Semisolid Enteral Nutrients Alter the Pharmacokinetics of Orally Administered Levetiracetam in Rats.

Enteral nutrients (ENs) affect the plasma drug concentration of orally co-administered drugs, particularly those of antiepileptic drugs, such as phenytoin and carbamazepine. However, few studies have reported the interactions of levetiracetam (LEV), an upcoming antiepileptic drug, with ENs. In this study we aimed to investigate the pharmacokinetics of LEV in 55 rats after oral co-administration of LEV with liquid or semisolid ENs. Compared with the control group, co-administration with Terumeal ® Soft significantly decreased the plasma LEV concentration at 0.5, 1, and 2 h and area under the plasma concentration-time curve from 0 to 3 h (AUC0→3h) (P < 0.01). However, the AUC0→3h of LEV remained unchanged following the administration of Terumeal ® Soft 2 h after the initial LEV administration. Moreover, co-administration with semisolid Racol® NF delayed the absorption of LEV without decreasing the AUC0→3h, whereas liquid Racol ® NF did not alter LEV pharmacokinetics. Thus, co-administration of LEV with Terumeal® Soft reduced the absorption of LEV from the gastrointestinal tract, which was prevented by administering Terumeal ® Soft 2 h after LEV administration. Semisolid Racol ® NF altered LEV pharmacokinetics without decreasing its gastrointestinal absorption. Our findings suggested that careful monitoring of the plasma LEV levels is necessary when co-administering LEV with Terumeal ® Soft, semisolid Racol ® NF, or any other semisolid ENs, to prevent the inadvertent effects of the interaction between LEV and ENs.

Interaction between phenytoin and enteral nutrients and its influence on gastrointestinal absorption.

The gastrointestinal absorption of phenytoin (PHT), an antiepileptic drug, is often affected by its interaction with co-administered enteral nutrients through a nasogastric (NG) tube, resulting in decreased plasma PHT concentration. In this study, we measured the recovery rate (%) of PHT (Aleviatin® powder) passed through an NG tube when co-administered with distilled water or enteral nutrients (F2α®, Racol® NF, Ensure Liquid® and Renalen® LP). We also measured plasma PHT levels in rats, after oral co-administration of PHT with enteral nutrients. We demonstrate that PHT recovery rate was close to 100 % in all cases after passage through the NG tube. In the rat study, the AUC0→∞ of PHT concentration after oral administration significantly decreased when it was co-administered with F2α® and Racol® NF compared to distilled water. However, the AUC0→∞ of PHT was unchanged when co-administered with F2α® 2 h after initial PHT administration. We therefore conclude that the co-administration of PHT with F2α® and Racol® NF caused a reduction in the absorption of PHT from the gastrointestinal tract to the blood, without adsorption to the NG tube. The administration of enteral nutrients 2 h after PHT is one clear way to prevent a decrease in plasma PHT concentration.

FOLFIRI plus bevacizumab as second-line therapy in patients with metastatic colorectal cancer after first-line bevacizumab plus oxaliplatin-based therapy: the randomized phase III EAGLE study.

BACKGROUND: A targeted agent combined with chemotherapy is the standard treatment in patients with metastatic colorectal cancer (mCRC). The present phase III study was conducted to compare two doses of bevacizumab combined with irinotecan, 5-fluorouracil/leucovorin (FOLFIRI) in the second-line setting after first-line therapy with bevacizumab plus oxaliplatin-based therapy. PATIENTS AND METHODS: Patients were randomly assigned to receive FOLFIRI plus bevacizumab 5 or 10 mg/kg in 2-week cycles until disease progression. The primary end point was progression-free survival (PFS), and secondary end points included overall survival (OS), time to treatment failure (TTF), and safety. RESULTS: Three hundred and eighty-seven patients were randomized between September 2009 and January 2012 from 100 institutions in Japan. Baseline patient characteristics were well balanced between the two groups. Efficacy was evaluated in 369 patients (5 mg/kg, n = 181 and 10 mg/kg, n = 188). Safety was evaluated in 365 patients (5 mg/kg, n = 180 and 10 mg/kg, n = 185). The median PFS was 6.1 versus 6.4 months (hazard ratio, 0.95; 95% confidence interval [CI] 0.75-1.21; P = 0.676), and median TTF was 5.2 versus 5.2 months (hazard ratio, 1.01; 95% CI 0.81-1.25; P = 0.967), respectively, for the bevacizumab 5 and 10 mg/kg groups. Follow-up of OS is currently ongoing. Adverse events, including hypertension and hemorrhage, occurred at similar rates in both groups. CONCLUSION: Bevacizumab 10 mg/kg plus FOLFIRI as the second-line treatment did not prolong PFS compared with bevacizumab 5 mg/kg plus FOLFIRI in patients with mCRC. If bevacizumab is continued after first-line therapy in mCRC, a dose of 5 mg/kg is appropriate for use as second-line treatment. CLINICAL TRIAL IDENTIFIER: UMIN000002557.

