The effect of dose escalation for large squamous cell carcinomas of the anal canal.

PURPOSE: Chemoradiation allows for organ preservation in patients with anal cancer, but patients with large tumors (> 5 cm) have elevated rates of locoregional recurrence. With conformal radiation techniques, there is interest in dose escalation to decrease local recurrence in patients with large tumor size. METHODS/PATIENTS: The National Cancer Database (NCDB) was used to identify patients with anal cancer from 2004 to 2013 with tumors > 5 cm. Adult patients who received definitive chemoradiation were included. Patients with prior resection were excluded. High dose was defined as greater than or equal to 5940 cGy. Statistical analyses were performed using logistic regression, Kaplan-Meier, and Cox proportional hazards for overall survival (OS). RESULTS: In total, 1349 patients were analyzed with 412 (30.5%) receiving high-dose radiation therapy (RT). 5-year OS was 58 and 60% for high and standard dose RT, respectively (p = 0.9887). On univariate analysis, high-dose RT was not associated with improved OS (HR = 0.998, CI 0.805-1.239, p = 0.9887). On multivariate analysis, high-dose RT (HR = 0.948, CI 0.757-1.187, p = 0.6420) was not associated with improved OS but older age (HR = 1.535, CI 1.233-1.911, p = 0.0001), male sex (HR = 1.695, CI 1.382-2.080, p < 0.0001), comorbidities (HR = 1.389, CI 1.097-1.759, p = 0.0064), and long RT (HR = 1.299, CI 1.047-1.611, p = 0.0173) were significantly associated with decreased OS. CONCLUSIONS: There was no observed difference in OS for dose escalation of anal cancers > 5 cm in this population-based analysis. Differences in local control and salvage therapy cannot be assessed through the NCDB. Whether dose escalation of large tumors may improve local control and colostomy-free survival remains an important question and is the subject of ongoing trials.

Hemostatic status and fibrinolytic response potential at different phases of the menstrual cycle.

Coagulation and fibrinolytic variables including platelet function and endogenous fibrinolytic response were determined in 30 normal healthy women volunteers not on any known medication during the period of study. They were between 18 years and 38 years old and had normal menstrual cycles of between 28 days and 30 days. Blood samples were obtained within one menstrual cycle and after having fasted overnight within days 1 to 3 (menstruation), 5 to 9 (follicular), 10 to 14 (mid-cycle), and 21 to 26 (luteal) of the menstrual cycle. Analysis of variance (ANOVA) showed no significant differences in the hemostatic parameters studied between the phases of the menstrual cycle except for a reduced D-dimer level at midcycle. Significant fibrinolytic response was seen after venous occlusion but they were not significantly different between the phases of the menstrual cycle. The women were then divided into either normal weight (n=22) or overweight (n=8) according to World Health Organization (WHO) classification and the data reanalyzed. Elevated tissue plasminogen activator antigen and plasminogen activator inhibitor-1 levels except at menstruation and total protein S except at follicular phase were observed in overweight women together with increased plasminogen level only at luteal phase. Significant endogenous fibrinolytic response seen during the menstrual cycle was not different between normal and overweight women. The study demonstrated that systemic coagulation, fibrinolysis, and platelet function were probably not influenced by natural hormonal changes occurring during the menstrual cycle except for an associated reduced fibrinolytic state at mid-cycle. The hemostatic system in this small group of healthy overweight women studied appeared to be physiologically compromised.

Modification of the 5' position of purine nucleosides. 1. Synthesis and biological properties of alkyladenosine-5'-carboxylates.

A series of esters of adenosine-5'-carboxylic acid has been prepared. Most of the compounds were nontoxic, causing prolonged increases in coronary sinus PO2 when administered to anesthetized dogs; the ethyl ester was most active. Nitrosation and oxidation of the ethyl ester 12 gave respectively inactive inosine ethyl ester 30 and the fairly active N1-oxide ethyl ester 29.

