Effects of hypophysectomy, thyroidectomy, and thyroxine on specific prolactin receptor sites in kidneys and adrenals of male rats.

The effect of T4 on specific PRL binding in the kidneys and adrenals was measured in intact, hypophysectomized, and thyroidectomized male rats. PRL binding in the kidneys was reduced from 12.1 +/- 1.1% in the intact group to 4.5 +/- 0.5% after hypophysectomy; 4-day replacement with T4 returned PRL binding to intact values. T4 administered to intact rats significantly increased PRL binding above intact values. Thyroidectomy reduced PRL binding in the kidneys from 14.9 +/- 1.2% to 7.0 +/- 0.6%, and T4 treatment restored PRL binding to intact values. PRL binding was measured at 2, 3, 5, 7, and 10 days after thyroidectomy in kidneys and found to decrease progressively from 8.2+/-0.5% in the intact rats to 2.3+/-0.3% on day 10. A single injection of T4 doubled PRL recetor binding in kidneys of thyroidectomized rats at 12 h and returned binding to intact levels at 24 h. In contrast to the effects of T4 on kidney PRL binding, adrenal PRL binding was only slightly altered by thyroidectomy and T4. These results suggest that T4 has a specific role in regulating PRL receptors in the kidneys but not in the adrenals. Since PRL receptors in the adrenals were only slightly altered by thyroid status, it is believed that the changes in kidney receptors represent a specific rather than a general metabolic effect of T4.

Patterns of sex steroid and gonadotropin secretion in aging female rats.

Serum estradiol, progesterone, LH, and FSH were determined by RIA in 20- to 30-month-old constant estrous (CE), irregular pseudopregnant (PP), and anestrous (AS) female rats and from 4- to 5-month-old cycling female rats. Disruption of the estrous cycle in aging rats was associated with major changes in secretion of pituitary gonadotropins and ovarian steroids. None of the old rats, in contrast to the young rats, showed cyclic changes in any of the hormones studied. Serum progesterone was much higher in the PP than in the other two old groups, serum estradiol averaged somewhat higher in the CE than in the other two aged groups, and all four hormones were lower in the AS rats than in any other group. Basal serum FSH values were higher in the old CE rats than in either of the other old age groups and were slightly higher than in young rats on the afternoon of proestrus or morning of estrus. Serum FSH values were lower in the old PP and AS rats than in young rats on the afternoon of proestrus or morning of estrus. Serum FSH values were lower in the old PP and AS rats than in young rats on the afternoon of proestrus or morning of estrus. Serum values in the old CE rats were about the same as in young rats on the morning of proestrus or estrus, about the same in old PP rats as in young rats during diestrus, and were undectable in old AS rats. Since the ovaries of old rats are capable of near normal function under appropriate gonadotropic stimulation, it is concluded that the major cause for cessation of regular estrous cycles in old rats lies in altered hypothalamo-pituitary function.

Serum and pituitary TSH and response to TRH in developing male and female rats.

Serum and pituitary thyroid-stimulating hormone (TSH) was measured by radioimmunoassay in male and female Sprague-Dawley rats from 21 through 80 days of age. In males, serum TSH levels increased progressively from days 30 through 50, and were found to be lower on days 60, 70, and 80. In females, serum TSH levels were elevated on days 40 and 50, compared with day 30, but declined on days 60-80. A sex difference in serum TSH levels, with those of the male higher than those of the female, appeared by day 30 and was maintained through day 80. The anterior pituitary (AP) content of TSH in males increased from days 21 through 50 and remained constant through day 80; in females the AP content increased between days 25 and 60 and remained constant through day 80. In males, thyrotropin-releasing hormone (TRH) induced a significant elevation in serum TSH at all ages tested, but was less effective in increasing serum TSH on day 25 than on days 15 or 40 or in 3-4-month-old rats. The response to TRH appeared to be sustained longer in adults than in all other age groups. These observations indicate that serum TSH levels increase in both male and female rats at about the time of puberty and then decline, and that changes in the response to TRH may account in part for the increase in serum TSH levels during development.

Effects of hyper- and hypothyroidism on serum LH and FSH levels in intact and gonadectomized male and female rats.

