Pharmacokinetics of single ascending doses of the P-glycoprotein inhibitor tariquidar in healthy subjects.

We assessed the pharmacokinetics (PK), tolerability and safety of tariquidar (TQD), a P-glycoprotein (Pgp) inhibitor, after intravenous administration of single ascending doses. Employed doses were up to 4-fold higher than in previous clinical trials in cancer patients and are capable of inhibiting Pgp at the blood-brain barrier. Fifteen male healthy volunteers were randomized to receive single intravenous doses of TQD at 4, 6 or 8 mg/kg body weight and underwent blood sampling for over 24 h. TQD concentrations were determined in plasma samples with high-performance liquid chromatography mass spectrometry. No dose-limiting toxicities of TQD were observed. The area under the plasma concentration-time curve from start until 24 h after the end of infusion was positively correlated with an administered TQD dose (r = 0.8981, p < 0.0001). Moreover, we found a positive correlation for volume of distribution at steady state (r = 0.7129, p = 0.0004) with TQD dose. Dose dependency of volume of distribution at steady state points to non-linear PK of TQD, which was in all likelihood caused by transporter saturation at high TQD doses. Acceptable safety and tolerability as well as dose-linear increases in plasma exposure support the future use of TQD at doses up to 8 mg/kg to inhibit Pgp at the human blood-brain barrier.

The third-generation P-glycoprotein inhibitor tariquidar may overcome bacterial multidrug resistance by increasing intracellular drug concentration.

OBJECTIVES: The use of efflux pump inhibitors may be a powerful strategy to overcome transporter-mediated bacterial multidrug resistance. In the present study, we set out to investigate the potency of tariquidar, a third-generation P-glycoprotein inhibitor in clinical development, for overcoming bacterial resistance towards ciprofloxacin. METHODS: Staphylococcus aureus 29213 (SA29213) and S. aureus 1199B (SA1199B), which overexpresses the multidrug transporter NorA, as well as Pseudomonas aeruginosa 27853 and Stenotrophomonas maltophilia BAA-85, which expresses SmeDEF, were exposed to ciprofloxacin in the presence and absence of tariquidar or, for comparative reasons, elacridar. Activity of both P-glycoprotein inhibitors was evaluated by determination of MICs and time-kill curves, and by quantification of uptake of ciprofloxacin into bacterial cells. RESULTS: Activity of tariquidar and elacridar was comparable for S. aureus strains, and both dose-dependently increased susceptibility towards ciprofloxacin. Highest effects were observed for SA1199B, where the addition of tariquidar resulted in a 10-fold reduction of the ciprofloxacin MIC, while no effect was observed for P. aeruginosa. For S. maltophilia, elacridar but not tariquidar improved susceptibility. Uptake of [14C]ciprofloxacin and modification of susceptibility showed significant correlations (r=0.89, P<0.0001). Tariquidar had no intrinsic activity against any strain tested. CONCLUSIONS: We conclude that tariquidar has potent inhibitory effect against certain bacterial efflux pumps in vitro. Their high activity at clinically achievable concentrations might yield this class of drugs promising for future applications in infectious diseases.

FDG uptake is a surrogate marker for defining the optimal biological dose of the mTOR inhibitor everolimus in vivo.

This study aimed to test whether [(18)F]fluoro-D-glucose (FDG) uptake of tumours measured by positron emission tomography (PET) can be used as surrogate marker to define the optimal biological dose (OBD) of mTOR inhibitors in vivo. Everolimus at 0.05, 0.5, 5 and 15 mg kg(-1) per day was administered to gastric cancer xenograft-bearing mice for 23 days and FDG uptake of tumours was measured using PET from day 1 to day 8. To provide standard comparators for FDG uptake, tumour volume, S6 protein phosphorylation, Ki-67 staining and everolimus blood levels were evaluated. Everolimus blood levels increased in a dose-dependent manner but antitumour activity of everolimus reached a plateau at doses >or=5 mg kg(-1) per day (tumour volume treated vs control (T/C): 51% for 5 mg kg(-1) per day and 57% for 15 mg kg(-1) per day). Correspondingly, doses >or=5 mg kg(-1) per day led to a significant reduction in FDG uptake of tumours. Dose escalation above 5 mg kg(-1) per day did not reduce FDG uptake any further (FDG uptake T/C: 49% for 5 mg kg(-1) per day and 52% for 15 mg kg(-1) per day). Differences in S6 protein phosphorylation and Ki-67 index reflected tumour volume and changes in FDG uptake but did not reach statistical significance. In conclusion, FDG uptake might serve as a surrogate marker for dose finding studies for mTOR inhibitors in (pre)clinical trials.

