENIGN INSULINOMA Snt,—At blood-levels similar to those attained in the of epilepsy, diphenylhydantoin (D.P.H.) is a potent inhibitor of insulin release. 1-3 We have investigated a 65-year-old man with a benign insulinoma who was treated with separate courses of D.P.H. and diazoxide. The patient gave a 15-year history of periodic dizziness, weakness, and mental confusion which was secondary to fasting hypoglycaemia. His body-weight had remained stable at 80 kg. (height 170 cm.). The findings on physical examination were normal except for mild hypertension treatment
(150/90).
Complete blood-count,
glutamic-oxalophosphatase, blood-urea-nitrogen, electrolytes, urinalysis, urinary 17hydroxycorticosteroids, 17-ketosteroids, and vanilmandelic acid, upper-gastrointestinal series, barium enema, liver and pancreatic scan, and coeliac angiography gave results in the normal range. Mean fasting plasma glucose and immunoreactive insulin (I.R.I.) were 34 3 mg. per 100 ml. and 33-6 (J.D. per ml., respectively. Proinsulin constituted 40% of the fasting I.R.I.4 A 9-day course of D.P.H. (100 mg. every 6 hours) was begun, followed by a separate 7-day course of diazoxide acetic
transaminase,
bilirubin,
serum
alkaline
TABLE I-EFFECT OF D.P.H. AND DIAZOXIDE ON FASTING GLUCOSE, INSULIN, AND INSULIN/GLUCOSE RATIO (MEAN ± S.E.)
We do not suggest that treatment was successful. We have no doubt, however, that the infant improved initially and a second course might have been beneficial. Department of Pediatrics and Department of Microbiology and Immunology, Mayo Clinic and Mayo Foundation, Rochester, Minnesota 55901, U.S.A.
ROY F. HOUSE, JR. DONALD A. PERSON THOMAS F. SMITH LLOYD E. HARRIS.
INCREASED LITHIUM ERYTHROCYTE/ PLASMA RATIO IN MANIC-DEPRESSIVE PSYCHOSIS
Snt,—Lithium concentration in red blood-cells versus plasma differs significantly between apparently healthy female controls and female patients with manic-depressive psychosis on lithium therapy. There is also a significant difference between male and female manic-depressive patients with lithium at therapeutic plasma concentrations. Our findings were:
(100 mg. every 8 hours) with frusemide (40 mg. daily) and potassium (30 meq. daily). Both D.P.H. and diazoxide effectively raised the mean fasting plasma-glucose concentration and improved the I.R.i./glucose ratio (table i). On the final day of each regimen 1 g. of tolbutamide was given intravenously over 2 minutes, followed in 16 minutes by 25 g. of glucose intravenously over 2 minutes. Insulinomas will respond rapidly when stimulated with tolbutamide, and using this method it is possible to obtain important insulin data without endangering the patient by further hypoglycasmia. The I.R.I. responses to both tolbutamide and glucose were blunted during treatment with D.P.H. (table 11). On diazoxide, the I.R.I. responses to these stimuli were actually augmented. The ability of tolbutamide, but not of glucose alone, to the diazoxide blockade of insulin release has In addition, when dogs are pretreated been reported.6 with diazoxide and then challenged with tolbutamide and glucose, the I.R.I. release to the combined tolbutamide/ glucose stimulus is additive.6 A similar pattern of I.R.I. release to the tolbutamide/glucose stimulus occurred in
reverse
*
t
Significantly different Significantly different
from from
healthy females (p < 0-05). manic-depressive females (p < 0.05).
patient (table 11). currently accepted that pancreatic insulin secretion is biphasic and involves the immediate release from a small labile pool as well as the subsequent provision of insulin to our
An increased erythrocyte/plasma lithium ratio in females versus males and in diseased females versus controls may reflect a difference in membrane properties of fundamental importance for the understanding of the manic-depressive disease. A full report of this study will be published
elsewhere. Psychiatric Research Center, University of Uppsala, Ulleráker Hospital, S-750 17 Uppsala, Sweden. 6. 7.
It is
1. 2. 3.
L. LYTTKENS U. SÖDERBERG L. WETTERBERG.
Stern, H., Tucker, S. M. Lancet, 1965, ii, 1268. Weller, T. H. New Engl. J. Med. 1971, 285, 203, 267.
4. 5. 6.