The effects of hypo- and hyper-thyroidism on serum LH and FSH were determined in both intact and castrated male and female rats. Thyro-parathyroidectomy (Tx) for 30 days in rats with intact gonads resulted in a significant reduction in serum LH and FSH, and also in a decrease in serum testosterone in males. Administration of 2.5 mug thyroxine (T4)/100 g BW to Tx rats of both sexes returned serum LH and FSH levels to those of intact rats, and in males also restored normal serum testosterone levels. Tx superimposed upon castration resulted in a significantly greater increase in serum LH and FSH than produced by castration alone. Administration of 2.5 mug T4/100 g body weight to castrate-Tx rats reduced serum LH and FSH values to those of castrate rats, whereas 10 mug T4/100 g BW evoked a further decrease in serum LH but no additional reduction in serum FSH. When both 2.5 mug T4/100 g BW and 2 mug estradiol benzoate were injected into Tx-ovariectomized rats, the decrease in serum LH and FSH was much greater than produced by T4 alone. These observations indicate that hypothyroidism results in decreased release of LH and FSH in rats with intact gonads, and in increased release of LH and FSH in castrate rats of both sexes. Administration of a replacement dose of T4 can restore LH and FSH release to normal in Tx rats with intact gonads, and to castration levels in Tx-castrate rats.

Effects of thyroid and ovaries on prolactin binding activity in rat liver.

125I-radiolabeled ovine prolactin (oPRL) binding activity was measured in microsomal membranes of liver tissue from intact, ovariectomized, ovariectomized-thyroidectomized, and ovariectomized-thyroidectomized rats injected with thyroxine (T4) or estradiol benzoate (EB). Thyroidectomy and ovariectomy each reduced PRL binding activity in liver tissue significantly. The combination of ovariectomy and thyroidectomy decreased PRL binding activity more than thyroidectomy or ovariectomy alone. Doses of 2.5 mug or 10 mug T4/100 g BW daily returned PRL binding activity in the thyroidectomized rats to intact control values, and in the ovariectomized-thyroidectomized rats to the ovariectomized values. A dose of 2 mug EB/rat increased PRL binding activity significantly in ovariectomized-thyroidectomized rats, and a combination of 2 mug EB and 2.5 mug T4/100E that of intact controls. Scatchard analysis showed that ovariectomy and thyroidectomy decreased the number of PRL binding sites in the liver as compared to those in intact controls or in ovariectomized-thyroidectomized rats treated with EB and T4. It is concluded that the thyroid and ovaries are important regulators of PRL binding activity in the liver of the rat.

beta-Endorphin in the human pancreas.

Using a specific antiserum, beta-endorphin was quantitated in 8 human pancreas obtained at autopsy by radioimmunoassay and localized by immunocytochemistry. The mean (+/- SE) concentration of beta-endorphin in pancreatic extracts of 5 non-diabetic adults was 13.5 +/- 9.8 ng/gm with a range of 2.1 to 52.8 ng/gm of tissue. Pancreatic beta-endorphin concentration in two premature infants were within the range found in adults. In one diabetic pancreas, there was no measurable beta-endorphin. Specific beta-endorphin immunofluorescence is localized within the pancreatic islets. This finding suggests that beta-endorphin may participate in intraislet regulation of pancreatic hormone secretion.

Steady-state kinetics of valproic acid in epileptic patients.

Pharmacokinetic evaluation and prediction were carried out in 20 epileptic patients. Using conventional pharmacokinetic techniques and a one-compartment model, predicted and observed valproic acid plasma concentrations were compared. Valproic acid assay was performed by gas-liquid chromatography. There was good agreement between predicted and observed plasma concentrations. Most patients had predicted half-lives (t1/2s) of 6 to 8 hr, independent of the plasma concentration of valproic acid. Five patients had predicted t1/2s of 12 hr. The correlation between dose and plasma level was poor. Most patients had valproic acid plasma levels between 55 and 100 microgram/ml. Administration of valproic acid three times a day with determination of individual plasma concentrations offers a reliable method of monitoring. Constant levels are maintained in individual patients, but there is substantial intersubject variation.

Reduction of polypharmacy in epileptic patients.

