Impaired immune response by isoniazid treatment during intravesical BCG administration in the guinea pig.

At present, isoniazid (INH) is being used prophylactically to reduce the side effects of intravesical BCG therapy for superficial bladder cancer, although it is not clear whether or not this reduces the antitumor efficacy of BCG. In this study the impact of INH treatment on the immune response after repeated intravesical BCG administration was investigated in guinea pigs. INH was given on the 3 days around each BCG instillation. We found that the administration of INH severely impaired the immunological effects of BCG. The induction of mononuclear cell infiltration in the bladder wall was reduced. Enlargement of the regional lymph nodes (weight and number of cells), and increase of MHC Class II expression on the lymph node cells, normally observed after intravesical BCG administration, were inhibited by INH. Systemic immunity, measured by the DTH reaction in the skin to PPD, was also diminished due to the combined treatment of BCG with INH. When INH was administered during the last 4 of 6 BCG instillations, the immune response to BCG was still impaired. A five-fold increase of the dose of BCG did not overcome the effect of INH. INH probably did not exert a direct suppression of the immune system of the guinea pig as the DNCB skin reactivity was not influenced. Although INH concentrations in the urine were high at the onset of the instillation, in vitro experiments indicated that the effect of INH may not be caused by killing of the BCG organisms shortly after application in the bladder. In conclusion, our data in guinea pigs suggest that the use of INH may impair the immune response to intravesical BCG. As this response may be important for the antitumor effect of BCG, urologists should be cautious with the prophylactic use of INH. The influence on the antitumor efficacy is now investigated in man.     

Recombinant tissue-plasminogen activator (rt-PA) in acute myocardial infarction in the Chinese in Hong Kong.

Eighty-nine consecutive Chinese patients (69 males, 20 females) with acute myocardial infarction treated by 100 mg recombinant tissue-plasminogen activator (rt-PA) (7 intracoronarily, 82 intravenously) at 3.7 +/- 1.0 hours after onset, and intravenous heparin or dipyridamole therapy started at 3 hours, were studied prospectively. Their mean age was 59.6 +/- 10.6 years. Forty-six patients (51.7%) had anterior and 39 patients (43.8%) had inferior infarcts. Clinical evidence of reperfusion was seen in 63 patients (72.8%), while new complications included hypotension (5.6%), heart failure (6.7%), cardiac arrhythmias (76.4%), hematoma around vascular access sites (23.6%), melena (2.2%) and cerebral infarction (2.2%). Maximal changes in coagulation profiles were seen at 3 hours, including a decrease in fibrinogen (by 64.2%), an increase in FDP by 11.7 times and D-dimers by 4.4 times. Nine patients (10.1%) had recurrence of angina and 6 patients (6.9%) died due to pump failure (5) and reinfarction (1). Angiogram at 14 days confirmed TIMI (2 or 3) patency of infarct related arteries in 62/81 (76.5%) patients, with a mean global ejection fraction of 52.5 +/- 12.4%. Nearly all survivors could maintain class I-II functional status after discharge. The safety and promises of rt-PA for acute myocardial infarction in the Chinese were confirmed.

     

Excursion of the flexor digitorum profundus tendon: a kinematic study of the human and canine digits

The most common problem following primary flexor tendon repair is the failure of the tendon apparatus to glide, secondary to the formation of adhesions. Early motion following tendon repair has been shown to be effective in reducing adhesions between the tendon and the surrounding sheath. Therefore, it is important to determine the amount of flexor tendon excursion along the digit during joint motion. In this study, the excursion between the flexor digitorum profundus (FDP) tendon and the sheath was examined in both human and canine digits. Based on roentgenographic measurements and joint kinematic analysis, the motion of the bones, the FDP tendon, and the sheath were measured with respect to joint rotations. It was found that the canine flexor tendon apparatus behaved similarly to that of the human for the motions studied. The amount of tendon excursion was very small in regions distal to the joint in motion (approximately 0.1 mm/10 degrees of joint rotation). There was little displacement of the sheath (0.2-0.3 mm), except at the metacarpal joint region during metacarpophalangeal (MCP) joint motion and at the proximal interphalangeal (PIP) joint region during PIP joint motion. Tendon excursion relative to the tendon sheath was the largest in zone II during PIP joint rotation (1.7 mm/10 degrees of joint rotation). These results suggest that PIP joint motion may be most effective in reducing adhesions following tendon repair in zone II.     

