Long-acting Products Research Articles

Differences in hypoglycemia event rates and associated cost-consequence in patients initiated on long-acting and intermediate-acting insulin products

ABSTRACTObjective: To compare hypoglycemia event rates in patients initiated on long-acting insulin analog (glargine) or intermediate-acting insulin (NPH) and to analyze the associated cost-consequence from a managed care perspective.Study design: A retrospective analysis of pharmacy and medical claims and electronic laboratory result data using a southeastern United States managed care health plan.Methods: Patients newly initiated on glargine or NPH between July 1, 2000 and August 31, 2002 were included. Hypoglycemia events were identified from medical claims by their ICD-9-CM codes. Multivariable techniques were used to compare hypoglycemia event rates between cohorts.Results: A total of 1434 patients were eligible (glargine = 310, NPH = 1124). The mean age was 53 years ± 17 years and 51% of patients were male. The mean treatment duration was 8.6 months ± 4.5 months. Multivariate analyses showed that patients in the NPH group had a higher hypoglycemia event rate than the glargine group (18.3 versus 7.3 per 100 patients per year; p = 0.009). The number needed to treat (glargine versus NPH) to avoid one hypoglycemia event per patient per year was nine patients at an A1C of 7%. The mean annual index medication cost was $47 more for glargine ($390) than for NPH ($343) per patient per year ( p = 0.042). The mean cost per hypoglycemia event was $1087 (95% CI: $764–$1409).Conclusions: Patients treated with glargine had significantly lower hypoglycemia event rates compared to the NPH group. The risk difference indicated that one hypoglycemia event would be avoided for every nine patients treated with glargine instead of NPH. The cost increase associated with treating nine patients with glargine rather than NPH is less than the cost of treating one hypoglycemia event. In this population, the savings associated with reduced hypoglycemic events more than offset the increased acquisition cost associated with glargine.

Comparative Bioavailability of Sustained-Release Morphine Sulfate Capsules versus Pellets

Kadian™ is an oral formulation of sustained-release morphine sulfate pellets contained in a gelatin capsule, indicated for the treatment of moderate to severe chronic pain. A randomised, single-dose, open-label, 4-way crossover study in 25 healthy male and female volunteers evaluated whether in the fasted and fed state Kadian™ capsules swallowed whole were bioequivalent to Kadian™ pellets sprinkled on apple sauce. A 50mg dose of study medication was administered 7 days apart after either an overnight fast of 10 hours or after a standard high-fat meal. Serial blood samples were taken for 48 hours postdose and were analysed for morphine by high-performance liquid chromatography using electrochemical detection. Kadian™ capsules swallowed whole and Kadian™ pellets sprinkled on apple sauce were bioequivalent fasted. Furthermore, Kadian™ capsules swallowed whole were bioequivalent when given both fasted and fed, and Kadian™ capsules swallowed whole and Kadian™ pellets sprinkled on apple sauce were bioequivalent under fed conditions. Both the 90% confidence intervals and mean ratios were within the bioequivalence limits for area under the plasma morphine concentration-time curve (AUC0–48and AUC0-∞) for Kadian™ pellets sprinkled on apple sauce administered under fed and fasted conditions. However, food reduced the mean maximum plasma drug concentration (Cmax) value to 79% of the fasted value, which was just outside the lower bioequivalence limit. Because the extent of absorption of morphine from Kadian™ pellets was not significantly affected by food, this reduction in Cmax would not be clinically significant on a once-a-day administration regimen. This study confirmed and extended previous results derived in vitro that showed that the rate of release of morphine from Kadian™ pellets was not affected when the pellets were poured on to foodstuffs and liquids. In conclusion, Kadian™ capsules swallowed whole were bioequivalent to Kadian™ pellets sprinkled on apple sauce in both the fed and fasted states. Therefore, because it can be administered via an alternative dosing method (sprinkling), which is not possible with other long-acting morphine products, Kadian™ may well offer a significant advantage in the management of patients with cancer pain, particularly those with general debility or difficulty in swallowing. Kadian™ is also know as either Kapanol™ or Morcap SR™.

