Generic daclatasvir plus sofosbuvir, with or without ribavirin, in treatment of chronic hepatitis C: real-world results from 18 378 patients in Egypt.

BACKGROUND: Treatment of chronic hepatitis C using combination of sofosbuvir (SOF) and daclatasvir (DCV) was used in several clinical trials and multicentre studies, which were somewhat limited to genotypes 1-3. The national program in Egypt is using SOF-DCV combination for large scale treatment. AIM: To assess the efficacy and safety of combined SOF-DCV in treating patients with HCV-G4 in a real-world setting. METHODS: Data and outcome of chronic HCV patients who were treated for 12 weeks with generic medications: DCV 60 mg plus SOF 400 mg ± ribavirin (RBV) within the national hepatitis C treatment program in Egypt are presented. Treatment-naïve patients without cirrhosis were treated without RBV, and those who had cirrhosis or were treatment-experienced (interferon experienced or SOF experienced) received RBV. Efficacy and safety were assessed, and baseline factors associated with sustained virological response at post-treatment week 12 (SVR12) were explored. RESULTS: During the first 2 months of the programme, 18 378 patients with HCV-G4 started treatment with SOF-DCV with or without RBV. Overall, 95.1% achieved SVR12 (95.4% among patients treated without RBV and 94.7% for patients treated with RBV, P = .32). Treatment was prematurely discontinued in only 1.5% of patients. The most common events leading to discontinuation were patient withdrawal (n = 76) and pregnancy (n = 5). Five deaths occurred within this group. CONCLUSIONS: Real-world experience of generic SOF-DCV in patients with chronic HCV-G4 proved to be safe and associated with a high SVR12 rate, in patients with different stages of fibrosis.

Prevalence and morbidity of schistosomiasis among rural fishermen at two Egyptian villages (Gharbia Governorate).

210 fishermen and 210 farmers from two Egyptian villages (Gharbia Governorate) were selected. Their main clinical manifestations were terminal haematuria in 17.1% and 10%, dysuria in 16.7% and 6.7%, renal colic in 13.3% and 2.4%, dysentery in 10.5% and 3.8%, bloody stool in 8.1% and 2.9%, pallor in 28.8% and 15.2%, hepatomegaly in 10.5% and 4.3% and splenomegaly in 8.6% and 3.8% in fishermen and farmers respectively with significant values among fishermen when compared with farmers. Abdominal ultrasonography of fishermen showed higher morbidity rates than farmers as regards hepatosplenomegaly, grades of periportal fibrosis, portal vein diameter, stones in Kidneys and urinary bladder as well as calcification of urinary bladder. S. mansoni prevalence was 72.4% in fishermen and 4.57% in farmers with highly significant value in fishermen when compared with farmers (P < 0.01). Geometric egg count (gm/stool) was 430 +/- 259 and 236 +/- 161 in fishermen and farmers respectively with highly significant difference (P < 0.001). All urine samples were negative for S. haematobium. The socioeconomic status of all individuals showed no significant difference between the two groups. It was concluded that fishermen had a higher S. mansoni prevalence, infection intensity and morbidity than farmers. This may be due to more water contact activities. A snail population survey of the river and main canals was recommended.

Interaction of butorphanol, with monoamine oxidase inhibitor, tranylcypromine.

This investigation examines the possibility of interaction between tranylcypromine and butorphanol in comparison to pethidine. The LD50 of pethidine and butorphanol were determined in mice pretreated with the non-selective monoamine oxidase (MAO) inhibitor, tranylcypromine orally for 8 days or with oral saline solution. Tranylcypromine decreased the LD50 of both pethidine and butorphanol by 78% and 41%, respectively. Anesthetized rabbits with halothane pretreated with tranylcypromine or saline were given pethidine (5 mg/kg i.v.) or butorphanol (0.5, 1 and 2 mg/kg i.v.). Pethidine produced a marked increase in blood pressure in rabbits pretreated with tranylcypromine and did not affect significantly the heart rate. Butorphanol did not affect either blood pressure or heart rate at doses of 0.5 or 1 mg/kg. However, the largest dose of butorphanol (2 mg/kg) produced hypotension and tachycardia in rabbits pretreated with tranylcypromine. Neither pethidine nor butorphanol affected the temperature of anesthetized rabbits pretreated with tranylcypromine or saline.

Effect of aspirin and indomethacin on the serum and urinary calcium, magnesium and phosphate.