Fariss, B. L., Lutcher, C. L. Diabetes, 1971, 20, 177. Malherbe, C., Burrill, K. C., Levin, S. R., Karam, J. H., Forsham, P. H. New Engl. J. Med. 1972, 286, 339. Levin, S. R., Grodsky, G. M., Hagura, R., Smith, D. Diabetes, 1972, 21, 856. Sherman, B. M., Pek, S., Fajans, S. J., Floyd, J. C., Conn, J. W. J. clin. Endocr. Metab. 1972, 35, 271. Basabe, J. C., Lopez, N. L., Viktora, J. K., Wolff, F. W. Diabetes, 1971, 20, 449. Anderson, J. H., Byrd, G. W., Blackard, W. G. Metabolism, 1971, 20, 1023.
nor
liver-function
tests
improved during this period. Colchicine, 1 to 2 mg. per day, was given to the 7 patients. When they developed diarrhcea colchicine was stopped for 1 or 2 days. After 2 weeks of treatment all patients showed a striking clinical improvement, and most of them were discharged in fair condition and have continued taking only colchicine. Bilirubin, which was high in 6 patients (1-0 to 5-5 mg. per 100 ml.), returned to almost normal values ( < 0,5 mg.) in 5 of them. When bilirubin was higher than 4 tc 5 mg. the fall after colchicine treatment was 50% or more during che lst week of treatment. In patients with bilirubin values close to 1 mg. per 100 ml. the fall was slower. Serum-glutamic-oxaloacetic transaminase and serum-glutamic-pyruvic transaminase were normal in 3 patients and only slightly raised (100 to 600 u. per ml.) in the other 4, in whom they returned to normal values ( < 60 U. per ml.) after 2 weeks of treatment. In 1 patient who had been under treatment for more than 3 weeks serum-albumin rose from 1-6 g. per 100 ml. to normal (>3-5 g. per 100 ml.). These preliminary findings suggest that a further trial of colchicine in chronic liver disease would be worth while. We have already begun a double-blind trial in a group of patients who had a liver biopsy before treatment. This will enable us to evaluate not only the clinical and laboratory changes caused by the drug but also histological modifications in the liver after 2 or 3 months of treatment. Departamento de Biologia Celular Centro de Investigación y de Estudios Avanzados del IPN, México 14. D.F.
Departamento de Gastroenterologia Instituto Nacional de Nutrición, México 22, D.F.
MARCOS
ROJKIND.
MISAEL URIBE DAVID KERSHENOBICH.
CYTOMEGALIC INCLUSION DISEASE TREATED WITH IDOXURIDINE AND NOVOBIOCIN
S1R,-’1’here is no established treatment for congenital cytomegalic inclusion disease (c.l.D.). Only a few studies, including adequate virological monitoring, of antiviral chemotherapy have been reported. 1-4 Few physicians have treated more than an occasional case. The use of the antiviral agent, idoxuridine (5-iodo-2’-deoxyuridine), in C.LD. has met with limited success.1,2 A report5 that novobiocin enhanced the antiviral activity of idoxuridine against herpes simplex and vaccinia viruses in vitro suggested the use of this combined therapy in c.l.D. A 1-day-old White male infant because of progressive lethargy. He
referred to this clinic the product of a normal mild non-specific maternal was
was
pregnancy complicated only by a illness in the first month of pregnancy. Delivery was precipitous at 41 weeks. At birth, hepatosplenomegaly, mild jaundice,
small purpuric lesions over the face and thorax, petechise on the soft palate, a grade 2/6 whining systolic murmur, and an undescended right testis were noted. Birth-weight was 2-67 kg.; the head circumference was 32 cm. When seen here, the infant was lethargic and had a poor The anterior fontanelle was patent and desucking reflex. pressed. No chorioretinitis was observed, and X-rays of the skull and chest were normal. The initial laboratory data included: hemoglobin 22 g. per 100 ml.; leucocyte-count 17,800 per c.mm.; platelet-count 48,000 per c.mm.; bilirubin, direct 5-7 and indirect 5-85 mg. per 100 ml.; serum glutamic-oxaloacetic trans1.
Conchie,
A. F.,
Barton, B. W., Tobin, J.
O’H. Br.
med. J. 1968, iv
162. 2. 3.
Barton, B. W., Tobin, J. O’H. Ann. N.Y. Acad. Sci. 1970, 173, 90 Plotkin, S. A., Stetler, H. Antimicrob. Agents Chemother. 1969, 9
4.
Kraybill, E. N., Sever, J. L., Avery, G. B., Movassaghi,N. J. Pediat 1972, 80, 485. Chang, T. W., Weinstein, L. Antimicrob. Agents Chemother. 1970 10, 165.
372.
