Endocrine Disorders

PHT has been shown to influence endocrine function in a number of ways (see Basic Mechanisms-Metabolic and Endocrine Regulatory Effects). It modulates the hypothalamic and other neuronal systems that regulate pituitary function. It alters hormone release directly by its effects on calcium-dependent secretion processes, and can alter hormone metabolism and protein binding.

Labile Diabetes

Fabrykant and Pacella, Annals of Internal Medicine (1948),92 detailed the use of PHT in the treatment of three cases of labile diabetes. In each case, PHT stabilized insulin requirements and reduced negative reactions. In addition, the patients showed remarkable improvement in mood. As a control, when PHT was discontinued for periods of from five to thirty-three days, the patients reverted to frequent reactions and nervousness.

92. Fabrykant, M. and Pacella, B. L., Labile diabetes: electroencephalographic status and effect of anticonvulsive therapy, Ann. Intern. Med., 29: 860-877, 1948.

Wilson, Canadian Medical Association Journal (1951),382 described three cases of labile diabetes whose control was unsatisfactory and not compatible with life outside the hospital. In all instances abnormal electroencephalograms were found. Prior to PHT treatment, these patients presented extremely labile diabetes, characterized by frequent reactions, uncontrollable glycosuria, and personality changes. The institution of PHT therapy resulted in a marked improvement in diabetic control and enabled these individuals to lead a relatively normal life, not necessitating a return to the hospital.

382. Wilson, D. R., Electroencephalographic studies in diabetes mellitus, Canad. Med. Assn., J., 65: 462-465, 1951

Fabrykant, Annals of Internal Medicine (1953),91 again reported the effectiveness of PHT therapy in the management of labile diabetes associated with electrocerebral dysfunction. In this study of seven patients, five showed an appreciable diminution in the frequency and severity of insulin reactions along with a decrease in insulin requirement. This resulted in better control of diabetes and psychologic improvement. The other two patients did not adhere to therapy, but the author noted that in one case there was a marked improvement while on PHT. (See also Ref. 430.)

91. Fabrykant, M., Further studies on electrocerebral dysfunction and the use of anticonvulsants in labile diabetes, Ann. Intern. Med., 38: 814-823, 1953.
430. Fabrykant, M., Pseudohypoglycemic reactions in insulin-treated diabetics: etiology, laboratory aids and therapy, J. Amer. Geriat. Soc., 12: 221-238, 1964.

Roberts, Journal of the American Geriatrics Society (1964),429 reported an extensive study entitled, “The Syndrome of Narcolepsy and Diabetogenic (‘Functional’) Hyperinsulinism.” Although the use of PHT was not the major focus of his work, the author stated that with regard to the symptoms of labile diabetes his experiences with PHT confirm those of others who have observed clinical and electroencephalographic improvement following its administration.

429. Roberts, H. J., The syndrome of narcolepsy and diabetogenic (“functional”) hyperinsulinism, with special reference to obesity, diabetes, idiopathic edema, cerebral dysrhythmias and multiple sclerosis (200 patients), J. Amer. Geriat. Soc., 12: 926-976, 1964.       

Av Ruskin, Tio and Juan, Clinical Research (1979),2149 demonstrated that PHT has a modulating effect on basal glucagon in eight type-1 juvenile diabetes mellitus patients. PHT lowered arginine-induced blood glucose and glucagon responses. The authors suggest that PHT be considered as adjunctive therapy in diabetes mellitus when hyperglucagonemia is present.

See also Basic Mechanisms-Metabolic and Endocrine Regulatory Effects.

2149. AvRuskin, T.W., Tio, S.L. and Juan, C.S., Modulating effects of acute and chronic Dilantin administration on the hyperglucagonemia of type-1 diabetes mellitus, Clin. Res., 27(4): 625A, 1979.