Pilot PET Study to Assess the Functional Interplay Between ABCB1 and ABCG2 at the Human Blood-Brain Barrier.

ABCB1 and ABCG2 work together at the blood-brain barrier (BBB) to limit brain distribution of dual ABCB1/ABCG2 substrates. In this pilot study we used positron emission tomography (PET) to assess brain distribution of two model ABCB1/ABCG2 substrates ([(11) C]elacridar and [(11) C]tariquidar) in healthy subjects without (c.421CC) or with (c.421CA) the ABCG2 single-nucleotide polymorphism (SNP) c.421C>A. Subjects underwent PET scans under conditions when ABCB1 and ABCG2 were functional and during ABCB1 inhibition with high-dose tariquidar. In contrast to the ABCB1-selective substrate (R)-[(11) C]verapamil, [(11) C]elacridar and [(11) C]tariquidar showed only moderate increases in brain distribution during ABCB1 inhibition. This provides evidence for a functional interplay between ABCB1 and ABCG2 at the human BBB and suggests that both ABCB1 and ABCG2 need to be inhibited to achieve substantial increases in brain distribution of dual ABCB1/ABCG2 substrates. During ABCB1 inhibition c.421CA subjects had significantly higher increases in [(11) C]tariquidar brain distribution than c.421CC subjects, pointing to impaired cerebral ABCG2 function.

Rationale for insulin management in gestational diabetes mellitus.

A prospective study was undertaken to test the hypothesis that insulin treatment in patients with gestational diabetes mellitus (GDM) with fasting plasma glucose (FPG) greater than 5.3 mM significantly reduces adverse perinatal outcome. Assigned to insulin or diet treatment based on FPG were 471 GDM women. Four factors believed to be associated with infants large for gestational age (LGA) were evaluated: FPG, overall glycemic control, maternal weight, and treatment regimen. We found that when glycemic control was optimized, the key factors related to large infants were FPG and treatment modality. In the low-FPG group (less than 5.3 mM), diet therapy achieved an incidence of 5.3% LGA. When insulin therapy was used to optimize control, an incidence of 3.5% LGA was found. Patients in the mid-FPG group (5.3-5.8 mM) had a higher increased rate of LGA (28.6%) for diet-treated versus insulin-treated women (10.3%). In addition, a fourfold increased risk for LGA was found in the diet-treated obese subjects in the mid-FPG group compared with insulin-treated obese women. Finally, treatment with insulin resulted in similar incidence of LGA within all FPG groups. We concluded that FPG greater than 5.3 mM can be the basis for initiation of insulin treatment in GDM subjects with optimization of glycemic control as the goal. This approach may contribute significantly to reduced neonatal risk and may foster a standardized method for rapid and effective assignment to treatment.

Maternal glycemic criteria for insulin therapy in gestational diabetes mellitus.

In the last decade, it has become clear that gestational diabetes is a clinical entity associated with perinatal mortality and morbidity. Thus, the attention to and management of gestational diabetes during pregnancy are mandatory. In this review, results of 58 original studies (spanning the past 20 years) addressing criteria for insulin management in gestational diabetes were assessed. The level of glycemic control and its evaluation through self-monitoring of blood glucose are the foundation for ascertaining optimal pregnancy outcome. This review addresses the criteria for insulin initiation: insulin requirements, identification of the right patient, the timing for insulin initiation, and the behavioral adjustment and compliance during insulin therapy. It is recommended that patients with fasting plasma glucose on the oral glucose tolerance test (OGTT) of < 96 mg/dl (and ideally nonobese) be assigned to diet therapy. Obese women or those with fasting plasma glucose > 95 mg/dl on the OGTT should be referred to insulin therapy in order to minimize exposure of the fetus to a hyperglycemic environment.

Scientific rationale for management of diabetes in pregnancy. Recent approaches with innovative computer-based technology.

