Safety and immunogenicity of the epicutaneous reactivation of pertussis toxin immunity in healthy adults: a phase I, randomized, double-blind, placebo-controlled trial.

OBJECTIVES: Protection induced by acellular vaccines can be short, requiring novel immunization strategies. Objectives of this study were to evaluate safety and capacity of a recombinant pertussis toxin (PTgen) -coated Viaskin® epicutaneous patch to recall memory responses in healthy adults. METHODS: This double-blind, placebo-controlled randomized trial (Phase I) assessed the safety and immunogenicity of PTgen administered on days 0 and 14 to healthy adults using Viaskin® patches applied directly or after epidermal laser-based skin preparation. Patch administration was followed by Boostrix®dTpa on day 42. Antibodies were assessed at days 0, 14, 28, 42 and 70. RESULTS: Among 102 volunteers enrolled, 80 received Viaskin-PT (Viaskin-PT 25 µg (n = 25), Viaskin-PT 50 µg (n = 25), laser + Viaskin-PT 25 µg (n = 5), laser + Viaskin-PT 50 µg (n = 25)), Viaskin-placebo (n = 10) or laser + Viaskin-placebo (n = 2). Incidence of adverse events was similar across groups (any local event: 21/25 (84.0%), 24/25 (96.0%), 4/5 (80.0%), 24/25 (96.0%), 8/10 (80.0%), 10/12 (83.0%), respectively). Direct application induced no detectable response. On day 42, PT-IgG geometric mean concentrations were significantly higher following laser + Viaskin-PT 25 µg and 50 µg (139.87 (95% CI 87.30-224.10) and 121.76 (95% CI 95.04-156.00), respectively), than laser + Viaskin-placebo (59.49, 95% CI 39.37-89.90). Seroresponse rates were higher following laser + Viaskin-PT 25 µg (4/5 (80.0%), 95% CI 28.4-99.5) and 50 µg (22/25 (88.0%), 95% CI 68.8-97.5) than laser + Viaskin-placebo (0/12 (0.0%), 95% CI 0.0-26.5). CONCLUSIONS: Viaskin-PT applied after laser-based epidermal skin preparation showed encouraging safety and immunogenicity results: anti-PT booster responses were not inferior to those elicited by Boostrix®dTpa. This study is registered at ClinicalTrials.gov (NCT03035370) and was funded by DBV Technologies.

Phase I study of 2-amino-5-bromo-6-phenyl-4(3H)-pyrimidinone (ABPP), an oral interferon inducer, in cancer patients.

2-Amino-5-bromo-6-phenyl-4(3H)-pyrimidinone (ABPP) was given to 59 patients in a Phase I study. The agent was selected because it is an interferon inducer and an immunotherapeutic agent in animal tumor models. The study was conducted in two phases. In the first phase, the drug was administered as a single oral dose of 25-2,000 mg/m2. In the second part, the highest tolerated dose reached during part one was used as the initial dose in a multiple-dose scheme of treatment. Patients were treated weekly. The dose was escalated each week, starting with a dose of 2 g/m2 and escalating to 3, 4, and 5 g/m2. No cardiac, hematologic, hepatic, or renal toxicity was observed. The most common toxicity was nausea and vomiting, which occurred in 18% of the patients; others were headache (8%), abdominal pain (8%), and diarrhea (6%). No consistent induction of interferon and no major modification of host defense parameters occurred. One patient with malignant melanoma showed evidence of tumor regression. Pharmacologic studies demonstrated a significant decrease in the bioavailability of the drug as it was administered in this study. Further studies of ABPP with a preparation that has good availability are indicated to determine the potential antitumor activity of this agent or this class of agents in humans.

The effect of a 15(S)-15-methyl prostaglandin F2 alpha (methyl ester) suppository upon termination of early pregnancy.

