Papaya (Carica papaya) consumption is unsafe in pregnancy: fact or fable? Scientific evaluation of a common belief in some parts of Asia using a rat model

Using controlled in vivo and in vitro pharmacological methods, we evaluated the safety of papaya (Carica papaya) consumption in pregnancy with reference to its common avoidance during pregnancy in some parts of Asia. Ripe papaya (Carica papaya L. (Caricaecae) blend (500 ml/l water) was freely given to four groups of Sprague-Dawley rats at different stages of gestation (days 1-5, 6-11, 12-17 and 1-20). The control group received water. The effect of ripe papaya juice and crude papaya latex on pregnant and non-pregnant rats' uteri was also evaluated using standard isolated-organ-bath methods. The daily volumes (ml) of ripe papaya blend consumed by the treated group were significantly (P<0.05) more than water consumed by the control (control 40.3 (sd 11.6) v. treated 64 (sd 19.0)). There was no significant difference in the number of implantation sites and viable fetuses in the rats given ripe papaya relative to the control. No sign of fetal or maternal toxicity was observed in all the groups. In the in vitro study, ripe papaya juice (0.1-0.8 ml) did not show any significant contractile effect on uterine smooth muscles isolated from pregnant and non-pregnant rats; conversely, crude papaya latex (0.1-3.2 mg/ml) induced spasmodic contraction of the uterine muscles similar to oxytocin (1-64 mU/ml) and prostaglandin F(2 alpha) (0.028-1.81 microm). The response of the isolated rat uterine smooth muscles to 0.2 mg crude papaya latex/ml was comparable to 0.23 microm prostaglandin F(2 alpha) and 32 mU oxytocin/ml. In the 18-19 d pregnant rat uterus, the contractile effect of crude papaya latex was characterized by tetanic spasms. The results of the present study suggest that normal consumption of ripe papaya during pregnancy may not pose any significant danger. However, the unripe or semi-ripe papaya (which contains high concentration of the latex that produces marked uterine contractions) could be unsafe in pregnancy. Though evaluation of potentially toxic agents often relies on animal experimental results to predict risk in man, further studies will be necessary to ascertain the ultimate risk of unripe papaya-semi-ripe papaya consumption during pregnancy in man.     

Retrospective study of management of uterine sarcomas at Oxford 1990-1998: role of adjuvant treatment

We report a retrospective study of 47 consecutive patients with uterine sarcoma treated at the Churchill Hospital in Oxford between 1990-1998. The mainstay of treatment was surgery with adjuvant chemotherapy and radiotherapy reserved for selected patients with early stage disease. Overall 1 and 2 year survival was 49% and 30% respectively compared with 73% and 55% in the group who received adjuvant chemotherapy/radiotherapy. Median survival was 11 months for the group as a whole compared to 32.9 months in the adjuvant therapy group. This is a retrospective review with small numbers and considerable selection bias, however, given the poor survival of patients with this disease, adjuvant treatment should be considered in future trials of patients with uterine sarcoma.     

Phase II study of the oxygen saturation curve left shifting agent BW12C in combination with the hypoxia activated drug mitomycin C in advanced colorectal cancer

BW12C (5-[2-formyl-3-hydroxypenoxyl] pentanoic acid) stabilizes oxyhaemoglobin, causing a reversible left-shift of the oxygen saturation curve (OSC) and tissue hypoxia. The activity of mitomycin C (MMC) is enhanced by hypoxia. In this phase II study, 17 patients with metastatic colorectal cancer resistant to 5-fluorouracil (5-FU) received BW12C and MMC. BW12C was given as a bolus loading dose of 45 mg kg(-1) over 1 h, followed by a maintenance infusion of 4 mg kg(-1) h(-1) for 5 h. MMC 6 mg m(-2) was administered over 15 min immediately after the BW12C bolus. The 15 evaluable patients had progressive disease after a median of 2 (range 1-4) cycles of chemotherapy. Haemoglobin electrophoresis 3 and 5 h after the BW12C bolus dose showed a fast moving band consistent with the BW12C-oxyhaemoglobin complex, accounting for approximately 50% of total haemoglobin. The predominant toxicities--nausea/vomiting and vein pain--were mild and did not exceed CTC grade 2. Liver 31P magnetic resonance spectroscopy of patients with hepatic metastases showed no changes consistent with tissue hypoxia. The principle of combining a hypoxically activated drug with an agent that increases tissue hypoxia is clinically feasible, producing an effect equivalent to reducing tumour oxygen delivery by at least 50%. However, BW12C in combination with MMC for 5-FU-resistant colorectal cancer is not an effective regimen. This could be related to drug resistance rather than a failure to enhance cytotoxicity.     