Modification of the 5' position of purine nucleosides. 2. Synthesis and some cardiovascular properties of adenosine-5'-(N-substituted)carboxamides.

We have shown previously that the esters of adenosine-5'-carboxylic acid (10) represent a new class of potent nontoxic coronary vasodilators. For example, the ethyl ester (12), which is active by an intraduodenal or intravenous route in dogs, causes a large increase in coronary sinus PO2 and coronary blood flow. Because of the pronounced vasoactive properties of the esters of adenosine-5'-carboxylic acid, a systematic study of the corresponding amides (14--50) was undertaken. In addition, several other analogues containing the N1-oxide function (51--52) or 2',3' substituents (3--9, 53--54) were studied.

Cardiovascular effects of nucleoside analogs.

Short-chain aliphatic esters and amides of adenosine-5'-carboxylic acid caused marked increases in coronary sinus oxygen tension (PO2) in the dog; the amides were generally more potent, causing additionally marked hypotension and tachycardia. The hypotensive effect was observed also in the spontaneously hypertensive rat. That the increase in coronary sinus PO2 paralleled an increase in coronary flow was verified with ethyl adenosine-5'-carboxylate hydrochloride. This compound also increased the reactive hyperemic response. Aminophylline blocked the increase in coronary flow. A representative amide and ester were very poor substrates for adenosine and adenylate deaminase in vitro; the amide exhibited a weak inhibitor effect on the enzymic activities while the ester was inactive. The observations that the compounds (1) cause marked pharmacological effects within seconds after intravenous administration, (2) are blocked by aminophylline like adenosine, (3) are not deaminated significantly in vitro by either adenosine or adenylate deaminase, and (4) cannot be phosphorylated at the 5' terminus because the 5'-OH has been removed chemically, support the hypothesis that they are acting directly on an "adenosine receptor" and have a prolonged duration of action because they are not metabolized significantly by the normal physiological pathways of adenosine degradation.

Evacuation interval after vaginal misoprostol for preabortion cervical priming: a randomized trial.

OBJECTIVE: To determine the optimal interval for evacuation after preabortion cervical priming with vaginal misoprostol. METHODS: One hundred eighty healthy nulliparas requesting legal termination of pregnancy between 6 and 11 weeks' gestation were assigned randomly to receive 400, 600, or 800 microg of intravaginal misoprostol. Vacuum aspiration was done after 3 hours in the 400-microg group and after 2 hours in the 600- and 800-microg groups. The degree of cervical dilatation before operation was measured with a Hegar dilator. Preoperative and intraoperative blood loss and associated side effects were also assessed. RESULTS: Eleven (18.3%) and 15 (25.0%) women in the 600-and 800-microg groups, respectively, had cervical dilatation of at least 8 mm after an interval of 2 hours; 55 (91.7%) women who received 400 microg for a 3-hour interval had similar cervical dilatation. Using 400 microg as a baseline, the odds ratio (OR) was 0.02; 95% confidence interval (CI) was 0.01, 0.06 for 600 microg and OR 0.03; 95% CI 0.01, 0.09 for 800 microg for achieving successful preabortion cervical dilatation of at least 8 mm. The mean cervical dilatation of 6.7 mm and 6.8 mm for the higher doses was also significantly less than that of 8.1 for the 400-microg dose (P<.001). The mean preoperative and intraoperative blood loss was only statistically different when the 400- and 800-microg groups were compared (P = .03). There were also significantly more side effects, namely abdominal pain and fever above 38.0 C, in the 600- and 800-microg groups (P<.001), compared with the 400-microg group. When the 600- and 800-microg groups were compared, there were still significantly more women complaining of abdominal pain (P<.001). None of the women in the study required analgesics for pain or antipyretics for fever. CONCLUSION: The minimal evacuation interval should be at least 3 hours for successful preabortion cervical priming.

