Phase I clinical study to select a novel oral formulation for ibandronate containing the excipient sodium N-[8-(2-hydroxybenzoyl) amino] caprylate (SNAC).

The aim of this study was to select a novel oral formulation for ibandronate (IBN, CAS number: 13892619). In four cohorts of 28, 21, 19 and 29 healthy volunteers, the impact of the carrier molecule sodium N-[8-(2-hydroxybenzoyl) amino] caprylate (SNAC, CAS number: 203787-91-1) on the bioavailability of IBN was investigated. Within each cohort different oral formulations with one dose of ibandronate (30 mg) and three different ratios of IBN:SNAC (1:5, 1:10 and 1:20) were compared to the approved oral IBN tablet formulations (150 and 50 mg IBN) in a 4-way cross-over design and a one week washout between the administrations. The highest mean IBN exposure was achieved with a capsule formulation containing drug-coated beadlets and an IBN:SNAC ratio of 1:5. AUC(last) and C(max) of IBN were approximately 1.3- and 2.2-fold higher compared to the reference treatment (150 mg IBN without SNAC). Increasing the post-dose fasting duration from 15 to 30 min resulted in a more than 2-fold increase in AUC(last), while superimposable IBN serum concentration-time profiles were achieved after a 30 and 60 min fast. The tolerability of the IBN/SNAC treatments in all cohorts was similar to that in the IBN reference groups and most adverse events (AEs) were of mild to moderate intensity.

Critical processing factors affecting rheological behavior of a wax based formulation.

The use of a wax-based vehicle is one approach to stabilize a drug which is susceptible to hydrolysis and/or oxidation. The drug used in the study, as a microfine powder, is dispersed in the wax mixture and encapsulated in a soft gelatin capsule. To ensure reproducibility of drug content uniformity and encapsulability of the soft gelatin capsule dosage form, optimal viscosity and lot to lot uniformity of the viscosity of the suspension are required. The objective of the study was to identify the critical processing factors which could affect the rheological behavior of the wax based vehicle. Rheological behavior of the vehicle at temperatures ranging from 15 to 90 degrees C was evaluated using a CSL Rheometer equipped with parallel plates and a shear rate sweep mode, unless otherwise specified. Viscosity vs. temperature profiles of the vehicle were determined using the same conditions at different cooling rates ranging from 1.3 to 20 degrees C per min. Three distinct regions of phase transition of the wax mixture can be seen in the Arrhenius plot: (i) a sol region at temperatures above 50 degrees C, (ii) a transition of gel to sol at temperatures ranging from 30 to 45 degrees C, and (iii) a gel region at temperatures below 30 degrees C. The vehicle in a sol region behaved as a Newtonian fluid, indicating minimal interactions between the hydrocarbon chains of the vehicle. The vehicle in a gel region behaved thixotropic in nature, as indicated by a hysteresis loop. The shear rate had a more pronounced effect on the area of thixotropy than the shear time. The cooling rate had a pronounced effect on the resultant viscosity. At the same applied shear rate, the vehicle which was cooled at a faster rate, may cause a recrystallization of the wax mixture in different crystalline forms, resulting in a higher viscosity than the vehicle cooled at a slower rate. This effect was more pronounced when the shear was applied at a lower rate. The results of this study indicate that shear rate and cooling rate are the critical processing factors in controlling the viscosity of the final product and must be well controlled in the manufacturing procedure.

Release performance of a poorly soluble drug from a novel, Eudragit-based multi-unit erosion matrix.

Mechanisms governing the release of drugs from controlled delivery systems are mainly diffusion, osmosis and erosion. For poorly soluble drugs, the existing mechanisms are limited to osmosis and matrix erosion, that are commonly observed in single unit matrix dosage forms. This study reports formulation and dissolution performance of Eudragit L 100 55 and Eudragit S 100 based multi-unit controlled release system of a poorly soluble thiazole based leukotriene D(4) antagonist, that was obtained by an extrusion/spheronization technique. Effect of triethyl citrate, that was incorporated in the matrix, on the dissolution performance of the drug was also evaluated. In vitro matrix erosion and drug release from the pellets were determined by the use of USP Dissolution Apparatus I, pH 6.8 phosphate buffer, gravimetry and UV spectrophotometry, respectively. Results obtained demonstrated that matrix erosion and drug release occurred simultaneously from the pellets. Pellets eroded with a consequent reduction in size without any change in the pellet geometry for over 12 h. Matrix erosion and drug release followed zero order kinetics. Data obtained strongly suggested a polymer controlled, surface erosion mechanism.