Genetic mechanisms of age regulation of human blood coagulation factor IX.

Blood coagulation capacity increases with age in healthy individuals. Through extensive longitudinal analyses of human factor IX gene expression in transgenic mice, two essential age-regulatory elements, AE5' and AE3', have been identified. These elements are required and together are sufficient for normal age regulation of factor IX expression. AE5', a PEA-3 related element present in the 5' upstream region of the gene encoding factor IX, is responsible for age-stable expression of the gene. AE3', in the middle of the 3' untranslated region, is responsible for age-associated elevation in messenger RNA levels. In a concerted manner, AE5' and AE3' recapitulate natural patterns of the advancing age-associated increase in factor IX gene expression.

Activation of human factor IX (Christmas factor).

Human Factor IX (Christmas factor) is a single-chain plasma glycoprotein (mol wt 57,000) that participates in the middle phase of the intrinsic pathway of blood coagulation. It is present in plasma as a zymogen and is converted to a serine protease, Factor IXabeta, by Factor XIa (activated plasma thromboplastin antecedent) in the presence of calcium ions. In the activation reaction, two internal peptide bonds are hydrolyzed in Factor IX. These cleavages occur at a specific arginyl-alanine peptide bond and a specific arginyl-valine peptide bond. This results in the release of an activation peptide (mol wt approximately equal to 11,000) from the internal region of the precursor molecule and the generation of Factor IXabeta (mol wt approximately equal to 46,000). Factor IXabeta is composed of a light chain (mol wt approximately equal to 18,000) and a heavy chain (mol wt approximately equal to 28,000), and these chains are held together by a disulfide bond(s). The light chain originates from the amino terminal portion of the precursor molecule and has an amino terminal sequence of Tyr-Asn-Ser-Gly-Lys. The heavy chain originates from the carboxyl terminal region of the precursor molecule and contains an amino terminal sequence of Val-Val-Gly-Gly-Glu. The heavy chain of Factor IXabeta also contains the active site sequence of Phe-Cys-Ala-Gly-Phe-His-Glu-Gly-Arg-Asp-Ser-Cys-Gln-Gly-Asp-SER-Gly-Gly-Pro. The active site serine residue is shown in capital letters. Factor IX is also converted to Factor IXaalpha by a protease from Russell's viper venom. This activation reaction, however, occurs in a single step and involves only the cleavage of the internal arginyl-valine peptide bond. Human Factor IXabeta was inhibited by human antithrombin III by the formation of a one-to-one complex of enzyme and inhibitor. In this reaction, the inhibitor was tightly bound to the heavy chain of the enzyme. These data indicate that the mechanism of activation of human Factor IX and its inhibition by antithrombin III is essentially identical to that previously shown for bovine Factor IX.

An intragenic deletion of the factor IX gene in a family with hemophilia B.

A family of seven patients severely afflicted with hemophilia B has been studied for their factor IX genes through the use of factor IX cDNA and genomic DNA probes. The patients had detectable (less than 10% of normal) factor IX antigen in urine and no detectable inhibitors in sera to factor IX protein. Based on the DNA hybridization analysis, these patients showed a partial intragenic deletion in their factor IX gene. The deletion included two exons (exons V and VI) coding for the amino acid sequence from number 85 to 195 of the factor IX protein. The deleted portion of the gene contained the entire factor IX activation peptide. The length of the deletion was estimated to be 10 +/- 0.3 kilobase pairs. This specific gene has been named FIXSeattle. In this family both the deletion and a Taq 1 restriction fragment length polymorphism can be used as a useful marker for accurate detection of female carriers of the deficient factor IX gene.