Randomized trial to determine optimal dose of vaginal misoprostol for preabortion cervical priming.

OBJECTIVE: To determine the optimal dosage of vaginal misoprostol for cervical priming before vacuum aspiration abortion. METHODS: One hundred twenty women were assigned randomly to receive 200, 400, 600, or 800 microg of misoprostol given vaginally. Vacuum aspiration was performed 3-4 hours after the insertion of misoprostol tablets. The degree of cervical dilation before operation was measured with a Hegar dilator. Preoperative and intraoperative blood loss and associated side effects also were assessed. RESULTS: Twenty-nine (96.7%) women in the 400-microg group and all in the 600-microg and 800-microg groups achieved cervical dilation of at least 8 mm. The success rate for the 200-microg group was only 23.3%, significantly less efficacious than the 400-microg dose (odds ratio 95.3; 95% confidence interval 10.9, 830.9; P < .001). There was no significant difference among the 400-, 600-, and 800-microg groups (P = .364) with respect to achieving cervical dilation at least 8 mm. However, 800 microg was associated with significantly more side effects than 600 microg (preoperative and intraoperative blood loss, P < .001; abdominal pain, P = .005; products of conception at os, P < .001; fever higher than 38.0C, P = .002). When 400 microg and 600 microg were compared, we found that the higher dose also was associated with significantly more side effects. The 600-microg group was used twice in the comparison, but all P values remained significant even after the Bonferroni adjustment for multiple comparisons. CONCLUSION: Vaginal application of 400 microg of misoprostol is the optimal dose for vacuum aspiration preabortion cervical dilation in first-trimester nulliparas.

Effect of polyphloretin phosphate on the response of non-gravid rat uterus to folkloric and standard oxytocics in vitro.

Polyphloretin phosphate (PPP) has been reported by previous workers to be a specific antagonist of prostaglandin (PGE(1), PGE(2) & PGF(2 alpha))-induced contractions of isolated jird colon, gerbil colon, guinea pig ileum, and rabbit jejunum. In the present study, we examined the effect of PPP on uterotonic activities of crude papaya latex (a folkloric oxytocic), PGF(2 alpha), oxytocin, acetylcholine, and 5-hydroxytryptamine (standard oxytocics) on non-gravid, oestrogen-primed (50 microg/kg) rats in vitro. The effect of PPP on the oxytocics was evaluated qualitatively by incubating the tissues in PPP (25 - 400 microg/ml) for 20 min prior to the addition of a constant concentration of each oxytocic. PPP concentration dependently inhibited the contractile response of the uterine muscles to all the oxytocics. The inhibition was reversible after washing out the drugs. Results of the present study suggest that PPP is a non-specific and reversible antagonist of the response of non-gravid rat uterine smooth muscle to oxytocics in vitro. The specificity of PPP as a prostaglandin antagonist could therefore be species/tissue dependent.

Preinduction cervical priming with PGE2 vaginal film in primigravidae--a randomised, double blind, placebo controlled study.

Previous reports with an 850 micrograms prostaglandin E2 film for cervical ripening before induction of labour in term pregnancy have been favourable. These studies however had no controls. The present study compares this PGE2 vaginal film with a nonmedicated similar vaginal film (placebo) for preinduction cervical ripening in primigravid women at term. A total of 69 women with modified Bishop's cervical scores 1-5 were assigned randomly to either the PGE2 group (33 women) or placebo group (36 women). Cervical score assessments were made at 12 and 24 hours after which labour was induced by amniotomy and oxytocin infusion. Although the cervical scores between placebo and PGE2 groups at 12 and 24 hours were not significantly different, the scores were marginally better with the prostaglandin film. Pregnancy outcome was satisfactory in both groups with no perinatal or maternal mortality and morbidity. The caesarean rate was 30.6% in the placebo group and 24.2% in the PGE2 group. This study emphasizes the need for a control group when studying the success of agents used for ripening the pregnant cervix at term.