Recent data have shown that administration of prostaglandin inhibitors to patients with hypercalciuric nephrolithiasis decreased urinary calcium excretion, implying a possible role for prostaglandins in calcium excretion. To explore this hypothesis, we investigated the effect of single dose or 7 days' administrations of aspirin (100 mg/kg orally) or indomethacin (20 mg/kg, orally) on the urinary and serum concentrations of calcium, magnesium and inorganic phosphate. Experiments were performed in normocalcaemic and hypercalcaemic rats. Hypercalcaemia and hypercalciuria were induced in male Wistar albino rats by administration of vitamin D3 (20,000 IU/daily) for 7 days. Aspirin and indomethacin both significantly lowered the urinary calcium excretion in normocalciuric and hypercalciuric rats. The acute administration of indomethacin caused greater reduction of calcium excretion than that produced by the acute administration of aspirin, whereas aspirin showed greater activity than indomethacin after the long-term use of each. Aspirin induced hypocalcaemia in normocalcaemic rats and abolished the hypercalcaemia in hypercalcaemic rats. On the contrary, indomethacin, a specific prostaglandin biosynthesis inhibitor, increased serum levels of calcium. Hypophosphataemia was observed only after the administration of a single dose of aspirin in normocalcaemic rats, while the reduction of urinary phosphate excretion was investigated in hypercalciuric rats after the acute and chronic administration of indomethacin. Serum levels of phosphate were not altered significantly by acute or chronic administration of indomethacin. A single dose of indomethacin significantly reduced urinary excretion of magnesium in both groups of rats. However, the acute and chronic administration of aspirin resulted in non-significant changes in serum and urinary concentrations of magnesium. These data suggest that aspirin has hypocalcaemic and hypocalciuric actions while indomethacin has only a hypocalciuric effect. Aspirin may produce these actions by two mechanisms, one of them like that of indomethacin which is dependent on the inhibition of biosynthesis of prostaglandins, and another possible mechanism that is not related to the inhibition of prostaglandin biosynthesis. This suggestion may be supported by the discrepancy between the effects of aspirin and indomethacin on the renal handling and serum concentrations of magnesium and inorganic phosphate.

Modification of morphine-induced analgesia, tolerance and dependence by bromocriptine.

The effect of two doses of bromocriptine, a dopamine agonist, on morphine-induced analgesia, tolerance and dependence was investigated in mice. Bromocriptine at doses of 0.04 and 0.08 mg/kg did not affect the baseline tail flick latency of mice but potentiated the morphine analgesia. Pretreatment of mice with 5 mg/kg of sulpiride, a D-2 antagonist, not only blocked the effect of 0.08 mg/kg of bromocriptine but also antagonized the morphine analgesia. Control animals given daily injections of 10 mg/kg of morphine rapidly developed tolerance to the analgesic effect. A combined treatment of bromocriptine with morphine given daily suppressed the development of tolerance to morphine analgesia. However, development of tolerance to morphine analgesia was not significantly modified in the animals treated daily with bromocriptine (0.08 mg/kg) plus sulpiride (5 mg/kg). Acute dependence was induced by the administration of 100 mg/kg of morphine. The administration of bromocriptine 30 min before naloxone significantly decreased the ED50 value for naloxone for inducing jumping in mice. Coadministration of sulpiride and bromocriptine attenuated the ability of bromocriptine to potentiate the withdrawal syndrome of morphine dependence. The results indicate that bromocriptine potentiates morphine analgesia, suppresses the development of tolerance to morphine analgesia but exacerbates opiate withdrawal signs in morphine-dependent mice. These effects of bromocriptine appear to be mediated via D-2 receptors.

Adenosine triphosphate blocks opiate withdrawal symptoms in rats and mice.

The effect of adenosine triphosphate (ATP) on the expression of opiate withdrawal was examined using a chronic model of morphine-dependence. ATP was studied for its ability to modify or block jumping in morphine-abstinent mice. In mice administered 2 mg/kg ATP intravenously, the naloxone ED50 for withdrawal jumping increased by 11-fold in comparison to saline-treated mice. Nalaxone-precipitated morphine-withdrawal in the rats, has been shown to induce a specific pattern of intestinal hypermyoelectric activity and to increase the arterial blood pressure. Administration of ATP at dose of 1 and 2 mg/kg intravenously inhibited the induction of hypermyoelectric activity pattern in 80 and 100% of animals tested respectively. ATP also blocked the increase in mean arterial blood pressure seen during withdrawal in a dose-dependent fashion. Investigations were carried out to determine if blocking of the alpha 2-adrenoreceptors with yohimbine would result in an alteration in antiwithdrawal action of ATP. Yohimbine reversed the effect of ATP in blocking naloxone-precipitated withdrawal on the myoelectric activity of jejunum and colon, however, it failed to antagonize the effect of ATP on withdrawal jumping and to block the effect of ATP on the pressor response produced by naloxone in morphine-dependent animals.

Characteristics of analgesia induced by adenosine triphosphate.