Evaluation of toremifene for reversal of multidrug resistance in renal cell cancer patients treated with vinblastine

Purpose: Expression of P-glycoprotein (Pgp), which confers the multidrug resistance (MDR) phenotype, is thought to contribute to the insensitivity of renal cell cancer (RCC) to chemotherapy. The development of Pgp inhibitors for clinical application has been hampered by unacceptable toxicity at doses required to achieve adequate cellular concentration. Toremifene is able to reverse MDR and sensitise RCC to vinblastine in vitro. However, in vivo toremifene is tightly bound to serum proteins, in particular the acute phase protein α₁-acid glycoprotein (AAG), which may limit tissue availability. In this phase I–II study we assessed the tolerability of short courses of high dose toremifene in combination with vinblastine and evaluated the key determinants of MDR reversal in vivo. Methods: Twenty-seven patients with metastatic RCC received escalating doses of oral toremifene for 3 days every 2 weeks in combination with vinblastine 6 mg/m² i.v. on day 3 of each cycle. The serum concentration of toremifene, its metabolites and AAG were measured and the effect of patients' serum on inhibition of Pgp in vitro was determined. Results: Twenty-six patients were evaluable for response. Eight patients (31%) had stable disease and 18 patients (69%) progressive disease. The mean serum concentration of toremifene at 780 mg daily for 3 days was 7.82 μM [standard deviation (SD) 2.48, range 2.50 to 14.70], which exceeds that known to reverse MDR in vitro. The serum concentration of the major metabolite of toremifene, N-demethyltoremifene, which also reverses MDR, was 5.13 μM (SD 1.78, range 1.80 to 9.00). In 60% of patients the pre-treatment AAG concentration was above that known to block the effects of toremifene in vitro. However, addition of serum from patients on toremifene to MCF-7 adr cells in vitro inhibited Pgp-mediated efflux of rhodamine 123. Conclusions: We have shown that short course, high-dose toremifene in combination with vinblastine is generally well tolerated and that the concentration of toremifene required to reverse MDR in vitro is achievable in vivo. Received: 7 July 1999 / Accepted: 15 November 1999     

Interaction of dexrazoxane with red blood cells and hemoglobin alters pharmacokinetics of doxorubicin

Purpose: The mechanism of the cardioprotective action of dexrazoxane against doxorubicin cardiotoxicity is not fully understood. It has been suggested that its hydrolysis product, ICRF-198, chelates and removes free iron and iron associated with doxorubicin-iron complex and, therefore, prevents the formation of free radical, lipid peroxidation and cardiotoxicity. Dexrazoxane is also known to inhibit topoisomerase II, to prevent the inactivation of cytochrome c oxidase by Fe³⁺-doxorubicin and to increase the levels of transferrin receptor (trf-rec) mRNA and cellular iron uptake. This sequestration of iron and its effect on cellular iron homeostasis may also contribute to its protective effect against doxorubicin cardiotoxicity. The present project was designed to investigate the interaction of dexrazoxane with hemoglobin and red blood cells and the subsequent effect on the pharmacokinetics and toxicodynamics of doxorubicin. Methods: In an in vitro investigation the binding of doxorubicin (0.5–25 μg/ml) to red blood cells, erythrocyte ghosts and hemoglobin in the presence of dexrazoxane was evaluated. In an in vivo study female Sprague Dawley rats were pretreated with 100 mg/kg of dexrazoxane by intravenous injection 1 h before the injection of ¹⁴C-doxorubicin (specific activity 0.4 μCi/mg, 10 mg/kg). The time-course of doxorubicin associated with blood cells and plasma was evaluated with simultaneous characterization of doxorubicin and its metabolites in the bile and urine. The serum concentration of endothelin was measured as a biomarker of cardiotoxicity in separate groups of animals. Results: The in vitro data indicated that dexrazoxane inhibited the binding of DOX to red blood cells in a concentration-dependent manner. At 1 μg/ml it reduced the binding of doxorubicin to red blood cells by about 30% and at 100 μg/ml by about 60%. It had no effect on the association of doxorubicin with erythrocyte ghosts. The investigation of binding of doxorubicin to hemoglobin revealed the existence of two distinct binding sites and dexrazoxane reduced the association constant of doxorubicin with the low-affinity and high-capacity class of binding sites significantly. The pharmacokinetic analysis showed that pretreatment with dexrazoxane (100 mg/kg) reduced the area under plasma concentration-time curve of doxorubicin, its mean residence time and plasma clearance significantly. Similar reductions were also shown with the pharmacokinetic analysis of doxorubicin associated with blood cells. The biliary and urinary elimination of unchanged doxorubicin increased significantly. The pretreatment reduced the serum concentration of endothelin from about 20 ng/ml to about 12 ng/ml. The per cent of this reduction was proportional to the reduction in the AUC of blood cells. Conclusion: The cardioprotective effect of dexrazoxane is due, in part, to its interaction with hemoglobin and red blood cells and this interaction modifies the pharmacokinetics of DOX. Received: 29 July 1999 / Accepted: 11 February 2000     