Nutrients and hormones in heat-dried human placenta.

This cross-sectional study was to assess the nutrients in terms of protein, fat, minerals, and hormones in heat-dried human placenta. Thirty heat-dried human placentas, 15 from male and 15 from female, were analyzed for protein (amino acids), fiber, fat, moisture, minerals (sodium, potassium, phosphorus, calcium, iron, magnesium, zinc, copper, manganese), hormones (estradiol, progesterone, testosterone, growth hormone). Heat-dried female human placentas had slightly higher fiber content than male, but protein and fat components were not different. Mineral levels in placentas were high especially sodium, potassium and phosphorus. There were no significant differences in the amount of minerals and hormonal profile between female and male placentas. However, hormone levels in heat-dried placenta were low compared to physiologic level in human beings. The results of this study suggest that the amount of nutrients particularly protein and minerals in heat-dried human placentas were enriched.

The effect of parity on lipid profile in normal pregnant women.

A cross sectional study was carried out at Ramathibodi Hospital between June and August 1997. The objective of this study was to determine maternal serum lipid levels at delivery and the effect of parity on maternal lipid profile. Study population was normal term pregnant women aged 20-35 years who delivered normal infants with a birthweight > or = 2,500 grams. Maternal serum lipid levels at delivery were determined from 177 normal term pregnant women. Their mean age was 27.6 +/- 4.5 years. The first parity (P1) was about 52 per cent, whereas, the second and third parity (P2 and P3) were 37 and 11 per cent, respectively. Mean maternal serum total cholesterol (TC) levels in P1, P2 and P3 were 258.3 +/- 46.9, 266.7 +/- 47.1 and 295.7 +/- 61.2 mg/dl, respectively. Serum triglyceride (TG) levels in P1, P2 and P3 were 265.2 +/- 81.1, 280.3 +/- 72.1 and 260.7 +/- 82.8 mg/dl, respectively; serum low density lipoprotein-cholesterol (LDL-C) in P1, P2 and P3 were 136.9 +/- 45.2, 144.9 +/- 43.3 and 173.4 +/- 62.1 mg/dl, respectively; and serum high density lipoprotein-cholesterol (HDL-C) levels were 64.6 +/- 16.6, 65.7 +/- 17.8, 67.2 +/- 16.0 mg/dl, respectively. Serum TC and LDL-C levels increased with parity. There was a significant difference between maternal TC and parity (F = 4.702, p = 0.01) as well as LDL-C and parity (F = 4.883, p < 0.01), especially P1 and P3. There was no significant difference between maternal TG and parity as to HDL-C and parity (p > 0.05).

Plasma HIV-1 RNA viral load and serum vitamin A and E levels in HIV-1 infected pregnant women.

The aim of this study was to assess the correlation between plasma HIV-1 RNA viral load and serum vitamin A and E concentrations and vitamin E/cholesterol ratio in HIV-1 infected pregnant women not receiving antiretroviral therapy There were no significant correlations between plasma HIV-1 RNA viral load and serum vitamin A and E concentrations and vitamin E/cholesterol ratio. However, the presence of underlying vitamin A deficiency in these pregnant women was common.

Effect of formulation and process variables on porosity parameters and release rates from a multi unit erosion matrix of a poorly soluble drug.

The effect of drug loading, water required for granulation and spheronization time on porosity parameters (intrusion-extrusion isotherms, pore size distribution, total pore surface area, mean pore diameter, shape and morphology of pores) and drug release rates from pellets of a poorly soluble drug was investigated. Porosity parameters were determined by mercury intrusion porosimetry. The drug loading was found to have a profound effect on the porosity parameters. Pellets with low drug loading showed increased pore surface area with small mean pore diameters and an increased number of total pores. On the other hand, pellets with high drug loading had decreased pore surface areas with larger mean pore diameters and a reduction in the total number of pores. With high drug loading, the drug release rate decreased. Water required for granulation had a direct effect on the total porosity of the pellets. Spheronization time from 2 to 10 min had a pronounced effect on porosity parameters and release rates. No changes in porosity parameters and release rates were observed from 10 to 20 min of spheronization time. It was shown that each porosity parameter investigated was well correlated with drug release rates and thus it is important to study the effect of porosity parameters in evaluating the in vitro performance of the multi-unit erosion matrix for the controlled release of a poorly soluble drug.