Alpha-methyldopa induces a naltrexone-insensitive antinociception and hypomotility in rats.

1. This study served to investigate whether endogenous opioid peptides play a role in the putative antinociceptive and the sedative actions of alpha-methyldopa. 2. In conscious normotensive rats, alpha-methyldopa induced hypotension, starting around 1 h and reaching a maximum 3-4 h after administration. Pretreatment with naltrexone resulted in an inhibition of alpha-methyldopa-induced hypotension. 3. alpha-Methyldopa dose-dependently increased hot plate latency which became evident after a 4 h lag period and reaching a maximum effect at 6 h. The antinociceptive effect of alpha-methyldopa was not affected by naltrexone. 4. In a small open field, alpha-methyldopa dose-dependently suppressed locomotion and sniffing behaviour. These effects of alpha-methyldopa were apparent 1 h after administration and were naltrexone-insensitive. 5. No changes in the level of beta-endorphin-like immunoreactivity in plasma and cerebrospinal fluid were observed after administration of alpha-methyldopa. 6. The results indicate that endogenous opioid peptides are involved in the hypotensive action of alpha-methyldopa but not in alpha-methyldopa-induced hypomotility and antinociception.     

An Unusual Form of Skin Tuberculosis Following B.C.G. Vaccination

A 25-year-old female has had brown to erythematous telangiectatic patches and grouped papules on her face, neck, arm, and trunk since childhood following B.C.G. vaccination. Histopathologically, the lesions consisted of hyperkeratosis, slight acanthosis, tuberculoid granulomas with some Langerhans type giant cells in the mid-dermis. Although various forms of cutaneous tuberculosis after B.C.G. vaccination have been reported, it was difficult for us to assign the patient's skin lesion to any specific disease entity. Remission of her cutaneous lesions occurred clinically and histopathologically after treatment with isoniazid and rifampin.     

Reproducibility of angiotensin converting enzyme inhibitor induced cough: A double-blind randomised study

1 The reproducibility of angiotensin converting enzyme inhibitor induced cough was examined in a double-blind cross over study in patients previously shown to have exhibited this side effect.

2 Ninety-seven patients who had experienced angiotensin converting enzyme inhibitor cough within the last 2 years were challenged with enalapril 20 mg daily for 4 weeks to establish eligibility. Eighty-eight of 97 (91%) patients experienced a repeat of their cough symptoms. Sixty-four patients entered the double-blind part of the study where they were treated with enalapril 20 mg and a renin inhibitor for up to 4 weeks in random order. These periods were separated by a minimum 4 week placebo wash out.

3 Of 59 evaluable patients who received enalapril a second time, 37 (62.7%) experienced cough again. Of 62 patients on the renin inhibitor 16 (25.8%) experienced cough, however as it was not equi-efficacious to enalapril no valid comparison could be made.

4 Angiotensin converting enzyme inhibitor cough is not reproducible within patients, as other factors are involved in the aetiology. Objective testing with blinded assessment together with symptom reporting, would give a more accurate measure of the incidence, and mechanism of this side effect.

     

Astigmatism and visual recovery after phacoemulsification and conventional extracapsular cataract extraction

In this study we wanted to investigate the post-operative astigmatism and visual acuity after phacoemulsification and conventional extracapsular cataract surgery. Patients operated between April and June 1993 (n=150) were retrospectively analyzed. The patients were examined prior to surgery and at day 1, at day 10, and in week 6 post-operatively. The difference between the post-operative log mean visual acuity in the Phaco group and in the CECCE group was significant after 1 and 10 days, however it was not significant (p=0.191) after 6 weeks. The mean astigmatism was significantly less in the Phaco group than in the CECCE group during the whole post-operative check-up period. This study suggests that Phaco results in a lower post-operative astigmatism and an earlier visual rehabilitation compared to the CECCE technique.Abbreviations Phaco Phacoemulsification - CECCE Conventional extracapsular cataract extraction     

Treatment planning for asymmetric jaws on a commercial TP system.