Diabetic Neuropathy

Ellenberg, New York State Journal of Medicine (1968),431 recognized the urgent need for a beneficial therapeutic agent in diabetic neuropathy and stated that this need was underscored by the frequent use of narcotics to control the severe pain, with the ever-present threat of addiction. The author noted that PHT was not addictive, did not sedate and, on the assumption that the symptoms of diabetic neuropathy might have a similar background to tic douloureux in which PHT was used with success, a therapeutic trial was undertaken. PHT was used to treat painful diabetic peripheral neuropathy in sixty patients. Based on symptomatic relief of pain and paresthesias, excellent results were obtained in forty-one patients and fair response in ten patients. Improvement was noted in from twenty-four to ninety-six hours. As a feature of control, when the drug was discontinued, symptoms frequently recurred. A salutary response was uniformly repeated on reinstitution of PHT. In two of the sixty cases skin rash occurred, one associated with fever. These reactions disappeared upon withdrawal of the medicine. Nine years later, in JAMA,1819 Ellenberg repeated his recommendation of the use of PHT in the treatment of painful diabetic neuropathy, eliminating the use of narcotics.

431. Ellenberg, M., Treatment of diabetic neuropathy with diphenylhydantoin, New York J. Med., 68: 2653-2655, 1968.
1819. Ellenberg, M., Unremitting painful diabetic neuropathy, JAMA, 237(18): 1986, 1977.

Kannan, Dash and Rastogi, Journal of Diabetic Association of India (1978),1920 in a double-blind crossover study of sixteen patients with diabetic neuropathy, found that thirteen had significant relief of pain and/or paresthesias with 100 mg PHT t.i.d.

1920. Kannan, K., Dash, R. J. and Rastogi, G. K., Evaluation of treatment of painful diabetic neuropathy with diphenylhydantoin, J. Diabetic Assoc. India, 18; 199-202, 1978.

Chadda and Mathur, Journal of the Association of Physicians in India (1978),1767 in a double-blind study with PHT found significant improvement in pain and paresthesias in twenty-eight of thirty-eight patients with diabetic neuropathy. The authors conclude that PHT is an effective and well-tolerated drug for the relief of pain in diabetic neuropathy, and is preferred to narcotics.

1767. Chadda, V. S. and Mathur, M. S., Double blind study of the effects of diphenylhydantoin sodium on diabetic neuropathy, J. Assoc. Phys. Ind., 26: 403-6, 1978.

See also Clinical Uses: Treatment of Pain.

Hypoglycemia

Knopp, Sheinin and Freinkel, Archives of Internal Medicine (1972),1222 reported that PHT inhibited the stimulated insulin release in a patient with an islet cell tumor. They noted that their observations indicate that PHT may warrant consideration as a safe therapeutic adjunct in inoperable or poorly controlled islet cell tumors.

1222. Knopp, R. H., Sheinin, J. C., and Freinkel, N., Diphenylhydantoin and an insulin-secreting islet adenoma, Arch. Intern. Med., 130: 904-908, 1972.

Cohen, Bower, Fidler, Johnsonbaugh and Sode, Lancet (1973),909 reported the effect of PHT on a patient with a benign insulinoma. PHT was found effective in raising the mean fasting plasma glucose concentration and improved the immunoreactive insulin to glucose ratio. The authors conclude that PHT appears to be a promising agent in the treatment of certain patients with insulinoma.

909. Cohen, M. S., Bower, R. H., Fidler, S. M., Johnsonbaugh, R. E., and Sode, J., Inhibition of insulin release by diphenylhydantoin and diazoxide in a patient with benign insulinoma, Lancet, 40-41, 1973.

Stambaugh and Tucker, Diabetes (1974),1583 describe the successful use of PHT in the treatment of five patients with functional hypoglycemia previously unresponsive to dietary management. Clinical reversal of hypoglycemia, including marked improvement in mood and emotional stability, was observed in all five cases. Laboratory tests were confirmatory in both six-hour glucose tolerance and insulin level tests, performed before and after PHT therapy.

1583. Stambaugh, J. E. and Tucker, D., Effect of diphenylhydantoin on glucose tolerance in patients with hypoglycemia, Diabetes, 23: 679-683, 1974.