A series of recent studies in women with gestational diabetes mellitus is reviewed. During the studies, which were designed to gain a better understanding of the etiology of perinatal morbidity, a novel means of collecting ambulatory blood glucose values was employed. Subjects used specially modified reflectance meters with onboard memories to record each value with corresponding time and date. The data were transmitted to a microcomputer and rapidly analyzed to permit effective follow-up in the study population. The system enabled the investigators to characterize metabolic control, evaluate different treatment modalities, and measure the association between glycemic control and fetal outcome. These studies indicate that patients with one elevated blood glucose value during formal glucose tolerance testings have higher blood glucose values under ambulatory conditions. Furthermore, these elevated ambulatory glucose values were significantly correlated with fetal macrosomia. Treatment regimens designed to lower verified ambulatory blood glucose measurements may help reduce fetal macrosomia in women with milder forms of gestational diabetes or in women with relative glucose intolerance without a substantial increase in severe hypoglycemia.

Primary, secondary, and tertiary prevention. Program for diabetes in pregnancy.

Over the past 2 yr the effectiveness of a program in primary, secondary, and tertiary prevention of diabetes in pregnancy was studied. The purpose of the program was to determine the degree to which preventive medicine in terms of early screening and diagnosis, rapid initiation of treatment, and close follow-up surveillance could reduce the morbidity and mortality associated with pregestational and gestational diabetes. The study compared the program in prevention with previous programs, and its results were measured against national criteria established by the Centers for Disease Control. A significant increase in early identification of gestational diabetes and a decrease in fetal and maternal complications were detected.

Ambulatory glucose profile: representation of verified self-monitored blood glucose data.

Sixty-nine individuals with diabetes (23 with type I, 15 with pregestational, and 31 with gestational) used specially modified reflectance meters containing memory chips enabling the instruments to store 440 individual blood glucose values with corresponding time and date. These data were organized into 14-day periods and then collapsed into a graphic depiction, the Ambulatory Glucose Profile (AGP), which was represented as the pattern of the 25th, 50th, and 75th percentiles of blood glucose values. These three curves illustrate the median level of control and provide an index of variability in control at each hour of a "typical day." We observed distinctive AGPs related to the variability in metabolic control and the type of diabetes. Comparisons between diagnostic groups showed consistent differences between groups, independent of level of glycemic control. Review of serial AGPs obtained for sequential 2-wk periods for 23 non-pregnant individuals with type I diabetes and 10 women with gestational diabetes revealed changes in AGP corresponding to alterations in regimen. The AGP provides a new approach to the evaluation of glycemic control, with applications to patient and physician education, clinical investigation, and individual patient care.

Use of a more physiologic oral glucose solution during testing for gestational diabetes mellitus.

A lower osmolar oral glucose solution (50 g glucose in 450 mL fluid, 0.62 mol/L) was administered in addition to the standard hyperosmolar oral glucose solution (100 g glucose in 300 mL fluid, 1.85 mol/L) for oral glucose tolerance testing 1 week apart to 102 pregnant women. The standard oral glucose solution creates delayed gastric emptying and is associated with frequent nausea and vomiting. Results using the modified, lower osmolar glucose solution, when compared to the standard hyperosmolar glucose solution showed (1) statistically equivalent glucose excursion values 30 minutes after ingestion, (2) statistically significant decreased plasma glucose values greater than or equal to 60 minutes, (3) no statistically significant difference in insulin excursion values 30 minutes after ingestion, (4) equal area under the curve for glucose at 30 minutes using either solution, and (5) a markedly decreased incidence of nausea and vomiting. These data suggest that the modified, lower osmolar glucose solution empties rapidly from the stomach and allows the glucose to be absorbed and enter the peripheral circulation in an expeditious manner.

Emotional adjustment to diagnosis and intensified treatment of gestational diabetes.

OBJECTIVE: To determine, in women having newly diagnosed gestational diabetes mellitus, the effect of intensified treatment on the patients' emotional status and the relation between metabolic control and emotional well-being. METHODS: English-speaking women with newly diagnosed gestational diabetes mellitus (N = 206) and nondiabetic controls (N = 95) were compared for maternal characteristics and test results on the Profile of Mood States-Bipolar test, a standardized Likert scale measuring mood dimensions in terms of six bipolar affective states. Women with gestational diabetes mellitus were stratified according to treatment modality (diet or insulin therapy) and level of glycemic control (good control, mean blood glucose less than 105 mg/dL; poor control, mean blood glucose 105 mg/dL or greater). Because emotional profile can be influenced by actual glucose values depicted on the memory reflectance meter, glucose determinations were categorized as hypoglycemia, normoglycemia, mild hyperglycemia, and hyperglycemia. An Average Mood Disturbance score was used to determine the relation between total mood status and categories of glucose determinations. RESULTS: There was no significant difference between women with gestational diabetes mellitus in either the diet- or insulin-managed group and nondiabetic controls on each of the subscales of the Profile of Mood States-Bipolar test. Patients with stringent glycemic control were less distressed than those having poor control. Intensified therapy (self-monitoring of blood glucose levels and liberal use of insulin) for gestational diabetes mellitus does not negatively affect patients' emotional status. Insulin therapy by multiple injection does not adversely affect mood state. Stepwise regression analysis found a significant association between Average Mood Disturbance score and the number of determinations within the normoglycemic and hyperglycemic categories, marital status, and maternal age. CONCLUSION: Intensified management of newly diagnosed gestational diabetes mellitus does not increase patient anxiety and depression. Moreover, achievement of glycemic control contributes to patient reassurance. Psychological adjustment to the temporary disease state is then equal to that of a nondiabetic individual.