The PHSRN sequence induces extracellular matrix invasion and accelerates wound healing in obese diabetic mice.

The PHSRN sequence of the plasma fibronectin (pFn) cell-binding domain induces human keratinocytes and fibroblasts to invade the naturally serum-free extracellular matrices of sea urchin embryos. The potency of acetylated, amidated PHSRN (Ac-PHSRN-NH(2)) is significantly increased, making it more active on a molar basis than the 120-kDa cell-binding domain of pFn. Arginine is important to this activity because PHSAN and PHSEN are inactive, as is a randomized sequence peptide, Ac-HSPNR-NH(2). One treatment with Ac-PHSRN-NH(2) stimulates reepithelialization and contraction of dermal wounds in healing-impaired, obese diabetic C57BL6/KsJ db/db mice. Wound closure is equally rapid in treated db/db and db/+ mice and may be more rapid than in untreated nondiabetic db/+ littermates. In contrast, treatment with either Ac-HSPNR-NH(2) or normal saline (NS) has no effect. Analysis of sectioned db/db wounds shows that, in contrast to treatment with Ac-HSPNR-NH(2) or NS, a single Ac-PHSRN-NH(2) treatment stimulates keratinocyte and fibroblast migration into wounds, enhances fibroplasia and vascularization in the provisional matrix, and stimulates the formation of prominent fibers that may be associated with wound contraction.

Anti-invasive, antitumorigenic, and antimetastatic activities of the PHSCN sequence in prostate carcinoma.

Using naturally serum-free SU-ECM basement membranes as invasion substrates showed that plasma fibronectin was necessary to stimulate invasion by DU 145 human and metastatic MATLyLu (MLL) rat prostate carcinoma cells. This activity mapped to the PHSRN sequence, which induced invasion through alpha5beta1 integrin. PHSCN, a competitive inhibitor, blocked both PHSRN- and serum-induced invasion. Acetylated, amidated PHSCN (Ac-PHSCN-NH2) was 30-fold more potent; however, Ac-HSPNC-NH2 was inactive. Rats receiving injections s.c. with 100,000 MLL cells were treated systemically by i.v. injection three times weekly with 1 mg of either Ac-PHSCN-NH2 or Ac-HSPNC-NH2 beginning 24 h later, three times weekly with 1 mg of Ac-PHSCN-NH2 beginning only after surgery to remove large (2 cm) MLL tumors, or were left untreated. MLL tumors grew rapidly in Ac-HSPNC-NH2-treated and in untreated rats. MLL tumor growth in rats treated with Ac-PHSCN-NH2 beginning 1 day after MLL cell injection was reduced by 99.9% during the first 16 days of treatment, although subsequent tumor growth occurred. MLL tumor cryosections immunostained with anti-PECAM-1 showed that Ac-PHSCN-NH2 inhibited neovascularization by 12-fold during this time. Whether initiated after MLL cell injection or only after MLL tumor removal, Ac-PHSCN-NH2 treatment reduced the numbers of MLL lung colonies and micrometastases by 40- to >100-fold, whereas Ac-HSPNC-NH2 was inactive. Thus, Ac-PHSCN-NH2 may be a potent antitumorigenic and antimetastatic agent for postsurgical use prior to extensive metastasis.

The major component of a large, intracellular proteinase accumulated by inhibitors is a complex of alpha 2-macroglobulin and thrombin.

A large, intracellular proteinase accumulated by inhibitors (PABI) was found in cultured mammalian cells as a large, multicatalytic proteinase with a greatly elevated concentration in the presence of small peptide proteinase inhibitors (Tsuji and Kurachi (1989) J. Biol. Chem. 264, 16093). Electron microscopic analysis showed that the tertiary structure of PABI highly resembled that of alpha 2-macroglobulin complexed with a proteinase(s). Isolation of the anti-PABI cross-reacting material from calf serum added to the culture media of baby hamster kidney cells further supported that the primary component of PABI was alpha 2-macroglobulin. Immunoblot analyses and the substrate specificity of PABI indicated that the major proteinase component contained in PABI was thrombin. When alpha 2-macroglobulin was added to the PABI-depleted serum, a significant accumulation or a degradation of the intracellular alpha 2-macroglobulin was observed in the presence or absence of leupeptin, respectively. Similarly, when thrombin was added to the PABI-depleted fetal calf serum supplemented with fresh alpha 2-macroglobulin, a significant amount of intracellular thrombin was found only in the presence of leupeptin. These results indicate that the major component of the intracellular PABI molecules is a complex of alpha 2-macroglobulin with thrombin which is internalized from the culture media. Intracellular accumulation of PABI, therefore, is a phenomenon primarily relevant to the culture cells. Whether or not PABI is also generated in certain physiological or pathological conditions requires further study.