Brodows and Campbell, Journal of Clinical Endocrinology and Metabolism (1974),872 describe the successful control of refractory hypoglycemia with therapeutic doses of PHT in a patient with a suspected functional islet cell tumor. The authors state that the adequacy of the control of the hypoglycemia by PHT was evidenced by normal overnight fasting glucose levels and the absence of hypoglycemia during total fasting up to twenty-four hours. They note that it is of interest that there was a high degree of correlation between post-absorptive glucose and serum PHT levels and also a significant lowering of basal insulin levels during PHT therapy.

872. Brodows, R. G. and Campbell, R. G., Control of refractory fasting hypoglycemia in a patient with suspected insulinoma with diphenylhydantoin, J. Clin. Endocr., 38: 159-161, 1974.

Hofeldt, Dippe, Levin, Karam, Blum and Forsham, Diabetes (1974),1154 reported on the use of PHT in three patients with surgically proven insulinomas, tested with oral and intravenous glucose. The authors found that PHT had no significant effect on basal glucose or insulin values, but was useful in reducing insulin secretion after stimuli.

1154. Hofeldt, F. D., Dippe, S. E., Levin, S. R., Karam, J. H., Blum, M. R., and Forsham, P. H., Effects of diphenylhydantoin upon glucose-induced insulin secretion in three patients with insulinoma, Diabetes, 23: 192-198, 1974.

Bricaire, Luton, Wechsler, Messing and Halaby, Annales de Medecine Interne (1976),1756 reported the successful use of PHT in a case of organic hypoglycemia due to insulinoma for a period of five months prior to surgical removal of tumor.

1756. Bricaire, H., Luton, J. P., Wechsler, B., Messing, B. and Halaby, G., Inappropriate secretion of insulin by an islet cell adenoma. Trial treatment with diphenylhydantoin, Ann. Med. Intern., 127(5): 403-7, 1976.

Agapova and Mikhalev, Therapeutic Archives (1977),1714 reported the control with PHT of hypoglycemia attacks in a patient with an adenoma of the pancreas during the preoperative period until the adenoma was surgically removed.

See also Refs. 2533, 2610, 2925, 2932.

1714. Agapova, E. N. and Mikhalev, I. D., Effectiveness of the use of diphenine in insuloma, Ter. Arkh., 49(9): 124-5, 1977.
2533. Gedik, O., Sayek, I., Raucan, S., Telatar, F., Adalar, N., Usman, A., Akalin, S., Insulinoma. (Clinical, diagnostic and therapeutic features of 3 cases), Hacettepe Bull. Med. Surg., 15: 13-9, 1982.
2610. Imanaka, S., Matsuda, S., Ito, K., Matsuoka, T., Okada, Y., Studies of pharmacotherapy of inoperable insulinoma. Effectiveness of the combined use of diphenylhydantoin and calcium antagonists, Nippon Naika Gakkai Zasshi, 74: 590-6, 1985.
2925. Scandellari, C., Zaccaria, M., Sicolo, N., Casara, D., Erle, G., Federspil, G., Medical treatment of endogenous organic hyperinsulinism, Horm. Metab. Res., 6: 46-54, 1976.
2932. Schless, G. L., Functional hypoglycemia: diagnosis and treatment, Diabetes, 31(2): 167a, 1982.

Cushing’s Syndrome

Starkova, Marova, Lemescheva, Goncharova, Atamanova and Sedykh, Problemy Endokrinologii (1972),2090 studied fifteen patients with Cushing's syndrome given PHT, 300 mg per day, for a period of three weeks. This treatment led to normalization of the urinary excretion of ketosteroids and of aldosterone and pregnanediol, and to a normalization of the content of 17-hydroxyke-tosteroids in blood. There was also an increase in the potassium content in blood. The rate of secretion of cortisol decreased for all patients. The authors noted that all the patients displayed a reduction or normalization of blood pressure and body weight, and a decrease in headaches and in weakness. (See also Ref. 427.)