Antioxidant nutrients and lipid peroxide levels in Thai preeclamptic pregnant women.

OBJECTIVE: To compare the antioxidant nutrients and lipid peroxide levels in preeclampsia and normal pregnant women. METHODS: Antioxidant nutrients (vitamin A and E) were measured by high-pressure liquid chromatography, vitamin C was measured by the dinitrophenyl hydrazine method, lipid peroxides were measured by the malondialdehyde method in 20 severe preeclampsia, 30 mild preeclampsia and 60 normal pregnant women as controls. RESULTS: Vitamin C levels in severe and mild preeclampsia were significantly less than those in control group. The corrected vitamin E and vitamin A levels were significantly decreased only in severe preeclampsia. While the lipid peroxide levels in both mild and severe preeclampsia were significantly increased when compared with the nomal pregnancy. CONCLUSIONS: Preeclampsia is associated with the imbalance between lipid peroxides and antioxidant nutrients (vitamin C and E). The imbalances favour lipid peroxides with the increasing severity of preeclampsia.

Maternal and umbilical cord serum vitamin A, E levels and mother-to-child transmission in the non-supplemented vitamin A, E HIV-1 infected parturients with short-course zidovudine therapy.

This study was undertaken to assess the maternal and umbilical cord serum vitamin A, E levels at delivery and mother-to-child transmission in nonsupplemented vitamin A, E HIV-1 infected parturients who received short-course zidovudine therapy. Maternal and umbilical cord serum vitamin A, E levels were quantitated by high-performance liquid chromatography in 67 HIV-1 infected parturients who received short-course zidovudine therapy. Mother-to-child transmission occurred in 13.4 per cent of HIV-1 infected parturients. There were no significant differences in the mean concentrations of vitamin A, E and vitamin E/cholesterol ratio between parturients with HIV-1 infected and non-infected infants. While maternal serum vitamin E level was adequate, nearly one-third of the parturients in the study had vitamin A deficiency. In conclusion our study has shown that there was no correlation between maternal serum vitamin A, E levels and mother-to-child HIV transmission in HIV-1 infected parturients who received short-course zidovudine therapy. However, the presence of underlying vitamin A deficiency in these parturients was common, adequate and intensive maternal-infant nutritional support should be emphasized especially in developing countries as an adjunctive measure in the reduction of mother-to-child transmission of HIV as well as the reduction in maternal and perinatal morbidity.

Maternal viral load and vertical transmission of HIV-1 in mid-trimester gestation.

BACKGROUND: It is now accepted that the majority of HIV-1 vertical transmissions occur in late gestation and at the time of delivery. However, there is wide variation in the prevalence rate of mid-trimester vertical transmission. We assessed the maternal HIV-1 RNA viral load and in utero transmission during mid-trimester gestation. METHODS: Patients were enrolled when they decided to have their pregnancies terminated between 17 and 24 weeks of gestation. Prostaglandin-induced abortion with PGE1 analogue vaginal administration was carried out in all patients. Maternal plasma HIV-1 RNA viral load and plasma HIV-1 RNA (qualitative) from abortus heart blood were assessed. RESULTS: Amongst 41 HIV-1 seropositive pregnant women not receiving antiretroviral therapy plasma HIV-1 RNA was detected in the abortus heart blood from two women (4.9%; 95% confidence interval (CI), 0.6-16.5). Transmission occurred in one out of nine (11.1%; 95% CI, 0.3-48.2) with maternal viral load > or =100000 copies/ml versus one out of 32 (3.1%; 95% CI, 0.1-16.2) of those with <100000 copies/ml (P = 0.39). CONCLUSIONS: The frequency of HIV-1 vertical transmission during mid-trimester was approximately 5% as detected by plasma HIV-1 RNA (qualitative) method in the fetuses aborted from the prostaglandin termination of pregnancy. During mid-trimester gestation there was no correlation between high maternal viral load and vertical transmission.