A POSSIBLE ROLE OF CORPORA LUTEA WITH REGARD TO OESTROGEN-INDUCED CHANGES IN PITUITARY RESPONSIVENESS TO LH-RH

The effect of oestradiol benzoate (OeB; 3 micrograms sc) on LH-RH-induced LH-secretory responses was investigated in: (1) long-term ovariectomized (OVX) rats; (2) intact (i.e. sham-OVX) and 24 h-OVX persistent oestrous (PO) rats (intact PO rats do not possess corpora lutea); (3) intact and 24 h-OVX cyclic (dioestrous) rats (intact cyclic rats possess "not-activated" corpora lutea), and (4) intact and 24 h-OVX phase-2-pseudopregnant (phase-2-PSP) rats (phase 2 of PSP lasts from day 2 to day 10. Experiments were performed on days 7--8. Intact phase-2-PSP rats possess "activated" corpora lutea). A "positive" effect of OeB was observed in: (1) long-term OVX rats; (2) intact and 24 h-OVX PO rats; (3) 24 h-OVX cyclic rats and (4) 24 h-OVX phase-2-PSP rats. In intact cyclic and phase-2-PSP rats OeB was completely ineffective. From these observations it is concluded that only in the absence of corpora lutea OeB can exert a "positive" effect on LH-RH-induced LH-secretory responses. Ovariectomy alone, however, may have a negative impact on LH-RH-induced LH-secretory responses. This holds for PO- and phase-3-PSP rats (phase 3 of PSP begins once the corpora lutea come to lysis, i.e. on or shortly before day 10, and lasts until the end of PSP), but not for phase-2-PSP rats. In cyclic rats, on the other hand, ovariectomy performed on dioestrus-1 "only" interferes with the normal development of pituitary responsiveness to LH-RH and this can be nullified by OeB. Our observations suggest that (1) relatively long-acting products of corpora lutea "stabilize" (phase-2-PSP rats), c.q. limit the (almost certainly oestrogen-dependent) development of pituitary responsiveness to LH-RH (cyclic and phase-3-PSP rats); (2) in ovariectomized rats the influence of these products vanishes and that (3) this results in a situation in which OeB can become effective. It is also suggested that in the course of the ovulatory cycle and phase 3 of PSP a similar disappearance of corpora luteal products occurs "spontaneously" as a result of the process of luteolysis with as a consequence that the pituitary responsiveness to LH-RH, under the influence of endogenous oestrogens, develops continuously until, on pro-oestrus, an LH-surge occurs. Evidence is presented that the corpora luteal products, postulated in this paper, are not identical to progesterone.

PRESENT STATUS OF INJECTABLE CONTRACEPTIVES

2 experimental contraceptive injection programs are reported. 1 method provides for administration of a combined long-acting estrogen-progestogen product once a month the other uses a long acting progestogen alone once every 90 days. In the once-a-month injection program in Los Angeles 615 patients representing 871 admissions were studied; treatment data are for both 1st and all admissions. Age distribution was 21-25 years. Patients received 150 mg of progestogen/10 mg estrogen injection. 88.1% reported cycles of 22-30 days/on admission. Some results are: For 1st and all admissions average duration of flow was 6.6 days; for 1st admission group complaints consisted of breast tenderness 46% dysmenorrhea 61.8% weakness or dizziness 42.8% local reaction to injection 37.4%. For all admissions complaints were: breast tenderness 43.3% dysmenorrhea 59.6% weakness 40.2% local reaction 33%. Reasons for dropout for both groups included rigidity of protocol about 52% moved away 4.5% extraneous illness 1.5%; 64.4% of all admissions discontinued treatment due to unrelated reasons. No pregnancies were reported. The once every 90 day injection of medroxyprogesterone acetate given in doses of 150 mg were given to 243 women of whom 57% were aged 20-29. Some results are: 1) number of days of bleeding ranged from 6-20 days 2) 4.6% reported nervousness 3.4% nausea 2.1% headaches 3) main reasons for dropouts were moving away 11.8% bleeding 4.6% and 4) 1/3 resumed ovulation within 1/2 year. Both methods are found to be extremely effective.

Latentiation of Dihydrostreptomycin by Pamoate Formation

Dihydrostreptomycin was formulated as its pamoate salt as part of a search for a long-acting product. In dogs, an intramuscular injection of a cottonseed oil suspension of dihydro-streptomycin pamoate was absorbed more slowly than equivalent doses of dihydrostreptomycin sulfate suspended in cottonseed oil or dissolved in water. Pharmacokinetic studies suggest that plasma data can be described by the one-compartment open model, and that both salts are equally available.