2090. Starkova, N. T., Marova, E. I., Lemesheva, S. N., Goncharova, V. N., Atamanova, T. M. and Sedykh, L. P., The effect of diphenin on functional condition of the adrenal cortex in patients with Itsenko-Cushing disease, Problemy Endokrinologii, 18: 35-8, Nov/Dec, 1972.

427. Werk, E. E., Jr., Sholiton, L. J., and Olinger, C. P., Amelioration of non-tumorous Cushing’s syndrome by diphenylhydantoin, Proc. 2nd Int. Cong. Hormonal Steroids, Excerpta Medica, No. 111, Milan, 1966.

Frenkel, Safronova, Marova and Lemesheva, Problemy Endokrinologii (1976),2510 treated nine Cushing's syndrome patients with PHT, 300 mg/day, for three weeks.

With PHT, reduction or normalization of blood pressure, decrease in headaches, decrease in fatigue, and reduction in excretion of 17-hydroxyketosteroids and ketosteroids were observed. In seven of the patients, there was also normalization of the EEG parameters, especially those indicating diencephalic disturbances.

2510. Frenkel, G. M., Safronova, N. A., Marova, E. I., Lemesheva, S. N., A change in electrical activity of the brain under the effect of diphenylhydantoin in patients with Itsenko-Cushing disease, Probl. Endokrinol., 1: 19-22, 1976.

Inappropriate Antidiuretic Hormone Syndrome

Lee, Grumer, Bronsky and Waldstein, Journal of Laboratory Clinical Medicine (1961),219 using acute water loading as a diagnostic test for the inappropriate antidiuretic hormone (ADH) syndrome in hyponatremia, treated two patients with confirmed inappropriate ADH syndrome with intravenous PHT (250 mg). Both patients showed an increase in free-water clearance. In one patient with tuberculous meningitis, a normal response to acute water loading was noted after one month of therapy.

219. Lee, W. Y., Grummer, H. A., Bronsky, D., and Waldstein, S. S., Acute water loading as a diagnostic test for the inappropriate ADH syndrome, J. Lab. Clin. Med., 58: 937, 1961.

Fichman, Kleeman and Bethune, Archives of Neurology (1970),97 studied the effect of intravenous PHT on antidiuretic hormone (ADH) activity in six patients with inappropriate ADH syndrome. PHT markedly increased the excretion of a 20 ml/kg water load and markedly decreased minimum urine osmolality in four of the patients in three hours. Two of the patients with bronchogenic carcinoma did not respond. The authors state that their data suggests that, in man, PHT affects water balance by inhibiting ADH release.

97. Fichman, M. P., Kleeman, C. R. and Bethune, Inhibition of antidiuretic hormone secretion by diphenylhydantoin, Arch. Neurol., 22: 45-53, 1970.

Landolt, Acta Endocrinologica (1974),1256 reported an eight-year-old patient who, following surgery for craniopharyngioma, developed diabetes insipidus followed by inappropriate ADH secretion. Intravenous PHT resulted in an increase in urine output. Serum sodium values returned to normal and the patient became more alert. During a subsequent recurrence of inappropriate ADH secretion, PHT again increased the urine output. The author concludes that PHT regulates water metabolism during periods of inappropriate ADH secretion, but has no effect in patients with normal water balance.

1256. Landolt, A. M., Treatment of acute post-operative inappropriate antidiuretic hormone secretion with diphenylhydantoin, Acta Endocr., 76: 625-628, 1974.

Tanay, Yust, Peresecenschi, Abramov and Aviram, Annals of Internal Medicine (1979),2101 reported on the use of PHT in the treatment of a sixty-eight-year-old female who had been admitted to hospital because of precordial pain, headache, nausea, and blurring of vision. In addition, confused behavior and diminished orientation in time and place were observed. A diagnosis of inappropriate antidiuretic hormone secretion was made and confirmed by laboratory findings. The authors state that treatment with PHT, 100 mg t.i.d., resulted in reversal of the clinical and laboratory findings and demonstrated the effectiveness of PHT in treating this syndrome.