The administration of prostaglandin vaginally to 15 pregnant patients in the first trimester caused abortion in 73% of the cases. Although other regimens have been reported to be effective and well tolerated, the single 3 mg. suppository of 15(S)-15-methyl prostaglandin F2 alpha (methyl ester) utilized in the present study was associated with a significant incidence of side effects and a relatively high failure rate. However, if an analogue or improved treatment regimen could be found which is more efficient, as well as more pleasant in its affects, the availability and the cost of early abortion would be improved with a concomitant effect on the incidence of late abortion and its complications.

PIP: The efficacy of 15(S)-15-methyl-prostaglandin F2 alpha (methyl ester) as a first trimester abortifacient was studied when delivered via vaginal suppository in 15 women. Each patient received 1 vaginal suppository containing 3 mg of the methyl ester and each was closely observed for the following 10 hours. Rate of complete abortion as demonstrated by examination and negative pregnancy tests 2 weeks postadministration of the suppository was 73%; 27% of the cases were judged to have had incomplete abortions. These incomplete aborters were completed by suction or regular curettage. 13% of patients showed a moderate decrease in systolic and diastolic pressure. 93% of women started to bleed within 10 hours; blood loss estimate averaged 41.5 ml. Diarrhea was the main side effect, occurring in 73% of cases, whereas 47% suffered up to 3 episodes of vomiting. Though failure rate and side effects were too high, it is thought that another analog may overcome these problems.

(15S)-15 methyl prostaglandin F2 alpha levels in amniotic fluid and blood in second trimester abortions.

A single intra-amniotic injection of (15S)-15 methyl prostaglandin F2 alpha (THAM) was used to induce second trimester abortion in five patients. Serial levels of (15S)-15 methyl prostaglandin F2 alpha were subsequently measured in amniotic fluid and plasma by radioimmunoassay. The slow removal of this drug from the amniotic fluid was documented. Plasma levels of (15S)-15 methyl prostaglandin F2 alpha increased fourfold to sevenfold after clinical rupture of the membranes in three patients, supporting the fact that prostaglandins are well absorbed from the vagina. Because this analogue of prostaglandin can cause marked peripheral bronchoconstriction when administered systemically, it is best to avoid its use in patients with a history of asthma.

Vaginal prostaglandin E2 in the management of fetal intrauterine death.

The results of a multicentre clinical trial of prostaglandin E2 (PGE2) administered by the vaginal route in the management of intrauterine fetal death and missed abortion showed an overall efficacy of 97 per cent. The mean induction-abortion interval was 10.7 hours with a mean total dose of 60.4 mg of PGE2. Side effects were tolerated well and there was no evidence of significant alterations in hepatic or renal function.

Clinical comparison of abortifacient activity of vaginally administered prostaglandin E2 in two dosage forms.

PIP: The effect of prostaglandin E2 (PGE2) release rate from an intravaginal suppository on induced abortion was investigated in a randomized, double-blind study of 71 women who were 7-22 weeks pregnant. 2 dosage forms were compared. Base A was selected to provide a more hydrophilic character than base B. 6 vaginal suppositories, inserted at 4-8 hour intervals as deemed necessary for the clinical progress of abortion, were available for each patient. If abortion did not occur within 48 hours, the trial was discontinued. When time for 50% dissolution of PGE2 (t50%) was plotted as a function of pH for the 2 suppository formulations, the curve for base A was sigmoidal in shape, showing a more rapid release of PGE2 and pH increase. In contrast, base B demonstrated a t50% value of 30 hours which was independent of pH. This independence suggested the hypothesis that the clinical performance of base B would be more uniform than a base A formulation and would exhibit a longer duration of biologic action. Use of base A was found to produce a slight increase in the frequency of successful abortions (79% with base A versus 70.3% with base B). There were no significant differences in the mean times from treatment initiation to complete abortion, the number of incomplete abortions, or failure to abort between the 2 study groups. There was a nonsignificant trend toward reduced total drug use in the base A group. Examination of side effects indicated that women receiving PGE2 in base B had a greater but nonsignificant tendency to experience nausea (62.2% in group B, 58.8% in group A) and vomiting (83.8% group B, 76.5% group A); however, there was a significantly greater amount of diarrhea in the base B group (70.3%) than in the base A group (41.2%). It was concluded that there are no major differences in abortifacient efficiency or the general incidence of side effects when PGE2 therapy in 2 dosage forms is compared. However, a more hydrophilic base, which exhibits a more rapid release of PGE2, appears to slightly reduce side effects and efficacy.^ieng

Management of intrauterine fetal demise and missed abortion using prostaglandin E2 vaginal suppositories.