Adenosine triphosphate (ATP) injected intravenously in mice was found to have dose-dependent analgesic activity in the hot plate and phenylquinone-induced stretching assays. ATP prolonged the hot plate latency (ED50 value of 1 (0.7-1.4) mg/kg) and inhibited phenylquinone-induced writhing (ED50 value of 0.4 (0.31-0.52) mg/kg). Low doses of ATP produced a potent antinociceptive effect without any significant depression of locomotor activity. Treatment of mice for either 4 days or 14 days with ATP did not result in development of physical dependence on or tolerance to ATP. The analgesic action of ATP was not antagonized by naloxone at 1 and 5 mg/kg. ATP analgesia was antagonized, in a dose-related fashion, by Ca++ ion injected intracerbroventricularly which may indicate that Ca++ plays a role in ATP-induced antinociception.

Influence of aspirin on the pharmacokinetics of norethindrone.

The influence of a single dose of aspirin on the pharmacokinetics of the synthetic progestogen norethindrone was studied in rabbits. It was found that neither the 24-hr plasma levels nor the pharmacokinetic parameters of norethindrone following intravenous dosing were significantly altered by aspirin. However, after oral administration of norethindrone, the area under the plasma norethindrone versus time curve was significantly decreased by aspirin from 0.72 +/- 0.058 ng/ml X hr to 0.49 +/- 0.046 ng/ml X hr (mean +/- S.E) and the oral bioavailability was reduced from 56 +/- 4.2% to 38 +/- 3.6%, perhaps due to increased gut wall metabolism of norethindrone by aspirin.

Levonorgestrel concentrations in maternal and infant serum during use of subdermal levonorgestrel contraceptive implants, Norplant, by nursing mothers.

The transfer of levonorgestrel to infants was studied in 42 lactating women in whom the contraceptive subdermal implants, Norplant, were inserted 30 to 40 days postpartum. The women breastfed their infants for one year. Simultaneous mother and infant blood samples were taken once during the year. The levonorgestrel serum concentrations were measured by radioimmunoassay. During the first postinsertion month, the levonorgestrel concentration in the infants serum amounted, on the average, to 5% of the maternal concentration. Thereafter, the ratio ranged from 8 to 13%. The implications of this finding are discussed.

The effect of thiabendazole on pain threshold.

Thiabendazole significantly increased the reaction time to thermal stimulus. However, in mice treated with morphine, the reaction time was not in any way different from those treated with combined doses of thiabendazole and morphine. Thiabendazole was found to have an antinociceptive action. The protective dose for 50% of animal (ED50) against p-benzoquinone-induced writhing reflex was found to be 310 mg/kg. The ED50 for aspirin alone was 140 mg/kg. When the ED50 of aspirin was determined in combination with different dose levels of thiabendazole, it showed a marked reduction in the values reaching 50 mg/kg, when 300 mg of thiabendazole was used in combination. Toxicological studies revealed that the oral LD50 for thiabendazole in mice was 2200 mg/kg, and when combined with 140 mg/kg of aspirin, the LD50 was reduced to 900 mg/kg. These findings indicate that thiabendazole possesses an analgesic activity which is potentiated by aspirin, though aspirin was found to significantly enhance its toxicity.

Hormonal changes during the first year of use of subdermal levonoregestrel implants, Norplant.

Sixty-three women had NORPLANT implants inserted during the first eight days of the menstrual cycle. Blood specimens were withdrawn at the time of insertion and every three days during one of the following months of observation; the first, third, sixth, ninth and twelfth month after insertion. Ten subjects were sampled at multiple times during implant use. A total of 83 months of observation was available. The serum concentrations of levonorgestrel (LNG), FSH, LH, prolactin (PRL), estradiol (E2) and progesterone (prog) were measured in each specimen. LNG concentration rapidly declined during the first 15 days of use, the decline became more gradual during the subsequent two weeks, and an almost steady level was reached during the remainder of the year. There were no significant trends of change in the levels of FSH, LH, E2 and prog during the year. Frequent peaks in E2 concentration were observed and were generally associated with or followed by LH surges. PRL concentration showed a slight but significant rise during the second half of the year. Rises in prog concentration suggestive of ovulation occurred in 36 percent of the months of observation. However, in all these instances, there were evidences suggestive of deficient luteal phase. The bleeding episodes were usually, but not always, related to decline in E2 and prog concentrations.

A study of interaction between levonorgestrel and ethanol.

Female Wistar rats were pair-fed a diet containing either ethanol (5%) or isocaloric carbohydrate substituent. After 6 weeks, a single dose (5 micrograms/kg) of levonorgestrel was given to the animals in each group either orally, subcutaneously or intravenously. Plasma levels of levonorgestrel at different time intervals were measured by RIA. Chronic alcohol administration did not affect plasma levels of levonorgestrel after oral administration. When the drug was given subcutaneously, plasma levels and AUC were significantly decreased in the alcoholic compared to control group. Following intravenous administration, the elimination half-life of levonorgestrel was shorter while the metabolic clearance was higher in the alcohol-treated group rather than the control group.