An attempt was made to reduce polypharmacy in 90 epileptic patients. All patients received their original drug regimen for at least six months and were followed up for a minimum of 16 months after reduction of polypharmacy. In 72 patients (80%), the average number of drugs administered was reduced from 2.75 to 1.49. In 39 of these (54%), a reduction was made to single drug therapy. Either no change or an improvement in seizure control was observed, and side effects decreased in many patients. In 18 patients (20%), medications could not be withdrawn. In nine of these, another drug was required for seizure control. In the remaining nine, more frequent seizures necessitated a return to the previous regimen. The critical variable predicting unsuccessful reduction of polypharmacy was the presence of multiple concurrent seizure types.

Valproic acid therapy for complex partial seizures. Its efficacy and toxic effects.

Twenty-four adult outpatients with poorly controlled complex partial seizures were treated with valproic acid. Previous therapy with antiepileptic agents was continued to maintain stable plasma drug levels. Initially 12 patients experienced greater than 50% seizure reduction. Only five patients maintained longterm benefit. In the other seven patients a tolerance developed to valproic acid's efficacy. Duration of seizure control seemed to be a function of initial seizure frequency. Toxic effects were generally mild. No hepatotoxic effect was noted and no hematological abnormalities developed. Weight changes occurred in 17 patients (14 gained weight) and five patients experienced a postural tremor. Eighteen patients experienced nausea.

Valproic acid. Review of a new antiepileptic drug.

Valproic acid is a new antiepileptic drug. It has a marked effect on generalized spike-wave discharges. The exact mechanism of action is uncertain; however, some evidence suggests an effect on the metabolism of gamma-aminobutyric acid. It is rapidly absorbed from the gastrointestinal (GI) tract. Concurrent administration with phenobarbital may result in elevated phenobarbital plasma concentrations. Administration with phenytoin sodium may transiently result in lower total phenytoin plasma levels. Side effects are generally mild and include fatigue, GI disturbances, weight gain, a fine postural and resting tremor, mild thrombocytopenia, and an increase in hepatic enzymes. Platelet counts and liver function monitoring should be done during valproic acid therapy. Drowsiness may be seen in patients receiving other antiepileptic drugs concurrently.

Lymph node metastasis and cell movement: ultrastructural studies on the rat 13762 mammary carcinoma and Walker carcinoma.

The aim of this study was to determine whether tumor cells move actively through the linings of lymph node sinuses. Using 13762 carcinoma in F344 rats, and Walker carcinoma in Wistar rats, 20 X 10(6) tumor cells were injected into the footpad, and the ipsilateral popliteal lymph node examined by transmission electron microscopy. The same tumors were examined by making standard cell spots on plastic or glass surfaces, and examining these by phase and reflection contrast microscopy, fluorescent microscopy after anti-actin and phallacidin staining and transmission electron microscopy. The 13762 cells do not migrate through the lining of the lymph node sinusoid, nor move actively in vitro. Ultrastructural appearances of the Walker rat carcinoma cells suggest that they move actively through the sinus lining. After 24 h in vitro the Walker rat carcinoma cells in the centre of the spot are adherent to the surface. There is some movement of the edge of the sheet, and individual tumor cells at the edge of the sheet move actively and independently. We conclude that the Walker rat carcinoma invades the lining of the lymph node sinusoid by active cell movement, and the 13762 carcinoma does not.

Effects of carbamazepine and its epoxide metabolite on amygdala-kindled seizures in rats.

Fourteen animals with stable generalized kindled seizures received three doses of carbamazepine and its epoxide (12.5 to 50 mg/kg IP) in a crossover design. Both compounds suppressed the secondarily generalized convulsion but only affected the partial seizure from the amygdala to a limited extent. The parent drug and the metabolite were equipotent against both seizure types. The results confirm the belief that carbamazepine epoxide has anticonvulsant properties and suggest that it may exert a major therapeutic effect in humans.

Primary intramedullary malignant lymphoma of the spinal cord.

The clinical and histologic features of a malignant intramedullary lymphoma of the spinal cord are reported. The duration of the disease was 9 months and the course was similar to other malignant intramedullary cord tumors. The tumor was confined to the cervical segment of the cord and histologically was composed of lymphocytes and plasmacytoid histiocytes. Effective treatment depends on tissue diagnosis.