5.
Age, cloys
Upper: Effect of treatment on bilirubin (mg. per 100 ml.), heemoglobin (g. per 100 ml.), and platelet-count (per c.mm.). Lower: Cytomegalovirus in urine and throat cultures in terms of 50% tissue-culture infective doses (T.C.LD.so) in WI-38 cells.
aminase,
372 units per
litre; and IgM, 1-05
mg. per ml.
The
initial clinical impression of a congenital viral infection was confirmed by the demonstration of typical cytomegalic inclusionbearing cells in the urinary sediment, the production of the classic cytopathic effects of cytomegalovirus (c.M.v.) in WI-3S cell cultures inoculated with the patient’s urine, and an initial
complement-fixing antibody titre to c.M.v. Because of the severity of the disease,
of 1/16. a trial of idoxuridine and novobiocin was recommended to the parents; the experimental nature of the therapy was specifically defined, and they fully agreed to the drug trial.*Treatment was begun when the infant was 16 days old. A total of 600 mg. of idoxuridine per kg. body-weight was given by intravenous infusion divided over seven days, and a total of 280 mg. of novobiocin was given during the same seven days in divided doses (20 mg. intramuscularly each morning and 20 mg. in 10 ml. of saline intravenously each evening after the idoxuridine infusion). Except for thrombocytopenia (platelets, 40,000 per c.mm.), the infant continued to do well throughout the treatment period (see accompanying figure). The platelet-count remained low after therapy, and eventually a generalised petechial rash developed, associated with gingival bleeding and a decrease in hxmoglobin concentration to 9-8 g. per 100 ml. Prednisone (5 mg. a day) was started on day 29 and continued for one month; it produced a good bone-marrow response. At age 3 months the infant was smiling, holding his head up, and observing his hands; he had rolled over once. Thereafter, development progressively lagged. By 18 months he was saying a few single words and following a few simple commands, but he had difficulty sitting alone and he had not yet crawled. Reflex changes were in keeping with his chronological age. The liver gradually decreased in size, becoming normal at 7 months. Bilirubin levels returned to normal. The spleen, however, remained enlarged and firm throughout the period of observation. Virological findings are shown in the figure. Before treatment, c.M.v. was not recovered from stool or cerebrospinal fluid. Virus persisted in the urine and throat despite treatment, but the amount decreased considerably; the virus was no longer recoverable after twelve months. At age 7 months, when the patient had * Permission for use of idoxuridine and Drug Administration.
was
obtained from the Food
40
clinically
apparent chickenpox, c.M.v. could not be recovered from the throat or urine. At a follow-up examination five weeks later, C.M.V. was recovered from the urine and a rhinovirus from the throat. Complement-fixing antibody titre to c.M.v. was 1/4 at 9 months of age.
Accumulating evidence suggests that c.M.v. produces broad spectrum of disease in general and in the congenitally infected infantIn 2 of 3 patients treated with idoxuridine viuria decreased 2 as in our patient, but the clinical response was disappointing. However, these patients were severely damaged, and treatment began at 14 weeks in 2 cases and at 2t years in the 3rd. We agree with Barton and TobinZ that idoxuridine should be used only in selected cases. Our patient was ideal for antiviral chemotherapy. He had severe disease without irreparable damage to the central nervous system. Therapy was specifically directed to protecting the central nervous system, allowing repair of visceral damage, and inhibiting viral replication and excretion. The poor clinical responses in the published cases 1,2 and the in-vitro data suggesting enhanced antiviral activity with both idoxuridine and novobiocin 6 prompted our use of the combination. No serious complications arose. Whether the thrombocytopenia with slight bleeding was drug-induced or secondary to the infection is unknown. Although the head circumference was small at birth, it was not out of proportion to birth-weight and size, and it was not until later that we judged our patient a
truly microcephalic.
INHIBITION OF INSULIN RELEASE BY DIPHENYLHYDANTOIN AND DIAZOXIDE IN A PATIENT WITH BENIGN INSULINOMA Snt,—At blood-levels similar to those attained in the of epilepsy, diphenylhydantoin (D.P.H.) is a potent inhibitor of insulin release. 1-3 We have investigated a 65-year-old man with a benign insulinoma who was treated with separate courses of D.P.H. and diazoxide. The patient gave a 15-year history of periodic dizziness, weakness, and mental confusion which was secondary to fasting hypoglycaemia. His body-weight had remained stable at 80 kg. (height 170 cm.). The findings on physical examination were normal except for mild hypertension treatment
(150/90).