Glucose tolerance test periodicity: the effect of glucose loading.

OBJECTIVE: To test the hypothesis that glucose abnormality, as shown by glucose tolerance test (GTT) periodicity, is not affected by different glucose loads, allowing for the identification of gestational diabetes mellitus (GDM) under varying glucose challenges. METHODS: Eighty subjects were tested by multiple GTTs 1 week apart. Each woman served as her own control, undergoing a standard 3-hour, 100-g GTT; then, half of the subject group randomly underwent a 50-g and the other half a 75-g, 2-hour GTT. Subjects were classified using National Diabetes Data Group thresholds for the 100-g GTT. Those with two or more abnormal values were classified as gestational diabetic (GDM group); the rest of the women were considered to be nondiabetic. The projected time for the GTT to revert to fasting value, GTT periodicity, was then determined for each glucose load in the GDM and nondiabetic groups. RESULTS: All glucose values for the nondiabetic group were significantly lower at 1 and 2 hours than those for the GDM group, regardless of the glucose load (P < .04). There was a statistically significant difference within the GDM and nondiabetic groups between glucose values of the 100- and 50-g GTTs at 1 hour (P < .02) and between all loads at 2 hours (P < .04). The GTT periodicity for the 3-hour, 100-g test was significantly longer for patients with GDM, as shown previously (5.6 +/- 1.9 versus 3.2 +/- 1.7 hours, P < .0001). In addition, similar values were found for nondiabetic and GDM subjects for the 75-g (5.1 +/- 2 versus 3.6 +/- 1.8 hours, P < .04), but not the 50-g load (2.2 +/- .6 versus 1.34 +/- .8 hours, P < .01). CONCLUSION: Glucose tolerance test periodicity will identify subjects with GDM regardless of GTT load because the physiologic disturbance of glucose level measured by this time period remains comparably longer than in normal subjects. We speculate that the relatively shorter cycle of the 50-g load may reflect an insufficient challenge to pancreatic function.

Glucose tolerance test: degree of glucose abnormality correlates with neonatal outcome.

OBJECTIVE: To determine how well the extent of glucose abnormality, as reflected by the number of abnormal values on the 3-hour oral glucose tolerance test (GTT), correlates with the level of carbohydrate intolerance during pregnancy and with the severity of adverse outcome. METHODS: We followed 764 gestational diabetic women under a once-per-week fasting and 2-hour postprandial serum glucose monitoring system. The subjects were stratified by the number of abnormal values on their GTTs. The level of glucose control and incidence of large for gestational age (LGA) infants were then determined and compared with the findings in 636 gravidas with abnormal screening but all normal GTT values. RESULTS: Patients with one or more abnormal GTT values had comparable incidences of LGA infants, which were all significantly greater than that in the 0-abnormal group (23-27% versus 13%; P < .01). This difference was due to subjects with poor glucose control. The means of the GTT values for each sampling time were greater and the GTT periodicity (the time for the GTT curve to return to the fasting level) was longer with an increasing number of GTT abnormal values (zero versus one versus two versus three versus four abnormal values, P < .02). The mean fasting, 2-hour postprandial, and overall mean glucose values during the study were positively associated with the number of abnormal GTT values. CONCLUSIONS: One or more abnormal GTT values were associated with comparably elevated incidences of LGA infants in patients with poor glycemic control. Achievement of recommended glucose control decreased adverse outcomes to near normal levels.

The effect of maternal obesity on the accuracy of fetal weight estimation.