Phagocytic function of monocytes of rhesus monkeys during Plasmodium knowlesi infection and the effect of treatment with chloroquine.

The effect of chloroquine on the phagocytic function of monocytes was studied in normal and Plasmodium knowlesi-infected rhesus monkeys during a course of therapy. In normal animals, chloroquine inhibited phagocytic activity after three doses. The effect of the drug and concentration was greatest after six to eight days. Recovery in function of monocytes was noticed after the drug had been excreted. In P. knowlesi-infected monkeys, the degree of inhibition of phagocytosis depends on the level of parasitaemia. Chloroquine treatment reversed the trend of inhibition in the animals that received the drug when parasitaemia was less than 30%.

Tocolytic and toxic activity of papaya seed extract on isolated rat uterus.

Carica papaya L. seeds extracted with 80% ethanol (EEPS) caused concentration-dependent tocolysis of uterine strips isolated from gravid and non-gravid rats. Prostaglandin F2alpha and oxytocin-induced contractions of the isolated rat uterus were also inhibited in a concentration-dependent fashion by EEPS. Recoveries of the uterine activity after EEPS-induced uterine quiescence were very weak. Higher concentration of EEPS caused prompt uterine quiescence, which was also significantly irreversible. Pre-incubation of the rat uterus in Ringer Locke solution containing 10 mg/ml of EEPS for 1 hour prior to suspension in tissue baths led to significant depression of the spontaneous and KCl (60 mM)-induced uterine contractions relative to the solvent control (P<0.05). Cross sections of EEPS-pretreated non-gravid rat uterus (stained with hematoxyline and eosin) examined under light microscope revealed degeneration of the endometrium and myometrium with obvious cytoplasmic vacuolation indicating that EEPS could have direct toxic effect on the uterine tissues. Previous workers have reported benzyl isothiocyanate (BITC) as the main bioactive and anthelmintic compound in different extracts of papaya seeds. Using electron impact ionization methods, the presence of BITC in EEPS was also shown in this study. Mass spectra of both EEPS and standard BITC showed a base peak of benzyl/tropylium ion at m/z 91 (indicative of an aromatic compound) and the molecular ion peak of BITC (m/z 149). Our earlier studies have demonstrated BITC-induced functional and morphological derangement of isolated uterus. We thus conclude that at high concentration, EEPS is capable of causing irreversible uterine tocolysis probably due to the damaging effect of BITC (its chief phytochemical) on the myometrium.

Aphrodisiac properties of Tribulus Terrestris extract (Protodioscin) in normal and castrated rats.

Tribulus terrestris (TT) has long been used in the traditional Chinese and Indian systems of medicine for the treatment of various ailments and is popularly claimed to improve sexual functions in man. Sexual behaviour and intracavernous pressure (ICP) were studied in both normal and castrated rats to further understand the role of TT containing protodioscin (PTN) as an aphrodisiac. Adult Sprague-Dawley rats were divided into five groups of 8 each that included distilled water treated (normal and castrated), testosterone treated (normal and castrated, 10 mg/kg body weight, subcutaneously, bi-weekly) and TT treated (castrated, 5 mg/kg body weight, orally once daily). Decreases in body weight, prostate weight and ICP were observed among the castrated groups of rats compared to the intact group. There was an overall reduction in the sexual behaviour parameters in the castrated groups of rats as reflected by decrease in mount and intromission frequencies (MF and IF) and increase in mount, intromission, ejaculation latencies (ML, IL, EL) as well as post-ejaculatory interval (PEI). Compared to the castrated control, treatment of castrated rats (with either testosterone or TT extract) showed increase in prostate weight and ICP that were statistically significant. There was also a mild to moderate improvement of the sexual behaviour parameters as evidenced by increase in MF and IF; decrease in ML, IL and PEI. These results were statistically significant. It is concluded that TT extract appears to possess aphrodisiac activity probably due to androgen increasing property of TT (observed in our earlier study on primates).