Serum vitamin A and E in pregnant women with hemoglobinopathies.

OBJECTIVE: To evaluate the relationship between the status of serum vitamin A, E and hemoglobinopathies among Thai pregnant women. METHODS: This was a cross-sectional study in which serum vitamin A and E were assessed in 323 pregnant women with normal hemoglobin and 73 with hemoglobinopathies (47 with hemoglobin E and 26 with thalassemia) during the first trimester. RESULTS: There were no significant differences in the mean serum vitamin A, E concentrations and vitamin E/cholesterol ratio between pregnant women with normal hemoglobin and hemoglobinopathies, while confounding variables that might affect serum vitamin levels i.e. maternal age, gravida, BMI, gestational age, hematocrit, hemoglobin, mean corpuscular hemoglobin concentration and blood group were not different. CONCLUSION: The results of this study suggest that antenatal care in terms of micronutrients-vitamin A, E in Thai pregnant women with hemoglobinopathies should not be different from normal pregnant women.

Umbilical Doppler velocimetry prediction of discordant twins.

OBJECTIVE: To evaluate the role of umbilical Doppler velocimetry as a comprehensive test for the prediction of discordant twins. METHODS: The sets of twins were studied with duplex Doppler velocimetry for umbilical artery in third trimester. A systolic/diastolic ratio was measured for each twin. The average difference in the ratios between each twin > or = 0.4 was used to indicate abnormal test. Discordancy was identified when the birth weight difference of > 25%. RESULTS: Among the 52 sets of twin pregnancies studied, 40 sets of twins fulfilled the study criteria. Eight sets of twins were discordant (20%). The mean gestational age at delivery was 37.15 +/- 2.24 weeks (range 28 to 41 weeks). The test correctly identified 6 of the 8 growth discordant twins which had a sensitivity of 75%, specificity of 68.75%, and accuracy of 70%. CONCLUSION: Umbilical Doppler velocimetry is useful in prediction of discordant twins.

HIV screening in pregnant women.

Abstract. The following recommendations are made for prenatal screening for HIV infection 1) Routine voluntary screening for HIV infection in all pregnant women is feasible and worthwhile. 2) Every seropositive result should be repeated for confirmation before coming to a definititve conclusion to avoid a misdiagnosis. 3) Fetal blood sampling in the mid-trimester for PCR and p24 antigen assay seems inappropriate as a diagnostic tool for in utero HIV infection of the HIV seropositive pregnant women as the infection mostly occurs after this time. 4) Routine screening of seronegative pregnant women should be repeated during the third trimester to detect seroconversion since this offers a chance for antiretroviral administration to the seroconverted pregnant women for reduction of perinatal transmission. 5) There should be available the appropriate back up services for seropositive pregnant women. There is sufficient evidence indicating a higher vertical HIV-1 transmission rate in the last trimester and during labour compared with the first and second trimesters. Antiretroviral therapy either single or in combination given to the mother during the last trimester and delivery can reduce the viral load in the maternal circulation. Vertical HIV-1 transmission during delivery can be minimized by appropriate timing and route of delivery. Elective Cesarean section before the onset of labour with an intact bag of forewaters provides the least mother-to-fetus microtransfusion compared to other modes of delivery. Since an effective combination of HIV-1 immunoglobulin and HIV-1 vaccine given to the HIV-1 exposed newborns to prevent HIV-1 transmission similar to the viral hepatitis B model is not firmly established at present, postexposure antiretroviral prophylaxis and nonbreast-feeding are advocated for infants born from the HIV-1 infected mothers. In cases of advanced stage of maternal HIV-1 infection, and in developing areas where malnutrition prevails, an adequate supply of essential micronutrients is proposed as an adjunctive measure to reduce HIV-1 perinatal transmission.

Five-year thyrotropin screening for congenital hypothyroidism in Ramathibodi Hospital.