OBJECTIVE: To determine if maternal obesity affects the accuracy of either clinical or sonographic fetal weight estimations. METHODS: In a year-long study, 998 singleton pregnancies of 26-43 weeks' gestation underwent both clinical (Leopold) and sonographic (Shepard and Hadlock) fetal weight estimation within 5 days of delivery (mean 1.1, 95% confidence interval 1.0-1.3). Patients were stratified into four different groups based on increasing maternal body mass index (BMI): underweight (less than 19.8), normal weight (19.8-26.0), overweight (26.1-29.0), and obese (more than 29.0). The various estimations of fetal weight were compared with actual birth weight, and the mean absolute percent error was calculated for each specific method and analyzed among the four BMI groups. RESULTS: For each method of weight estimation, there was no difference (specifically, no increase) in the magnitude of the absolute percent error with increasing maternal obesity. Regardless of maternal size, almost half of the weight predictions were within 5% of the actual birth weight. CONCLUSION: Increasing maternal obesity does not alter or decrease the accuracy of either clinical or sonographic fetal weight estimations. Therefore, fetal weight predictions provide equally accurate and valid guidelines for determining management decisions in women, regardless of body size.

Glucose tolerance test periodicity as a descriptor of glucose tolerance abnormality.

The periodicity of the standard 100-g glucose tolerance test (GTT) was examined in a prospective study of 194 pregnant patients to determine how well gestational diabetes could be identified. A simplified formula, the GTT periodicity, was used to estimate the time for the GTT curve to return to the fasting level. One hundred one study subjects had all normal glucose values by the National Diabetes Data Group criteria (0-abnormal group), 47 had one value greater than normal (1-abnormal group), and 46 had more than one value abnormal or gestational diabetes. The 0-abnormal patients had a significantly shorter GTT periodicity than did 1-abnormal or gestational diabetic mothers (3.6 versus 4.8 versus 6.6 hours, respectively; P less than .04). Calculating the periodicity for the corresponding insulin excursions yielded significantly increasing values in a graduated fashion for each group (5.2 versus 6.9 versus 9.6 hours, respectively; P less than .05). Examination of the oscillation of the GTT curve about the fasting level allows a physiologic description of normal and abnormal glucose responses in pregnancy. Furthermore, our findings suggest that glucose and insulin periodicities are useful predictors of gestational diabetes in patients with positive screening.

Efficiency of lower threshold criteria for the diagnosis of gestational diabetes.

OBJECTIVES: To determine the incidence of adverse outcome in normal untreated gravidas with minimal hyperglycemia, classified as having gestational diabetes mellitus (GDM) by threshold criteria lower than current standards; to determine how efficient the different criteria are in identifying infants at risk for morbidity; and to explore the pathophysiology of minimal hyperglycemia using the glucose tolerance test (GTT) periodicity concept. METHODS: Seven hundred eight subjects considered nondiabetic by current ACOG criteria were reclassified by the criteria of Coustan (fasting 95, 1 hour 180, 2 hours 155, and 5 hours 140 mg/dL), Sacks (96, 172, 152, and 131 mg/dL), or Langer (at least one abnormal ACOG value). Glucose tolerance test periodicity, the incidence of large for gestational age (LGA) neonates, and macrosomia were then determined for each gravida diagnosed as having GDM by these criteria. RESULTS: Both Coustan and Langer criteria identified a significantly greater incidence of LGA infants compared with non-GDM (23.6 and 25.3%, respectively, versus 14%, P < .05), and identified them as efficiently as current criteria, approximately one LGA infant for every four GDM subjects treated. The incidence of LGA did not differ between the Sacks GDM and non-GDM groups. Glucose tolerance test periodicity for newly diagnosed GDM gravidas was significantly longer than non-GDM for Coustan and Langer criteria (3.9 and 4.06 versus 3.3 hours, P < .01) but not for the Sacks criteria. CONCLUSION: Using lower threshold criteria to diagnose GDM identified morbidity at an incidence and efficiency comparable to current standards. These newly diagnosed GDM gravidas had abnormal GTT characteristics, with each group exceeding the 3.5-hour GTT periodicity limit previously found for nondiabetic gravidas. Sack's conversion of existing standards may be too low to efficiently identify pregnant subjects at risk for increased morbidity.

Induction of labor in the nineties: conquering the unfavorable cervix.

