Due to the obvious advantages of long-acting peptide and protein drugs, strategies to prolong plasma half life time of such compounds are highly on demand. Short plasma half life times are commonly due to fast renal clearance as well as to enzymatic degradation occurring during systemic circulation. Modifications of the peptide/protein can lead to prolonged plasma half life times. By shortening the overall amino acid amount of somatostatin and replacing l-analogue amino acids with d-amino acids, plasma half life time of the derivate octreotide was 1.5 hours in comparison to only few minutes of somatostatin. A PEG2,40 K conjugate of INF-α-2b exhibited a 330-fold prolonged plasma half life time compared to the native protein. It was the aim of this review to provide an overview of possible strategies to prolong plasma half life time such as modification of N- and C-terminus or PEGylation as well as methods to evaluate the effectiveness of drug modifications. Furthermore, fundamental data about most important proteolytic enzymes of human blood, liver and kidney as well as their cleavage specificity and inhibitors for them are provided in order to predict enzymatic cleavage of peptide and protein drugs during systemic circulation.

Strategies to improve plasma half life time of peptide and protein drugs

RESEARCH into the neuroendocrine control of reproduction by gonadotropin-releasing hormone (GnRH) has witnessed a remarkable two decades. From the isolation and chemical characterization of GnRH in 1971 through the awarding of the Nobel Prize to Drs. Serially and Guillemin for these accomplishments shortly thereafter, the translation from basic discovery to clinical usefulness has been swift. Food and Drug Administration approvals of GnRH-agonist analogues for the treatment of prostate cancer, endometriosis, and precocious puberty, as well as the use of natural GnRH to induce ovulation, are examples of the clinical usefulness of these fundamental observations. Numerous clinical therapies designed to stimulate . . .

https://www.nejm.org/doi/pdf/10.1056/NEJM199101103240205?listPDF=true

Gonadotropin-releasing hormone and its analogues.

Microspheres composed of biocompatible, biodegradable poly(DL-lactide-co-glycolide) (DL-PLG) and staphylococcal enterotoxin B (SEB) toxoid were evaluated as a vaccine delivery system when subcutaneously injected into mice. As measured by circulating immunoglobulin G (IgG) antitoxin titers, the delivery of SEB toxoid via DL-PLG microspheres, 1 to 10 microns in diameter, induced an immune response which was approximately 500 times that seen with nonencapsulated toxoid. The kinetics, magnitude, and duration of the antitoxin response induced with microencapsulated toxoid were similar to those obtained when an equal toxoid dose was administered as an emulsion with complete Freund adjuvant. However, the microspheres did not induce the inflammation and granulomata formation seen with complete Freund adjuvant. The adjuvant activity of the microspheres was not dependent on the superantigenicity of SEB toxin and was equally effective at potentiating circulating IgG antitrinitrophenyl levels in response to microencapsulated trinitrophenyl-keyhole limpet hemocyanin. Empty DL-PLG microspheres were not mitogenic, and SEB toxoid injected as a mixture with empty DL-PLG microspheres was no more effective as an immunogen than toxoid alone. Antigen-containing microspheres 1 to 10 microns in diameter exhibited stronger adjuvant activity than those greater than 10 microns, which correlated with the delivery of the 1- to 10-microns, but not the greater than 10-microns, microspheres into the draining lymph nodes within macrophages. The antibody response induced through immunization with microencapsulated SEB toxoid was protective against the weight loss and splenic V beta 8+ T-cell expansion induced by intravenous toxin administration. These results show that DL-PLG microsphere vaccine delivery systems, which are composed of pharmaceutically acceptable components, possess a strong adjuvant activity for their encapsulated antigens.

https://iai.asm.org/content/iai/59/9/2978.full.pdf

Biodegradable and biocompatible poly(DL-lactide-co-glycolide) microspheres as an adjuvant for staphylococcal enterotoxin B toxoid which enhances the level of toxin-neutralizing antibodies.

Prostate cancer is the second leading cause of death from cancer among men; 25 percent of men with prostate cancer die of the disease1. Moreover, many patients who do not die of prostate cancer require treatment to ameliorate symptoms such as pain, bleeding, and urinary obstruction. Thus, prostate cancer is also a major cause of suffering and of health care expenditures. The high rate of mortality from prostate cancer may be due to late detection. In recent studies, screening for prostate cancer has combined the measurement of serum prostate-specific antigen (PSA) -- the most accurate single test for the . . .

https://www.nejm.org/doi/pdf/10.1056/NEJM199410133311507?listPDF=true

Management of Cancer of the Prostate

General practitioners and community nurses were asked to rate the likelihood of dementia for each of their elderly patients. Cases of dementia were identified by research psychiatrists using the Cambridge mental disorders of the elderly examination (CAMDEX), a new structured diagnostic interview. General practitioners correctly identified dementia as at least a possibility in 121 of the 208 cases found. Nevertheless, they mistakenly rated as demented several patients suffering from functional psychiatric disorders, in particular depression. Community nurses correctly identified dementia as at least a possibility in 64 of the 74 demented patients known to them, but they incorrectly suspected dementia in a greater proportion of instances. Both general practitioners and families appeared to have low expectations of what general practice has to offer demented elderly people. General practitioners should take the initiative in diagnosing dementia in very elderly patients who show signs of the condition. In some cases it may be secondary to treatable disorders, and in others all that may be required are understanding, support, and advice to families.

https://www.bmj.com/content/bmj/297/6656/1107.full.pdf

Do general practitioners miss dementia in elderly patients

Randomised controlled study of orchidectomy vs long-acting d-trp-6-lhrh microcapsules in advanced prostatic carcinoma

Summary— One hundred and four patients were randomised for the study. Fifty-five were entered into the D-Trp-6-LHRH group and 49 into the orchiectomy group. All pre-treatment patient characteristics were similar and testosterone levels at 1 month or later were in the castrate range in both groups.



Forty-six patients (83%) in the D-Trp-6-LHRH group and 40 (82%) in the orchiectomy group had a partial remission or stable disease at 3 months or later. There was no significant difference between the groups for response or survival.



Three patients in the D-Trp-6-LHRH group had a disease “flare” in the first 10 days of treatment. The flare symptoms resolved by the end of 4 to 8 weeks.



The incidence of flushing, decreased libido and impotence was similar in both groups. Although there was less psychological morbidity in the D-Trp-6-LHRH group the difference did not reach statistical significance. Our results indicate that long-acting D-Trp-6-LHRH offers a safe and highly effective alternative to orchiectomy.

L. Allen

Papers

Randomised controlled study of orchidectomy vs long-acting d-trp-6-lhrh microcapsules in advanced prostatic carcinoma

Orchiectomy versus Long-acting D-Trp-6-LHRH in Advanced Prostatic Cancer

Orchiectomy Versus Long-Acting D-Trp-6-LHRH in Advanced Prostatic Cancer