Comparative metabolic effects of three types of combined oral contraceptive pills in Chinese women.

The results of a prospective longitudinal controlled study comparing some metabolic effects of a low-dose levonorgestrel-ethinyl oestradiol combined oral contraceptive (Microgynon 30), a desogestrel-ethinyl oestradiol-containing pill (Marvelon) and a levonorgestrel-ethinyl oestradiol triphasic preparation (Triquilar) after one year of treatment in ethnic Chinese women are presented. Serum cholesterol levels are similar for the three pills at 6 and 12 months of treatment. Marvelon and Triquilar users showed rises in triglyceride levels while Microgynon 30 users had no change after one year of treatment. Lipoprotein fractions showed favourable changes in Triquilar and Marvelon users with significant rise in HDL fractions at 6 and 12 months; Microgynon 30 users had equivocal changes in HDL fractions. Carbohydrate metabolism as reflected by glucose tolerance showed deterioration with all 3 pills, being least with Microgynon 30 and greatest with Marvelon at 12 months.

PIP: Synthetic estrogens and gonane progestagens aggravate a predisposition to cardiovascular disease by altering carbohydrate and lipoprotein metabolism. This paper compares the metabolic effects of the triphasic oral contraceptive Triquilar (3 mcg ethinyl estradiol + 50 mcg levonorgestrel for 6 days, 40 mcg ethinyl estradiol + 75 mcg levonorgestrol for 5 days, and 30 mcg ethinyl estradiol + 125 mcg levonorgestrel for 10 days) and a combined oral contraceptive Marvelon (30 mcg ethinyl estradiol + 150 mcg desogestrel) with the standard low-dose combined oral contraceptive Microgynon 30 (30 mcg ethinyl estradiol + 150 mcg levonorgestrel) on an ethnic Chinese population. 125 fertile women aged 18-34 with regular menstrual cycles, who had not taken any form of hormonal contraceptive for the preceeding 6 months, were randomly allocated to Microgynon 30 (30 women), Triquilar (39 women), or Marvelon (32 women). Blood samples were examined for lipids, lipoproteins, and glucose before treatment and after 6 and 12 month. Serum triglyceride levels were unchanged by Microgynon 30 but were elevated 30-40% by Triquilar and Marvelon. Serum cholesterol levels were not altered by any of the 3 pill types. Microgynon 30 did not alter triglyceride lipoprotein fractions, but both Triquilar and Marvelon elevated them, with the high density lipoprotein fraction. Cholesterol lipoprotein fraction (free and total) were altered by all 3 pill types. Microgynon 30 lowered both low and high density (free and total cholesterol) lipoproteins. Marvelon and Triquilar had no effect on very low density lipoprotein levels but effected 10% decrease in the level of low density (free and total cholesterol) lipoproteins. The high density lipoprotein (free and total cholesterol) fraction rose 10% with Triquilar and 20% with Marvelon. Thus the triphasic and desogestrel oral contraceptives brought about a favorable alteration in the low density lipoprotein: high density lipoprotein cholesterol ratios. All 3 pill types caused a deterioration in glucose tolerance, but the effect was least with Micrognon 30.

Effects of three types of combined O.C. pills on blood coagulation, fibrinolysis and platelet function.

The results of a prospective longitudinal controlled study comparing the coagulation effects of a standard low-dose combined oral contraceptive (Microgynon 30), a desogestrel-containing pill (Marvelon) and a triphasic preparation (Triquilar) after one year's treatment in ethnic Chinese women is presented in this paper. In general the changes in coagulation parameters are similar to those seen in Caucasian women. The rise in Factor VII levels seen at 6 and 12 months in Marvelon users was not present to a significant degree in the other pill users. Antithrombin III levels remained unchanged in Microgynon and Marvelon users but with Triquilar there was a significant fall at 6 and 12 months of use. Whether these differences have any clinical relevance in the local Chinese population with low incidence of thromboembolism remains to be seen.

