Research & development in the dark: what does it take to make one medicine? And what could it take?

Earlier this year a series of advertisements appeared in London's Westminster tube stations asking viewers to consider a seemingly simple question, 'what does it take to make one medicine?' But as it turns out, this question is not so simple to answer. In this commentary we highlight some key considerations and questions on what it takes to make one medicine, and what it could take to develop medicines that meet people's health needs and are accessible and affordable for all who need them.

Outbreak of Salmonella Braenderup infections associated with Roma tomatoes, northeastern United States, 2004: a useful method for subtyping exposures in field investigations.

Salmonella Braenderup is an uncommon serotype in the United States. In July 2004, a multistate outbreak of Salmonella Braenderup diarrhoeal infections occurred, with 125 clinical isolates identified. To investigate, we conducted a case-control study, enrolling 32 cases and 63 matched controls. Cheese, lettuce and tomato eaten at restaurants all appeared to be associated with illness. To further define specific exposures, we conducted a second study and asked managers of restaurants patronized by patients and controls about cheese, lettuce and tomato varieties used in dishes their patrons reported consuming. This information was obtained for 27 cases and 29 controls. Roma tomatoes were the only exposure significantly associated with illness (odds ratio 4.3, 95% confidence interval 1.2-15.9). Roma tomatoes from two restaurants were traced back to a single tomato packing house. The methods used in this field investigation to define specific exposures may be useful for other foodborne outbreaks.

Efficacy of three artemisinin combination therapies for the treatment of uncomplicated Plasmodium falciparummalaria in the Republic of Congo

Background: Presented here are the results of a comparative trial on the efficacy of three artemisinin-based combinations conducted from May to October 2004; in Pool Province; Republic of Congo.Methods: The main outcome was the proportion of cases of true treatment success at day 28. Recrudescences were distinguished from re-infections by PCR analysis. A total of 298 children of 6-59 months were randomized to receive either artesunate + SP (AS+SP); artesunate + amodiaquine (AS+AQ) or artemether + lumefantrine (AL); of which 15 (5) were lost to follow-up. Results: After 28 days; there were 21/85 (25) recurrent parasitaemias in the AS+SP group; 31/97 (32) in the AS+AQ group and 13/100 (13) in the AL group. The 28-day PCR-corrected cure rate was 90.1[95CI 80.7-95.9] for AS+SP; 98.5[95CI 92.0-100] for AS+AQ and 100[95.8-100] for AL; thereby revealing a weaker response to AS+SP than to AL (p=0.003) and to AS+AQ (p=0.06). A potential bias was the fact that children treated with AL were slightly older and in better clinical condition; but logistic regression did not identify these as relevant factors. There was no significant difference between groups in fever and parasite clearance time; improvement of anaemia and gametocyte carriage at day 28. No serious adverse events were reported. Conclusions: Considering the higher efficacy of AL as compared to AS+SP and the relatively high proportion of cases with re-infections in the AS+AQ group; we conclude that AL is clinically more effective than AS+SP and AS+AQ in this area of the Republic of Congo. Implementation of the recently chosen new national first-line AS+AQ should be monitored closely

Comparison of alpha-fetoprotein with some other tumour markers in Malaysians with hepatocellular carcinoma.

Although alpha-fetoprotein (AFP) is regarded as the reference marker for hepatocellular carcinoma (HCC), it sometimes produces false results. The objective of this study was to see if some of the readily available laboratory markers could complement AFP to improve the laboratory diagnosis of HCC. The markers tested and their sensitivities were: CA 125, 92%; ferritin, 71.3%; CA 19-9, 69.8%; beta-2-microglobulin (B2M), 53.3%; CA 72-4, 13.6%; and carcinoembryonic antigen (CEA), 10.6%. In comparison, AFP had a sensitivity of 58.8%. CA 72-4 and CEA (at the "tumour" cut-off level of 20 ng/ml) had specificities of 100%, and AFP, 97.4%. The specificities of the other markers were less impressive: CEA, 77.8% (at the cut-off level of 5 ng/ml); ferritin, 48.6%; CA 125, 48.5%; B2M, 39.6%; and CA 19-9, 37.3%. The efficiencies of the markers for HCC, which are based on the consideration of sensitivity and specificity together, were as follows: AFP, 77.6%; CA 125, 71.3%; ferritin, 60.5%; CA 19-9, 55.3; B2M, 46.9%; CEA, 40.8%; and CA 72-4, 34.5%. The receiver-operating characteristic plots confirmed AFP to be the most efficient marker for HCC. Nevertheless, it is proposed that CA 125 be combined with AFP for HCC screening because of their excellent sensitivity and specificity, respectively: a negative result for both, or even just CA 125 alone, would indicate that the disease is unlikely while a positive AFP (which would likely occur with a positive CA 125) would make its presence highly probable. A positive CA 125 and negative AFP would be equivocal for HCC. Other markers in combination with AFP are less useful.