Construction of human factor IX expression vectors in retroviral vector frames optimized for muscle cells.

Development of a highly refined human factor IX (hFIX) expression vector system is critical for establishing a durable hemophilia B gene therapy. Here we report construction of a series of retroviral vectors and identification of an optimal basic structure and components for expressing hFIX in skeletal muscle cells. These vectors, which are derived from Moloney murine leukemia virus (MoMLV) with its enhancer sequence in the 3' long terminal repeat (LTR) deleted, contained internal hFIX expression units inserted in forward configuration without or with a viral vector intron sequence (pdL or pdLIn vector frame, respectively) or in inverted configuration without a viral vector intron sequence (pdLi frame). Internal expression units contained a hFIX cDNA or hFIX minigene (hIXm1 or hIXm2) derived from the hFIX cDNA by insertion of a shortened first intron sequence of the hFIX gene. Regardless of the promoter and vector frame used, both hIXm1 and hIXm2 gave 10- to 14-fold higher hFIX expression compared to those with hFIX cDNA. Internal hFIX transcriptional control units of these vectors were composed of various promoters linked with or without the muscle creatine kinase enhancer (Me) sequence. Promoters tested included those of alpha-actin (alpha A775), beta-actin (beta A280), cytochrome oxidase (CO1250 and CO650), myogenin (Mg1031 and Mg353), and Rous sarcoma virus (RSV). beta A200, which was derived from beta A280 by eliminating potential polyadenylation sites, was also tested. As extensively examined with the myogenin promoter, presence of one or multiple copies of Me in the vectors elevated the expression activity in myotubes by 4.5- to 19-fold over those without Me, but not significantly in myoblasts. Similar enhancements in expression activity with Me were also observed with other promoters, except those of RSV and CO. The latter two showed only modest enhancements in the presence of Me. As assayed with myotubes in culture, the general order of hFIX expression activity of various promoters with four copies of Me in the three different vector frames was beta A280 approximately beta A200 > Mg353 > Mg1031 approximately RSV approximately CO650 approximately alpha A775 > CO1250. One exception was that CO650 showed significantly less activity in pdLi-type vectors than in the pdLIn vectors. Based on the systematic analyses of various structural components, a group of pdLi vectors consisting of beta A200, two to four copies of Me, and hIXm2 was identified to have the optimal basic vector structure to be used in retrovirus for hFIX expression in differentiated skeletal muscle cells. The present studies provide the critical first step for establishing a highly refined hemophilia B gene therapy based on skeletal muscle-targeted hFIX gene transfer.

Loss of expression of a retrovirus-transduced gene in human keratinocytes.

Retroviral-mediated transfer of new genetic information into keratinocytes is a key step in epidermal gene therapy. An obstacle to the use of retroviruses for gene therapy is that although high levels of expression of the transduced gene can be maintained in tissue culture, expression is often lost when the cells are transplanted to an animal host. To examine some of the factors involved in this instability of expression, we transduced keratinocytes with a retrovirus encoding the gene for human factor IX and monitored secretion of the transduced gene. We observed continued secretion of factor IX through five passages in culture. When, however, sheets of these cells were grafted to athymic mice, factor IX expression was reduced or lost within 6 wk. We show that the reduction of factor IX expression in grafted keratinocytes did not result from a loss of grafted cells, nor was there a block to systemic delivery of a secreted endogenous product.

Formation of 5alpha-reduced C19-steroids from progesterone in vitro by a pathway through 5alpha-reduced C21-steroids in ovaries of late prepubertal rats.