2101. Tanay, A., Yust, I., Peresecenschi, G., Abramov, A. L. and Avriam, A., Long-term treatment of the syndrome of inappropriate antidiuretic hormone secretion with phenytoin, Ann. Intern. Med., 90: 50-2, 1979.

Sordillo, Matarese, Novich, Zabetakis and Michelis, Clinical Nephrology (1981),2971 report two patients with inappropriate ADH syndrome who were successfully treated with PHT. The authors state that PHT can suppress drug-induced, as well as excess endogenous, ADH secretion.

2971. Sordillo, P., Matarese, R. A., Novich, R. K., Zabetakis, P. M., Michelis, M. F., Specific modalities of therapy for inappropriate antidiuretic hormone secretion, Clin. Nephrol., 15(3): 107-10, 1981.

Lowe and Wilkins, 3351 Letter to the Ediotor, Journal of Paediatrics and Child Health (1995), report the use of phenytoin in the management of severe acute syndrome of inappropriate secretion of antidiuretic hormone (SIADH). The patient was a 6-year-old girl who had sustained a head injury in an automobile accident. For SIADH, she was treated with water restriction and sodium replacement. For seizure prophylaxis, she was given phenytoin (15 mg/kg), after which there was an immediate diuresis of dilute urine and an improvement in her level of consciousness to normal. Water restriction was lifted the next day, but there was no recurrence of the SIADH. The authors state that, for their patient, phenytoin may have resolved the SIADH, or it may have been coincidental. They conclude that if water restriction alone with or without diuretics is not effective, a trial of the use of phenytoin may be warranted.

3351. Lowe, K.G. and Wilkins, B.H., Phenytoin in the management of severe acute SIADH, J. Paediatr. Child Health, 31(2):155, 1995.

See also Ref.

3352. Sone, H., Okuda, Y., Bannai, C., Suzuki, S., Yamaoka, T., Asakura, Y., Kawakami, Y., Odawara, M., Matsushima, T., and Kawai, K., Syndrome of inappropriate secretion of antidiuretic hormone (SIADH) and Gerhardt syndrome associated with Shy-Drager syndrome, Intern. Med.,33(12):773-8, 1994.

Polydipsia

Vieweg, Weiss, David, Rowe, Godleski and Spradlin, Biological Psychiatry (1988), 3353 treated six patients (five males and one female) with psychosis, intermittent hyponatremia and polydipsia (PIP syndrome) with multiple treatment regimens over a twenty-month time period. The sequence of treatments was salt-added diet, lithium and phenytoin, and lithium alone. The combination of lithium and phenytoin provided a morning basal serum sodium level of 140 ± 3.2 meq/l, which was superior to all other treatment modalities. Lithium alone was not tolerated by the patients.

3353. Vieweg, W.V., Weiss, N.M., David, J.J., Rowe, W.T., Godleski, L.S., Spradlin, W.W., Treatment of psychosis, intermittent hyponatremia, and polydipsia (PIP syndrome) using lithium and phenytoin, Biol. Psychiatry, 23: 25-30, 1988.

Hyperthyroidism

Romero, Maranon and Bobillo, Revista Iberica de Endocrinologia (1970),1479 describe a variety of treatments for hyperthyroidism including thyroidostatic therapy, surgical resection, and radioisotope therapy, noting these methods have complications and side effects. The authors state that about twenty years ago they started using PHT, 50 mg t.i.d., in combination with hydrazides. The treatment consisted of alternating PHT one week with hydrazides the next week. As a result of their long experience with PHT, the authors initiated a detailed study of nineteen patients. Eight patients showed very favorable improvement; four, moderate improvement; one, slight improvement; and two, no improvement. Marked relief of nervousness, characteristic of this disorder, was observed. The authors state that in some patients treated with PHT there was decrease in size of goiter and exophthalmus. (See also Refs. 1125, 2499, 2846, 2964.)