The value of liver function tests in hepatocellular carcinoma.

This study was undertaken to see if liver function tests (LFT) served a worthwhile purpose in the investigation of hepatocellular carcinoma (HCC). Sera from 80 HCC, 76 benign liver disease (BLD) and 152 healthy adult (HA) subjects were assayed for alkaline phosphatase (ALP), gamma-glutamyltransferase (GGT), aspartate aminotransferase (AST), alanine aminotransferase and lactate dehydrogenase, bilirubin and albumin. Cut-off values were determined from the HA. ALP, GGT, AST and albumin were abnormal in about 90% of the HCC. With the exception of bilirubin, the LFT were abnormal more frequently in HCC than in chronic hepatitis and cirrhosis, the conditions which preceed it. Raised ALP in the presence of normal bilirubin was more often a feature of HCC than BLD although this relationship was not statistically significant. It seems unlikely that LFT serve a useful function in HCC.

Serum CA 125 as a marker of hepatocellular carcinoma.

This study was undertaken to investigate whether serum CA 125 could complement alpha-fetoprotein (AFP) to improve the diagnosis of hepatocellular carcinoma (HCC). CA 125 showed a sensitivity of 92% for HCC against the 58.8% sensitivity of AFP at the cutoff value of 200 ng/ml. However, the former was less specific (48.5% versus 97.4%) in relation to benign liver diseases (BLD). CA 125 had a higher negative predictive value (NPV) of 84.6% compared to 69.2% for AFP; when both markers were combined, however, the NPV rose to 91.7%. Overall, AFP was more efficient than CA 125 for the diagnosis of HCC. While a positive AFP result was highly indicative of HCC, a negative result did not rule out the disease; however, negative AFP and CA 125 meant that the likelihood of the disease was low. In situations of low HCC prevalence, CA 125 could serve as a first-line screening test followed by confirmation of positives by AFP.

Hepatitis markers in Malaysians with hepatocellular carcinoma.

Sera from 80 Malaysians with confirmed hepatocellular carcinoma were tested for five markers of the hepatitis B virus, anti-HCV and anti-HDV by enzyme immunoassay, and alpha fetoprotein (AFP) was measured by radioimmunoassay. Of the patients, 98.8% had evidence of HBV infection and 75% were positive for HBsAg--which latter correlated with AFP raised above cut-off values of 500 ng/ml (P = 0.0001) and 200 ng/ml (P = 0.005). Males correlated significantly with the presence of HBsAg (P = 0.002). Thirty-one per cent of HBsAg positive patients were also positive for HBeAg and 74% for anti-HBe. Twenty per cent of the cases were concurrently positive for both HBsAg and anti-HBs. Six of 70 (8.6%) patients were positive for anti-HCV, of whom four were also positive for HBsAg. None of 67 patients tested for anti-HDV were positive. The results strongly indicate an important aetiological role for hepatitis B virus in causation of hepatocellular carcinoma among Malaysians.

Quantitation of hepatitis B virus DNA in serum of patients with hepatoma.

Hepatitis B virus (HBV) DNA in the serum of 31 patients with histologically confirmed primary hepatocellular carcinoma (PHC) from Malaysia and Indonesia was quantitated by densitometric scanning of autoradiograms obtained by Southern blot DNA hybridization, after electrophoresis using a 32P DNA cloned into plasmid pBR325 as a probe. This quantitation after electrophoresis is more informative than the usual spot hybridization technique. Five of the 31 sera were positive for HBV DNA. Levels ranged between 1.36 pq and 143.18 pq per ml of serum, and the levels of HBsAg, anti-HBs, anti-HBc, HBeAg and anti-HBe in the serum were serologically determined. All five sera positive for HBV DNA were also positive for HBsAg. Three of the five positive for HBV DNA were positive for HBeAg and negative for anti-HBe. Two of the sera positive for HBV DNA were negative for HBeAg but positive for anti-HBe. All sera negative for HBV DNA were also negative for HBeAg. Many sera which were negative for HBV DNA and HBeAg were positive for HBsAg. Of the 31 sera from PHC patients, 23 had at least one HBV marker positive (74.2%).

Hepatitis B virus DNA in liver and white blood cells of patients with hepatoma.