Valproic acid and plasma levels of phenytoin.

Eight patients were treated concurrently with a constant dose of phenytoin and valproic acid for 1 year. During initial therapy with valproic acid, total plasma phenytoin levels decreased. The interaction was transient and was not observed at the end of 1 year. Total plasma phenytoin levels returned to pre-valproic-acid levels in seven patients.

Valproic acid: interaction with other anticonvulsant drugs.

The interaction of valproic acid and other antiepileptic drugs was studied in 25 patients for 5 to 9 months. Clinical evaluations, seizure records, and antiepileptic drug levels were followed regularly. Eleven of the 13 patients required a reduced phenobarbital dose when concurrently treated with valproic acid. This reduction was prompted by sedation. An average dose reduction of 46 percent resulted in an average serum phenobarbital decrease of 15 percent. Ten of 15 patients had decreased phenytoin concentrations during concurrent administration with valproic acid. No definitive conclusion was reached about other antiepileptic drugs. Decreased phenobarbital excretion because of urine acidification and displacement of phenytoin from protein binding sites may account for the observations. Careful monitoring of anticonvulsant levels is required in anticipation of the documented interactions.

Effect of valproic acid on hepatic function.

Altered hepatic function tests occurred in four of 25 patients treated with valproic acid. An average dose reduction in three patients of 10 mg per kilogram per day resulted in reversion of serum glutamic oxaloacetic transaminase (SGOT) and serum glutamic pyruvic transaminase (SGPT) to normal. The drug was discontinued in one patient. Careful monitoring of hepatic function is required of patients being treated with valproic acid, but our experience suggests that dose reduction alone may be effective in preventing untoward hepatic side effects.

Clinical efficacy and long-term effects of valproic acid therapy on spike-and-wave discharges.

Twenty-two patients with absence seizures and other seizure types were treated with valproic acid and followed up for 1 year. Results were excellent with more than 75% improvement in 80% of patients with absence seizures, in 40% of those with tonic-clonic seizures, in all of those with myoclonic seizures, and in 43% of those with partial seizures. Fifty-seven percent of the patients had more than a 75% reduction in the total number of paroxysmal spike-wave discharges, and 62% had more than a 75% reduction in the number of spike-wave discharges lasting longer than 3 seconds. Photosensitivity and activation by hyperventilation decreased. More patients achieved good EEG control in 1 year than in 10 weeks.

A double-blind study comparing carbamazepine with phenytoin as initial seizure therapy in adults.

Carbamazepine was compared with phenytoin in a double-blind study. Of 87 patients, data on 70 patients were complete and used for analysis. Thirty-five patients were treated with each drug. The incidence of major side effects, minor side effects, and complete control (85%) was the same in both groups. A mild but significant elevation of WBC count was found before initiation of drug treatment in the patients presenting with generalized convulsive seizures. Sporadically, elevations in SGOT and LDH were seen; WBC counts below 4,000 were reported, but these were not clinically significant.

Interactions of valproic acid with phenytoin.

The interaction of phenytoin and valproic acid was studied in four adults. We studied serial changes in total phenytoin concentrations, protein binding, urinary hydroxyphenylphenylhydantoin (HPPH) excretion, and half-life. In all four patients valproic acid caused an increase in the free fraction of phenytoin. Total phenytoin plasma concentrations decreased transiently in three patients and remained low throughout the study period in one patient. HPPH excretion increased transiently and then decreased, corresponding to changes in total phenytoin plasma concentrations. Biologic half-life transiently decreased in three patients (not statistically significant) and subsequently increased significantly in all four patients. The data suggest that valproic acid displaced phenytoin from protein-binding sites in all four patients and subsequently inhibited phenytoin metabolism in three patients.

Protein binding of valproic acid in uremic patients.

Protein binding of valproic acid was studied in four uremic patients on long-term hemodialysis. Before dialysis, the free fraction was 0.31 +/- 0.11 (SD); this was larger than in nonuremic subjects. During hemodialysis, the free fraction increased significantly (p less than 0.01) in three patients (mean, 0.64 +/- 0.32 SD).