PIP: 81 healthy Chinese women of proven fertility and between the ages of 18-34 years were recruited for this prospective and longitudinal controlled study comparing the coagulation effects of a standard low-dose combined oral contraceptive (Microgynon 30), a desogestrel-containing pill (Marvelon), and a triphasic preparation (Triquilar) after 1 year's treatment. Study participants were randomly allocated to 1 of the 3 pill types and were followed up at 3 and 6 months and thereafter yearly. The subjects were encouraged to come earlier if they experienced any problems. Each volunteer acted as her own control. Blood sampling was performed at pretreatment (control value) and at 6 months and 12 months of treatment. The samples were taken between days 22-24 of the menstrual cycle at the same time of the day. There were 24 subjects recruited for Marvelon, 27 for Microgynon 30, and 30 for Triquilar treatment. Physical characteristics of the subjects were comparable on entry and showed no statistically significant mean weight or blood pressure change at the end of 12 months of treatment when compared with pretreatment values. In the screening tests, there was no change in hemoglobin concentration and maximum elasticity of the clot, even after 12 months of treatment for all OC subjects under treatment when compared with pretreatment levels. A lowered hematocrit was seen only in Marvelon subjects at 6 months treatment; the hematocrit returned to pretreatment levels after 12 months of treatment. Significant shortening of Activated Partial Thromboplastin Time (APTT) was observed both with Microgynon 30 and Triquilar subjects but not with Marvelon subjects after 12 months of treatment. Significant shortening of prothrombin time was seen at both 6 and 12 months of Microgynon 30 treatment; this change was seen only after 12 months of Marvelon treatment and absent at 12 months in Triquilar subject. In thromboelastogram (TEG), a shortening of reaction and clotting time was observed in all subjects after 12 months of treatment without affecting any change in maximum clot elasticity. There was no significant change seen in Fibrinogen, Coagulation Factor VIIIC, and Factor VIIIR:Ag, even after 12 months of treatment in all subjects. No appreciable change in Factor II was seen in Microgynon 30 and Triquilar subjects, but in Marvelon treatment a significant increase was observed after 12 months treatment. Factor V showed an increase in Microgynon 30 subjects only at 12 months treatment and 6 months treatment for Triquilar subjects, but no change was seen in Marvelon subjects.

Termination of early pregnancy (menstrual induction) with 16-phenoxy-omega-tetranor PGE2 methylsulfonylamide.

PIP: The efficacy and side effects of a new synthetic compound, 16-phenoxy-W-17, 18, 19, 20-tetranor prostaglandin E2 methylsulfonylamide, for menstrual induction. The study was conducted in an outpatient clinic in 240 patients with a delay in menstruation of 6-14 days. In 206 patients (86%) the immunologic pregnancy test was positive before prostaglandin administration. Most of the remaining 34 (14%) patients with a negative pregnancy test had symptoms suggestive of pregnancy. Whenever there was doubt that amenorrhea was due to reasons other than pregnancy, the patients were not treated with prostaglandins. The patients' age range was 16-32 years; the parity range was 0-6. The treatment was successful in 228 patients (95%), i.e., there was uterine bleeding after prostaglandin administration followed by a negative pregnancy test within 14 days. In 6 patients with failed treatment, there was uterine bleeding after prostaglandin administration lasting for 2-13 days but the pregnancy remained positive. Prostaglandin failed to induce bleeding in 4 patients. In 3 of the patients the pregnancy test was positive before and 14 days after prostaglandin administration. The uterus was evacuated by vacuum aspiration in 9 patients. In 1 patient who had no uterine bleeding, pregnancy test was negative both before and 2 weeks after prostaglandin administration. 2 patients were admitted to the hospital the day after prostaglandin treatment for excessive bleeding. Curettage was carried out in both these patients and the bleeding stopped. 1 patient was readmitted to the hospital 8 hours after prostaglandin administration with severe pain in the lower abdominal region. On further examination a tubal pregnancy was diagnosed and confirmed by laparotomy. 2 patients were successfully treated for pelvic infection with antibiotics 7-10 days after prostaglandin administration. All patients experienced mild uterine pain a few minutes after prostaglandin administration. 16 patients required analgesics. The majority of the patients described the bleeding as heavier and longer in duration than their normal menstrual period. The average length of bleeding was 7.3 days with a range of 2-13 days. Side effects included 1 or 2 episodes of vomiting in 13 patients and headache in 9 patients.^ieng