OBJECTIVES: To detect newborns with congenital hypothyroidism (CH) and to treat the affected infants as early as possible. STUDY DESIGN: Cord blood thyrotropin (TSH) screening for CH in Ramathibodi Hospital began in 1993. From October 1993 to December 1998, 35,390 neonates were screened. The infants with elevated TSH level of greater than 30 mU/L were recalled for verification of CH. Confirmation tests included total thyroxine, free thyroxine and TSH level. Thyroid scan and uptake were performed in some affected infants. RESULTS: Twelve infants with CH were detected resulting in an incidence of one in 2,949 live-births. All affected infants were asymptomatic at birth. Of 12 infants with CH, one premature neonate had a delayed TSH elevation and was diagnosed as having primary hypothyroidism at 2 months of age. The recall rate for validation of CH based on a cut-off value at serum TSH level of greater than 30 mU/L is 1.1 per cent. If the cut-off value of serum TSH level was raised to greater than 40 mU/L, the recall rate would decrease to 0.43 per cent. None of the affected infants had cord blood TSH level of less than 50 mU/L except one premature patient. Therefore, beginning in January 1997, the cut-off value of TSH was raised to 40 mU/L or greater. Pitfalls in this program include incomplete blood-specimen collection and incomplete follow-up. To strengthen the program, improvements were made in the follow-up system from 1996 onward. Therefore, the coverage for blood-specimen collection progressively increased from 84 per cent in 1994 to 96 per cent in 1998. Simultaneously, the patients' return after recalls also increased from 38 per cent to 100 per cent. CONCLUSIONS: The incidence of CH in Ramathibodi Hospital is approximately 1:3,000 live-births. The optimal cord blood TSH level for recall is 40 mU/L or greater. The intensification of follow-up strategy resulted in better response to recall and earlier treatment in the affected infants.

Maternal and umbilical cord serum zidovudine levels in human immunodeficiency virus infection.

The aim of this study was to determine the maternal and umbilical cord serum ZDV levels at delivery in HIV-1 infected parturients treated with a short-course ZDV regimens in late pregnancy and labour. Serum ZDV and its metabolite were measured by high-performance liquid chromatography. Concentrations of ZDV and its metabolite in umbilical cord blood appeared similar to maternal concentrations. There was a significant positive correlation between serum ZDV and its metabolite in maternal and umbilical cord concentrations. At delivery, maintenance of optimal virustatic ZDV concentration with oral antenatal and oral intermittent intrapartum ZDV dosage regimen can be achieved in only 53% of cases. The regimens used in this study were useful but not as effective as the ACTG 076 regimen with an intravenous dose intrapartum plus the oral administration to the infants for 6 weeks.

Timing and mechanism of perinatal human immunodeficiency virus-1 infection.

There is sufficient evidence indicating a higher vertical HIV-1 transmission rate in the last trimester and during labour compared with the first trimester. Antiretroviral therapy either single or in combination given to the mother during the last trimester and delivery can reduce the viral load in the maternal circulation. Vertical HIV-1 transmission during delivery can be minimized by appropriate timing and route of delivery. Elective Caesarean section before the onset of labour with an intact bag of forewaters provides the least mother-to-fetus microtransfusion compared to other modes of delivery. Since an effective combination of HIV-1 immunoglobulin and HIV-1 vaccine given to the HIV-1 exposed newborns to prevent HIV-1 transmission similar to the viral hepatitis B model is not firmly established at present, postexposure antiretroviral prophylaxis and nonbreast-feeding are advocated for infants born from the HIV-1 infected mothers. In cases of advanced stage of maternal HIV-1 infection, and in developing areas where malnutrition prevails, an adequate supply of essential micronutrients is proposed as an adjunctive measure to reduce HIV-1 perinatal transmission.

Effect of zidovudine treatment in late pregnancy on HIV-1 in utero transmission.

In Thailand, the prevalence of paediatric HIV-1 infection has increased rapidly through vertical transmission. According to the ACTG 076 trial regimen, zidovudine treatment in HIV-infected pregnancy can reduce vertical transmission. However, this treatment is complex and costly. It is not applicable for developing countries. We conducted a study to evaluate the effect of zidovudine treatment in late pregnancy on HIV-1 in utero transmission. Fifty cases of asymptomatic HIV-1 infected-women were voluntarily enrolled to the study. Zidovudine 250 mg orally twice a day was given to these patients from gestational age 36 weeks until labour. The newborns were evaluated at birth by a neonatologist and peripheral blood was tested for HIV genome by PCR technique within 48 hours of birth. The study revealed that no HIV genome was detected from the peripheral blood of newborns. It is suggested that zidovudine treatment in late pregnancy could reduce HIV-1 in utero transmission.

