Scheduling of deliveries

Delivery regimen - Baclofen intrathecal is most often administered in a continuous infusion mode immediately following implant. For those patients implanted with programmable pumps who have achieved relatively satisfactory control on continuous infusion, further benefit may be attained using more complex schedules of delivery. 

Scheduling of delivery by ground or air transportation is the key to a successful and economically viable distribution of 18F-FDG. All the orders of FDG dosages are received a day before, and deliveries to different client sites by a courier are scheduled with minimal routing. Deliveries to widely separated sites that cannot be served by one courier are made by separate couriers. Production schedule of 18F-FDG batches must be synchronized with the different deliveries by separate couriers. 

The source process outlines the ordering and obtaining of goods and services. This includes for example the scheduling of deliveries, shipment validation, and acceptance of supplier invoices (SCOR 10.0). 

Review the logistical requkements and the schedule of delivery of supplies (qualitative, quantitative, time frame)... 

Other constrains (availability and delivery schedule of tools, production schedules)... 

One aspect of a contract often overlooked is shipment of finished goods. You have ascertained the delivery schedule, the place of delivery, but how do you intend to ship it by road, rail, ship, or air. It makes a lot of difference to the costs. Also delivery dates often mean the date on which the shipment arrives not the date it leaves. You therefore need to build into your schedules an appropriate lead time for shipping by the means agreed to. If you are late then you may need to employ speedier means but that will... 

Especially in an industrial environment conditional demand is an important concept. This is because orders usually allow for some delivery time. This delivery time is in many cases long enough to be taken into account in production scheduling. As the deadline for orders for a certain date of delivery comes closer one can compare the original forecast with the orders that were already received. It is intuitively clear that if many orders were already received this implies a somewhat increasing forecast with less uncertainty. Sometimes orders that were already received can be used to automate the forecast to a certain extent because one knows that usually 25% are ordered four weeks in advance, 50% are ordered two weeks in advance and the like. We assume here that there is a valid latest forecast at the point in time where a decision on the next production volume is necessary and the orders that were already received are taken into account at that fixed point in time. 

Customer order schedules need to be integrated with deliveries, production orders and procurement orders. Volumes and values are already defined. Therefore, the focus is on a time schedule of orders considering production and distribution lead times. Fig. 21 illustrates the main task in value chain operations also now focused on a geographical region such as Europe. The individual schedules of sales orders and purchase orders have to be integrated with distribution and production schedules. 

Intercenter consultation CDER, when lead Center, will consult with CDRH if CDER determines that a specific device is required as part of the NDA process. CDRH as lead center will consult with CDER if the device is intended for use with a marketed drug and the device creates a significant change in the intended use, mode of delivery (e.g., topical, IV), or dose/schedule of the drug. 

LeSage MG, Burroughs D, Pentel PR (2006) Effects of nicotine withdrawal on performance under a progressive-ratio schedule of sucrose pellet delivery in rats. Pharmacol Biochem Behav 83 585-591... 

Concurrent schedule of chemotherapy and radiation therapy is defined as the delivery of radiation and chemotherapy simultaneously either early or late in the treatment schedule. The advantage of this schedule is that by giving the radiation and chemotherapy together early in the treatment course one can possibly prevent the development of resistant tumor cells. However, the disadvantages include increased toxicides and the decreased ability to deliver full dose chemotherapy (36). 

To clarify the reason why different circadian schedules of 5-FU delivery have distinct cytotoxic effects, we used the cell cycle automaton model to determine the time evolution of the fraction of cells in S phase in response to different patterns of circadian drug administration, for a cell cycle variability of 15%. The results, shown in Fig. 10.5, correspond to the case considered in Fig. 10.4, namely, entrainment of a 22-h cell cycle by the circadian clock. The data for Fig. 10.5a clearly indicate why the circadian schedule with a peak at 4 a.m. is the least toxic. The reason is that the fraction of cells in S phase is then precisely in antiphase with the circadian profile of 5-FU. Since 5-FU only affects cells in the S phase, the circadian delivery of the anticancer drug in this case kills but a negligible amount of cells. 

The effect of variability on drug cytotoxicity markedly depends on the temporal pattern of 5-FU delivery. When the peak in the circadian delivery of 5-FU occurs at 4 p.m., i.e. when the circadian schedule of 5-FU administration is most toxic to the cells, whether in the absence or presence of entrainment by the circadian clock, cytotoxicity increases as the degree of variability decreases. The effect is more marked in the conditions of entrainment a threshold in cytotoxicity then exists between... 

Numerical simulations therefore indicate that the least damage to the cells occurs when the peak of 5-FU circadian delivery is at 4 a.m., and when cells are well synchronized, i.e., when cell cycle variability V is lowest. In contrast, when the peak of 5-FU circadian delivery is at 4 p.m., cytotoxicity is enhanced when cells are well synchronized. The cytotoxic effect of the drug, therefore, can be enhanced or diminished by increased cell cycle synchronization, depending on the relative phases of the circadian schedule of drug delivery and the cell cycle entrained by the circadian clock. Continuous infusion of 5-FU is nearly as toxic as the most cytotoxic circadian pattern of anticancer drug delivery. 

Here, as in a previous publication [33], we used the cell cycle automaton model to probe the cytotoxic effect of various patterns of circadian or continuous 5-FU delivery. The results provide a framework to account for experimental and clinical observations, and to help us predict optimal modes of drug delivery in cancer chronotherapy. By explaining the differential cytotoxicity of various circadian schedules of 5-FU delivery, the model clarifies the foundations of cancer chronothera-peutics. In view of its versatility and reduced number of parameters, the automaton model could readily be applied to probe the administration schedules of other types of anticancer medications active on other phases of the cell cycle. 

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