1479. Romero, E., Maranon, A. and Bobillo, E. R., Antithyroid action of hydantoin derivatives, Rev. Iber. Endocr., 101: 363-375, 1970.
1125. Hansen, J. M., Skovsted, L., Lauridsen, U. B., Kirkegaard, C., and Siersbaek-Nielsen, K., The effect of diphenylhydantoin on thyroid function, J. Clin. Endocrinol. Metab., 39: 785-786, 1974.
2499. Finucane, J. F., Griffiths, R. S., Effect of phenytoin therapy on thyroid function, Br. J. Clin. Pharmacol., 3, 1041-4, 1976.
2846. Oyama, Y., Minagawa, K., Miura, H., Koshimizu, T., Effects of long-term administration of antiepileptic drugs on the pituitary-thyroid system in children, Acta Paediatr. Jpn., 21(l): 68-9, 1979.
2964. Smith, P. J., Surks, M. I., Multiple effects of 5,5-diphenylhydantoin on the thyroid hormone system, Endocr. Rev., 5(4): 514-24, 1984.

Menstrual Disturbances

Mick, JAMA(1 973),1359 reported the case of a girl who had edema of the legs, fingers and puffiness of the face, accompanied by dizzy spells. These symptoms occurred about ten days before each menstrual cycle. Diuretics had been tried without success. On 100 mg of PHT, twice daily, the patient became completely free of her episodic edema. Improvement in dizziness was also noted.

1359. Mick, B. A., Diphenylhydantoin and intermittent edema, JAMA, 225: 1533, 1973.

Kramer, American Journal of Diseases of Children (1977),1936 described a thirteen-year-old girl with a pattern of recurrent psychotic episodes, which seemed to coincide with her menstrual periods. After four to seven days of bizarre, catatonic behavior, the patient would return to a normal state. The episodes were virtually eliminated by treatment with PHT, 400 mg a day. During a three-and-a-half year follow-up, the patient continued to be symptom-free, as long as she was maintained on adequate PHT.

1936. Kramer, M. S., Menstrual epileptoid psychosis in an adolescent girl, Amer. J. Dis. Child., 131: 316-7, 1977.

Ryabtzeva, Medvedva and Shapovalova, International Journal of Psychophysiology (1994), 3354 conducted a clinical and laboratory study of 25 female patients who suffered from obesity, menstrual disorders and infertility. All women received traditional complex treatment. As additional treatment, 12 hyperglycemic patients (group 1) received biguanidins. For group 2, those patients (13) with a "flat" sugar curve, received phenytoin as added therapy. In group 1, the patients lost 5 - 8 kg of body weight in 6 months. The menstrual cycle was restored in 9 of them, and 3 became pregnant. In group 2, the body weight was normalized for all the patients (6 - 10 kg lost); the menstrual cycle was restored for 10 women; and 4 became pregnant. Based on their results, the authors believe it would be useful to include phenytoin as therapy for normalization of gonadotrophic functions of the hypophysis.

3354. Ryabtzeva, I.T., Medvedva, T.G., and Shapovalova, K.A., Phenytoin in hypothalamic disorders, Int. J. Psychophysiol., 18(2):145, 1994.

Diabetes, General

Lahtela, Epilepsia (1986), 3350 evaluated the effect of anticonvulsants on glucose metabolism in six subjects with epilepsy plus type 1 diabetes mellitus. They had received phenobarbital (PB), carbamazepine (CBZ) and phenytoin (PHT) for > 8 years. Three groups -- type 1 diabetics, persons with epilepsy and healthy subjects -- matched for sex and weight, served as controls. Tissue sensitivity to insulin (euglycemic clamp technique) and liver microsomal enzyme activity (oral antipyrine test) were measured.

Glucose metabolism was faster in subjects treated with PHT, PB and CBZ as compared with controls. The treated subjects also had enhanced insulin sensitivity. The authors suggest that these findings may be of significance when one is balancing glucose control in patients with epilepsy.