Hepatitis B virus (HBV) DNA was studied in liver DNA of 23 patients with primary hepatocellular carcinoma and in white blood cell DNA of 11 of these patients by Southern blot hybridization analysis probed with 32P-labeled HBV DNA cloned in plasmid pBR325. Of the 23 hepatoma DNA samples, 16 were positive for HBV DNA, and 15 of these showed integration of HBV DNA into the host liver DNA. In 5 patients, free HBV DNA was found in addition to integrated HBV DNA and in only one was free HBV found alone. All patients serologically positive for HBV surface antigen (HBsAg) were positive for HBV DNA in tumor samples. The pattern and the degree of hybridization differed considerably among different cases. HBV DNA was found in tumor and in adjacent nontumor tissue in two patients. Of 11 white blood cell DNA samples, two were positive for HBV DNA. The HBV DNA in the white blood cells was not integrated into the host DNA. In the undigested white blood cell DNA, the free HBV DNA gave a positive signal at 5.5 kb and often also at 9.5 kb. After Eco RI digestion, these 5.5-kb and 9.5-kb positive fragments disappeared, while a strong positive band at 3.2-kb appeared. Hind III digestion produced the same positive fragments as in the undigested white blood cell DNA and failed to produce the 3.2-kb fragment. Sometimes, especially after Hind III digestion, a positive fragment at a position corresponding to about 16.2 kb was also demonstrable in addition to the 5.5-kb and 9.5-kb positive fragments.(ABSTRACT TRUNCATED AT 250 WORDS)

Clinical and chemotherapeutic study of hepatocellular carcinoma in Malaysia: a comparison with African and American patients.

Twenty Malaysian patients with unresectable primary liver cell cancer were prospectively studied at the General Hospital, Kuala Lampur, and were compared for clinical features with an equal number each of African and American patients being studied by the Eastern Cooperative Oncology Group. The patients received intravenous 5-FU and oral MeCCNU which was used for the first time in an Asian country. Most of the Malaysian patients were Chinese, belonged to younger age groups, and presented with massive hepatomegaly, jaundice, and fever. Toxicity to MeCCNU invariably occurred in the form of leukopenia or thrombocytopenia, but none life threatening. Partial response was seen in 20% of Malaysians as compared to 16% in Americans and none in Africans. Malaysians achieved a median survival of 16 weeks compared to 28 weeks in Americans and only eight weeks in Africans. Malaysian Chinese patients were all HBc Ab + ve. Other factors which may have played an etiologic role in the induction of primary liver cancer included alcohol, Chinese herbal medicines, aflatoxin and habitual use of medicated rubbing oils.

Hepatic resection: the logical approach to surgical management of major trauma to the liver.

Recent reports on the management of hepatic trauma have discouraged hepatic resection and supported hepatic artery ligation, "resectional debridement" and even packing. These nonresectional procedures are based on misguided principles and should never replace resection. Traditional methods of conducting hepatic resection in an emergency as used in the West probably cause delay in achieving immediate hemostasis, thus contributing to mortality. Compared with Western reports, our mortality for major hepatic resections is considerably low. This is probably due to faster resection and achievement of hemostasis by our clamping techniques. We conclude that it is quite logical to perform resection as the first line of treatment in major hepatic trauma.

Hepatic resection. Pillars of success built on the foundation of 15 years of experience.

Two hundred eight-eight hepatic resections performed over the past 15 years are discussed. The safety and success achieved are attributed to the original work in Malaysia on the anatomy of the liver and its anomalies, the use of surgical instruments specially designed for hepatic resection, various types of resections devised and studies on aids to liver regeneration after resection. The diversity of the principles and practice of surgery in the Western countries compared with those in Malaysia is illustrated.

Hepatic resections 1964-1979: vignettes drawn from the Malaysian experience.

We present a study of 288 hepatic resections carried out in Malaysia for the past fifteen years. First, we describe our indications for hepatic resectins which are not limited to hepatic trauma and hepatomas, but also include hepatic abscesses, cysts, intrahepatic calculi and hemangiomas. Second, we give a simplified classification of hepatic resections using accurate terminology. Third, we describe the safety of hepatic resections in our hands which we believe is due to specially designed surgical instruments and the accurate decision making process at surgery. We have had minimum postoperative mortality and no intraoperative deaths so far. Finally, while analysing each indication we have drawn vignettes from our experience for the past fifteen years.

Hepatic resection for malignant tumors of the liver: essentials for a unified surgical approach.

A unified surgical approach to hepatic resection and a simplified terminology in the classification of hepatic resections are presented based on experience with several hundred hepatic resections using specially designed instruments.

5'-Nucleotide phosphodiesterase isozyme-V in health, in cancer, and in viral hepatitis.

An abnormal, fast-moving 5'-nucleotide phosphodiesterase isozyme was found in 90.0% of 20 Malaysian patients with primary hepatoma and in 23.5% of 391 Malaysian patients with various malignant diseases; it was also discovered in 42.9% of 14 Malaysian and American patients with clinically active hepatitis B infection; in 16.7% of 18 healthy American blood bank donors who were positive for hepatitis B surface antigen (HBsAg); in 13.9% of 287 healthy Malaysian blood bank donors, some positive for HBsAg; and in none of 160 healthy American donors who were negative for HBsAg. A correlation of this abnormal isozyme with hepatoma and with infectious hepatitis B is clearly evident.