Complete blood-count,
glutamic-oxalophosphatase, blood-urea-nitrogen, electrolytes, urinalysis, urinary 17hydroxycorticosteroids, 17-ketosteroids, and vanilmandelic acid, upper-gastrointestinal series, barium enema, liver and pancreatic scan, and coeliac angiography gave results in the normal range. Mean fasting plasma glucose and immunoreactive insulin (I.R.I.) were 34 3 mg. per 100 ml. and 33-6 (J.D. per ml., respectively. Proinsulin constituted 40% of the fasting I.R.I.4 A 9-day course of D.P.H. (100 mg. every 6 hours) was begun, followed by a separate 7-day course of diazoxide acetic
transaminase,
bilirubin,
serum
alkaline
TABLE I-EFFECT OF D.P.H. AND DIAZOXIDE ON FASTING GLUCOSE, INSULIN, AND INSULIN/GLUCOSE RATIO (MEAN ± S.E.)
We do not suggest that treatment was successful. We have no doubt, however, that the infant improved initially and a second course might have been beneficial. Department of Pediatrics and Department of Microbiology and Immunology, Mayo Clinic and Mayo Foundation, Rochester, Minnesota 55901, U.S.A.
ROY F. HOUSE, JR. DONALD A. PERSON THOMAS F. SMITH LLOYD E. HARRIS.
INCREASED LITHIUM ERYTHROCYTE/ PLASMA RATIO IN MANIC-DEPRESSIVE PSYCHOSIS
Snt,—Lithium concentration in red blood-cells versus plasma differs significantly between apparently healthy female controls and female patients with manic-depressive psychosis on lithium therapy. There is also a significant difference between male and female manic-depressive patients with lithium at therapeutic plasma concentrations. Our findings were:
(100 mg. every 8 hours) with frusemide (40 mg. daily) and potassium (30 meq. daily). Both D.P.H. and diazoxide effectively raised the mean fasting plasma-glucose concentration and improved the I.R.i./glucose ratio (table i). On the final day of each regimen 1 g. of tolbutamide was given intravenously over 2 minutes, followed in 16 minutes by 25 g. of glucose intravenously over 2 minutes. Insulinomas will respond rapidly when stimulated with tolbutamide, and using this method it is possible to obtain important insulin data without endangering the patient by further hypoglycasmia. The I.R.I. responses to both tolbutamide and glucose were blunted during treatment with D.P.H. (table 11). On diazoxide, the I.R.I. responses to these stimuli were actually augmented. The ability of tolbutamide, but not of glucose alone, to the diazoxide blockade of insulin release has In addition, when dogs are pretreated been reported.6 with diazoxide and then challenged with tolbutamide and glucose, the I.R.I. release to the combined tolbutamide/ glucose stimulus is additive.6 A similar pattern of I.R.I. release to the tolbutamide/glucose stimulus occurred in
reverse
*
t
Significantly different Significantly different
from from
healthy females (p < 0-05). manic-depressive females (p < 0.05).
patient (table 11). currently accepted that pancreatic insulin secretion is biphasic and involves the immediate release from a small labile pool as well as the subsequent provision of insulin to our
An increased erythrocyte/plasma lithium ratio in females versus males and in diseased females versus controls may reflect a difference in membrane properties of fundamental importance for the understanding of the manic-depressive disease. A full report of this study will be published
elsewhere. Psychiatric Research Center, University of Uppsala, Ulleráker Hospital, S-750 17 Uppsala, Sweden. 6. 7.
It is
1. 2. 3.
L. LYTTKENS U. SÖDERBERG L. WETTERBERG.
Stern, H., Tucker, S. M. Lancet, 1965, ii, 1268. Weller, T. H. New Engl. J. Med. 1971, 285, 203, 267.
4. 5. 6.
Fariss, B. L., Lutcher, C. L. Diabetes, 1971, 20, 177. Malherbe, C., Burrill, K. C., Levin, S. R., Karam, J. H., Forsham, P. H. New Engl. J. Med. 1972, 286, 339. Levin, S. R., Grodsky, G. M., Hagura, R., Smith, D. Diabetes, 1972, 21, 856. Sherman, B. M., Pek, S., Fajans, S. J., Floyd, J. C., Conn, J. W. J. clin. Endocr. Metab. 1972, 35, 271. Basabe, J. C., Lopez, N. L., Viktora, J. K., Wolff, F. W. Diabetes, 1971, 20, 449. Anderson, J. H., Byrd, G. W., Blackard, W. G. Metabolism, 1971, 20, 1023.