OBJECTIVE: To determine the efficacy, safety, and duration of induced labor using an integrative approach (prostaglandin, amniotomy, oxytocin) and to depict these findings graphically. METHODS: Five hundred ninety-seven pregnancies requiring induction of labor between October 1993 and May 1995 were analyzed prospectively. Patients were categorized by Bishop score at entry and by parity for comparison of success of induction, maternal and fetal complications, and duration of labor. RESULTS: The women who had a Bishop score at entry of 3 or less had significantly higher rates of failed induction (9.4 versus 0.7%, P < .01) and of cesarean delivery (29 versus 15.4%, P < .01) than those with a Bishop score above 3. Compared with spontaneous labor, the rates of cesarean delivery in induced labor remained significantly elevated. Complications of induction were infrequent, regardless of Bishop score. The time from initiation of induction to achievement of active phase was significantly longer in women with lower Bishop scores. CONCLUSION: Regardless of cervical status and parity, vaginal delivery can be anticipated in the majority of patients undergoing labor induction. The induction characteristics described may assist in the management of induced labor.

Group B streptococcus infection rate unchanged by gestational diabetes.

OBJECTIVE: Group B streptococcal colonization in pregnancy has been associated with adverse perinatal outcomes, including intra-amniotic infection, postpartum endometritis, and neonatal sepsis. We sought to determine whether gestational diabetes increases the risk of maternal and neonatal morbidity from group B streptococcal colonization. METHODS: Gestational diabetic and nondiabetic women who underwent vaginal or anogenital culture for group B streptococcus colonization in pregnancy were followed up for pregnancy outcome. Antibiotic prophylaxis was not routinely given. Major perinatal morbidity included intraamniotic infection, endometritis, and neonatal sepsis. Potential confounding variables included induction of labor, cesarean delivery, prematurity, maternal antibiotic use, and prolonged rupture of membranes. RESULTS: We compared 446 gestational diabetic women to 1,046 nondiabetic women for outcome. Overall, 12% were colonized with group B streptococcus, with no difference in colonization rates between gestational diabetic (12%) and nondiabetic (12%) women. There were no differences in intraamniotic infection rates between gestational diabetic and nondiabetic women, whether group B streptococcus positive (16% compared with 13%) or group B streptococcus negative (10% compared with 11%). Likewise, endometritis did not differ (6-9%) regardless of diabetes or group B streptococcus status. Neonatal sepsis was higher in group B streptococcus-positive women overall (3% compared with 1%, odds ratio 3.71, 95% confidence interval 1.23, 10.81), but did not differ between diabetic and nondiabetic pregnancies. CONCLUSION: Gestational diabetes does not alter the perinatal morbidity associated with group B streptococcal colonization in pregnancy.

Dietary therapy for gestational diabetes: how long is long enough?

OBJECTIVE: To determine the length of time required for dietary therapy alone to effect good glycemic control and whether the need for insulin treatment can be predicted at diagnosis of gestational diabetes mellitus (GDM). METHODS: Women with GDM were treated with dietary therapy for 4 weeks. Each measured her blood glucose using a memory-based reflectance glucometer, and those in poor glycemic control (mean glucose exceeding 105 mg/dL) after 4 weeks of dietary therapy were prescribed insulin. Women were stratified by fasting plasma glucose value of 3-hour glucose tolerance tests (GTTs). RESULTS: Women with fasting glucose at or below 95 mg/dL were significantly more likely to achieve good glycemic control after 2 weeks of dietary therapy than were those with values above 95 mg/dL whose control did not improve during the study. Receiver operating characteristic (ROC) analysis determined that fasting values of GTT between 91 and 95 mg/dL best predicted that insulin would be needed for good glycemic control. CONCLUSION: Women with GDM should be prescribed dietary therapy alone for at least 2 weeks before they are prescribed insulin. In those with fasting glucose above 95 mg/dL, insulin may be prescribed after 1 week of dietary therapy, or at diagnosis.

Changes in the pattern of uterine contractility in relationship to coitus during pregnancies at low and high risk for preterm labor.

This is a preliminary, prospective study of uterine contractility in response to sexual intercourse. The study population consisted of 30 pregnant subjects. Group I included 15 women treated for an episode of preterm labor with intravenous and oral tocolysis in this pregnancy, and group II was a matched control group of low-risk volunteers. The availability of home uterine tocodynamometric systems permitted monitoring of uterine contractility for three 60-minute time periods related to coitus. A significant increase in uterine contractility in the immediate postcoital period was observed for the high-risk women, but not for the controls. This increased uterine activity subsided spontaneously within 2-3 hours, returning to baseline. These initial preliminary observations of uterine response to coitus in a home environment are interesting; however, further research is suggested to establish their clinical implications.