Two hundred and twelve patients diagnosed as having a missed abortion or intrauterine fetal death were managed by the use of prostaglandin E2 vaginal suppositories. The method had a high efficacy rate with 98% of the patients experiencing successful evacuation of the uterine contents. The mean time to abortion was 10.9 hours with a mean dose of 60 mg (3 suppositories). Side effects were well tolerated. Transient pyrexia was present in 36% of the patients during therapy, but returned to pretreatment levels after abortion. No intrauterine infection was observed. The risks associated with active treatment can be avoided. The ease of administration permits initiation of therapy as soon as the diagnosis is confirmed.

The termination of human pregnancy with prostaglandin analogs.

The investigational use of prostaglandins to establish a safe, alternative method for the termination of pregnancy has shown significant development in the United States. The introduction of second generation compounds was initiated by chemically attaching a methyl group in the 15 carbon position of prostaglandins E2 and F2alpha. These compounds prevented enzymatic degradation by the enzyme prostaglandin 15 dehydrogenase. (15S)-15 methyl prostaglandin E2 methyl ester administered by intramuscular injection has been used successfully to therapeutically terminate pregnancy in 208 women of gestational age six through 20 weeks. Side effects, not major and considered acceptable by the investigator, were vomiting, diarrhea and temperature elevations associated with shaking and chills. (15S)-15 methyl prostaglandin F2alpha (THAM), administered by intramuscular injection, has been used to terminate pregnancy in 283 women. Efficacy rates under optimal dosage regimens have reached 100% with a complete abortion rate of 96%. Gastrointestinal side effects of vomiting and diarrhea occurred, but temperature elevations with associated shaking and chills were infrequent. The mean time from initial therapy to abortion with both compounds has remained under 16 hours. A route of drug therapy for therapeutic termination of human pregnancy has been explored and developed which avoids invasion of the uterus.

Vocational potential assessment.

Determination of employment potential will become increasingly important in the foreseeable future, largely due to pending Federal legislation which relates to welfare reform. The heretofore "permanently and totally disabled versus able-bodied" principle in welfare reforms is being abbandoned. Pending legislative proposals dealing with welfare reform provide for considering physically impaired persons as partially disabled and partially employable simultaneously. Thus, the need to systematically and effectively assess physically impaired citizens' capacities to participate in the job market will increase. Unquestionably, rehabilitation medicine in general, and the emerging art and science of vocational evaluation in particular, will contribute much to supplying these services. While it is widely acknowledged that the vocational potential of physically impaired persons should be evaluated in an organized manner, there are differences of opinion among professional evaluators as to which approach, or approaches, are the most meritorious; The four principal approaches are: (1) mental testing, (2) work sampling, (3) situational analysis, and (4) job tryouts. Each of these approaches is explained, contrasted, and evaluated in this paper.

The use of prostaglandins for the therapeutic termination of pregnancy.

PIP: The investigational use of (PGs) prostaglandins to induce termination of early pregnancy has developed rapidly in the U.S. PGF2alpha administered by intraamniotic instillation has demonstrated a high efficacy rate ( 95%) with a low incidence of side effects in over 1600 midtrimester terminations. Acceptable abortifacient efficacy with minimal side effects was also shown in 500 documented cases investigating the action of PGF2alpha instilled extraamniotically in gestational ages ranging from 8-16 weeks. Expanded studies using PGE2 vaginal suppositories inserted at 4-8 hour intervals has combined ease of administration with a high degree of effectiveness. Initial clinical studies with an analog of PGE2((15S)-15-methyl-PGE2methyl ester) have documented increased potency in regard to uterine stimulation and duration of activity, with induction of abortion occurring after a single intramuscular injection.^ieng