3350. Lahtela, J.T., Effect of long-term anticonvulsant therapy on glucose metabolism in humans, Epilepsia, 27(6): 711-17, 1986.

Male Sexual Dysfunction

Brunet, Rodamilans, Martinez-Osaba, Santamaria, To-Figueras, Torra, Corbella and Rivera, Pharmacology & Toxicology (1995), 3356 compared sex hormone binding globulin (SHBG) and testosterone levels in 51 epileptic men and 20 healthy controls (age 18-45). Patients receiving polytherapy (34) or monotherapy with carbamazepine (8) or phenytoin (9) showed higher levels of SHBG and testosterone, and lower levels of free testosterone (p < 0.03) than controls. Reduced excretion of androsterone and normal levels of etiocholanolone indicated that there was no increase in the mean catabolism pathway of testosterone. The authors suggest that induction of the hepatic signals of SHBG may be the mechanism by which antiepileptic drugs lower the levels of free testosterone in serum.

3356. Brunet, M., Rodamilans, M., Martinez-Osaba, M.J., Santamaria, J., To-Figueras, J.,Torrra, M., Cobella, J., and Rivera, F., Effects of long-term antiepileptic therapy on the catabolism of testosterone, Pharmacol. Toxicol., 76:371-75, 1995.

See also Ref.

3357. Duncan, S., Blacklaw, J., Beastall, G.H., Brodie, M.J., Antiepileptic drug therapy and sexual function in men with epilepsy, Epilepsia, 40(2): 197-204, 1999.

3358. Herzog, A.G., Altered reproductive endocrine regulation in men with epilepsy: Implications for reproductive function and seizures, Ann.Neurol., 51(5):539-542, 2002.

Eclampsia/Pre-eclampsia

The role of phenytoin in the treatment of eclampsia and pre-eclampsia has been controversial. Please refer to the following references.

See also Ref.

3359. Lucas, L.S. and Jordan, E.T., Phenytoin as an alternative treatment for preeclampsia, J. Obstet. Gynecol., Neonatal. Nurs., 26: 263-269, 1997.

3360. Sungani, F.C.M., Malata, A., and Masanjika, R., Pre-eclampsia/eclampsia: a literature review, Cent. Afr. J. Med., 44(10): 261-263, 1998.

3361. Bhagwanjee, S., Paruk, F., Moodley, J., and Muckart, D.J.J., Intensive care unit morbidity and mortality from eclampsia: an evaluation of the acute physiology and chronic health evaluation II score and the Glasgow coma scale score, Crit. Care Med., 28(1): 120-124, 2000.

3362. Duley, L., Gulmezoglu, A.M., and Henderson-Smart, D.J., Anticonvulsants for women with pre-eclampsia [Systematic Topic Review], Cochrane Database of Systematic Reviews, 4, 1998.

3363. Young, G.L., Magnesium sulphate prevented eclampsia better than phenytoin, [Therapeutics], Evidence-Based Medicine, 1: 45, 1996.

3364. Young, G.L., Magnesium sulphate was superior to diazepam or phenytoin for eclampsia [Therapeutics], Evidence-Based Medicine, 1: 44, 1996.

3365. Sawhney, H., Sawhney, I.M.S., Mandal, R., Subramanyam, and Vasishta, K., Efficacy of magnesium sulphate and phenytoin in the management of eclampsia, J. Obstet. Gynaecol. Res., 25(5): 333-338, 1999.

3366. Naidu, S., Moodley, J., Botha, K., and Mcfadyen, L., The efficacy of phenytoin in relation to serum levels in severe pre-eclampsia and eclampsia, Br. J. Obstet. Gynaecol., 99: 881-886, 1992.

3367. Chatterjee, A. and Mukheree, J., Comparative study of different anticonvulsants in eclampsia, J. Obstet. Gynaecol., 23(3):289-293, 1997.