Hb Leiden-beta (0) thalassemia in a Chinese with severe hemolytic anemia

The first case of Hb Leiden (alpha2beta2 6 or 7 Glu---O)-beta (0) thalassemia in a young patient with chronic severe hemolytic anemia, which improved after splenectomy, is described. His parents were Chinese. The patient's blood showed no Hb A or normal beta chains when no blood transfusion was given. His mother was heterozygous for beta(0) thalassemia, and his father and brother had a trait for the unstable Hb Leiden. The Hb Leiden level of the father was 22.6% and that of the brother was 19.3%. It is probable that the abnormal hemoglobin in this Chinese family resulted from an independent gene mutation, unrelated to the one found in 2 Caucasian families reported earlier.     

Recurrent vesical calculi, hypercalciuria, and biochemical evidence of increased bone resorption in an adult male with paraplegia due to spinal cord injury: is there a role for intermittent oral disodium etidronate therapy for prevention of calcium phosphate bladder stones?

STUDY DESIGN: Clinical case report with comments by colleagues from Sweden, Poland, Spain, Brazil, Japan, Belgium and Switzerland. OBJECTIVES: To discuss the role of disodium etidronate therapy for prevention of calcium phosphate vesical calculi in persons with spinal cord injury, who have hypercalciuria and biochemical evidence of increased bone resorption. SETTING: Regional Spinal Injuries Centre, Southport, UK. METHODS: A 21-year-old male sustained paraplegia (T-10; ASIA scale: A) in a road traffic accident in June 2001. He had an indwelling urethral catheter until the end of August 2001, when he started self-catheterisation. He developed bladder stones and electrohydraulic lithotripsy (EHL) was performed in May 2002. All stone fragments were removed. Recurrence of vesical calculi was noted in October 2002. These stones were fragmented by lithoclast lithotripsy in two sessions, in December 2002 and February 2003; all stone fragments were removed at the end of the second session. This patient reverted to indwelling catheter drainage when vesical calculi recurred. In September 2003, X-ray of the abdomen showed recurrence of vesical calculi. By February 2004, the stones had increased in size and number. EHL of vesical calculi was again performed in April 2004. Complete clearance was achieved. RESULTS: A 24-h urinalysis detected hypercalciuria--18.7 mmol/day (reference range: 2.5-7.5). Biochemical analysis of vesical calculus revealed calcium phosphate (85%) and magnesium ammonium phosphate (15%). Plasma C-terminal telopeptide (CTX) was increased - 1.06 ng/ml (reference range: 0.1-0.5 ng/ml). Free deoxypyridinoline/creatinine ratio (fDPD/Cr) in urine was also increased - 20.2 (reference range: 2.3-5.4). In April 2004, this patient was prescribed disodium etidronate 400 mg day. Nearly 3 months after commencing therapy with etidronate, plasma CTX decreased to 0.87 ng/ml. fDPD/Cr in urine also decreased to 12.4. After 4 months of etidronate therapy, 24-h urinary calcium excretion had decreased to 6.1 mmol/day. CONCLUSION: Etidronate (400 mg daily) is a very effective inhibitor of calcium phosphate crystallisation. Etidronate decreased urinary excretion of calcium, an important factor in prevention of calcium phosphate bladder stones. Etidronate therapy is not a substitute for other well-established methods for prevention of vesical calculi in spinal cord injury patients, for example, large fluid intake, avoiding long-term catheter drainage. Intermittent therapy with etidronate may be considered in selected patients, in whom hypercalciuria persists after instituting nonpharmacological therapy for an adequate period, for example, early mobilisation, weight-bearing exercises, and functional electrical stimulation. However, possible side effects of etidronate, and the fact that etidronate is not licensed in United Kingdom for prevention of urolithiasis, should be borne in mind.