Ovarian homogenates from 10-150-day-old rats were incubated with [3H]progesterone and NADPH. Also, ovarian homogenates from 28-day-old rats were incubated for 5-180 min with either [14C]progesterone, [3H]5alpha-pregnane-3,20-dione or [14C]progesterone plus [3H]5alpha-pregnane-3,20-dione. Following incubation, radioactive metabolites were isolated, identified, and measured by column and paper chromatography, with derivative formation and recrystallizations to constant specific activity. Prepubertal ovaries (10, 20, and 28 days of age) converted 15-60% of progesterone to C21-17-hydroxysteroids and C19-steroids. At 40 and 150 days of age (postpubertal), the formation of these steroids decreased to less than 2%. At 10 and 150 days of age, the major C19-steroids formed from progesterone were androstenedione and testosterone. At 20 and 28 days of age, however, no accumulation of these C19-delta4-3ketosteroids was found (less than 0.1% of each), at which time the conversion of progesterone to 5alpha-reduced C19-steriods, such as androsterone and 5alpha-androstane-3alpha,17beta-diol, reached 30%. In ovaries of 28-day-old rats, the results from incubation studies for the detection of metabolic pathways indicated two biosynthetic pathways leading to 5alpha-reduced C19-steroids, one from progesterone via 5alpha-reduced C21 steroids, such as 3alpha-hydroxy-5alpha-pregnan-20-one and 3alpha,17alpha-dihydroxy-5alpha-pregnan-20-one, and a second via 17-hydroxyprogesterone, androstenedione, and testosterone. It seems that the active 5alpha-reduction of C19-delta4-3-ketosteroids and the formation of 5alpha-reduced C19-steroids by the pathway through 5alpha-reduced C21-steroids, are present in the ovaries of older prepubertal rats and may be the biological significance.

Suppression of luteinizing hormone in castrated women by the administration of human chorionic gonadotropin.

The suppressive effect of human chorionic gonadotropin (hCG) on luteinizing hormone (LH) and/or LH-beta was studied by specific LH-beta radioimmunoassay following hCG administration. Eight castrated women were each administered 10,000 IU of hCG in a single intramuscular injection and five women in the control group were injected with saline. The serum level of hCG increased after the injection, reaching 217.6 mIU/ml after 8 h. There was a significant suppression of LH levels as compared to those of the control group and the pre-injection levels: 68.2% 1 h after injection, 64.7% after 2h, 65.5% after 4 h, 77.0% after 8 h, 78.6% after 12 h, and 78.2% after 24 h. There was no significant suppression of the follicle-stimulating hormone (FSH) as compared to the preinjection and control values. Serum concentration of estradiol1 was not detectable either before or after the hCG injection. We conclude that hCG has a suppressive effect on LH and/or LH-beta secretion not mediated by estradiol.

Influence of surgical stress under general anesthesia on serum gonadotropin levels in male and female patients.

Effects of surgical stress under the same general anesthesia (nitrous oxide, oxygen and halothane following induction with thiopental and succinylcholine chloride) on serum LH levels were studied in 18 postmenopausal females, 15 menstruating females and 17 males. In addition, serum FSH levels in female patients and testosterone levels in male patients were estimated. As controls without surgery and anesthesia, serum levels of LH, FSH and testosterone were estimated at identical time intervals to the experimental group in 15 normal postmenopausal females, 15 normal menstruating females and 10 normal males. In male patients, serum LH levels at 30 min and 1 hr after onset of anesthesia increased significantly over those of pre-anesthesia, while no significant intra-operative increase in LH levels was found in female patients. In male and female patients, the LH levels decreased slightly 5-6h and 2 days after onset of anesthesia, though the decreases were not statistically significant except in postmenopausal females. On the 7th postoperative day, the LH levels returned toward the baseline. In female patients, no significant intra-operative changes in FSH levels were found. In male patients, there were significant intra- and post-operative decreases in testosterone levels. In control subjects, no significant changes in serum levels of LH, FSH and testosterone were demonstrated. These observations suggest that significant intraoperative increases in serum LH levels occur in males but not in females.

Effect of triiodothyronine treatment on prolactin secretion in patients with amenorrhea-galactorrhea.