In this work, the accuracy of the asymmetric jaws planning feature in a commercial treatment planning (TP) system is assessed. In the latest version of this software, the off-axis beam quality variation is handled by a function g(d,r), which is derived from measured horizontal beam profiles at four different depths. The calculated and measured isodoses for a 6-MV linear accelerator with asymmetric jaws agree to +/- 0.5% along the central axis and to within 2 mm at the beam edge. Formulas for treatment time calculations using the output data reported by the computer program are described, as well as formulas for manual calculations based on pregenerated data tables. Doses calculated based on these formulas are compared to measurement and the accuracy is +/- 1% and +/- 2% for the computer and manual calculations, respectively. It is concluded that this version of the treatment planning system as well as the treatment time calculation formulas can be used adequately for asymmetric jaw computerized and manual treatment planning.     

When poor solubility becomes an issue: From early stage to proof of concept

Drug absorption, sufficient and reproducible bioavailability and/or pharmacokinetic profile in humans are recognized today as one of the major challenges in oral delivery of new drug substances. The issue arose especially when drug discovery and medicinal chemistry moved from wet chemistry to combinatorial chemistry and high throughput screening in the mid-1990s. Taking into account the drug product development times of 8–12 years, the apparent R&D productivity gap as determined by the number of products in late stage clinical development today, is the result of the drug discovery and formulation development in the late 1990s, which were the early and enthusiastic times of the combinatorial chemistry and high throughput screening. In parallel to implementation of these new technologies, tremendous knowledge has been accumulated on biological factors like transporters, metabolizing enzymes and efflux systems as well as on the physicochemical characteristics of the drug substances like crystal structures and salt formation impacting oral bioavailability. Research tools and technologies have been, are and will be developed to assess the impact of these factors on drug absorption for the new chemical entities.

The conference focused specifically on the impact of compounds with poor solubility on analytical evaluation, prediction of oral absorption, substance selection, material and formulation strategies and development. The existing tools and technologies, their potential utilization throughout the drug development process and the directions for further research to overcome existing gaps and influence these drug characteristics were discussed in detail.     

Intracranial ependymoma in children: analysis of prognostic factors

Summary Between 1955 and 1986, 25 children (aged 2 weeks to 15 years) were treated for intracranial ependymoma at M.D. Anderson Cancer Center. Nine patients had supratentorial primaries (5 high-grade, 4 low-grade), and 16 had infratentorial primaries (9 high-grade, 7 low-grade). Five patients had gross complete resection and 20 had incomplete resection. Seven patients received craniospinal irradiation (25–36 Gy to the neuroaxis, 45–55 Gy to tumor bed), 12 received local field irradiation (29–60 Gy, median 50 Gy). Five infants had adjuvant chemotherapy without radiotherapy, and 6 children had postradiotherapy adjuvant chemotherapy, and 12 patients had salvage chemotherapy with various agents and number of courses. Eight patients are alive, disease-free and without relapse from 1 year to 12 1/2 years from diagnosis (median 42 months). The primary failure pattern was local recurrence. The data suggest that 1) the long-term cure rate of children with ependymoma is suboptimal; 2) histologic grade may be of prognostic importance for supratentorial tumors; 3) prognosis appears worse for girls and infants under 3 years of age; 4) in well-staged patients routine spinal irradiation could be omitted; 5) the role of adjuvant chemotherapy is unclear. Address for offprints: Shiao Y. Woo, Department of Radiation Oncology, 6565 Fannin, M.S. DB1-37, Houston, Texas 77030, USA