PIP: In 1995, Ramathibodi Hospital in Bangkok, Thailand, introduced zidovudine (ZDV) treatment in late pregnancy to prevent vertical transmission of HIV infection. The effectiveness of this strategy was assessed in 50 HIV-1-infected pregnant women who were receiving prenatal services at the hospital. The protocol consisted of 250 mg of ZDV orally twice a day from 36 weeks of gestation until the onset of labor. No ZDV was administered in the intrapartum and newborn period. Mothers were urged not to breast feed. The mean duration of ZDV treatment was 24.8 +or- 9.3 days. The most common side effect was nausea and vomiting (16%). Mean birth weight was 3010.25 +or- 301.0 g. No HIV-1 genome was detected in the peripheral blood of any of the 50 infants within 48 hours of birth. This preliminary finding suggests that a short course of ZDV late in pregnancy reduces in utero transmission of HIV infection as effectively as the more complex ZDV regimen. The 50 infants will be followed for up to 18 months to assess the rate of intrapartum and postpartum HIV and the long-term effects of treatment.

Use of Norplant implants in asymptomatic HIV-1 infected women.

The study of Norplant implants use in HIV-1 infected women was conducted at the Family Planning Clinic, Department of Obstetrics and Gynaecology. Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand, from January 1993 to June 1996. The purpose of the study was to evaluate efficacy, clinical effects, side effects, and menstrual patterns of the Norplant system in HIV-1 infected acceptors. Forty one cases of asymptomatic HIV-1 positive women voluntarily participated in using Norplant implants after delivery or abortion. The mean age was 25.4 years. The most common menstrual pattern was irregular bleeding (63.4%). Mean blood pressure, body weight, and hemoglobin level were not different at insertion and at 12 months (p > 0.05). No pregnancy occurred during a 12-month period. It was concluded that the Norplant system was safe, efficacious, and well tolerated in HIV-1 positive women and is an appropriate contraception in these women.

PIP: Although Thailand's National Family Planning Program introduced Norplant contraceptive implants in 1986, few women infected with human immunodeficiency virus (HIV) select this method, and its efficacy, clinical effects, and side effects in this population have not been investigated. To address these issues, a prospective cohort study was conducted during 1993-96 of 41 asymptomatic HIV-infected women who presented to the Family Planning Clinic at Ramathibodi Hospital in Bangkok, Thailand, and voluntarily accepted Norplant implants. All implants were inserted within 4 weeks after delivery or abortion. 63.4% of acceptors had not used any contraceptive method prior to pregnancy. At 6 and 12 months after insertion, 26% and 23%, respectively, reported irregular menstrual periods and 24.4% and 36.6%, respectively, reported amenorrhea. Side effects, reported by 3-10% of women, included headache, acne/chloasma, anorexia, and nausea. There were no significant changes in body weight, blood pressure, and hemoglobin between insertion and the 12-month follow-up. No pregnancies occurred during the study period. These findings suggest that Norplant implants are an effective, appropriate contraceptive method for HIV-infected women who want to avoid pregnancy but are not interested in sterilization.

Pheochromocytoma during pregnancy: case report.

Pheochromocytoma during pregnancy is rare. Only a few hundred cases have been published in the literature. We report patients with pheochromocytoma diagnosed at antepartum period. Manifestation include hypertension with various clinical presentation, possibly resembling those of pregnancy-induced hypertension. Confirmation necessitates special biochemical examination and the use of different radiological imaging tool. Treatment combines medical procedures with surgical exploration, mandating a team approach of diverse medical expertise. In the first and second trimesters, tumor resection has a good fetal outcome; in later pregnancy, delivery by elective cesarean section followed by tumor resection is recommended. The overall prognosis is mainly affected early diagnosis and multidisciplinarian management.