In order to determine the role of thyroid hormone in prolactin (PRL) secretion in patients with amenorrhea-galactorrhae, PRL response to 500 mug of iv thyrotropin-releasing hormone (TRH) was studied before and after the administration of triiodothyronine (T3) in 10 patients with amenorrhea-galactorrhea. Seven of these patients were euthyroid and the other 3 had hypothyroidism. The patients in the euthyroid group received 50 mug of T3 daily for 7 days and 75 mug q.d. for the ensuing 14 days. The hypothyroid patients received T3 at progressively increasing doses from 10 mug q.d. to 75 mug q.d. during 34 to 68 days. In the initial test, the elevated basal levels of PRL, 61.9 +/- 9.8 ng/ml (Mean +/- SE) exhibited a slight but insignificant net increase (7.7 +/- 2.1 ng/ml) after TRH injection in the euthyroid group. However, a marked response to TRH with a net increase of 147.2 +/- 26.3 ng/ml from the basal level of 47.3 +/- 11.2 ng/ml was observed in the hypothyroid patients. After treatment with T3, both the basal level (56.9 +/- 8.3 ng/ml) and the net increase (9.9 +/- 3.6 ng/ml) of PRL following TRH stimulation remained virtually unchanged in the euthyroid group. The hypothyroid group, in contrast, displayed a significant depression of both the basal level (26.1 +/- 13.0 ng/ml) and the net increase (33.8 +/- 6.5 ng/ml) of PRL to TRH stimulation. The diminution of the basal levels and responses of thyroid-stimulating hormone (TSH) to TRH stimulation was observed in all cases of both groups. These results suggest that the level of thyroid hormone has little pathogenic role in PRL secretion in euthyroid patients with amenorrhea-galactorrhea, in contrast to its marked effect in hypothyroid patients with amenorrhea-galactorrhea.

Clinical and endocrinological analyses of patients with galactorrhea and menstrual disorders due to sulpiride or metoclopramide.

The clinical courses of galactorrhea and menstrual disorders were studied in 18 women with galactorrhea induced by sulpiride (SLP) or metoclopramide (MCP) given for the treatment of gastrointestinal diseases. The response of PRL and TSH to 500 micrograms iv TRH and the response of LH and FSH to 100 micrograms LRH were assessed by retrospective analysis during treatment in nine patients (six, SLP; three, MCP) and shortly after the end of treatment in nine patients (seven, SLP; two, MCP). The average time from the initiation of treatment to the onset of galactorrhea was 27.2 +/- 4.7 (mean +/- SE) days in the 13 SLP-treated patients and 23.2 +/- 5.8 days in the 5 MCP-treated patients. Five of the SLP-treated patients experienced amenorrhea, four had oligomenorrhea, and one had dysfunctional bleeding. In the MCP-treated patients, oligomenorrhea and dysfunctional bleeding occurred in one each. The average length of time from the end of treatment to disappearance of galactorrhea was 50.0 +/- 7.3 days in the SLP-treated patients and 56.6 +/- 12.1 days in the MCP-treated patients. Cyclic uterine bleeding returned within 2 months after treatment was stopped. Elevated PRL levels with good response to TRH were observed in four of six patients during SLP treatment, and in two of three patients during MCP treatment. Basal PRL levels and response to TRH were normal in almost all patients after the drugs were withdrawn. Normal HL and FSH levels with exaggerated responses of LH to LRH were observed in most patients during treatment, whereas the response of LH to LRH was normal in about half of the patients after treatment. Our findings suggest that hyperprolactinemia in patients treated with SLP or MCP may be in part the cause of both galactorrhea and menstrual abnormalities, and that these symptoms can be reversed by stopping treatment, provided the patients have not taken the drugs for longer than a year.

Increase in plasma thyrotropin-releasing hormone in normal human pregnancy.

Maternal thyroid regulation in pregnancy was examined by measuring the concentrations of TRH, T4, T3, free T4 (by RIA), T4-binding globulin, TSH, PRL, and hCG in the sera of 30 normal pregnant women, 10 puerperally lactating women, and 10 normal pregnant women, 10 puerperally lactating women, and 10 normal nonpregnant female controls. Results showed that serum T4, T3, T4-binding globulin, PRL, and hCG, but not free T4 (by RIA), increased significantly during pregnancy. The plasma level of TRH was significantly higher (P less than 0.01) in the second trimester and significantly lower (P less than 0.05 1 month post partum than those values in nonpregnant controls. No significant correlations, however, were observed between the serum level of TRH and those of the thyroid hormones TSH, PRL, and hCG in pregnancy. The TRH-degrading activity of the plasma in the second trimester was normal. These results indicate that TRH secretion may be increased in the second trimester of pregnancy.