Randomized comparison of different prostaglandin analogues and laminaria tent for preoperative cervical dilatation. World Health Organization Special Programme of Research, Development and Research Training in Human Reproduction: Task Force on Prostaglandins for Fertility Regulation.

In an eleven-centre study, 627 nulliparous subjects in the 8th to 12th week of gestation admitted for termination of pregnancy were allocated to one of five treatments to induce pre-operative cervical dilatation. The treatments were: 0.5 mg PGE2 methyl sulphonylamide; 1.0 mg PGE1 methyl ester; 30 mg 9-methylene PGE2 free acid, 0.5 mg 15-methyl PGF2 alpha; a single medium-sized laminaria tent. The results indicate that the three PGE analogues are at least equally effective as one medium sized laminaria tent and more effective than 0.5 mg 15-methyl PGF2 alpha in producing adequate pre-operative cervical dilatation prior to vacuum aspiration. It is concluded that both pre-treatment with prostaglandin analogues and laminaria tent are effective methods for preoperative cervical dilatation and both types of treatment are associated with a low incidence of side effects. Prostaglandin analogue treatment can be administered by paramedical personnel but laminaria tent insertion has to be performed by medical staff.

Postcoital contraception with levonorgestrel during the peri-ovulatory phase of the menstrual cycle. Task Force on Post-ovulatory Methods for Fertility Regulation.

The contraceptive efficacy and side effects of postcoital levonorgestrel used repeatedly during the peri-ovulatory period of one cycle was examined in 259 women. All subjects were of proven fertility in their present union and had ovulatory cycles as assessed from pre-treatment BBT charts. The mean number of coital acts during the treatment cycle was 7.5 (SD:2.6) and the mean number of 0.75 mg levonorgestrel tablets taken during the peri-ovulatory period was 4.0 (SD:1.2). Two pregnancies, both considered to be method failures, occurred, giving a failure rate of 0.8% per treated cycle. Although the overall effect of levonorgestrel on menstrual cycle length was small and insignificant, menstrual cycle disturbances were not uncommon. Intermenstrual bleeding or spotting occurred in 8.5% of the treated cycles and 12.5% of the cycles were less than 20 or more than 35 days. Other side effects, mainly nausea, headache and dizziness, were reported by about 20% of the subjects but the apparent incidence of these complaints varied markedly between the nine participating centres from 0% to just over 50%. The data suggest that repeated postcoital use of levonorgestrel is probably not a viable approach to fertility regulation for the majority of women who have regular intercourse and wish to limit the number of their pregnancies.

Pregnancy outcomes following pre- and post-implantation exposure of Sprague-Dawley rats to benzyl isothiocyanate.