3368. Lucas, M.J., DePalma, R.T., Peters, M.T., Leveno, K.J., Person, D., and Cunningham, F.G., A simplified phenytoin regimen for preeclampsia, Am. J. Perinatol.,11(2):153-56, 1994.

3369. Robson, S.C., Redfern, N., Seviour, J., Campbell, M., Walkinshaw, S., Rodeck, C., and DeSwiet, M., Phenytoin prophylaxis in severe pre-eclampsia and eclampsia, Br. J. Obstet. Gynaecol., 100(7): 623-28, 1993.

3370. Guzman, E.R., Conley, M., Stewart, R., Ivan, J., Pitter, M., and Kappy, K., Phenytoin and magnesium sulfate effects on fetal heart rate assessed by computer analysis, Obstet. Gynecol., 82(3):375-379, 1993.

3371. Friedman, S.A., Lim, K.H., Baker, C.A., and Repke, J.T., Phenytoin versus magnesium sulfate in pre-eclampsia: A pilot study, Am. J. Perinatol., 10(3): 233-8, 1993.

3372. Mathias, L., Nobile, L., Barros, A.D., and Neme, B., The use of phenylhydantoin in eclamptic refractory convulsions, J. Bras. Ginec., 92(3): 153-156, 1982.

3373. Lucas, M.J., Leveno, K.J., and Cunningham, F.G., A comparison of magnesium sulfate with phenytoin for the prevention of eclampsia, N. Engl. J. Med., 333(4):201-5, 1995.

3374. Mandelkern, D. and Burger, A., Cortical blindness in postpartum pre-eclampsia progressing to eclampsia, Mt. Sinai J. Med., 59(1): 72-74, 1992.

3375. Appleton, M.P., Kuehl, T.J., Raebel, M.A., Adams, H.R., Knight, A.B., and Gold, W.R., Magnesium sulfate versus phenytoin for seizure prophylaxis in pregnancy-induced hypertension, Am. J. Obstet. Gynecol., 165: 907-13, 1991.

3376. Kaplan, P.W., Lesser, R.P., Fisher, R.S., Repke, J.T., and Hanley, D.F., A continuing controversy: Magnesium sulfate in the treatment of eclamptic seizures, Arch. Neurol., 47: 1031-1032, 1990.

3377. Coyaji, K.J. and Otiv, S.R., Single high dose of intravenous phenytoin sodium for the treatment of eclampsia, Acta. Obstet. Gynecol. Scand., 69: 115-18, 1990.

3378. Maheshwari, J.R., Desai, S.V., Hansotia, M.D., and Walvekar, V.R., Anticonvulsant therapy in eclampsia, J. Postgraduate Med., 35(2): 66-69, 1989.

3379. Dommisse, J, Phenytoin sodium and magnesium sulphate in the management of eclampsia, Br. J. Obstet. Gynaecol., 97: 104-109, 1990.

3380. Kaplan, P.W., Lesser, R.P., Fisher, R.S., Repke, J.T., and Hanley, D.F., No, Magnesium sulfate should not be used in treating eclamptic seizures, Arch. Neurol., 45: 1361-64, 1988.

3381. Slater, R.M., Wilcox, F.L., Donnai, P., Smith, W.D., Richardson, T., The use of a high dose phenytoin regime in pre-eclampsia, Clin. Exp. Hypertens., 6(1): 169,1987.

3382. Hauswald, M., Cortical blindness and late postpartum eclampsia, Am. J. Emerg. Med., 5: 130-2, 1987.

3383. Slater, R.M., Smith, W.D., Patrick, J., Mawer, G.E., Wilcox, F.L., Donnai, P., Richardson, T., D'Souza, S.W., and Anderton, J.M., Phenytoin infusion in severe pre-eclampsia, Lancet, 1(8547):1417-21, 1987.v

3384. Moosa, S.M. and El-Zayat, S.G., Phenytoin infusion in severe pre-eclampsia, Lancet, 2(8568): 1147-8, 1987.

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