Aggravation of thyrotoxicosis in early pregnancy and after delivery in Graves' disease.

The effect of pregnancy on the clinical course of Graves' disease was examined by studies on 41 pregnancies in 35 patients with Graves' disease, who were considered to be in a state of remission or near remission and were not receiving antithyroid drugs, during and after delivery. Eighteen of the 41 cases (44%) showed transient increases in the serum free T4 index (FT4 index) during weeks 10--15 of pregnancy, but normal thyroid function in the second and third trimesters. Similar transient increases in the serum free T3 index (FT3 index) were observed in early pregnancy in these patients. These early increases in the FT4 and FT3 indexes were specific to Graves' disease and were not observed in Hashimoto's disease. Two to 4 months postpartum, 32 cases (78%) developed various degrees of thyrotoxicosis, which was divided into 3 types: 1) persistent thyrotoxicosis with high radioactive iodine (RAIU) (10 cases), 2) transient thyrotoxicosis with normal or high RAIU) (10 cases), and 3) destruction-induced thyrotoxicosis with low RAIU (12 cases). An increase in the FT4 index in early pregnancy was significantly (P less than 0.001) associated with relapse of stimulation-induced thyrotoxicosis of either the persistent or transient type. Patients who developed destruction-induced thyrotoxicosis after delivery had significantly higher titers of antithyroid microsomal antibodies (P less than 0.001) and a longer euthyroid period before pregnancy (P less than 0.01) than patients who had recurrent persistent thyrotoxicosis. These data indicate that Graves' disease is aggravated in early pregnancy and after delivery and ameliorates in the latter half of pregnancy. Postpartum relapse of persistent hyperthyroidism could be predicted from an early increase in the FT4 index during pregnancy.

Augmentation of puerperal lactation by oral administration of sulpiride.

The effect of oral administration of sulpiride on PRL secretion and initiation of puerperal lactation was studied in 130 randomly selected primiparous nursing mothers. Sixty-six women were given 50 mg sulpiride orally twice a day during the first 7 days of the puerperium (sulpiride group). Sixty-four women were given a placebo in the same way (control group). The mean (+/-SE) total milk yield during the first 5 postpartum days in the sulpiride group (1211.7 +/- 65.0 ml) was significantly greater than that in the control group (916.0 +/- 66.0 ml). Every other day determinations of serum PRL levels revealed significantly higher concentrations in the sulpiride group than in the control group. A single oral dose of 50 mg sulpiride raised serum PRL levels for 12 h, with a peak level at 2 h after dosing in 7 women on the second postpartum day. These data suggest that sulpiride given orally promotes the initiation of lactation in puerperal women by stimulating PRL secretion.

Treatment of carcinoma of the uterine cervix by remotely controlled afterloading intracavitary radiotherapy with high-dose rate: a comparative study with a low-dose rate system.

From September, 1974 through December, 1979, a total of 249 patients with carcinoma of the cervix uteri Stage IIb and III were randomly allocated to either remotely controlled high-dose-rate intracavitary radiotherapy or manual afterloading low-dose-rate therapy, with radiotherapy of 20 Gy in 2 weeks to Point A to whole pelvis and 40 Gy in 4 weeks to the parametria. The dose to Point A by intracavitary radiotherapy was 40-60 Gy with one or two fractions in the low-dose-rate group and 30 Gy for the high-dose-rate group by 3 fractions with a once a week schedule. The purpose of this paper is to compare the results between the groups and to clarify the problems in the high-dose-rate group clinically. The local control rate was higher in the high-dose-rate group; however, the complication rate was also higher in this group than in the low-dose-rate group. The dose schedule and the place of rectal dose measurement is discussed. The overall cumulative survival rate was nearly the same in both groups (55% at 5 years), although some difference was noted in each stage. The most common cause of death was distant metastasis outside the pelvis and the second most common was intercurrent disease in Stage IIb and local failure in Stage III.