The present investigation examines the outcomes of rats' pregnancy following pre- and post-implantation maternal exposure (orally) to benzyl isothiocyanate (BITC; 12.5, 25 and 50 mg/kg body weight). Three maternal deaths were recorded in the group of rats treated with 50 mg/kg BITC. Obvious signs of toxicity characterized by hypo-activity, perinasal staining, piloerection, hunched posture and decrease in body weights were observed in BITC-treated rats during the treatment periods. Dose-dependent increase in early fetal resorptions was seen in rats treated with BITC prior to implantation, but was not statistically significant. There were no significant differences in the number of implantation sites in treatment groups compared with the control. Similarly, there were no significant differences in the number of fetal resorptions, relative weights of maternal liver, kidney and spleen of rats in post-implantation treatment groups compared with the control. The differences in the number of viable fetuses in treatment groups compared with the control were also not significant. However, fetal weights in rats treated with 25 and 50 mg/kg BITC and placental weights in all the treatment groups were significantly lower than the control. In conclusion, at 12.5-50 mg/kg, BITC did not cause significant pre- and post-implantation fetal loss in pregnant rats. BITC-induced low fetal and placental weights could be of obstetrical importance, but at levels/doses that would provoke maternal toxicity.

Prevalence of filariasis in rural areas of Shahjahanpur district (Uttar Pradesh).

Night blood survey was carried out during May, 1990 to December, 1991 in 18 villages of 5 Primary Health Centres of district Shahjahanpur (UP), to find out the prevalence of filariasis in the area. Out of 2141 individuals surveyed randomly, 217 were found positive for microfilariae of Wuchereria bancrofti. The microfilaria rate, filarial disease rate and filarial endemicity rates were 10.1, 11.4 and 18.8 per cent respectively. An entomological survey revealed Culex quinquefasciatus as the vector. The average man hour density was 25.8. It is clear from the results that filariasis is more endemic in rural areas than urban area of Shahjahanpur as observed by local filariasis control unit.

Effects on hemostasis after two-year use of low dose combined oral contraceptives with gestodene or levonorgestrel.

We studied 67 healthy women who were randomly allocated to receive third generation gestodene (Gynera) or second generation levonorgestrel (Microgynon 30) combination of low-dose estrogen oral contraceptives (OCs) for their hemostatic effects over 2 years. Hemostatic changes were apparent within 3 months of OC use. Hematocrit (Hct) was not affected, but hemoglobin (Hb) concentration decreased by 18 months. Shortened prothrombin time (PT) and activated plasma thromboplastin time (APTT) were associated with elevated fibrinogen within the 12-month use of both OCs. Factor VII was reduced only in Micro 30 during the 18 months of use. Enhanced thrombin-antithrombin (TAT)-complex level was seen at 18 months of Gynera use. Prothrombin fragment1+2 (F1+2) rise was seen at 3 months with Micro 30. Reduced antithrombin III (ATIII) activity was seen at 18 months with Gynera and at 24 months with Micro 30. Increased protein C activity was seen at 3 months and reduced protein S occurred at 18 months of Gynera use. Tissue plasminogen activator (t-PA) activity was enhanced for 6 months in both OCs with raised D-dimer levels for 12 months with Gynera and 6 months with Micro 30. Decreased t-PA antigen was seen at 18 months and decreased urokinaselike plasminogen activator (u-PA) antigen occurred throughout the 24 months of both OCs use. Enhanced u-PA activity was only seen in Gynera users. Elevated plasminogen levels were apparent throughout both OCs use. PAI-1 levels were significantly decreased with Micro 30. With Gynera, the decreased PAI-1 activity was seen only at 18 months and PAI-1 antigen at 12 months. No change in platelets and von Willebrand factor (vWF) were seen in long-term OC use except that beta-thromboglobulin (beta-TG) showed decreased trends reaching statistical significance by 18 and 24 months of Micro 30 use and by 24 months of Gynera use. A further significant decrease in beta-TG, u-PA antigen, ATIII, and protein S levels were seen 3 months after pill stoppage compared with pretreatment levels. Activated protein C resistance (APCR) was negative in all subjects before and during OC use. The study indicated dynamic balance between coagulation and fibrinolysis with no endothelial activation. However, because some hemostatic markers showed wide fluctuations during OC use, a longer term study is warranted to investigate any adverse hemostatic changes that might enhance the risks of venous thromboembolism in Asian subjects known to be less prone to thrombosis.